SEARCH · Search PubMed

Results for “CCL2”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

SourceResearch connectionFrom yearThrough year

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 19 recordsLinked to original sources

PubMed2026

BAP1 Loss in Pleural Mesothelioma Is Associated With Reduced Soluble CCL2 in Patient Effusion, Abrogated CCL2-Mediated Monocyte Recruitment In Vitro.

OBJECTIVES: Pleural mesothelioma is an incurable cancer of the cell layer lining the chest wall and lung. Patients frequently present with pleural effusion, which is often drained for symptom relief and enables minimally invasive sampling of the tumour environment, including immune cells and related soluble factors. Most of the mesothelioma tumours exhibit loss of BRCA1-associated protein 1 (BAP1), a multifunctional tumour suppressor protein. Here, we aim to elucidate the effect of BAP1 loss on the mesothelioma microenvironment through profiling soluble factors within pleural effusion. METHODS: A custom panel of 22 soluble factors was measured by Luminex assay and enzyme-linked immunosorbent assay in an initial cohort of 40 patients with known BAP1 status. Validation was performed by enzyme-linked immunosorbent assay in an independent cohort of 100 cases. Secretion of soluble factors and chemoattraction of monocytes were characterised using a CRISPR-mediated BAP1 deletion model in a mesothelioma and a lung cancer cell line. Immune cell infiltration, estimated by CIBERSORT, was further explored in the Cancer Genome Atlas -MESO cohort. RESULTS: Soluble C-C motif chemokine ligand 2 (CCL2) was approximately 55% to 60% lower in pleural effusion from BAP1-loss cases in both independent cohorts. Deletion of BAP1 reduced CCL2 secretion in vitro and abolished CCL2-mediated chemoattraction of monocytes in both mesothelioma and lung cancer cell lines. In the Cancer Genome Atlas -MESO cohort, BAP1-mutant tumours exhibited a reduction in estimated macrophage content. CONCLUSION: Loss of BAP1 impairs CCL2 secretion into pleural effusions, potentially influencing monocyte recruitment into the tumour microenvironment.

BAP1↗

PubMed2026

MYBL2 promotes malignant phenotypes and M2-like macrophage polarization through CCL2 in non-small cell lung cancer.

Hub genes associated with non-small cell lung cancer (NSCLC) were identified through bioinformatics screening. In vitro experiments analyzed the potential mechanisms by which these genes regulate tumor malignant phenotypes and macrophage polarization. Differentially expressed genes were identified from The Cancer Genome Atlas (TCGA)-NSCLC and GSE32175 datasets, followed by protein-protein interaction (PPI) network analysis to screen hub genes. The effects of MYB Proto-Oncogene Like 2 (MYBL2) on NSCLC progression and macrophage polarization were evaluated using in vitro models. The regulatory relationship between MYBL2 and C-C motif chemokine ligand 2 (CCL2) was investigated by Chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays, and rescue experiments were performed to validate the role of the MYBL2-CCL2 axis. Bioinformatics screening identified BUB1B, CDCA2 and MYBL2 as key hub genes with high expression in NSCLC, among which MYBL2 was significantly upregulated in NSCLC cells. Functional experiments confirmed that MYBL2 silencing markedly inhibited the malignant proliferation, migration and invasion of NSCLC cells. Tumor cell MYBL2 knockdown effectively reversed M2-like polarization and promoted M1-like polarization in the co-culture system. Mechanistically, MYBL2 directly bound to the CCL2 promoter region to enhance CCL2 transcriptional activity and upregulate CCL2 expression in NSCLC cells. Exogenous CCL2 supplementation significantly rescued the inhibitory effect of MYBL2 knockdown on macrophage M2-like polarization, verifying the mediating role of CCL2 in this regulatory axis. MYBL2 is strongly expressed in NSCLC cells and is associated with enhanced malignant phenotypes. It may affect macrophage M2-like polarization by upregulating CCL2, thus participating in NSCLC immune microenvironment remodeling.

CCL2↗

PubMed2026

Nucleolin promotes neuropathic pain by increasing chromatin accessibility at the Ccl2 promoter in primary sensory neurons.

Nerve injury-induced transcriptional alterations in primary sensory neurons of the dorsal root ganglion (DRG) constitute a key molecular basis for the development of neuropathic pain. Nucleolin (NCL), a highly conserved multifunctional nucleolar protein, regulates gene transcription. Here, we identify that NCL is expressed exclusively in the nuclei of DRG neurons. Peripheral nerve injury time-dependently upregulates Ncl mRNA and NCL protein levels in injured DRG neurons. Blocking this upregulation through DRG microinjection of the adeno-associated virus 9 (AAV9) expressing an shRNA targeting Ncl attenuates nerve injury-induced increases of C-C motif chemokine ligand 2 (CCL2) mRNA and its protein in injured DRG and alleviates the development and maintenance of mechanical, heat and cold hypersensitivities. Conversely, mimicking DRG NCL upregulation through DRG microinjection of AAV9 carrying the full-length Ncl coding sequence increases Ccl2 mRNA and CCL2 protein levels in microinjected DRGs and produces neuropathic pain-like symptoms in the absence of nerve injury. Mechanistically, peripheral nerve injury increases NCL occupancy at the Ccl2 promoter and enhances chromatin accessibility at this locus, resulting in elevated CCL2 expression in injured DRG neurons, which is reversed by NCL knockdown. Given that Ncl mRNA is co-expressed with Ccl2 mRNA in individual DRG neurons, our findings suggest that NCL upregulation in the DRG contributes to neuropathic pain likely by increasing chromatin accessibility at the Ccl2 promoter in primary sensory neurons.

Animals↗

PubMed2025

Rare damaging CCR2 variants are associated with lower lifetime cardiovascular risk.

BACKGROUND: Previous work has shown a role of CCL2, a key chemokine governing monocyte trafficking, in atherosclerosis. However, it remains unknown whether targeting CCR2, the cognate receptor of CCL2, provides protection against human atherosclerotic cardiovascular disease. METHODS: Computationally predicted damaging or loss-of-function (REVEL > 0.5) variants within CCR2 were detected in whole-exome-sequencing data from 454,775 UK Biobank participants and tested for association with cardiovascular endpoints in gene-burden tests. Given the key role of CCR2 in monocyte mobilization, variants associated with lower monocyte count were prioritized for experimental validation. The response to CCL2 of human cells transfected with these variants was tested in migration and cAMP assays. Validated damaging variants were tested for association with cardiovascular endpoints, atherosclerosis burden, and vascular risk factors. Significant associations were replicated in six independent datasets (n = 1,062,595). RESULTS: Carriers of 45 predicted damaging or loss-of-function CCR2 variants (n = 787 individuals) were at lower risk of myocardial infarction and coronary artery disease. One of these variants (M249K, n = 585, 0.15% of European ancestry individuals) was associated with lower monocyte count and with both decreased downstream signaling and chemoattraction in response to CCL2. While M249K showed no association with conventional vascular risk factors, it was consistently associated with a lower risk of myocardial infarction (odds ratio [OR]: 0.66, 95% confidence interval [CI]: 0.54-0.81, p = 6.1 × 10-5) and coronary artery disease (OR: 0.74, 95%CI: 0.63-0.87, p = 2.9 × 10-4) in the UK Biobank and in six replication cohorts. In a phenome-wide association study, there was no evidence of a higher risk of infections among M249K carriers. CONCLUSIONS: Carriers of an experimentally confirmed damaging CCR2 variant are at a lower lifetime risk of myocardial infarction and coronary artery disease without carrying a higher risk of infections. Our findings provide genetic support for the translational potential of CCR2-targeting as an atheroprotective approach.

Humans↗

PubMed1988

The mechanism of the suicidal, reductive inactivation of microsomal cytochrome P-450 by carbon tetrachloride.

1. Stoichiometric losses of microsomal haem and cytochrome P-450 were observed when carbon tetrachloride (CCl4) was incubated anaerobically with rat liver microsomes using NADPH or sodium dithionite as a reducing agent. A rapid destruction of haem was also observed during the non-enzymatic reductive incubation of CCl4 with soluble haem preparations (methaemalbumin) in presence of sodium dithionite. The results indicate that haem is both the site and the target of the suicidal activation of CCl4 by cytochrome P-450. 2. When an additional, fluorimetric assay for haem determination was used, an equimolar loss of protoporphyrin IX fluorescence was also observed in both the enzymatic and non-enzymatic system, indicating that the haem moiety of cytochrome P-450 has undergone a structural change, involving either loss or labilization of the porphyrin tetrapyrrolic structure. In both systems the loss of porphyrin was prevented by carbon monoxide (CO). 3. A dichlorocarbene-cytochrome P-450 ligand complex is partially responsible for the difference spectrum obtained on addition of CCl4 to anaerobically reduced rat liver microsomes. A molar extinction coefficient for this complex has been calculated. The carbene trapping agent 2,3-dimethyl-2-butene (DMB) strongly inhibited (greater than 95%) the formation of this spectrum but did not modify the loss of haem in reduced CCl4-supplemented microsomal incubations. The results suggest that dichlorocarbene (:CCl2) is not significantly involved in CCl4-dependent haem destruction. 4. Pretreatment of rats with different microsomal enzyme inducers was responsible for similar but not identical patterns of :CCl2 and CO formation and haem loss during incubation of CCl4 with reduced microsomes. This indicates a critical role of CCl4 metabolism in the suicidal destruction of cytochrome P-450 haem and suggests that the apoprotein of cytochrome P-450 is capable of modulating not only the metabolism of CCl4 to :CCl2 but also the hydrolysis of :CCl2 to CO. 5. Inactivation of cytochrome P-450 by CCl4 with reduced microsomes from Aroclor-pretreated rats was saturable and followed pseudo first-order kinetics. This provides further evidence to conclude that CCl4 activation is a suicidal process where the reactive metabolite(s) formed bind to haem, we predict, in a one to one stoichiometry. 6. The partition ratio between loss of cytochrome P-450 haem and CCl4 metabolism by liver microsomes from Aroclor pretreated rats has been investigated using limiting concentrations of CCl4. It was calculated that approximately 26 molecules of CCl4 had to be metabolised to achieve the loss of one molecule of haem.

Animals↗

PubMed1989

Studies on some specific Ap4A-degrading enzymes with the use of various methylene analogues of P1P4-bis-(5',5'''-adenosyl) tetraphosphate.

Six new methylenephosphonate analogues of P1P4-bis-(5',5'''-adenosyl) tetraphosphate, Ap4A, having P2-P3 carbon bridges CF2, CCl2 and CH2CH2 or P1-P2 and P3-P4 carbon bridges CF2, CCl2 and CH2CH2 in the tetraphosphate chain, were examined as substrates or inhibitors for two specific Ap4A-degrading enzymes: (asymmetrical) Ap4A hydrolase (EC 3.6.1.17) from yellow-lupin seeds and (symmetrical) Ap4A hydrolase (EC 3.6.1.41) from Escherichia coli. All analogues in which the central oxygen atom was replaced by a stable carbon bridge were hydrolysed by the asymmetrical hydrolase (CF2 greater than CCl2 greater than O greater than CHBr greater than CH2 greater than CH2CH2). As expected, these analogues were not hydrolysed by the symmetrical hydrolase, which was also unable to act on analogues having P1-P2 and P3-P4 carbon bridges.

Acid Anhydride Hydrolases↗

PubMed1977

[Metabolism of m-xylene in rats after administration of chlorinated hydrocarbons (author's transl)].

Male albino rats of the Donryu strain were divided into 4 groups: the normal control group, tetrachloromethane (CCl4, TCM) group, tetrachloroethylene (CCl2 = CCl2, PCE) group and trichloroethylene (CHCl = CCl2, TCE) group. Each group was consisted of 6 animals. TCM, PCE and TCE were administered orally at a dosage of 13 mmoles/kg as a 50% v/v olive oil solution to rats 24 hours prior to an oral administration of m-xylene (8.2 mmoles/kg as a 50% v/v olive oil solution). The normal control group was administered only olive oil (2.5 ml/kg) 24 hours prior to m-xylene dose. Urine was collected 24, 48, 72 and 96 hours after administration of m-xylene. The urine was analysed for m-methylhippuric acid (m-MHA) by the paper chromatographic method of Ogata et al. The results obtained were as follows: 1) Total urinary excretion of m-MHA in the normal control group was equivalent on a molar basis to about 58% of m-xylene received, and the major portions of the metabolites were excreted on the 1st day. 2) In TCM group, total urinary excretion of m-MHA was about a half of that in the normal control group. It was equivalent on a molar basis to about 30% of m-xylene received (p less than 0.01), and the urinary excretion of m-MHA on the 1st day was significantly less than those of the normal control group (p less than 0.001) and TCE group (p less than 0.05). 3) In PCE group, urinary excretion of m-MHA on the 1st day was significantly less than that of the normal control group (p less than 0.01) and the excretion was delayed. 4) In TCE group, total urinary excretion of m-MHA was slightly but not significantly less than that of the normal control group (p less than 0.05). 5) In TCM-ip group of rats which were given TCM orally 24 hours prior to the administration of m-xylene by intraperitoneal injection, urinary excretion of m-MHA on the 1st day and in 4 days after administration of m-xylene was less than that of the control-ip group.

Administration, Oral↗

PubMed2026

Revealing the cytokine-mediated embryo-maternal crosstalk during extended in vitro culture in the Arabian camel (Camelus dromedarius).

This study reports, for the first time, the establishment of endometrial organoids (EOs) from the Arabian camel (Camelus dromedarius) and evaluates their suitability as an in vitro model for embryo-maternal interactions during implantation. Endometrial tissues were collected from non-pregnant she-camels and cultured in Matrigel with a defined growth medium. By Day 7, organoids displayed a spherical morphology (200-250 µm), remained viable for up to 20 days, and expanded to approximately 1 mm. They exhibited epithelial characteristics and high proliferative activity, confirmed by expression of mucin-1, pan-cytokeratin, vimentin, and Ki67. Day 7 in vitro-produced embryos co-cultured with EOs showed significant improvements in development and trophoblast outgrowth. This was accompanied by upregulation of key developmental genes (OCT4, c-MYC, KLF4, CDX2). Cytokine profiling revealed enhanced bidirectional signaling: embryos increased secretion of CCL2, CCL4, IGF-1, IFNG, IL1α, IL12b, IL-8, LIF, IL-10, and NTF3, while EOs upregulated VEGFA, IL-8, CCL2, and TIMP1. Co-culture uniquely induced additional cytokines and amplified signaling intensity. Metabolomic analysis of embryo-conditioned medium identified 108 metabolites, including steroids associated with immunomodulation. Notably, embryos cultured in EO-conditioned medium developed up to Day 21 post-cleavage, reaching a mean diameter of 2.4 mm. Overall, camel EOs provide a physiologically relevant platform that supports embryo development and enables detailed investigation of cytokine-mediated embryo-maternal communication and implantation processes in the dromedary camel.

Camel↗

PubMed2026

Myeloma engraftment suppresses osteocytic ossification signatures rescued by loading in mice and reveals predictors of patient outcome.

Multiple myeloma (MM) is a malignant plasma cell disease inducing osteolytic lesions by disrupting bone homeostasis, fostering catabolic and suppressing anabolic functions. While the impact on osteoblast generation and function is well documented, alterations of osteocyte function and extracellular matrix (ECM) are not yet fully understood. Thus, using a syngeneic mouse model of MM by injecting MOPC315.BM cells intratibially into BALB/c mice (n = 95), we performed transcriptomic profiling of an osteocyte-enriched population and identified a mechanosensitive matrisomal gene signature, which was disrupted by tumor engraftment. Non-invasive tibial loading restored the expression of 94 ECM-associated genes, including collagens, fibronectin, and aggrecan. Cross-species integration with RNA-seq data from 387 MM patients revealed eight ECM-related genes whose expression correlated with overall survival (VEGFA, BCAN, FGF13, TNFSF8, SDC1, LAMC1, SEMA3A, and CCL2). Four of these genes (Vegfa, Sdc1, Sema3a, Ccl2) were also load-responsive in a murine osteocyte (IDG-SW3 cells) bioreactor model. Our findings indicate that an existing mechanosensitive osteocytic repair program is suppressed by MM cells, which can be reinvigorated via a brief single loading session. It suggests that exercise-based interventions may be beneficial to restore bone mass through endochondral ossification programs in patients with MM.

Bone disease↗

PubMed1989

Inactivation of O6-alkylguanine-DNA alkyltransferase in HeLa cells by cisplatin.

Inactivation of O6-alkylguanine-DNA alkyltransferase (O6-AGT) in HeLa CCL2 cells by cisplatin was studied. HeLa CCL2 cells treated with cisplatin showed a dose-dependent decline in O6-AGT activity. After cisplatin was removed and replaced with fresh medium, the transferase level began to rise slowly. By 72 h slightly more than 80% of the activity was recovered. It seems that the activity of the alkyltransferase can be inactivated by platinated DNA adducts. The data suggest that the O6-platinum-guanine formation and the O6-alkyltransferase depletion are not responsible for cytotoxicity but may result in a base substitution mutation in mammalian cells.

Cell Survival↗

PubMed1992

Bacterial cytochromes c biogenesis.

We report the primary sequence analyses of two loci, hel and ccl, whose gene products are required specifically for the biogenesis of c-type cytochromes in the Gram-negative photosynthetic bacterium Rhodobacter capsulatus. Genetic and molecular analyses show that the hel locus contains at least four genes, helA, helB, helC, and orf52, and the ccl locus contains two genes, ccl1 and ccl2, that are essential for cytochromes c biogenesis. HelA is homologous to a class of proteins called ABC transporters and helA, helB, and helC are proposed to encode an export complex. Cytochrome c2-alkaline phosphatase gene fusions were used to show that apocytochrome c2 synthesis and secretion are not affected by the hel and ccl defects. Ccl1 and Ccl2 possess typical signal sequences to direct them to the periplasm. The periplasmic orientation of Ccl1 was confirmed using a Ccl1-alkaline phosphatase gene fusion. The Ccl1-alkaline phosphatase gene fusion analysis also demonstrated that Ccl1 does not require hel genes for its synthesis and secretion. Ccl1 is homologous to proteins encoded by chloroplast and mitochondrial genes, suggesting analogous functions in these organelles. Taken together, these results support the hypothesis that the hel-encoded proteins are required for the export of heme to the periplasm where it is subsequently ligated to the c-type apocytochromes.

Alkaline Phosphatase↗

PubMed1992

Covalent alteration of the prosthetic heme of human hemoglobin by BrCCl3. Cross-linking of heme to cysteine residue 93.

Recent studies have shown that a protein-bound heme adduct formed from the reaction of BrCCl3 with myoglobin was due to bonding of the proximal histidine residue through the ring I vinyl of a heme-CCl2 moiety. The present study reveals that BrCCl3 also reacts with the heme of reduced human hemoglobin to form two protein-bound heme adducts. Edman degradation and mass spectrometry provided evidence that these protein-bound heme adducts were addition products in which heme-CCL2 or heme-CCl3 were bound to cysteine residue 93 of the beta-chain of hemoglobin. It appeared that the cysteine residue was bonded regiospecifically to the ring I vinyl group of the altered heme moiety, because the nonprotein-bound products of the reaction included the beta-carboxyvinyl and alpha-hydroxy-beta-trichloromethylethyl derivatives of the ring I vinyl moiety of heme. The absorption spectra of the protein-bound adducts in both the oxidized and reduced states were highly similar to those described for hemichromes, which are thought to be involved in the formation of Heinz bodies and subsequent red cell lysis.

Bromotrichloromethane↗

PubMed2026

Interleukin-1α Mediates Pancreatic Fibroblast Activation, Regulates Immune Cell Recruitment and Fibrosis in Acute and Chronic Pancreatitis.

Pancreatitis is a life-threatening inflammatory disease of the pancreas. The cytokine interleukin-1α has been demonstrated to act as an alarmin released by necrotic cells. In the present study, we investigated the influence of IL-1α on the immune response during acute and chronic pancreatitis. Following tissue injury, pancreatic acinar cells released IL-1α, which activates tissue-resident fibroblasts to differentiate toward a pro-inflammatory phenotype. By secreting chemokines and cytokines such as CXCL5, CCL2, and IL-6, these fibroblasts recruit immune cells to the pancreas. The absence of IL-1α reduces disease severity in acute pancreatitis and chemokine release. Furthermore, IL-1α primes fibroblasts to enhance the production of extracellular matrix-components by the up-regulation of pro-fibrotic receptors such as Il4ra, Il13ra1, and Tgfbr3. Therefore, the deletion of IL-1α significantly reduced the development of tissue fibrosis. A therapeutic blockade of the IL1R1-signaling by i.p. administration of the IL-1-receptor antagonist Anakinra showed the same effect; the severity of acute pancreatitis and fibrogenesis during chronic pancreatitis were reduced. In conclusion, the crosstalk between necrotic acinar cells and fibroblasts mediated by IL-1α plays a crucial role in acute inflammation of the pancreas and fibrogenic signaling. Blockade of IL1R1-signaling by Anakinra is therefore a promising therapeutic intervention for both acute and chronic pancreatitis.

Anakinra↗

PubMed2025

Plasma proteomic markers of pain and emotional dysfunction in fibrous dysplasia/McCune-Albright syndrome.

Pain in Fibrous dysplasia/McCune-Albright syndrome (FD/MAS) remains poorly understood and inadequately managed due to uncertainties regarding clinical or biological drivers. This cross-sectional pilot study aimed to use plasma proteomics to identify markers that inform on molecular pathways associated with pain and emotional symptoms in FD/MAS. Seventeen individuals (15 females, 2 males), aged 16 to 63 years, with confirmed diagnoses of monostotic FD, polyostotic FD, or MAS participated in a single study visit conducted at Boston Children's Hospital and Massachusetts General Brigham. During the visit, participants completed validated questionnaires assessing neuropathic pain characteristics, pain interference, anxiety symptoms, depression symptoms, and perceived stress, and provided plasma samples. These samples were analyzed for 57 proteins using Olink proximity extension assay. Associations between protein concentrations and symptom scores were evaluated using Spearman's correlations with false discovery rate correction (|r| > 0.5, p < 0.05). After FDR correction, the concentrations of seven proteins (TNF-α, LTA, CCL19, CSF2, CCL2, CCL4, CCL7) significantly correlated with pain interference, HADS-depression scores, or perceived stress. Four protein concentrations (TNF-α, CCL19, CSF2, CCL7) significantly correlated with multiple clinical measures. This pilot study identified several pain-associated proteins in individuals with FD/MAS, suggesting that proteomic profiling may be a promising approach for discovering pain biomarkers. Larger, longitudinal studies are needed to validate these results and investigate whether targeting immune pathways can alleviate pain and improve emotional health in FD/MAS.

Humans↗

PubMed2026

KEAP1 loss-of-function suppresses immunogenic ferroptosis and limits PD-1 blockade efficacy through an NRF2-FSP1 pathway.

Loss-of-function mutations in Kelch-like ECH-associated protein 1 (KEAP1) frequently occur in lung adenocarcinoma and are associated with poor prognosis and limited benefit from immunotherapy. However, the mechanisms linking KEAP1 deficiency to immune evasion remain elusive. We combined clinical data analysis, in vivo tumor models, and in vitro co-culture systems to investigate how KEAP1 deficiency shapes dendritic cell (DC) biology and response to PD-1 blockade. Ferroptosis induction assays, damage-associated molecular patterns (DAMPs) quantification, cytokine profiling, and mechanistic interrogation of the FSP1-CoQ10 axis were performed to delineate pathways.KEAP1 mutations correlated with poor response to PD-1 blockade and reduced DC infiltration. In mice, KEAP1-deficient tumors exhibited accelerated growth and reduced DC and CD8+ T-cell infiltration, consistent with an immune-cold phenotype. Mechanistically, KEAP1 loss impaired DC function in vitro, as evidenced by reduced maturation, phagocytosis, and naïve CD8+ T-cell priming capacity. This defect was linked to two mechanisms. First, KEAP1-deficient tumor cells resisted ferroptosis and failed to release immunogenic DAMPs, including extracellular ATP, HMGB1, and calreticulin. Second, KEAP1 deficiency reprogrammed the cytokine secretion profile, with downregulation of CCL2, IL-6, CXCL1, and CXCL2, thereby diminishing DC recruitment and inflammatory signaling. Notably, inhibition of the FSP1-CoQ10 antioxidant axis restored ferroptosis-associated immunogenic cell death. Our study identifies KEAP1 deficiency as a driver of immune-cold tumor microenvironments and resistance to PD-1 blockade, acting through impaired ferroptosis-induced immunogenic cell death and disrupted DC function. Genetic FSP1 deletion restored ferroptosis-associated immunogenicity and DC activation in KEAP1-deficient cells, supporting FSP1 as a potential therapeutic target for further in vivo evaluation.

DAMPs↗

PubMed2026

Glial Connexin-43 Is a Pathogenic Mechanism Promoting Gut Inflammation in Postoperative Ileus Induced by Gut Surgical Manipulation With Potential Relevance to Humans.

BACKGROUND & AIMS: Abdominal surgery often precipitates postoperative ileus (POI), a frequent and severe gastrointestinal (GI) motility disorder, through mechanisms that involve intestinal inflammation. Emerging data show that enteric glia acquire a reactive phenotype that aggravates POI, but how glia exert this effect remains unclear. Enteric glia express connexin-43 hemichannels (gCx43), which are implicated in neurological and inflammatory disorders. Thus, we aimed to decipher contributions of glial connexin-43 (Cx43) in the pathophysiology of POI. METHODS: We induced POI in mice using in vivo intestinal manipulation and used glial Cx43cKO (Sox10CreERT2;Cx43fl/fl) or RiboTag (Sox10CreERT2/Rpl22HA/+) mice to evaluate Cx43-dependent signaling. Human enteric glial cultures (hEGC) and muscularis externa obtained during intestinal surgery translated findings to patients. Transcriptome analysis, immunofluorescence co-labeling, Western blots, and Cx43 hemichannel activation were used for quantitative analysis. RESULTS: Cx43 is the highest expressed connexin in enteric glia in mice and humans. Up-regulation of Cx43 occurs in various disease models linked to POI, GI surgical trauma, inflammation, immune cell activation, and enteric gliosis. In the mouse POI model, glial Cx43-deletion reduces glial reactivity, pro-inflammatory signals, upregulates host protection genes, regulates immune cell activation, and prevents enteric neuropathy. In hEGCs, interleukin (IL)-1β induction opens Cx43 and stimulates release of IL-6 and C-C motif ligand 2 (CCL2). The Cx43 peptide inhibitor, 43Gap26, inhibits glial Cx43 activation, reduces IL-6 release, and blocks upregulation of macrophage activation factors and immune cell regulation factors. Surgical intestinal trauma in patients upregulates Cx43 during inflammation and enteric gliosis in mouse POI. CONCLUSIONS: Glial Cx43 signaling promotes enteric gliosis, immune cell activation, inflammation, and enteric neuropathy in mice with potential translatability to humans after intestinal surgical trauma and mechanical stress in POI. Interventions that block glial Cx43 activation may be protective against POI development.

Animals↗

PubMed1989

Recognition of beta beta'-substituted and alpha beta,alpha'beta'-disubstituted phosphonate analogues of bis(5'-adenosyl) tetraphosphate by the bis(5'-nucleosidyl)-tetraphosphate pyrophosphohydrolases from Artemia embryos and Escherichia coli.

A total of 13 phosphonate analogues of bis(5'-adenosyl) tetraphosphate (AppppA) have been tested as substrates and inhibitors of the asymmetrically cleaving bis(5'-nucleosidyl) tetraphosphatase (NppppNase) from Artemia and the symmetrically cleaving NppppNase from Escherichia coli. With the Artemia enzyme, the substrate efficiency of beta beta'-substituted compounds decreased with decreasing substituent electronegativity (O greater than CF2 greater than CHF greater than CCl2 greater than CHCl greater than CH2) such that AppCF2ppA and AppCH2ppA were hydrolyzed at 70% and 2.5% of the rate of AppppA, respectively. These compounds were competitive inhibitors of this enzyme with Ki values that generally also decreased with electronegativity from 12 microM for AppCF2ppA to 0.4 microM for AppCH2ppA (Km for AppppA = 33 microM). AppCH = CHppA and AppCH2CH2ppA were neither effective substrates nor inhibitors of the Artemia enzyme. Alpha beta,alpha'beta'-Disubstituted analogues were generally less effective inhibitors with Ki values ranging from 23 microM (ApCH2ppCH2pA) to greater than 1.5 mM (ApCH2CH2ppCH2CH2pA). However, they displayed a low and unexpected rate of symmetrical cleavage by the Artemia enzyme: e.g., ApCHFppCHFpA yielded ApCHFp at 3% of the rate of AppppA breakdown. Both sets of analogues were also competitive inhibitors of the E. coli NppppNase with Ki values ranging from 7 microM (AppCH2ppA) to 250 microM (ApCH2CH2ppCH2CH2pA) (Km for AppppA = 28 microM). The only alpha beta,alpha'beta'-disubstituted analogue to be hydrolyzed by the E. coli enzyme was ApCF2ppCF2pA at 0.2% of the rate of AppppA; however, several of the beta beta'-substituted compounds showed a limited degree of asymmetrical cleavage.(ABSTRACT TRUNCATED AT 250 WORDS)

Acid Anhydride Hydrolases↗

PubMed2026

FAP+ pericyte-like cells promote monocyte differentiation into tumor-associated macrophages in glioblastoma.

Glioblastoma (GBM) is a highly aggressive primary brain tumor characterized by profound immunosuppression that facilitates tumor progression and promotes therapeutic resistance. Fibroblast activation protein (FAP), a recognized theranostic target in multiple cancers, is upregulated in GBM and predominantly expressed by pericyte-like stromal cells. Here we identify a role for FAP⁺ pericyte-like cells in shaping the GBM immune microenvironment through monocyte recruitment and differentiation. Analysis of The Cancer Genome Atlas (TCGA) datasets, supported by reverse-transcription quantitative PCR and immunohistochemistry, revealed that elevated FAP expression-serving as a proxy for the abundance of FAP⁺ pericyte-like cells-is associated with an immune-enriched tumor microenvironment characterized by higher macrophage abundance and elevated expression of M2 polarization markers. Spatial analyses, including immunofluorescence and spatial transcriptomics, demonstrated that immunosuppressive macrophages preferentially localize in proximity to FAP⁺ pericytes. Single-cell RNA sequencing identified these FAP⁺ cells as a distinct perivascular stromal subset with a unique expression pattern of extracellular matrix components and cytokines, including CCL2 and CSF1, with corresponding receptors expressed on myeloid cells. Functional assays using patient-derived FAP⁺ pericyte-like cells confirmed their ability to attract monocytes via soluble mediators and to promote their differentiation and polarization into tumor-associated macrophages with immunoregulatory features, partly mediated by the CSF1-CSF1R axis. Orthotopic co-implantation experiments in mice further supported their capacity to enhance myeloid infiltration in vivo. Consistent with these biological effects, a transcriptional signature characteristic of FAP⁺ pericytes correlated with worse overall survival in patients with GBM. Together, these findings position FAP⁺ pericyte-like cells as modulators of the GBM immune landscape, fostering a tumor-permissive niche by promoting the differentiation of circulating monocytes into immunoregulatory macrophages. Targeting this stromal population may offer new therapeutic avenues to reprogram tumor-associated immune responses in GBM.

Journal Article↗