Ethylene biosynthetic enzymes, 1-aminocyclopropane-1-carboxylate (ACC) synthase (ACS) and ACC oxidase (ACO), participate in the floral sex differentiation of bitter gourd (Momordica charantia). However, the relationship between their structural features and developmental expression patterns remains to be further clarified. In this study, eight McACS and five McACO genes were identified using the Dali-11 reference genome. AlphaFold 3-based modeling showed structural differences between the two families, particularly regarding the diverse C-terminal flexibilities of McACS proteins. Targeted qRT-PCR profiling during the critical 1.0-3.0 mm early floral bud stage revealed that McACS7, a structurally stable Type III member, along with McACS1, McACS12, and McACO2, were significantly upregulated during natural female flower development. Furthermore, treatment with silver nitrate (AgNO3), an ethylene perception inhibitor, suppressed the transcription of these synthesis genes to basal levels and induced hermaphroditic flower formation. Instead of fully elucidating the downstream molecular mechanisms, these findings provide robust candidate-gene evidence and transcriptional profiling that link the ethylene biosynthetic machinery to the chemically induced sex reversal process, thereby laying a solid foundation for future functional characterization.

Hepatocellular carcinoma is one of the most aggressive malignancies worldwide, with limited therapeutic options. Boswellia serrata Roxb., an Indian medicinal tree, produces a resin rich in essential oil and boswellic acids, particularly acetyl-11-keto-β-boswellic acid (AKBA), with demonstrated antiproliferative and pro-apoptotic activities. This study investigated the cytotoxic effects of B. serrata essential oil and AKBA on hepatocarcinoma Huh-7 cells in both monolayer and three-dimensional spheroid cultures and characterized the underlying molecular targets. Essential oil was extracted and analyzed by gas chromatography-mass spectrometry (GC-MS). Cytotoxicity was assessed using the cell counting kit-8 (CCK-8). Three-dimensional spheroid cultures were also established to evaluate anti-tumoral potential. Expression of cyclin D1, cyclin-dependent of kinase 4 (CDK4) (cyclin-dependent kinase inhibitor 1A (p21), E-cadherin, (alpha fetoprotein) AFP, epithelial cell adhesion molecule (EpCAM), Myeloid cell leukemia-1 (Mcl-1), and caspase-3 was analyzed by western blot. In addition, an in silico analysis was performed on the main constituents of B. serrata essential oil targeting 5-lipoxygenase (5LO). The results showed cytotoxic effects, with AKBA exhibiting greater potency than the essential oil. Cytotoxicity was associated with caspase-3-mediated apoptosis, with minimal effects on cell cycle and epithelial-mesenchymal transition markers. The in silico analysis predicted that some compounds may act as competitive inhibitors of the 5LO at the catalytic site and partially activate pro-apoptotic pathways. These data support the potential of B. serrata-derived compounds as novel anti-hepatocarcinoma agents, with AKBA and longifolene as leads for further preclinical and clinical research.

Prostate cancer remains one of the most biologically heterogeneous malignancies in men and continues to present major therapeutic challenges despite advances in androgen receptor-targeted therapy and molecular stratification. Increasing evidence suggests that prostate cancer progression is influenced not only by tumor-intrinsic genetic alterations but also by complex interactions involving androgen receptor signaling, inflammatory pathways, metabolic reprogramming, oxidative stress, epigenetic remodeling, immune dysregulation, and gut microbiome-associated signaling. Within this evolving systems-level framework, natural products have attracted increasing attention because of their ability to modulate multiple interconnected molecular pathways. This review examines the molecular basis of prostate cancer progression with particular emphasis on crosstalk among androgen receptor signaling, microbiome-associated regulation, epigenetic adaptation, inflammatory signaling, and tumor microenvironment remodeling. The emerging role of the gut microbiome in androgen metabolism, microbial metabolite production, immune regulation, and endocrine resistance is critically discussed, together with current evidence describing the biological effects of selected phytochemicals including curcumin, epigallocatechin-3-gallate, resveratrol, sulforaphane, quercetin, and genistein. These compounds may influence prostate cancer-associated pathways through modulation of inflammatory signaling, oxidative stress, metabolic adaptation, chromatin remodeling, and microbiome dynamics. Major translational limitations including poor bioavailability, pharmacokinetic variability, microbiome heterogeneity, inconsistent clinical evidence, and incomplete mechanistic understanding are additionally discussed. Rather than considering natural products as isolated anticancer agents, this review adopts a systems-level perspective in which dietary bioactive compounds may function as modulators of interconnected regulatory networks relevant to prostate cancer biology and therapeutic responsiveness.

Treatment-induced neuroendocrine prostate cancer (t-NEPC) is the major form of resistance to androgen receptor signaling inhibitors (ARSI) in advanced prostate cancer, characterized by pronounced invasiveness and lineage plasticity. Through in-depth analysis of prostate cancer cohorts, we found that glutamate ionotropic receptor kainate (GRIK) family members, specifically GRIK2 and GRIK5, are highly expressed in neural lineage plastic prostate cancer cells, NEPC patient-derived xenografts (PDX), and NEPC patient samples. Their expression positively correlates with neuroendocrine markers and inversely correlates with androgen receptor (AR) activity. Additionally, functional analyses indicated that AR has a direct transcriptional inhibitory effect on GRIK2 and GRIK5, and the absence of AR signaling leads to the upregulation of GRIK2 and GRIK5. Further RNA sequencing analysis revealed that GRIK5 silencing reprograms the cellular transcriptome, resulting in significant downregulation of AR signaling and fatty acid metabolism, while simultaneously activating immune and inflammatory responses in enzalutamide-resistant prostate cancer cells. In both cell line and NEPC PDX organoid models, loss of GRIK5 impaired proliferation and clonogenic growth. Notably, GRIK5 also contributes to enzalutamide resistance. Pharmacological evaluation revealed that Pan-GRIK antagonists exhibit anti-tumor activity, although the required relatively high concentrations suggest that more potent therapeutic strategies should be developed. Collectively, this study establishes that GRIK family members play critical roles in enzalutamide resistance and NEPC progression, highlighting GRIK signaling as a potential therapeutic target for overcoming lineage plasticity in prostate cancer.

Snake venom is a remarkably complex cocktail of bioactive molecules capable of hijacking diverse host physiological processes, yet how individual venom components drive these cellular responses remains a bit of a black box. To map these dynamics, we ran a comparative transcriptomic analysis on human osteoclastogenic cultures, exposing them continuously to crude Bothrops moojeni venom and its high (HMM) and low (LMM) molecular mass fractions throughout differentiation. This allowed us to capture the cumulative transcriptional shifts that unfold across the entire lifecycle of osteoclast development. The crude venom triggered a sweeping response, deeply impacting neuroimmune, extracellular matrix remodeling, inflammatory, and apoptotic pathways-reflecting a massive reshuffling of cellular regulatory networks. When we looked at the fractions, clear dividing lines emerged. The HMM fraction, packed with metalloproteinases and serine proteases, mostly drove pathways tied to cytoskeletal remodeling, intracellular trafficking, and osteoclast-associated signaling. In contrast, the LMM fraction-home to phospholipases A2, disintegrins, and small peptides-steered a much more targeted course, influencing immune regulation, proliferative signaling, and metabolic homeostasis while noticeably turning down catalytic and binding functions. Interestingly, all venom-treated groups shared a drop-off in ATP-dependent and ligand-binding categories, pointing to a common disruption in core metabolic and signaling processes. Taken together, these findings offer a clearer mechanistic look at how different B. moojeni venom components target bone remodeling pathways, highlighting the power of transcriptomics for untangling complex venom-host interactions.

Gliomas account for over half of all primary malignant tumors of the central nervous system and remain associated with poor prognosis. Although irinotecan is an effective chemotherapeutic agent, its clinical utility is limited by systemic toxicity, prompting interest in phytochemicals such as ellagic acid (EA) as potential sensitizers. This study aimed to investigate whether EA enhances the antiproliferative and pro-apoptotic effects of irinotecan in C6 glioma cells. C6 glioma cells were treated with EA (100 µM), irinotecan (100 µM), or their combination for 24, 48, and 72 h. Cell proliferation was assessed by BrdU assay, p53 and caspase-3 protein expression by immunocytochemistry (H-SCORE), and multidrug resistance gene 1 (MDR1), MGMT, p53, and caspase-3 mRNA levels by RT-qPCR. EA significantly enhanced irinotecan-mediated suppression of proliferation at 24 h (p < 0.001), 48 h (p < 0.001), and 72 h (p < 0.001), with the combination producing the strongest inhibition across all time points. Immunocytochemical p53 expression increased significantly in all treatment groups at 24 h and 48 h (EA: p < 0.01; irinotecan: p < 0.01; EA + irinotecan: p < 0.01) and remained elevated at 72 h (p < 0.05). Caspase-3 immunoreactivity showed robust early activation at 24 h (Ir: p < 0.05; EA: p < 0.01), persisted at 48 h (p < 0.01), and remained significantly elevated in the EA group at 72 h (p < 0.001). At the mRNA level, irinotecan induced the highest p53 expression at 24 h (p < 0.001), with sustained elevation at 48 h and 72 h (p < 0.001 and p < 0.05, respectively). Caspase-3 mRNA peaked at 24 h only in the irinotecan group (p < 0.001). EA significantly increased MDR1 and MGMT transcription at 24 h and 48 h (p < 0.001), whereas the EA + irinotecan combination attenuated this increase and remained close to control levels at early time points. MGMT remained significantly elevated in EA and EA + irinotecan groups through 72 h (p < 0.001). EA cooperatively enhanced the antitumor activity of irinotecan primarily by enhancing proliferation inhibition and modulating drug-resistance gene expression, while maintaining, rather than further augmenting, apoptotic protein markers comparable to those induced by single-agent treatments. These findings support EA as a promising adjunct to irinotecan-based glioma therapy.

High-glucose exposure impairs intestinal metabolic homeostasis and barrier integrity in fish, but the transcriptional responses associated with high-glucose adaptation in fish intestinal epithelial cells remain incompletely understood. This study investigated whether exogenous 5-methylcytosine (5MC) alleviates high-glucose-induced metabolic and epithelial stress in grass carp (Ctenopharyngodon Idella) intestinal epithelial cells and whether these responses are associated with changes in DNA methyltransferase 3 beta (dnmt3b) expression and Caudal type homeobox 1b (cdx1b)/Sodium-glucose cotransporter 1 (sglt1)-related transcriptional responses. As exploratory in silico information, molecular docking predicted candidate complex conformations of DNMT3B with CDX1B and SGLT1, with binding energies of -37.2 and -25.9 kcal/mol, respectively. Functionally, dnmt3b knockdown significantly reduced dnmt3b, Interleukin 6 (il6), and Nuclear factor kappa B (nfκb) expression, while increasing cdx1b, sglt1, Solute carrier family 2 member 3a (slc2a3a), 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4a (pfkfb4a), and Amine oxidase copper containing 1 (aoc1) expression (p < 0.05). CDX2/CDX1B-like immunoreactive protein and SGLT1 protein levels were also increased after dnmt3b knockdown (p < 0.05). Under high-glucose stress, exogenous 5MC exerted concentration-dependent effects. Specifically, 6 mM 5MC significantly reduced residual extracellular glucose, lactate dehydrogenase and diamine oxidase activities, and malondialdehyde content, while increasing glutathione content, cell viability, and cell migration (p < 0.05). These effects remained detectable after replacement with high-glucose medium for an additional 12 h. By contrast, 24 mM 5MC markedly increased lactate dehydrogenase activity and reduced cell viability, suggesting potential cytotoxicity (p < 0.05). S-adenosylmethionine (SAM) levels were significantly lower in the NC and 6 mM groups than in the HG, 12 mM, and 24 mM groups, suggesting changes in SAM-related one-carbon metabolic status rather than direct evidence of altered DNA methylation (p < 0.05). Exogenous 5MC, particularly at 6 mM, alleviated high-glucose-induced metabolic and epithelial stress in grass carp intestinal epithelial cells. These effects were accompanied by changes in several glucose metabolism- and inflammation-related genes. However, the cellular uptake, metabolic fate, DNA incorporation, methylation consequences, and causal roles of these gene-expression changes remain to be further verified.

Cervical cancer is a malignant disease that affects women worldwide and is associated with both high incidence and a high mortality rate. miR-34 is a direct transcriptional-target of p53 and is downregulated in several types of cancers. 1,4-Naphthoquinones (NQs) have anticancer properties and have been used to modulate miR-34 expression. We tested (3-chloro-NQ-2-yl)-alanine (ANQCl), -methionine (MNQCl), -glycine (GNQCl), -phenylalanine (FNQCl), -asparagine (NNQCl), and (1,4-napthoquinon-2-yl)-asparagine (NNQ) in immortal and tumorigenic cells, both HPV-positive and -negative, simulating precancerous and cancerous status to observe the response of the p53-miR-34 system, migration and invasion. A dose-response was achieved to determine the IC50 of the compounds in SiHa, CaLo, C33-A and HaCaT cells. HaCaT cell migration inhibition was more potent than in SiHa, CaLo, and C33-A cells, while invasion hindrance was more evident in the tumorigenic SiHa, CaLo and C33-A. NNQCl, GNQCl, ANQCl and FNQCl compounds induced p53 overexpression in SiHa and CaLo cells. Compound ANQCl in SiHa and FNQCl in CaLo induced miR-34a overexpression, probably via p53. Migration and invasion of most compounds decreased independently of p53-miR-34. NQ-amino acids exert effect on cell proliferation, migration and invasion in cervical cancer cells, suggesting their potential use in the field of cancer treatment.

Hepatocellular carcinoma (HCC) is a lethal malignancy requiring novel therapeutic interventions. While Polyporus umbellatus exhibits anti-tumor properties, its specific bioactive pharmacophores and molecular mechanisms remain elusive. This study integrated network pharmacology, computational simulation, and experimental validation to decipher the anti-HCC efficacy of Polyporus umbellatus. Screening identified 11 bioactive sterols, with intersection analysis revealing 63 core targets. Clinical data stratified Checkpoint Kinase 1 (CHEK1) as a critical high-risk oncogene associated with poor prognosis. Molecular dynamics simulations (100 ns) demonstrated that polyporusterone E, a key constituent, forms a thermodynamically stable complex with CHEK1 via high-affinity hydrogen bonding. In vitro assays in HepG2 and HuH-7 cells confirmed that CHEK1 overexpression drives proliferation and metastasis, while its silencing reverses these phenotypes. Crucially, treatment with Polyporus umbellatus extract and purified polyporusterone E significantly compromised HCC cell viability and downregulated CHEK1 expression at transcriptional and translational levels. These findings suggest that polyporusterone E may downregulate CHEK1 expression and modulate CHEK1-associated signaling in HCC cells, providing preliminary evidence for the molecular basis of Polyporus umbellatus and highlighting its potential as a complementary therapeutic strategy for HCC management.

Cross-contamination of poultry feed with antimicrobials may cause unintended exposure to residual antibiotic doses, but the immunological consequences remain unclear. We tested whether six antimicrobials (colistin, doxycycline, flumequine, thiamphenicol, tiamulin, and tilmicosin) delivered in feed at 2% of the maximum approved dose modulate immune-related gene expression and splenic histology in broiler chickens. Female Ross 308 chicks received antibiotic-contaminated diets throughout the rearing. Spleen and caecal mucosa were sampled on days 7, 21, and 35, and analyzed by RT-qPCR. Spleen was sampled on day 35 for histopathology. Responses were strongly time- and tissue-dependent, with the largest effects on day 21. In spleen, selected antimicrobials showed selective down-regulation of IL-2, IL-4, IL-6, IL-8, IL-12p40, and IFN-ß, while IFN-γ was significantly up-regulated (p ≤ 0.05). In caecal mucosa, transcriptional modulation was weaker and more limited. Significant changes were restricted to MUC2 on day 21 and to IL-2 and IL-8 on day 35 (p ≤ 0.05). Splenic histopathology showed unchanged lymphatic nodule counts, but increased lymphoid atrophy, necrosis, and inflammatory infiltrates, most frequently in colistin- and doxycycline-fed birds. Overall, residual antimicrobials in feed are not biologically neutral and are associated with distinct structural changes in immune-related gene expression and splenic tissue development.

Cyanobacteria, the only prokaryotic oxygenic phototrophs, rely on sophisticated regulatory networks, including those mediated by small RNAs (sRNAs) to cope with environmental fluctuations. Here, we delineate the sRNA landscape of Synechocystis sp. PCC 6803 under short- and long-term ammonium stress, revealing a significant proportion of antisense RNAs (asRNAs). Functional characterization identified three asRNAs (sll0312-as, sll0873-as, and slr1667-as) as key regulators of ammonium stress tolerance, implicating their targets (sll0312, sll0873, and slr1667) as new players in nitrogen fluctuation acclimation. The sll0944-as and sll1515-as were also identified, revealing an additional regulatory layer targeting known carbon/nitrogen metabolism regulators. Mechanistically, we characterized the ammonium-induced asRNA ssr0692-as, demonstrating that it represses pirA translation via direct 5'UTR interaction. This finding, integrated with the known role of the nitrogen limitation-responsive sRNA NsiR4 targeting the same region, supports a synergistic model wherein these two sRNAs precisely modulate PirA protein levels-and thus the downstream nitrogen flux-across varying nitrogen availability. Together, our findings expand the functional repertoire of cyanobacterial sRNAs and elucidate a dynamic post-transcriptional mechanism to fine-tune nitrogen metabolism in response to fluctuating nutrient conditions.

Heparanase 1 (HPSE1) is the only mammalian endoglycosidase that cleaves heparan sulfate (HS), a glycosaminoglycan (GAG), and is frequently upregulated in cancers, thereby promoting tumor progression. Despite extensive efforts to develop inhibitors of its HS-degrading activity, its non-enzymatic functions limit therapeutic efficacy and pose a major challenge for therapeutic development. Thus, inhibiting HPSE1 expression is critical for controlling its enzymatic and non-enzymatic functions; however, no FDA-approved inhibitors are currently available. Here, we identify auranofin (AUF), an oral gold-containing drug used to treat rheumatoid arthritis, as a potent inhibitor of HPSE1 promoter activity. High-throughput screening revealed that an atypical protein kinase C (aPKC)-NF-κB signaling axis is a key regulator of HPSE1 expression. Notably, AUF treatment reduced HPSE1 expression and significantly suppressed the invasive capacity of MDA-MB-231 cells in a Transwell migration assay. We then investigated the role of HPSE1 in the invasive activity of MDA-MB-231 cells, which produce higher levels of hyaluronan (HA) and HS than non-invasive cells. Neither HS degradation, HA supplementation in Matrigel during Transwell migration, nor HPSE1 overexpression alone was sufficient to drive invasion, suggesting that invasive capacity depends on mesenchymal features and coordinated induction of HPSE1 and GAGs rather than HS degradation. Collectively, our findings demonstrate that AUF-mediated inhibition of aPKC suppresses HPSE1 expression, thereby inhibiting both its enzymatic and non-enzymatic functions and limiting cancer progression, metastasis, and angiogenesis. These results highlight the therapeutic potential of AUF for targeting HPSE1-driven tumor progression and support its repurposing for cancer treatment.

This study evaluates the antimicrobial and antibiofilm effects of chlorhexidine and related compounds against S. mutans, focusing on bacterial viability, biofilm formation, and expression of key biofilm genes. Eight compounds were tested for their chemical properties, MICs, and interactions via FIC analyses. Time-kill assays assessed bactericidal activity over 24 h, while cytotoxicity was evaluated in human gingival fibroblasts. Gene expression of biofilm-related genes was analyzed to determine transcriptional modulation. Chlorhexidine gluconate and alexidine showed the strongest antimicrobial activity, with MICs of 2 μg/mL against the reference strain and 4 μg/mL for clinical isolates. Time-kill results demonstrated bacterial reductions from ~7.2 to < 1.0 log CFU/mL in the reference strain but less effect in clinical isolates. Chlorhexidine reduced biofilm biomass by nearly 19% at 48 h, whereas amoxicillin increased biofilm formation by over 12%. Cytotoxicity varied, with proguanil showing high cell viability (90%), while chlorhexidine and alexidine reduced viability to 50-70%. Gene expression analyzes revealed significant downregulation of gtfD and brpA by chlorhexidine and analogs, contrasting with mild upregulation by amoxicillin. These findings highlight chlorhexidine compounds as effective anti-biofilm agents, emphasizing the need for continued exploration of alternatives and combination therapies to enhance dental caries treatment.

Advancing therapeutic strategies for chordoma requires a deep molecular understanding of tumor biology, supported by robust and reproducible experimental models. This chapter reviews recent progress in the development of in vitro and in vivo chordoma systems, including novel cell lines, genetically engineered models, and patient-derived xenografts. We detail the molecular and epigenetic features that underpin chordoma pathogenesis and resistance to therapy. Special attention is given to the design and testing of combinatorial therapeutic approaches-including immunotherapies, epigenetic modulators, and hydrogel-based drug delivery systems-that target distinct molecular vulnerabilities. Together, these innovations provide a translational framework for next-generation therapies tailored to the unique biology of chordoma.

Hyperproteinemia is characterized by an unusually high plasma protein concentration (PPC). It affects both humans and animals. In this study, we used a silkworm model of hyperproteinemia to explore the mechanisms by which high PPC impairs female reproduction. Analysis of ovarian transcriptomes and qRT-PCR revealed that high PPC reduced the expression of vitellogenin (Vg) in the fat body and vitellogenin receptor (VgR) in the ovary. Further biochemical and gene expression analyses showed that high PPC decreased the titer of 20-hydroxyecdysone (20E) and the expression of key genes in the 20E-Vg/VgR signaling pathway. Exogenous 20E supplementation restored the expression of pathway components and effectively rescued female reproductive function. These findings offer new evidence for how high PPC affects female reproduction and provide a useful reference for future clinical research.

Plasmid-mediated horizontal gene transfer plays a pivotal role in accelerating the dissemination of antimicrobial resistance. However, the molecular mechanisms linking antibiotic-induced envelope stress to conjugation remain incompletely understood. Here, we demonstrate that sub-inhibitory colistin significantly enhances conjugative transfer of the RP4 and multiple clinically relevant resistance plasmids in E. coli without affecting bacterial growth. This enhancement was also observed under biofilm-forming conditions. Mechanistically, colistin induces envelope perturbation characterized by increased membrane permeability, elevated lipopolysaccharide release, and structural damage to the membrane. This remodeling is accompanied by selective upregulation of the outer membrane porin OmpF, whereas OmpC remains unchanged. Genetic analyses showed that OmpF is important for the enhancement of plasmid transfer observed under colistin exposure in both donor and recipient strains. Upstream regulatory analysis identified the EnvZ/OmpR two-component system as the principal pathway mediating OmpF induction. Colistin exposure increased envZ and ompR transcription and promoted OmpR phosphorylation, while electrophoretic mobility shift assays confirmed that OmpR binds to the ompF promoter with enhanced activity. Further analyses showed that this activation is not attributable to classical osmotic stress, as neither NaCl nor sucrose induced comparable responses, whereas supplementation with Mg2 + or Ca2+ attenuated colistin-induced gene expression. Collectively, this study uncovers a potential molecular link between colistin-induced envelope stress and horizontal gene transfer in bacteria, providing mechanistic insight into antibiotic-induced horizontal gene transfer.

Extreme flooding driven by climate change demands strategies to enhance plant tolerance to low-oxygen stress. We investigated the ability of bioactive compounds to chemically prime plants for flooding events. A high-throughput chemical genetic screen of 2,237 bioactive molecules was performed using an Arabidopsis thaliana luciferase-based reporter line driven by the ALCOHOL DEHYDROGENASE promoter, a hypoxia-inducible gene involved in anaerobic metabolism. The screen identified chlorquinaldol (CQD), an 8-hydroxyquinoline derivative, as a potent inducer of hypoxia responses. CQD inhibits the activity of PLANT CYSTEINE OXIDASES (PCOs), which are crucial oxygen-sensing enzymes in plants, resulting in the stabilization of the ETHYLENE RESPONSE FACTOR type VII and activation of hypoxia-responsive transcription under normoxic conditions. Plants pretreated with CQD showed enhanced tolerance to waterlogging and submergence, indicating that chemical priming of hypoxia responses improves plant tolerance to flooding. This study demonstrates that chemical inhibition of PCOs is an effective strategy for priming hypoxia responses and improving flooding tolerance in plants.

Recognition of the bacterial product lipopolysaccharide (LPS) by Toll-like receptor 4 (TLR4) initiates inflammatory responses. The unfolded protein response (UPR) elicited by endoplasmic reticulum (ER) stress can strengthen TLR4-dependent inflammatory responses. Here, we report that the ER-localized E3 ubiquitin ligase TRIM13 restrained LPS-induced inflammatory responses in macrophages and in mice by protecting the cells from ER stress. TRIM13 mediated Lys33-linked polyubiquitylation of the ER-localized Ca2+ sensor STIM1, promoting its degradation. TRIM13 deficiency caused STIM1 accumulation and activated store-operated Ca2+ entry (SOCE) and the inositol-requiring enzyme 1 α (IRE1α) branch of the UPR. Suppressing SOCE, chelating extracellular Ca2+, relieving ER stress, or blocking IRE1α activation inhibited the amplification of inflammatory responses caused by the loss of TRIM13 in macrophages. Pharmacological inhibition of IRE1α ameliorated chemically induced colitis in TRIM13-deficient mice. Our study suggests that TRIM13 restrains inflammation by limiting LPS-induced activation of SOCE and the IRE1α branch of the UPR.

A molecular glue degrader tackles mutant BRAF in drug-resistant colorectal cancer by disrupting mRNA splicing.

Carbapenem-resistant Escherichia coli poses a serious threat to global health, with limited treatment options and potentially fatal outcomes. Beyond horizontally acquired resistance genes, other cellular pathways are remodeled in the resistant phenotype, but these systemic responses remain poorly understood. Here, tandem mass tag-based quantitative proteomics was used to characterize the response of E. coli strain CCUG 70745 to Meropenem. Two inhibitory concentrations (128 and 192 μg/mL), anchored to the MIC of the isolate (128 μg/mL), were compared with an antibiotic-free control after 15 min. The analysis quantified 60% of the theoretical proteome, identifying 172 and 813 differentially expressed proteins at 128 and 192 μg/mL, respectively. Canonical resistance determinants, including β-lactamases and efflux pumps, were altered, as well as proteins involved in cell-wall formation, membrane transport, and signal transduction. Gene set enrichment analysis highlighted oxidative phosphorylation, ABC transporters, two-component systems, and cofactor metabolism. Increased abundances of two-component-system and membrane-integrity proteins were consistent with a coordinated, dose-dependent stress response, and interaction networks linked a cell-division module to efflux and metabolic adaptation. These results suggest that Meropenem engages both primary and auxiliary resistance-associated processes, providing a proteomic framework that may guide therapies targeting bacterial metabolism and membrane functions.