Inflammatory Stimuli Research Articles

OGG1S326C variant frequent in human populations facilitates inflammatory responses due to its extended interaction with DNA substrate

8-oxoguanine (8-oxoGua) is one of the most frequent forms of oxidative DNA base lesions, repaired by 8-oxoguanine DNA glycosylase 1 (OGG1) via base excision repair (BER) pathway to maintain genome fidelity. The human allelic variant hOGG1S326C, prevalent in Caucasians and Asians, has been regarded as a susceptibility factor for various diseases, yet its pathogenic mechanism remains elusive. In this study, we demonstrate that Ogg1S326C/S326C mice exhibit increased and sustained airway inflammation compared with wild-type (WT) Ogg1S326/S326 mice. Mechanistically, in response to inflammatory stimulation, OGG1S326C undergoes reactive oxygen species-induced dimerization, which impairs its base excision function, but prolongs its association with promoter-embedded substrate(s), leading to an increase in NF-κB' DNA occupancy, subsequently the excessive expression of proinflammatory cytokines and chemokines, and the exacerbated lung inflammation. In contrast, Serine at position 326 in WT -OGG1 is constitutively phosphorylated by CDK4. To fulfill the requirement for its function in transcriptional regulation, the phosphorylated OGG1 needs to undergo dephosphorylation to rescue DNA binding ability. In this scenario, OGG1S326C lacks this phosphorylation site, disrupting this regulatory cycle. Notably, administration of a small molecule inhibitor of OGG1 prevents OGG1S326C from binding to DNA and significantly decreases gene expression and inflammatory responses. Our findings elucidate a molecular basis for the increased disease susceptibility of individuals carrying the hOGG1S326C variant and propose the therapeutic potential of OGG1 inhibitors in mitigating inflammation-driven pathologies.

The alterations of molecular repertoire of the RANKL-induced osteoclastogenesis in the M1 macrophage-derived inflammatory milieu

Inflammation have been linked to bone diseases such as osteoporosis or bone destruction. However, whether M1 inflammatory stimuli exert a stimulatory or inhibitory effect on the differentiation of osteoclasts remained controversial. Also, how inflammatory milieu influence cell proliferation and survival during osteoclastogenesis have not been determined. Here we reported the molecular repertoire alterations of RANKL-stimulated osteoclastogenesis from RAW264.7 at different stages in the inflammatory environments. Adding conditioned medium collected from LPS-stimulated macrophage, which are the primary source of extracellular inflammatory mediators, resulted in a biphasic change in cell number among differentiating preosteoclasts. The inflammatory milieu induced a transient proliferation of preosteoclasts during the initial 48 h, which was followed by a significant decline in cell numbers from the fourth day onwards. Proliferation-related AKT and ERK were transiently activated in the inflammatory environments, which also upregulated the expressions of c-myc, a major transcription factor for osteoclast differentiation, and pro-inflammatory genes, such as Tnf-a and Nos2. Following prolonged exposure to an inflammatory environment, undifferentiated osteoclast precursors undergo apoptosis. Our findings suggest that short-term inflammatory exposure transiently promotes the proliferation and differentiation of preosteoclasts, whereas long-term exposure leads to apoptosis, potentially due to the enhancement of inflammatory signals.

PI3K/mTOR Signaling Pathway Dual Inhibition for the Management of Neuroinflammation: Novel Insights from In Vitro Models

Neuroinflammatory responses are central to the pathogenesis of neurodegenerative diseases, affecting cells of both neuronal and glial origin that respond to immune-driven inflammatory stimuli. The PI3K/mTOR signaling pathway is essential for the regulation of these neuroinflammatory processes and is therefore a promising target for therapeutic intervention. Here, we investigated the consequences of PI3K/mTOR pathway inhibition on neuroinflammation employing PF-04691502, an agent with combined PI3K and mTOR inhibitory activity. We treated SH-SY5Y, C6, BV-2, and Mo3.13 cell lines with PF-04691502 at concentrations of 0.1, 0.5, and 1 µM to assess the modulation of neuroinflammatory responses. To induce inflammation, cells were stimulated with lipopolysaccharide (LPS, 1 μg/mL) and interferon-gamma (IFN-γ, 100 U/mL). The results from the MTT assays demonstrated that PI3K/mTOR inhibition preserved cell viability at 0.5 and 1 µM across all of the cell lines, indicating its potential to mitigate inflammation-driven cytotoxicity. Subsequent ELISA assays revealed a marked decrease in the NF-κB and pro-inflammatory cytokine levels, confirming the effective suppression of inflammation through PI3K/mTOR inhibition. In addition, the SH-SY5Y cell line was exposed to MPP+ to simulate Parkinson’s disease (PD)-like toxicity; then, cell viability, PD-associated markers, and apoptotic indicators were assessed. Our results indicate that inhibition of the PI3K/mTOR signaling axis may alleviate neurodegenerative processes by modulating both neuroinflammatory responses and apoptotic pathways. These findings highlight the therapeutic promise of targeting PI3K/mTOR in the context of neurodegenerative disorders and support the need for further validation through in vivo and clinical investigations.

Effect of Microbial Stimuli and Bone Morphogenetic Protein 2 on Ectopic Bone Formation.

Advancements in biomaterials design increasingly focus on material-host immune interactions as one of the strategies to promote new bone formation, referred to as osteoimmunomodulation. Recent studies indicate that inflammatory stimuli can synergize with growth factors such as bone morphogenetic protein 2 (BMP-2) to promote bone formation. Pathogen-associated molecular patterns (PAMPs) are motifs expressed by microbes that are recognized by immune cells and induce an immune-stimulatory response. In this study, we combined PAMPs with low-dose BMP-2 on a biphasic calcium phosphate (BCP) scaffold and evaluated its effect on ectopic bone formation in a subcutaneous implantation model. The PAMPs tested include gamma-irradiated whole microbes (γi-Staphylococcus aureus and γi-Candida albicans), a vaccine (Bacillus Calmette-Guérin containing Mycobacterium bovis), bacterial cell wall components (peptidoglycan [PGN], lipopolysaccharide [LPS], lipoteichoic acid, and Pam3CysSerLys4), an exopolysaccharide (Curdlan), and nucleic acid analogues (polyinosinic:polycytidylic acid [Poly(I:C)] and Cytidine-phosphate-guanosine [CpG]-containing oligonucleotides type C). Implants consisting of BCP, PAMPs, and BMP-2 were placed subcutaneously in rabbits and evaluated for ectopic bone formation after 5 weeks. Implants with only BMP-2 served as controls. Of the PAMPs tested, only PGN and BMP-2 showed a positive bone volume compared with the control, with borderline significance (+4.4%, p = 0.08). Decreased bone volume was seen for LPS (-7.4%, p = 0.03) and Poly(I:C) (-6.3%, p = 0.04). Fluorochrome labeling at weeks 2 and 3 assessed mineralization onset, revealing no mineralization in the first 2 weeks and some implants showing onset at week 3. We observed variability in ectopic bone formation across animals, associated with higher osteoclast numbers in those where ectopic bone occurred versus those that did not (p = 0.004). PAMPs can modulate bone formation, but their effects are variable, requiring further refinement to harness their osteoimmunomodulatory properties effectively. Additionally, we highlight osteoclasts' important role in stimulating ectopic bone formation.

Effect of isolated keratin 3 knockdown on gene expression of primary limbal epithelial cells without and with inflammatory stimuli.

Studies have shown that keratin 3 (KRT3) expression is reduced in paired box 6 (PAX6) haploinsufficient primary limbal epithelial cells (LECs). The downregulation of KRT3 expression due to PAX6 haploinsufficiency is likely a critical factor in the development and progression of aniridia associated keratopathy (AAK). In addition, the ocular surface of congenital aniridia patients exhibits an inflammatory environment. The objective of this study was to investigate the isolated effect of KRT3 knockdown, achieved via siRNA silencing in healthy LECs, on PAX6 and other related gene expressions, both under normal and inflammatory conditions. To achieve KRT3 knockdown, human primary LECs were transfected with KRT3 siRNA using Lipofectamine 2000. Inflammatory conditions were induced 48hours after transfection by treating the cells with 2mg/mL of lipopolysaccharides (LPS) or 1ng/mL of IL-1β. Subsequently, gene and protein expression levels were analysed using qPCR, Western blotting, and ELISA. Following KRT3 knockdown at protein level, there was DSG1, ADH7 and PPARγ upregulation and MAPK1 downregulation solely at transcriptional level (p≤0.031). Nevertheless, IL-6 downregulation could be observed both at transcriptional and at protein levels (p≤0.003). Following KRT3 siRNA knockdown, LPS induced inflammation decreased PPARγ mRNA level and IL-1β induced inflammation decreased DSG1 and ADH7 mRNA levels without changes at protein levels (p≤0.014). In contrast, in control knockdown LECs, IL-1β induced inflammation significantly decreased KRT3 mRNA and protein levels and IL-6 protein level (p≤0.02). In normal LECs, inflammatory stimuli slow differentiation and simultaneously induce IL-6 production. These mechanisms are absent in KRT3 knockdown LECs. As a result, despite the presence of inflammation, KRT3 knockdown LECs continue their differentiation unaltered while maintaining inflammatory IL-6 protein secretion.

ENTR1 regulates periodontitis by modulating macrophage M1 polarization via AMPK activation.

ENTR1 regulates periodontitis by modulating macrophage M1 polarization via AMPK activation.

The role of sevoflurane exposure on systemic inflammation and neuroinflammation: a systematic review and meta-analysis of in vivo and in vitro studies.

The role of sevoflurane exposure on systemic inflammation and neuroinflammation: a systematic review and meta-analysis of in vivo and in vitro studies.

Platelet-Released Growth Factors (PRGFs) Activate NRF2-ARE and Modulate Inflammatory Response in an NRF2-Dependent Manner in Primary Human Keratinocytes.

Platelet-released-growth factors (PRGF) and platelet-rich plasma (PRP) are blood-derived products used in regenerative treatments and in overall aesthetic rejuvenation. Keratinocytes possess distinctive characteristics responsible for protection against environmental stressors and oxidant clearance. One such mechanism is the transcription factor NRF2, which plays a critical role in regulating cytoprotective genes, inflammation, and oxidative stress response. Data on the activation of the NRF2-ARE and NF-κB axes by PRGF are very limited. This study aims to investigate whether PRGF activates NRF2 and, if so, is responsible for the described anti-inflammatory effect of PRGF/PRP in an invitro primary human keratinocyte model. NRF2 activation is analyzed by NQO1 and HO-1 western blotting, gene expression analysis, and by an ARE-promoter study using luciferase-based reporter gene assays in patient-derived keratinocytes. Besides direct determination of the PRGF-NRF2 interaction, we investigated the NF-κB response by treating cells with PRGF and the inflammatory stimuli TNF-α. Inflammatory parameters were analyzed using ELISAs for IL-1β, IL-4, Il-10, TNF-α and IL-6 in the supernatant, NF-κB luciferase reporter gene assays as well a-NF-κB western blotting. NRF2 involvement was tested by treating the cell-culture model with the NRF2-inhibitor ML-385. We were able to show that ARE activity was significantly upregulated in PRGF-treated keratinocytes, leading subsequently to increased NQO1 and HO-1 protein expression. Inflammatory IL-secretion showed an association with NRF2 availability. In summary, PRGFs activate NRF2 target proteins and downregulate NF-κB-associated inflammation in an NRF2-dependent manner. Therefore, we further suggest PRGF as an anti-inflammatory treatment after medical aesthetic procedures.

Inflammation via JAK-STAT/HIF-1α Drives Metabolic Changes in Pentose Phosphate Pathway and Glycolysis That Support Aortic Valve Cell Calcification.

Inflammation and metabolic reprogramming are hallmarks of cardiovascular disorders, wherein myocardiocytes switch from fatty acids to glucose to yield energy. This has also been found in the myocardium of patients with calcific aortic valve disease, a prevalent disease exhibiting features of inflammatory disease that lacks pharmacological treatments. Therefore, we posited that the analysis of proinflammatory and metabolic mechanisms might give cues to disclose therapeutic targets. The metabolic analysis of aortic valve interstitial cells (VIC) explanted from human valves was performed by Seahorse real-time cell metabolic analysis, fluxomics using ultra-performance liquid chromatography/mass spectrometry, quantitative polymerase chain reaction, metabolite quantitation, and loss-of-function experiments with gene silencing and pharmacological approaches. Findings were validated in quiescent VIC, 3-dimensional porcine VIC-valve endothelial cell cocultures, as well as in valve leaflets and VIC from human patients. The hyperglycolytic program present in calcific aortic valve disease was replicated in control/nonstenotic VIC by cytokine exposure and enhanced by pathogen-associated molecular patterns. Inflammatory stimuli increased fluxes in glycolysis, tricarboxylic acid cycle, and the pentose phosphate pathway. Inflamed VIC exhibited increased glycolytic ATP production and lactate secretion, as well as changes in redox state and metabolic gene profile, that is, upregulation of glycolytic enzyme expression and downregulation of G6PD (glucose-6-phosphate dehydrogenase), the rate-limiting enzyme of the oxidative phase of pentose phosphate pathway. Notably, these alterations were replicated in quiescent VIC and 3-dimensional VIC-valve endothelial cell cocultures and are observed in diseased valves from patients. Strikingly, metabolic rewiring in control VIC was required for inflammation-triggered calcification and differentiation. A Food and Drug Administration-approved JAK (Janus kinase) inhibitor blunted these changes, whose major drivers are the JAK-STAT system, HIF (hypoxia-inducible factor)-1α, and NF-κB (nuclear factor-κB). Inflammation reprograms VIC metabolism to support calcification by downregulating oxidative phase of pentose phosphate pathway and enhancing glycolytic flux and oxidative stress. These findings parallel the metabolic profile of stenotic VIC and provide novel therapeutic clues.

Enteroendocrine cells regulate intestinal barrier permeability.

The intestinal epithelial barrier is essential for nutrient absorption and protection against ingested pathogens and foreign substances. Barrier integrity is maintained by tight junctions, which are sensitive to inflammatory signals, thus creating a feed-forward loop with an increasingly permeable barrier that further drives inflammation and is the hallmark of inflammatory bowel disease. There are currently no therapeutic strategies to improve the intestinal epithelial barrier. We hypothesized that enteroendocrine cells may play an unappreciated role in maintaining barrier integrity. To test this hypothesis, we seeded human intestinal enteroids with genetic loss of enteroendocrine cells on Transwell filters and evaluated transepithelial electrical resistance, paracellular permeability, and the localization and abundance of junctional proteins. We found that enteroendocrine cells were required to maintain a healthy barrier in crypt-like "stem" and villus-like differentiated cultures. In addition, exogenous supplementation of enteroendocrine-deficient cultures with the hormones peptide tyrosine-tyrosine (PYY), and the somatostatin analog octreotide was sufficient to rescue many aspects of this barrier defect both at baseline and in the presence of the inflammatory cytokine tumor necrosis factor. Surprisingly, these improvements in barrier function occurred largely independently of changes in protein abundance of junctional proteins zona occludens 1, occludin, and claudin-2. These findings support a novel role for enteroendocrine cells in augmenting epithelial barrier function in the presence of inflammatory stimuli and present an opportunity for developing therapies to improve the intestinal barrier.NEW & NOTEWORTHY There are no therapies that directly improve the permeability of the intestinal epithelial barrier. This work uses a human intestinal epithelial model system to demonstrate that sensory enteroendocrine cells are necessary for healthy barrier function and that two of their secreted products, peptide YY and somatostatin, are sufficient to improve barrier function at homeostasis and in the presence of inflammatory cytokines. This could provide novel treatments for strengthening the epithelial barrier in human gastrointestinal disease.

Serum Interleukin-6 Exhibits Better Diagnostic Performance Than Serum C-Reactive Protein in Acute Periprosthetic Joint Infection.

Serum Interleukin-6 Exhibits Better Diagnostic Performance Than Serum C-Reactive Protein in Acute Periprosthetic Joint Infection.

Bifunctional sheets reduce the microbe and endotoxin contamination of tissue-derived collagen.

Bifunctional sheets reduce the microbe and endotoxin contamination of tissue-derived collagen.

Quercetin-calcium hydroxide scaffolds modulate dental pulp stem cell response invitro under a simulated inflammatory environment.

Tissue engineering can be applied to dentine regeneration, stimulating tissue repair by promoting mesenchymal cell migration and differentiation into odontoblast-like cells while modulating inflammation. This study aimed to investigate the effect of quercetin (QU) and calcium hydroxide (CH) incorporated into polycaprolactone (PCL)/polyethylene oxide (PEO) scaffolds on the differentiation of dental pulp stem cells (DPSCs) in a simulated inflammatory environment invitro. Dental pulp stem cells (DPSCs) were cultured and treated with different concentrations of quercetin (QU) to assess cell viability, mineralized matrix production and responses under inflammatory stimuli. Reactive oxygen and nitrogen species, as well as TNF-α synthesis, were quantified using fluorescence and ELISA methods. Scaffolds of PCL/PEO with calcium hydroxide and QU were fabricated via electrospinning, characterized and analysed for cell adhesion, viability, inflammatory and mineralisation-related genes in an artificial pulp chamber model. Statistical analysis was performed using anova, Kruskal-Wallis and confidence intervals with a significance level of 5%. Polycaprolactone/polyethylene oxide scaffolds incorporated with CH and QU showed cytocompatibility and support for DPSC differentiation at concentrations of up to 5 M diluted in the culture medium. After 14 days of treatment, the scaffolds upregulated ALPL gene expression under the inflammatory stimulus, with no differences between the control group and the nonincorporated scaffold. The expression of osteocalcin (OCN) and dentine sialophosphoprotein (DSPP) genes was significantly upregulated for the scaffold-treated group when stimulated with LPS. Incorporating QU and CH into PCL/PEO scaffolds modulated the inflammatory-related response and upregulated mineralisation-related genes of LPS-challenged dental pulp stem cells.

Systemic Inflammation and Anhedonic Responses to an Inflammatory Challenge in Adults With Major Depressive Disorder: A Randomized Controlled Trial.

The authors sought to determine whether an inflammatory challenge with lipopolysaccharide (LPS) differentially impacts symptoms of anhedonia in participants with major depressive disorder with high (≥3 mg/L) and low (≤1.5 mg/L) serum C-reactive protein (CRP) concentrations. Sixty-eight participants with major depressive disorder were randomly assigned, in a 1:1 ratio, to receive LPS (0.8 ng/kg body weight) or placebo (saline) in a parallel-group double-blind design. Participants were stratified according to baseline CRP concentrations, yielding four groups: high-CRP LPS (N=13), low-CRP LPS (N=19), high-CRP placebo (N=13), and low-CRP placebo (N=19). Blood was sampled at baseline, at 1, 1.5, 3.5, 6, and 24 hours, and 1 week after LPS or saline administration, with concurrent assessment of psychological outcomes. The primary outcome measure was the Snaith-Hamilton Pleasure Scale (SHAPS), and the primary contrast of interest was the change between baseline and 1.5 hours (peak of the inflammatory response) in the high-CRP versus low-CRP groups receiving LPS. Secondary outcomes included the Montgomery-Åsberg Depression Rating Scale (MADRS) and serum levels of three cytokines: interleukin-6 (IL-6), IL-10, and tumor necrosis factor (TNF). Data were analyzed with linear mixed models. Significantly greater increases in self-reported anhedonia (on the SHAPS) and IL-6 levels were observed between baseline and 1.5 hours in the high-CRP versus low-CRP LPS groups. There were no significant differences for TNF and IL-10. The MADRS was not administered at 1.5 hours; secondary analyses showed a significant group-by-condition-by-time interaction driven by a greater decrease in MADRS scores between baseline and 24 hours in the high-CRP group. Depressed individuals with systemic inflammation appeared to be biologically primed to respond more strongly to inflammatory stimuli, and psychologically, this sensitization impacted the symptom of anhedonia, the primary outcome.

Mixed lymphocyte reaction-conditioned MSC-derived extracellular vesicles enhance graft survival via miR-638-mediated immunoregulation.

Mesenchymal stem cells (MSCs) require priming by proinflammatory stimuli for optimal immunosuppressive effects. Our previous work identified mixed lymphocyte reaction-conditioned medium (MLR-CdM) as a potent enhancer of MSC immunosuppressive properties. This study evaluates the immunomodulatory potential of MSC-derived extracellular vesicles preconditioned with MLR-CdM (MSC-EVMLR) compared to IFN-γ (MSC-EVIFN), focusing on key miRNAs and mechanisms involved. We assessed the ability of MSC-EVMLR and MSC-EVIFN to modulate lymphocyte proliferation and cytokine expression in vitro. To identify potential effector molecules within MSC-EVMLR, we performed miRNA array analysis combined with dose-response experiments using MLR-CdM under varying stimulation conditions. We used a murine allogeneic heterotopic heart transplantation model to investigate the impact of MSC-EVMLR on graft survival and its immunomodulatory effects. MSC-EVMLR outperformed MSC-EVIFN in suppressing lymphocyte proliferation and steering cytokine expression toward an anti-inflammatory profile in vitro. Through miRNA array analysis and dose-response experiments with MLR-CdM, miR-638 was identified as a potential effector molecule in MSC-EVMLR. In vivo study demonstrated that MSC-EVMLR significantly prolonged graft survival, which was associated with a marked decreased proinflammatory cytokines IL6 and IFN-γ and increase in regulatory T cells (Tregs) and within the transplanted heart tissue. These effect was significantly reduced upon miR-638 knockdown. Additionally, the miR-638/Fosb axis was identified as a key pathway that promoted Treg differentiation and induced immune tolerance. Preconditioning MSCs with MLR-CdM, a blend of inflammatory stimuli, potentiates the immunoregulatory capacity of MSC-EV beyond the effects of IFN-γ stimulation alone. This study advances the understanding of MSC-EV-based therapies in transplantation.

Association of Helicobacter Pylori Infection with Gastric Carcinogenesis and the Impact of Eradication Therapy

Globally, gastric cancer, as a highly prevalent malignant tumor, exerts great pressure on the public health system with its high morbidity and mortality rates. Studies have shown that Helicobacter pylori (Hp) infection plays a key role in the pathogenesis of gastric cancer. This Gram-negative, spiral-shaped, microaerobic bacterium is able to specifically colonize the surface of gastric mucosal epithelial cells, leading to diseases such as chronic gastritis and peptic ulcers. Prolonged chronic inflammatory stimulation may trigger pathological changes in gastric mucosal cells, such as atrophy, intestinal chemotaxis, and heterogeneous hyperplasia, which are considered to be precancerous lesions of gastric cancer. Epidemiologic studies and clinical trials have confirmed a significant association between H. pylori infection and gastric cancer, which not only significantly increases the risk of gastric cancer but also accelerates its progression. Therefore, H. pylori eradication therapy is considered a core strategy for primary prevention of gastric cancer.

Abstract 3443: Bipotential role of retinoblastoma binding protein 9 in sporadic colorectal cancer and colitis-associated cancer

Abstract Retinoblastoma-binding protein 9 (RBBP9) is expressed in various human cancers and has been identified as a serine hydrolase promoting cancer progression by antagonizing TGFβ signaling. While its roles in pancreatic cancer have been explored, little is known about its function in intestinal tumorigenesis. Using human samples and mouse models, we investigated the bipotential role of RBBP9 in sporadic colorectal cancer (CRC) and colitis-associated cancer (CAC).Human surgical samples revealed that RBBP9 expression is significantly lower in CAC compared to sporadic CRC. Sporadic CRC is driven by Wnt/β-catenin activation, whereas CAC involves inflammation-associated pathways such as mTORC1 and IL6/JAK/STAT3 signaling. Consistent with these findings, Rbbp9-/- mice exhibited increased colitis severity and enhanced CAC tumorigenesis in the azoxymethane/dextran sulfate sodium (AOM/DSS) model. Transcriptomic analysis of AOM/DSS-treated tumors revealed upregulation of inflammatory and proliferation-associated pathways, such as mTORC1 and IL6/JAK/STAT3, while Wnt/β-catenin and mitotic signatures were downregulated, indicating inflammation-driven tumorigenesis independent of Wnt signaling in CAC.In the ApcMin/+ model of spontaneous intestinal tumorigenesis, RBBP9 loss led to fewer and smaller tumors in the small intestine, accompanied by reduced proliferative activity and downregulation of cell cycle-related pathways (e.g., Myc targets and G2M checkpoint). Interestingly, tumors from ApcMin/+;Rbbp9-/- mice exhibited enrichment of inflammatory and interferon-related signatures, including “oxidative phosphorylation” and “interferon alpha/gamma response, ” though these changes did not lead to increased tumor proliferation without inflammatory stimuli. However, when ApcMin/+;Rbbp9-/- mice were treated with DSS, a significant increase in inflammation-mediated tumorigenesis was observed in the colon, accompanied by elevated Ki67 and pS6 staining, markers of proliferative activity.Collectively, these findings highlight the bipotential role of RBBP9 in intestinal tumorigenesis. In human CAC, reduced RBBP9 expression correlates with inflammation-driven pathways, while in sporadic CRC, higher RBBP9 expression supports tumor progression via Wnt/β-catenin and cell cycle pathways. These results demonstrate that RBBP9 functions as a context-dependent regulator, suppressing inflammation-mediated tumorigenesis while supporting spontaneous tumorigenesis through proliferative pathways. Targeting RBBP9 may offer novel therapeutic strategies tailored to distinct CRC subtypes, depending on their inflammatory or non-inflammatory origins. Citation Format: Yuki Nakanishi, Kensuke Hamadaa, Yu Muta, Mayuki Omatsu, Kosuke Iwane, Munehiro Ikeda, Jiayu Chen, Yoko Masui, Naoki Aoyama, Hiroki Kitamoto, Nobuyuki Agatsuma, Go Yamakawa, Takahiro Utsumi, Makoto Okabe, Shuji Yamamoto, Akihisa Fukuda, Hiroshi Seno. Bipotential role of retinoblastoma binding protein 9 in sporadic colorectal cancer and colitis-associated cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3443.

Abstract 4277: EP601: Agonism of GPR84 activates myeloid cells and augments the response to anti-CTLA4 to promote tumor growth inhibition and prolong survival in a syngeneic (CT26) tumor model

Abstract GPR84 is a G-protein coupled receptor predominantly expressed on myeloid cells such as macrophages, NK cells, monocytes and neutrophils. It has previously been reported that GPR84 expression is induced by acute inflammatory stimuli and furthermore that GPR84 may be an interesting target to reverse the immunosuppressive tumor microenvironment1. In the current study, induced expression of GPR84 is confirmed as it is demonstrated that there is a 5-fold (or greater) expression of GPR84 on human (M1) macrophages polarized with either IFN-gamma or muramyl dipeptide-and-LPS (“MDP+LPS”). Compound A (CpdA) is a proprietary, selective, small-molecule agonist at GPR84 with similar potency at both the human and mouse GPR84 receptor orthologs (cAMP assay, EC50 = 13 nM and 9 nM, respectively). CpdA promotes TNF-alpha secretion from MDP+LPS-activated human macrophages in a concentration-dependent manner and this response is blocked by the GPR84 antagonist GLPG1205. The pharmacokinetic profile of CpdA has been established in rodents (t1/2 = 1h, oral bioavailability = 25%) and the compound is appropriate for in vivo testing. In the CT26 mouse tumor model, CpdA (30 mg/kg, PO, BID) significantly increased the response to anti-CLTA4 (2 mg/kg, IP, BIW) to >80% tumor growth inhibition and improved survival corresponding to altered immune cell infiltration into the tumor. These results demonstrate the potential of pharmacological activation of GPR84 as a novel approach relevant to cancer immunotherapy.1Li et al., Cancer Immunol Immunother (2024) Citation Format: Graeme L. Fraser, Catherine Sorlet, Nicolas Parmentier, Sarah Rorive, Guillaume Dutheuil. EP601: Agonism of GPR84 activates myeloid cells and augments the response to anti-CTLA4 to promote tumor growth inhibition and prolong survival in a syngeneic (CT26) tumor model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4277.

Association between periodontitis and prostate cancer: A case-control study.

Recent evidence suggests that chronic inflammation may play a role in the development and clinical course of cancer. In this context, periodontitis (PE) has been associated with prostate cancer (PC), but the results are still inconsistent. Therefore, the aim of this study was to evaluate the potential association between PE and PC, and their shared risk factors. This case-control study comprised 152 cases with PC and 220 controls. All participants underwent a complete periodontal examination, and sociodemographic and medical variables of interest were collected. The association between occurrence and severity of PC and covariates was assessed by binary and multinomial multivariate logistic regression, respectively. The cases had a higher prevalence (p=0.012) and severity (p=0.007) of PE. The occurrence of PC was associated with an educational level <9 years (adjusted odds ratio [OR]=1.93), smoking (adjusted OR=2.62), alcohol consumption (adjusted OR=3.45), diabetes (adjusted OR=0.32), chronic hypertension (adjusted OR=2.03), and PE (adjusted OR=1.80). Regarding the severity of PC, Gleason grades 1 and 2 were associated with PE (adjusted OR=1.96), but Gleason grades 3-5 were not. PE was associated with the occurrence of PC. Males diagnosed with PE would potentially benefit from being screened for prostate alterations. Periodontitis is an infectious disease that affects the supporting structures of the teeth. It has been characterized as a chronic inflammatory stimulus with potential risk for the occurrence or worsening of the clinical course of cancer. We evaluated the potential relationship between periodontitis and prostate cancer, as well as their shared risk factors, in a case-control study comprising 372 male individuals. The participants were recruited in a urology outpatient clinic and underwent a complete periodontal examination. The results showed that individuals with prostate cancer presented a worse periodontal status and a higher prevalence and severity of periodontitis. Prostate cancer was mainly associated with educational level, smoking, alcohol consumption, and periodontitis. Individuals with periodontitis were 1.8 times more likely to have prostate cancer. Prostate-specific antigen levels in individuals with periodontitis were also significantly higher. We concluded that periodontitis was associated with the occurrence of prostate cancer. Therefore, males diagnosed with periodontitis would potentially benefit from being screened for prostate alterations.

FABP7 Expression Modulates the Response of Astrocytes to Induced Endotoxemia.

Fatty acid binding proteins (FABPs) are a family of small proteins involved in fatty acid (FA) subcellular trafficking. In the adult central nervous system, FABP7, one of the members of this family, is highly expressed in astrocytes and participates in lipid metabolism, regulation of gene expression, and energy homeostasis. Reactive astrocytes in Alzheimer's disease and amyotrophic lateral sclerosis animal models upregulate FABP7 expression. This upregulation may contribute to the pro-inflammatory phenotype that astrocytes display during neurodegeneration and is detrimental for co-cultured neurons. Here, we explore how FABP7 expression modulates astrocyte response to inflammatory stimuli. Our results showed that silencing FABP7 expression in astrocyte cultures before treatment with different inflammatory stimuli decreases the expression of a luciferase reporter expressed under the control of NF-κB -response elements. Correspondingly, FABP7-silenced astrocytes display decreased nuclear translocation of the NF-κB-p65 subunit in response to these stimuli. Moreover, silencing FABP7 decreases the toxicity of stimulated astrocytes toward co-cultured motor neurons. Similar results were obtained after silencing FABP7 in human astrocytes differentiated from induced pluripotent stem cells. Finally, knockdown of astrocytic FABP7 expression invivo reduces glial activation in the cerebral cortex of mice after systemic bacterial lipopolysaccharide (LPS) administration. In addition, whole transcriptome RNA sequencing analysis from the cerebral cortex of LPS-treated mice showed a differential inflammatory transcriptional profile, with attenuation of NF-κB-dependent transcriptional response after FABP7 knockdown. Together, our results highlight the potential of FABP7 as a target to modulate neuroinflammation in the central nervous system.