Inflammatory Pathways Research Articles

Identification of potential immune-related genes and infiltrations in temporomandibular joint osteoarthritis

Objective: The aim of this study was to investigate the potential inflammatory cytokines and chemokines markers for temporomandibular joint osteoarthritis (TMJOA) diagnosis using a bioinformatics analysis. Methods: The differentially expressed genes of mRNA (DEGs) and transcripts of lncRNA (DETs) were identified between TMJOA samples and normal controls curated from GSE205389 by the “DESeq. 2” R package. KEGG and GO were conducted using the R package “ggplot2” and “clusterProfiler”. A PPI network was constructed to identify hub genes by using the STRING and Cytoscape. The co-expression network was constructed between mRNA and lncRNA to check the potential regulation and function of lncRNA on protein coding genes. Finally, the immune cell infiltration analysis was conducted with CIBERSORTx and confirmed with xCells. Results: We identified 171 DEGs and DETs, of which the DEGs were closely related to immune response, T cell activation, cytokine-cytokine-receptor interaction, and the muscle system process. PPI network of the DEGs screened the top 10 hub genes, including IL6, IL1B, IL10, CCL2, CCL5, CXCL1, CXCL10, ICAM1, CSF1 and MMP1. Additionally, the immune cell infiltration analysis showed that CD8+ T cells, M1 macrophage and B cells infiltration were increased in TMJOA samples. Finally, we demonstrated that the co-expression between mRNA and lncRNA was mainly enriched in inflammatory and muscle related pathways. Conclusions: We found that immune and muscle system related pathways as well as the immune infiltration played a significant role in the TMJOA development. Additionally, inflammatory cytokines and chemokines could be crucial markers for early-stage TMJOA diagnosis and personalized treatment strategies.

Nppb contributes to Sepsis-Induced myocardial injury by regulating Senescence-Related genes

BackgroundSepsis, a systemic inflammatory condition, is a leading cause of mortality due to cardiovascular injury. Sepsis and cellular senescence are closely related, yet the specific mechanisms are still unclear. This study aims to identify a novel therapeutic target for mitigating sepsis-induced myocardial injury. MethodsWe initially assessed serum inflammatory markers and myocardial injury indicators in septic mice. This involved observing inflammatory cell infiltration in ventricular muscle tissue, assessing cardiac function, and recording electrocardiograms. We examined the expression of connexin 40 (Cx40) and connexin 43 (Cx43) and analyzed mitochondrial structures in ventricular tissues. A conditional heart-specific Nppb knockout mouse model was then developed in mice to evaluate these changes. Ventricular tissues were analyzed via mRNA sequencing to identify differentially expressed genes (DEGs), which were cross-referenced with senescence-related genes to identify key hub genes. The expression and distribution of hub genes were subsequently analyzed by single-cell analysis. Finally, the expression of the senescence-related gene CCL2, along with cardiac structure and function, was validated in a conditional heart-specific Nppb knockout sepsis mouse model. ResultsMyocardial injury severity positively correlated with serum brain natriuretic peptide (BNP) in septic mice. Conditional heart-specific Nppb knockout improved myocardial injury outcomes in mice with sepsis. The DEGs identified in the conditional heart-specific Nppb knockout model overlapped with senescence-related genes, identifying seven upregulated genes associated with inflammation, cardiac contraction and apoptotic pathways. Single-cell analysis confirmed high CCL2 levels and an increased macrophage presence correlating with sepsis progression. Conditional heart-specific Nppb knockout reduced CCL2 levels, which were associated with improved cardiac structure and function. ConclusionThis study confirms that conditional heart-specific Nppb knockout reduces CCL2 expression, thereby ameliorating myocardial injury in septic mice. Targeting Nppb to regulate the senescence-related gene CCL2 may represent an effective strategy for treating myocardial injury in septic patients.

IL-1 Blockade Mitigates Autism and Cerebral Palsy Traits in Offspring In-Utero Exposed to Group B Streptococcus Chorioamnionitis

Group B Streptococcus (GBS) is one of the most common bacteria responsible for placental and neonatal infection and inflammation resulting in lifelong neurobehavioral impairments. In particular, GBS-induced chorioamnionitis is known in preclinical models to upregulate inflammatory pathways, primarily through the activation of the interleukin-1 (IL-1) pathway, leading to brain injury and subsequent neurodevelopmental issues. Previous studies from our laboratory using Lewis rat pups have shown that male offspring exposed in utero to GBS chorioamnionitis develop brain injuries leading to neurobehavioral impairments such as autistic traits. In the present study, we aimed to explore whether blocking the IL-1 pathway could prevent or mitigate these neurodevelopmental impairments in adulthood. Using our established preclinical model, we administered IL-1 receptor antagonist (IL-1Ra) to dams with GBS-induced chorioamnionitis. Here, we show that IL-1Ra administration to dams reversed autistic and cerebral palsy traits in male adult offspring exposed in utero to GBS. Hence, IL-1 blockade could serve as a therapeutic intervention against pathogen-induced neurodevelopmental disorders. This research supports the need for future human randomized controlled trials to assess IL-1 blockade administered during pregnancy or in newborns as a strategy to reduce the long-term neurobehavioral consequences of prenatal infections, such as autism, cerebral palsy, learning disabilities, and other neurodevelopmental disorders.

Fecal microbiota transplantation alters the proteomic landscape of inflammation in HIV: identifying bacterial drivers

BackgroundDespite effective antiretroviral therapy, people with HIV (PWH) experience persistent systemic inflammation and increased morbidity and mortality. Modulating the gut microbiome through fecal microbiota transplantation (FMT) represents a novel therapeutic strategy. We aimed to evaluate proteomic changes in inflammatory pathways following repeated, low-dose FMT versus placebo.MethodsThis double-masked, placebo-controlled pilot study assessed the proteomic impacts of weekly FMT versus placebo treatment over 8 weeks on systemic inflammation in 29 PWH receiving stable antiretroviral therapy (ART). Three stool donors with high Faecalibacterium and butyrate profiles were selected, and their individual stools were used for FMT capsule preparation. Proteomic changes in 345 inflammatory proteins in plasma were quantified using the proximity extension assay, with samples collected at baseline and at weeks 1, 8, and 24. Concurrently, we characterized shifts in the gut microbiota composition and annotated functions through shotgun metagenomics. We fitted generalized additive models to evaluate the dynamics of protein expression. We selected the most relevant proteins to explore their correlations with microbiome composition and functionality over time using linear mixed models.ResultsFMT significantly reduced the plasma levels of 45 inflammatory proteins, including established mortality predictors such as IL6 and TNF-α. We found notable reductions persisting up to 16 weeks after the final FMT procedure, including in the expression of proteins such as CCL20 and CD22. We identified changes in 46 proteins, including decreases in FT3LG, IL6, IL10RB, IL12B, and IL17A, which correlated with multiple bacterial species. We found that specific bacterial species within the Ruminococcaceae, Succinivibrionaceae, Prevotellaceae families, and the Clostridium genus, in addition to their associated genes and functions, were significantly correlated with changes in inflammatory markers.ConclusionsTargeting the gut microbiome through FMT effectively decreased inflammatory proteins in PWH, with sustained effects. These findings suggest the potential of the microbiome as a therapeutic target to mitigate inflammation-related complications in this population, encouraging further research and development of microbiome-based interventions.3bGeWVUV_8zBqrmtjgQWmWVideo

Heterogeneity of Inflammatory Processes and Pathways Driving Chronic Obstructive Pulmonary Disease Pathology

Two symposia occurred during the European Respiratory Society (ERS) Congress 2024, highlighting the heterogeneity in chronic inflammatory pathways that underlie chronic obstructive pulmonary disease (COPD) pathophysiology. In 'A Breath of Fresh Air: A Greater Understanding of COPD With Type 2 Inflammation', Henrik Watz (Chair), German Center for Lung Research, Grosshansdorf, Germany, provided an overview of both the pathophysiology and the burden of disease of COPD. He discussed how exacerbations, which may be increased in those with evidence of Type 2 inflammation, contribute to the cycle of worsening COPD. Mona Bafadhel, King’s College London, UK, provided an examination of the mechanisms and biomarkers of Type 2 inflammation in COPD. Finally, Alberto Papi, University of Ferrara, Italy, summarised the latest research on biological treatments targeting Type 2 inflammation in COPD. The second symposium, 'Targeting interleukin-33 (IL-33) in COPD: Exploring New Frontiers for COPD Management', discussed inflammation in COPD, focusing on the central role of IL-33 as a mediator for both Type 2 and Type 1/Type 3 inflammation. Klaus Rabe (Chair), LungenClinic, Grosshansdorf, Germany, reviewed the structure and function of IL-33 and its initial processes that lead to downstream immune responses. Stephanie Christenson, University of California, San Francisco, USA, explored how genetic and environmental factors contribute to IL-33 activity in COPD pathology. Next, Paola Rogliani, University of Rome ‘Tor Vergata’, Italy, presented an examination of IL-33 inflammatory processes and evidence from COPD animal models illustrating the role of IL-33 in airway inflammation and lung function decline. Klaus Rabe concluded with an examination of IL-33 as a target for new COPD treatment approaches.

Elevated Netrin-4 Expression and Its Action in Infrapatellar Fat Pad

Knee osteoarthritis (KOA) is a degenerative joint disease characterized by inflammation and cartilage degradation. The infrapatellar fat pad (IFP), located beneath the patella within the knee joint, serves as a key anatomical structure involved in cushioning and supporting the knee. It is also an active endocrine organ that secretes various bioactive substances, potentially influencing the local inflammatory environment and contributing to KOA pathogenesis. Netrin-4 (NTN4), a protein primarily known for its role in neuronal guidance, has been implicated in various non-neuronal functions, including inflammatory processes and tissue remodeling. This study aims to explore the involvement of NTN4 in KOA, focusing on its expression in the IFP and its potential impact on disease progression. This study involved 82 patients with radiographically confirmed KOA undergoing total knee arthroplasty (TKA). The correlation between NTN4 expression and OA pathology, including Kellgren–Lawrence (K/L) grades, was investigated. NTN4-expressing cells were identified in the stromal vascular fraction, including fibroblastic, hematopoietic, and endothelial cells of the IFP. To elucidate the molecular effects of NTN4, RNA sequencing (RNA-seq) was performed on fibroblastic cells treated with recombinant NTN4. Subsequent quantitative PCR (qPCR) was used to validate the RNA-seq findings. NTN4 expression was significantly elevated in the IFP of patients with advanced KOA (K/L grades 3 and 4) compared to those with early-stage disease (K/L grade 2). Higher NTN4 expression was found in fibroblastic cells, and RNA-seq analysis revealed upregulation of genes associated with pro-inflammatory pathways, including IL-17 and TNF-α signaling, and matrix degradation. Notably, genes including IL6, MMP1, CXCL1, and CXCL8 were significantly elevated, as confirmed by qPCR, indicating NTN4’s role in promoting an inflammatory and catabolic environment. Our findings suggest that NTN4 plays a significant role in the pathogenesis of KOA by promoting inflammation and matrix degradation within the IFP. Although NTN4 expression was not directly correlated with clinical symptoms, its elevated expression in fibroblastic cells and influence on inflammatory and degradative pathways suggest a potential mechanism for exacerbating joint damage. Targeting NTN4 could offer a novel therapeutic approach to mitigating inflammation and slowing disease progression in KOA, ultimately improving patient outcomes. Further research is needed to clarify NTN4’s specific roles and therapeutic potential in OA management.

Deleting fibroblast growth factor 2 in macrophages aggravates septic acute lung injury by increasing M1 polarization and inflammatory cytokine secretion.

Septic lung injury is strongly associated with polarization of M1 macrophages and excessive cytokine release. Fibroblast growth factor (FGF) signaling plays a role in both processes. However, the impact of FGF2 deficiency on macrophage polarization and septic acute lung injury remains unclear. To investigate this, we obtained macrophages from FGF2 knockout mice and examined their polarization and inflammatory cytokine expression. We also eliminated endogenous macrophages using clodronate liposomes and administered FGF2 knockout or WT macrophages intravenously in conjunction with cecal ligation and puncture (CLP) surgery to induce sepsis. In vitro analysis by flow cytometry and real-time PCR analysis demonstrated that FGF2 deficiency resulted in increased expression of M1 markers (iNOS and CD86) and inflammatory cytokines (CXCL1, IL1β, and IL6), especially after LPS stimulation. Additionally, immunofluorescence demonstrated increased nuclear translocation of p65 NF-κB in FGF2 knockout macrophages and RNA-seq analysis showed enrichment of differentially expressed genes in the IL17 and TNFα inflammatory signaling pathways. Furthermore, in vivo experiments revealed that depletion of FGF2 in macrophages worsened sepsis-induced lung inflammation, lung vascular leak, and lung histological injury, accompanied by an increase in CD86-positive cells and apoptosis. Our study suggests that FGF2 deficiency in macrophages plays a critical role in the pathogenesis of septic ALI, possibly because of the enhanced M1 macrophage polarization and production of proinflammatory cytokines. These findings provide empirical evidence for potential therapeutic interventions targeting FGF2 signaling to modulate the polarization of M1 and M2 macrophages in the management of sepsis-induced acute lung injury.

Acyclic sesquiterpenes nerolidol and farnesol: mechanistic insights into their neuroprotective potential.

Sesquiterpenes are a class of organic compounds found in plants, fungi, and some insects. They are characterized by the presence of three isoprene units, resulting in a molecular formula that typically contains 15 carbon atoms (C₁₅H₂₄). Nerolidol and farnesol are both sesquiterpene alcohols present in the essential oils of numerous plants. They have drawn attention due to their potential neuroprotective properties. Nerolidol and farnesol are structural isomers, specifically geometric isomers, haring the same molecular formula (C₁₅H₂₄O) but differing in the spatial arrangement of their atoms. This variation in structure may contribute to their distinct biological activities. Scientific evidence suggests that nerolidol and farnesol exhibit antioxidant and anti-inflammatory characteristics which are crucial for neuroprotection. Nerolidol has been specifically noted for its ability to alleviate conditions such as Alzheimer's disease, Parkinson's disease, encephalomyelitis, depression, and anxiety by modulating inflammatory and oxidative stress pathways. Moreover, research indicates that both nerolidol and farnesol may modulate the Nrf-2/HO-1 antioxidant signaling pathway to mitigate oxidative stress-induced neurological damage. Activation of Nrf-2/HO-1 signaling cascade promotes cell survival and enhances the brain's ability to resist various insults. Nerolidol has also been reported to alleviate neuroinflammation by inhibiting the TLR-4/NF-κB and COX-2/NF-κB inflammatory signaling pathway. Besides, this nerolidol also modulates BDNF/TrkB/CREB signaling pathway to improve neuronal health. To date, limited research has delved into the anti-inflammatory properties of farnesol concerning neurodegenerative diseases. Further investigation is warranted to comprehensively elucidate the mechanisms underlying its action and potential therapeutic uses in neuroprotection. Initial observations indicate that farnesol exhibits promising prospects as a natural agent for safeguarding brain functions. Henceforth, drawing upon existing literature elucidating the neuroprotective attributes of nerolidol and farnesol, the current review endeavors to provide a detailed analysis of their mechanistic underpinnings in neuroprotection.

Ammonia Exposure-Induced Immunological Damage in Chicken Lymphoid Organs via TLR-7/MYD88/NF-κB Signaling Pathway and NLRP3 Inflammasome Activation.

Ammonia (NH3) is a hazardous gas that pollutes the environment and causes irritation. Its harmful effects on chickens, including its impact on their immune system, have previously been observed. However, the mechanism by which NH3 exposure causes immune system disorders in chickens remains unclear. The bursa of Fabricius (BF) and thymus are the two main lymphoid organs responsible for the proliferation, differentiation, and selection of B- and T-lymphocytes, both critical for the innate immune response of the host. In this study, we investigated the mechanism of NH3-induced immune dysregulation in broiler chickens. Transmission electron microscopy (TEM) revealed swollen mitochondria and breakage of the large crista lining, membrane deformation, chromatin condensation, increased vacuolation, and blood vessel spasms in the NH3-exposed BF and thymus tissues. Immunofluorescent analysis showed clustering of CD4+ and CD8+ cells, indicating an active immune response to NH3 exposure. Furthermore, NH3 exposure enhanced the mRNA expressions of Toll-like receptor 7 (TLR-7), myeloid differentiation primary response 88 (MYD88), and nuclear factor-kappa B (NF-κB), along with their proteins, and led to activation of the TLR-7/MyD88/NF-κB signaling pathway and NLRP3 inflammasome in chicken thymus tissues. Both mRNA and protein levels of key inflammation-related genes and proteins were upregulated in the NH3-treated group, highlighting a robust inflammatory response due to NH3 exposure. The specific findings of significant structural damage to key lymphoid organs and activation of inflammatory pathways in broiler chickens upon NH3 exposure can provide guidance for future, targeted therapies to improve poultry health.

The Therapeutic Potential of GLP-1 Receptor Agonists in the Management of Hidradenitis Suppurativa: A Systematic Review of Anti-Inflammatory and Metabolic Effects

Background: Glucagon-like peptide-1 receptor agonists (GLP1-RAs) are synthetic peptides that mimic the natural activity of GLP-1, widely known for lowering blood glucose levels and promoting weight reduction. These characteristics make them a valuable tool in managing type 2 diabetes and obesity-related conditions. Recent findings indicate that GLP1-RAs may also offer therapeutic benefits in managing hidradenitis suppurativa (HS), a chronic inflammatory skin disorder closely associated with metabolic abnormalities, including obesity, diabetes, and dyslipidemia. This review explores the potential role of GLP1-RAs in managing HS. Methods: A systematic review was conducted by searching electronic databases, including MEDLINE and Google Scholar, without date limitations. Key search terms included “GLP-1” or “GLP-1 agonists” combined with “hidradenitis suppurativa” or “acne inversa”. Inclusion criteria were set for studies reporting on the use of GLP1-RAs as a treatment for HS, with articles discussing theoretical applications excluded. Data synthesis included findings from 25 relevant studies. Results: The analysis revealed that GLP1-RAs, specifically liraglutide and semaglutide, led to significant reductions in weight and systemic inflammation in HS patients. Notably, improvements in lesion severity and quality of life were reported. The anti-inflammatory effects of GLP1-RAs were attributed to the suppression of key inflammatory pathways involving TNF-α, IL-17, and NF-κB. Conclusions: GLP1-RAs demonstrate significant potential as an adjunct therapy for HS, addressing both the metabolic and inflammatory aspects of the condition. While early results are promising, further research is necessary to determine their long-term efficacy in managing HS.

What Is on the Horizon for Treatments in Idiopathic Pulmonary Fibrosis?

Idiopathic pulmonary fibrosis (IPF) is a progressive and often fatal lung disease most commonly encountered in older individuals. Several decades of research have contributed to a better understanding of its pathogenesis, though only two drugs thus far have shown treatment efficacy, i.e., by slowing the decline of lung function. The pathogenesis of IPF remains incompletely understood and involves multiple complex interactions and mechanisms working in tandem or separately to result in unchecked deposition of extracellular matrix components and collagen characteristic of the disease. These mechanisms include aberrant response to injury in the alveolar epithelium, inappropriate communication between epithelial cells and mesenchymal cells, imbalances between oxidative injury and tissue repair, recruitment of inflammatory pathways that induce fibrosis, and cell senescence leading to sustained activation and proliferation of fibroblasts and myofibroblasts. Targeted approaches to each of these mechanistic pathways have led to recent clinical studies evaluating the safety and efficacy of several agents. This review highlights selected concepts in the pathogenesis of IPF as a rationale for understanding current or future therapeutic approaches, followed by a review of several selected agents and their recent or active clinical studies. Current novel therapies include approaches to attenuating or modifying specific cellular or signaling processes in the fibrotic pathway, modifying inflammatory and metabolic derangements, and minimizing inappropriate cell senescence.

Acacetin alleviates rheumatoid arthritis by targeting HSP90 ATPase domain to promote COX-2 degradation

BackgroundInflammation plays a significant role in initiating and sustaining rheumatoid arthritis (RA). Acacetin, a natural flavonoid compound, exhibits excellent anti-inflammatory effects specifically for RA. However, its relevant targets and molecular mechanisms remain to be elucidated. PurposeThis study aims to investigate the mechanism of acacetin in the therapeutic efficacy of acacetin in RA and search for new therapeutic options for RA treatment. MethodsA collagen-induced RA mouse model was established to evaluate the therapeutic effect of acacetin. Acacetin functional probes were synthesized to capture potential target proteins in RAW264.7 cells. Various small molecule-protein interaction methods were conducted to verify the binding of acacetin to target protein. Molecular docking and site directed mutagenesis tests were performed to analyze the specific binding sites. Co-immunoprecipitation, immunofluorescence assay and western blot were engineered to explore the effect of acacetin on COX-2 degradation by targeting HSP90. ResultsAcacetin specifically binds to the ATP domain of HSP90, to facilitate the dissociation between HSP90 and COX-2, inducing the ubiquitin-degradation of COX-2 in macrophages. Acacetin suppressed the production of pro-inflammatory cytokines, as well as inflammatory related pathways, exerting excellent anti-inflammatory effects in RA. ConclusionsThis research proved that acacetin, a novel HSP90 ATPase inhibitor, inhibits the functional folding of the client protein COX-2, promoting its ubiquitin degradation for anti-inflammation. Targeting HSP90 is a viable strategy to inhibit inflammation, affording a distinct way to managing joint inflammation and pains associated with RA.

Decoding the multiple functions of ZBP1 in the mechanism of sepsis-induced acute lung injury.

Sepsis-induced acute lung injury (ALI), characterized by severe hypoxemia and pulmonary leakage, remains a leading cause of mortality in intensive care units. The exacerbation of ALI during sepsis is largely attributed to uncontrolled inflammatory responses and endothelial dysfunction. Emerging evidence suggests an important role of Z-DNA binding protein 1 (ZBP1) as a sensor in innate immune to drive inflammatory signaling and cell death during infections. However, the role of ZBP1 in sepsis-induced ALI has yet to be defined. We utilized ZBP1 knockout mice and combined single-cell RNA sequencing with experimental validation to investigate ZBP1's roles in the regulation of macrophages and lung endothelial cells during sepsis. We demonstrate that in sepsis, ZBP1 deficiency in macrophages reduces mitochondrial damage and inhibits glycolysis, thereby altering the metabolic status of macrophages. Consequently, this metabolic shift leads to a reduction in the differentiation of macrophages into pro-inflammatory states and decreases macrophage pyroptosis triggered by activation of the NLRP3 inflammasome. These changes significantly weaken the inflammatory signaling pathways between macrophages and endothelial cells and alleviate endothelial dysfunction and cellular damage. These findings reveal important roles for ZBP1 in mediating multiple pathological processes involved in sepsis-induced ALI by modulating the functional states of macrophages and endothelial cells, thereby highlighting its potential as a promising therapeutic target.

Air-Pollution-Mediated Microbial Dysbiosis in Health and Disease: Lung-Gut Axis and Beyond.

Growing evidence suggests physiological and pathological functions of lung and gut microbiomes in various pathologies. Epidemiological and experimental data associate air pollution exposure with host microbial dysbiosis in the lungs and gut. Air pollution through increased reactive oxygen species generation, the disruption of epithelial barrier integrity, and systemic inflammation modulates microbial imbalance. Microbiome balance is crucial in regulating inflammation and metabolic pathways to maintain health. Microbiome dysbiosis is proposed as a potential mechanism for the air-pollution-induced modulation of pulmonary and systemic disorders. Microbiome-based therapeutic approaches are increasingly gaining attention and could have added value in promoting lung health. This review summarizes and discusses air-pollution-mediated microbiome alterations in the lungs and gut in humans and mice and elaborates on their role in health and disease. We discuss and summarize the current literature, highlight important mechanisms that lead to microbial dysbiosis, and elaborate on pathways that potentially link lung and lung microbiomes in the context of environmental exposures. Finally, we discuss the lung-liver-gut axis and its potential pathophysiological implications in air-pollution-mediated pathologies through microbial dysbiosis.

Molecular Targets for the Novel Therapies of Inflammation and Wound Care

Anti-inflammatory drugs, particularly steroidal and non-steroidal, are already the sole treatment options for inflammatory illnesses. Chronic use of these medicines has been linked to gastrointestinal, cardiovascular, as well as other serious side effects. New anti-inflammatory and wound healing drugs with selective effect and lower toxicity are desperately needed. Novel therapies acting on different molecular targets have shown promising resultsRelevant studies (2003-2024) were identified through electronic searches of PubMed and Google scholar. The search used the keywords, including the following inflammation, wound care, signalling pathways, molecular targets of inflammation. Neutrophils and macrophages play a significant role in the release of mediators and phagocytosis at the site, Nf-kB signaling pathway and the JAK/Stat signaling pathway stimulate the production of mediators including IL-6, IL-1, and TNF-α, although their overproduction can have a variety of consequences. Cell therapy, MicroRNA, plasma protein therapy, COX-2 inhibitor with stem cells, combination of AMD3100 and Tacrolimus and combination of siRNAs with Plurogel for increasing wound healing time are among the approved and continuing clinical trial novel therapies mentioned. This study shows that these new therapeutics can interact with numerous targets and modify the dysregulated inflammatory pathways and mediators associated with normal and chronic wounds more effectively than standard anti-inflammatory medication treatments.

Curcumin attenuates smoking and drinking activated NF-κB/IL-6 inflammatory signaling axis in cervical cancer

BackgroundHigh-risk strains of HPV are known to cause cervical cancer. Multiple clinical studies have emphasized that smoking and drinking are critical risk factors for cervical cancer and its high-grade precursors. In this study, we investigated if smoking and/or drinking augment the molecular mechanisms of cervical carcinogenesis and defined a potential therapeutic approach for their attenuation.MethodsThe impact of benzo[a]pyrene (B[a]P) and/or ethanol (EtOH) exposure on cervical cancer cells was assessed by measuring changes in their cell migration and invasion characteristics. Expression of HPV16 E6/E7, NF-κB, cytokines, and inflammation mediators was determined using qRT-PCR, immunoblotting, ELISA, luciferase reporter assay, and confocal microscopy. Herein, we used curcumin (Cur), and PLGA nanoparticle formulation of curcumin (PLGA-Cur) and determined effectiveness of free Cur and PLGA-Cur formulation on smoking and drinking activated NF-κB/IL-6 mediated inflammatory signaling pathways using in vitro cervical cancer models.ResultsTreatments with B[a]P and/or EtOH altered the expression of HPV16 E6/E7 oncogenes and EMT markers in cervical cancer cells; it also enhanced migration and invasion. In addition, B[a]P and/or EtOH exposure promoted inflammation pathways through TNF-α and NF-κB signaling, leading to IL-6 upregulation and activation of VEGF. The molecular effects caused by B[a]P and/or EtOH exposure were effectively attenuated by curcumin (Cur)/PLGA-Cur treatment.ConclusionsThese data suggest a molecular link between smoking, drinking, and HPV infectivity in cervical carcinogenesis. In addition, attenuation of these effects by treatment with Cur/PLGA-Cur treatment, implies the role of curcumin in cervical cancer prevention and treatment.

Comparative Evaluation of the Chemical Components and Anti-Inflammatory Potential of Yellow- and Blue-Flowered Meconopsis Species: M. integrifolia and M. betonicifolia.

Background/Objectives:Meconopsis has long been used in traditional Tibetan medicine to treat various inflammatory and pain-related conditions. However, blue-flowered Meconopsis (M. betonicifolia) is becoming increasingly scarce due to overharvesting. As a potential alternative, yellow-flowered Meconopsis (M. integrifolia) shows promise but requires comprehensive characterization. This study aimed to evaluate and compare the anti-inflammatory potential of yellow- and blue-flowered Meconopsis species. Methods: Liquid chromatography-mass spectrometry (LC-MS) techniques were used to analyze the chemical profiles of yellow- and blue-flowered Meconopsis. Putative targets of shared constituents were subjected to GO and disease enrichment analysis. The LPS-induced RAW264.7 macrophage model was employed to assess anti-inflammatory effects. Metabolomics was applied to gain mechanistic insights. Results: LC-MS revealed over 70% chemical similarity between species. Enrichment analysis associated targets with inflammation-related pathways. In macrophage assays, both species demonstrated dose-dependent antioxidative and anti-inflammatory activities, with yellow Meconopsis exhibiting superior efficacy. Metabolomics showed modulation of key inflammatory metabolic pathways. Conclusions: This integrative study validated yellow-flowered Meconopsis as a credible alternative to its blue-flowered counterpart for anti-inflammatory applications. Metabolic profiling provided initial clues regarding their multi-targeted modes of action, highlighting their potential for sustainable utilization and biodiversity conservation.

Abstract A032: KRAS mutations have distinct effects on the tumor immune microenvironment in pancreatic cancer

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with abysmal survival rates. The highly immunosuppressive microenvironment of PDAC poses a major barrier to effective therapy. KRAS mutations are near-ubiquitous in PDAC, and studies indicate clinical outcomes vary depending on the specific KRAS genotype. Given that tumor genotype can shape the immune cell composition of tumors, we examined the immune cell composition of pancreatic tumors with specific KRAS mutations, focusing on KRASG12D mutations (representing 40% of PDAC cases which have the worst prognosis) and KRASG12R mutations (which make up 20% of PDAC cases and have a better prognosis). Orthotopically implanted Kras G12R/+ ;Trp53 KO mouse pancreatic tumors have a distinct immune profile in comparison to Kras G12D/+ ;Trp53 KO tumors, characterized by an influx of intratumoral CD3+ T cells and mature dendritic cells. Selective depletion of CD4+ T cells induces a rapid progression in KRASG12R, but not KRASG12D mouse tumors. RNA sequencing of KRASG12R tumor cells revealed enrichment of Type I interferon (IFN) pathways accompanied by related chemokines, CXCL9 and CXCL10 in comparison to KRASG12D tumors. Analysis of publicly available human PDAC cohorts revealed enrichment of genes in inflammatory pathways in KRASG12R tumors. Collectively, these data link the KRASG12R mutation to an immunogenic role that is distinct from KRASG12D tumors. Citation Format: Andrew Wenger, Tal Baron, Adrian Vega-Perez, Whitney Sisso, Maria Paz Zafra, Lukas Dow, Despina Siolas. KRAS mutations have distinct effects on the tumor immune microenvironment in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr A032.

NLRP3 regulates ferroptosis via the JAK2/STAT3 pathway in asthma inflammation: Insights from in vivo and in vitro studies

BackgroundFerroptosis, an iron-dependent form of cell death, plays a pivotal role in the pathologic progression of asthma. Electroacupuncture (EA) has demonstrated considerable efficacy in mitigating asthma airway inflammation, although its underlying mechanisms remain partially elucidated. MethodsWe investigated the regulatory effect of NLRP3 on ferroptosis using a lipopolysaccharide (LPS)-induced inflammation model in BEAS-2B cells, where NLRP3 expression was modulated with si-RNA and overexpression plasmids. The levels of inflammatory cytokines TNF-α, IL-1β, and IL-6 were quantified. We also assessed NLRP3 and JAK2/STAT3 pathway-related proteins, and evaluated lipid peroxidation, mitochondrial membrane potential (ΔΨm), and antioxidant system functionality. In vivo, we examined the impact of EA on ferroptosis and airway inflammation by modulating NLRP3 activation. Asthma inflammation severity was evaluated using H&E, Masson, and PAS staining, alongside ELISA. NLRP3 and JAK2/STAT3 pathway-related proteins, as well as ferroptosis indicators, were also analyzed. The mechanism by which NLRP3 activates ferroptosis was investigated through in vitro assays. ResultsLPS exposure resulted in increased intracellular inflammatory cytokines, and activation of the NLRP3 and JAK2/STAT3 pathways, leading to enhanced lipid peroxidation, decreased ΔΨm, and disruption of antioxidant system balance, ultimately inducing ferroptosis. Si-NLRP3 countered the effects of LPS, whereas oe-NLRP3 exacerbated symptoms. In vivo studies revealed that EA reduced airway inflammation, inhibited NLRP3 activation, and decreased phosphorylation of JAK2/STAT3, effectively lowering ferroptosis-related indicators. Utilizing JAK2/STAT3 activators and inhibitors, we confirmed that NLRP3 mediates ferroptosis via the JAK2/STAT3 pathway. ConclusionsEA alleviates HDM-induced asthma, primarily through the inhibition of NLRP3 activation, which modulates the JAK2/STAT3 pathway and mediates ferroptosis.

Editorial: Community series in the role of toll-like receptors and their related signaling pathways in viral infection and inflammation, volume II

Editorial: Community series in the role of toll-like receptors and their related signaling pathways in viral infection and inflammation, volume II