Interleukin-1β is one of the major cytokines involved in the initiation and persistence of airway inflammation in chronic obstructive pulmonary disease (COPD). However, the association between plasma interleukin-1β and lung function decline remains unclear. We aimed to explore the association between plasma interleukin-1β and lung function decline. This longitudinal evaluation of data from the Early COPD study analysed the association between the plasma interleukin-1β concentration, lung function decline, and COPD exacerbation. Overall, 1,328 participants were included in the baseline analysis, and 1,135 (85%) completed the 1-year follow-up. Increased plasma interleukin-1β was associated with accelerated lung function decline in non-smokers (forced expiratory volume in 1 s: per unit natural log-transformed increase, adjusted unstandardised β [95% confidence interval] 101.46 [16.73-186.18] mL/year, p=0.019; forced vital capacity: per unit natural log-transformed increase, adjusted unstandardised β [95% confidence interval] 146.20 [93.65-198.75] mL/year, p<0.001), but not in smokers. In non-smokers, participants with an interleukin-1β concentration in the top 30% (>5.02 pg/mL) had more respiratory symptoms, more severe emphysema and air trapping, and higher levels of inflammation-related biomarkers. In this study, a subgroup with increased plasma interleukin-1β was identified among non-smokers, and increased plasma interleukin-1β was associated with lung function accelerated decline.

Tumor-promoting inflammation significantly impacts cancer progression, and targeting inflammatory cytokines has emerged as a promising therapeutic approach in clinical trials. Interleukin (IL)-1α, a member of the IL-1 cytokine family, plays a crucial role in both inflammation and carcinogenesis. How IL-1α is secreted in the tumor microenvironment has been poorly understood, and we previously showed that calpain 1 cleaves pro-IL-1α for mature IL-1α secretion, which exacerbates hepatocellular carcinoma by recruiting myeloid-derived suppressor cells. In this study, we report that calpain 2 also modulates IL-1α secretion. Notably, a deficiency in calpain 2 resulted in enhanced hepatocellular carcinoma development within an IL-1α-enriched tumor microenvironment. Further investigations revealed that calpain 2 deficiency increased calpain 1 expression, implying a compensatory mechanism between the two calpains. Mechanistically, calpain 2 deficiency led to increased expression of FoxO3, which is a forkhead transcription factor that promotes calpain 1 expression. Collectively, these results suggest that calpain 2 modulates calpain 1 expression, and therefore IL-1α secretion through the induction of FoxO3, offering novel potential therapeutic targets for cancer treatment.

All implanted materials inevitably trigger an acute inflammatory response. The long-term outcome, however, is dependent on the trajectory of this response. This study investigates the effects of aging on the immune response to two commercially available biomaterials. Extracellular matrix-based urinary bladder matrix (UBM) and synthetic polypropylene mesh (PPM) were implanted in young (4 months) and aged (18 months) C57BL/6J mice. Overall, PPM led to a sustained inflammatory response regardless of the age of the mice. In contrast, UBM induced an initial inflammatory response that matured into a pro-regenerative/remodeling response with time, though aged mice exhibited a delayed resolution of inflammation. The PPM-induced response was predominantly pro-inflammatory with consistently higher M1-like macrophage phenotype, whereas the response to UBM was characterized by an anti-inflammatory M2-like phenotype, especially in young mice. RNA sequencing revealed marked age-related differences in gene transcription. At day 7 post-implantation, the young mice with UBM showed a robust upregulation of both pro- and anti-inflammatory pathways as compared to young mice implanted with PPM, however, by day 14, the gene expression profile transitioned into an anti-inflammatory profile. Intriguingly, in aged mice, the response to UBM was distinct with consistent downregulation of inflammatory genes compared to PPM, while the response to PPM in both young and aged animals was largely consistent. Upstream analysis identified cytokines as key drivers of the host response, with IL-4 and IL-13 in young mice, and TNF-α and IL-1β driving chronic inflammation in aged mice. These findings highlight the importance of host age in biomaterial outcome, and the potential of ECM-based materials to mount a favorable response even in the presence of age-related immune dysregulation.

Stroke is a leading cause of disability and death worldwide. In this study, we identified potential therapeutic targets for stroke using a data mining, network analysis, enrichment, and docking analysis approach. We first identified 1991 genes associated with stroke from two publicly available databases: GeneCards and DisGeNET. We then constructed a protein-protein interaction (PPI) network using the STRING database and identified 1301 nodes and 5413 edges. We used Metascape to perform GO enrichment analysis and KEGG pathway enrichment analysis. The results of these analyses identified ten hub genes (TNF, IL6, ACTB, AKT1, IL1B, TP53, VEGFA, STAT3, CASP3, and CTNNB1) and five KEGG pathways (cancer, lipid and atherosclerosis, cytokine-cytokine receptor interaction, AGE RAGE signaling pathway in complications, and TNF signaling pathway) that are enriched in stroke genes. We then performed molecular docking analysis to screen potential drug candidates for these targets. The results of this analysis identified several promising drug candidates that could be used to develop new therapeutic strategies for stroke.

Ulcerative colitis (UC) is a long-term inflammatory bowel disease (IBD) associated with significant morbidity. It is marked by inflammation and damage to the colon's mucosal lining. Studies have shown that NLRP3 inflammasome activation, apoptosis, and impaired autophagy are critical in its pathogenesis. Verapamil, a calcium channel blocker, has been found to inhibit NLRP3 inflammasome activation in various preclinical models. However, the potential influence of verapamil on the TXNIP in UC remains unexplored. This study investigates the effects of verapamil on an UC rat model induced chemically by acetic acid. Verapamil effectively inhibited the TXNIP-NLRP3-caspase-1 axis, reducing inflammasome activation and the release of IL-1β and IL-18. Additionally, verapamil suppressed NFκB, the priming step of NLRP3 activation. The drug enhanced autophagic activity, as indicated by increased expression of LC3-II and Beclin-1, along with reduced LC3-I and mTOR expression. Moreover, it demonstrated anti-apoptotic effects mediated by regulating Bax and cleaved caspase-3. These molecular changes contributed to mucosal healing and improved microscopic and macroscopic outcomes in the colitis model. Furthermore, verapamil improved the colon weight-to-length ratio and disease activity scores and mitigated oxidative stress. As verapamil has been safely used in clinics to treat hypertension, our findings suggest it may be a safe therapeutic option for ameliorating inflammation and apoptosis and activating autophagy in UC pathology. Since hypertension demonstrates a strong association with UC, the use of verapamil merits particular attention in hypertensive patients fighting against IBD.

Activation of NOD-like receptor protein 3 (NLRP3) can lead to the production of inflammatory factors and perturbation of macrophage polarization, leading to an intestinal immune imbalance that promotes the progression of ulcerative colitis (UC). In this study, we investigated the therapeutic effect of Kurarinone and Nor-kurarinone on UC and their regulatory mechanisms relating to NLRP3 inflammasome activation and macrophage polarization. UC mice were induced using dextran sulfate sodium (DSS) and treated with Kurarinone and Nor-kurarinone. Results showed that Kurarinone and Nor-kurarinone could alleviate weight loss, decrease the disease activity index (DAI) score, shorten colon length, inhibit formation of the NLRP3 inflammasome in the colon and regulate macrophage polarization in UC mice. The THP-1 cells were used as an in vitro model of the NLRP3 inflammasome, conducted by treatment with lipopolysaccharide (LPS) and ATP/Nigericin. Kurarinone and Nor-kurarinone can inhibit the NLRP3 inflammasome formation response by disrupting the NLRP3/ASC interaction to inhibit NLRP3 assembly and then regulating the polarization of macrophages. In conclusion, Kurarinone and Nor-kurarinone inhibited NLRP3 inflammasome assembly to counteract activation of the NLRP3 inflammasome. This inhibition led to a reduction in M1 polarization of intestinal macrophages in UC mice to keep the balance of M1/ M2 macrophages. Our study suggests that Kurarinone and Nor-kurarinone may be novel therapeutic modalities for UC.

In recent years, epidemiological studies have emerged indicating a potential association between chronic exposure to pesticides and the development of chronic neurodegenerative nervous system diseases such as Alzheimer's disease. In this study, we aimed to investigate the potential role of long-term nonfatal exposure to Deltamethrin in spreading this disease. To this end, a range of aspects of brain damage were discussed in rats administered deltamethrin in oral doses of 0.65 mg/kg b.w. and 1.3 mg/kg b.w. for 30 days. The activation of beta-amyloid, the primary component of plaques characteristic of Alzheimer's disease, and the NG2, a type 1 transmembrane protein, was assessed by immunohistochemistry and western blot methods in rat brain. In addition, the expression level of the APP, GFAP, NfL, TNF-alpha, CXCL9, CCL5, and IL-1 alpha genes in deltamethrin-exposed brain tissue was measured using qRT-PCR. In addition, levels of pTau181 and Abeta42 were measured with ELISA. A strong positive immunohistochemical reaction for beta-amyloid was detected in the deltamethrin-exposed brain tissues. A decrease in NG2 immunofluorescence positivity was found in the application groups compared to the control group. It was demonstrated that deltamethrin exposure significantly up-regulated the expressions of APP, GFAP, NfL, TNF-alpha, CXCL9, CCL5, and IL-1 alpha genes, also significantly higher the levels of pTau181 and Abeta42 (pg/ml) in rat brain tissues. This study provides scientific evidence that exposure to chronic doses of deltamethrin may play a positive role in the development of diseases such as Alzheimer's. Future studies should investigate similar projects and expand knowledge on the topic.

Pentachlorophenol (PCP) and dibutyltin dichloride (DBT) contaminate the environment due to their diverse applications. PCP has been found from 0.26 to 5 μM in the serum of exposed individuals and at an average of 0.15 μM in the unexposed. DBT has been detected in human blood at levels up to 0.3 μM. Exposure to these contaminants is linked to pathological conditions including cancer. Interleukin-1 beta (IL-1β) and IL-6 are pro-inflammatory cytokines that when produced inappropriately can cause chronic inflammation, which is linked to pathologies including autoimmune diseases and cancer. PCP and DBT have been shown to increase the production of IL-1β and IL-6 by immune cells in a MAP kinase (MAPK) dependent process. Toll-like receptors (TLRs) activate the signaling pathways linked to MAPK that lead to production of these cytokines. This study demonstrates that PCP-induced production of IL-1β and IL-6 is dependent on TLR4 and TLR8, and independent of TLR1/2, TLR2, and TLR3. Additionally, DBT-induced IL-6 production depends on TLR1/2, whereas IL-1β production does not. Blocking the TLR-linked adapter protein, MyD88, lead to a loss of both PCP and DBT stimulation of IL-1β and IL-6. These findings indicate that both PCP and DBT interact with selected TLRs as part of their mechanisms of elevating the levels of critical pro-inflammatory cytokines, which may contribute to chronic inflammation and its related pathologies.

Cyclin-dependent kinase 5 (CDK5) plays a critical role in the inflammatory response. Macrophages are pivotal orchestrators of inflammation, fibrosis, and wound repair. However, the effectiveness of CDK5 in macrophages on cutaneous wound healing remains inadequately characterized. We determined the role of CDK5 signaling pathway in macrophages in mouse cutaneous wound healing through the established macrophage-specific deletion of CDK5 (myeCDK5-/-) mice and the pharmacological CDK5 inhibitor Roscovitine. Phosphorylated proteomics, western blotting, Masson staining, and dualimmunofluorescence staining were performed to investigate the potential mechanisms underlying CDK5-mediated inflammatory regulation in macrophages in wound healing. CDK5 expression and phosphorylation were both elevated significantly in cutaneous wound healing process in mice. Moreover, an accelerated wound healing in myeCDK5-/- mice was exhibited with the reduced pro-inflammatory mediators (IL-1β and iNOS) and the elevated anti-inflammatory markers (IL-10 and CD163) expression significantly. CDK5 deficiency in macrophages enhanced tissue remodeling, evidenced by increased collagen deposition and capillary density (CD31+ cells). Consistently, Roscovitine-treated mice also showed accelerated wound healing, accompanied by decreased pro-inflammatory factors and increased anti-inflammatory markers at the wound site. Mechanistically, the decreased phosphorylation of SIRT1 at the Ser14 and Ser47 sites, as a substrate of CDK5, was confirmed in myeCDK5-/- mice. These data are the first to indicate that CDK5 signaling-dependent regulation of SIRT1 phosphorylation in macrophage-mediated inflammation is required for the wound healing process, warranting consideration of the CDK5-SIRT1 pathway as a therapeutic target for cutaneous wound healing.

Although chikungunya virus (CHIKV)-caused cardiovascular diseases are frequently reported in clinics, the underlying mechanisms are poorly understood, which is primarily due to a lack of animal models. In this study, we report that CHIKV infection in homozygous interferon α/β receptor-deficient (ifnar1-/-) and interferon α/β/γ receptor-deficient (ifnag-/-) mice resulted in high viral loads in the hearts as early as day (D) 1 post-infection (p.i.) but with 100% mortality within three days p.i. In contrast, the heterozygous ifnar1+/-and ifnag+/- mice survived CHIKV infection and bore higher viral burdens in the heart tissues than the wild-type (WT) controls. Immunohistochemistry and flow cytometry revealed that more leukocytes, particularly neutrophils, infiltrated the heart of ifnag+/- and ifnar1+/- mice than WT mice. In addition, the Hematoxylin and Eosin staining analysis showed that CHIKV infection caused vasculitis in the left ventricles on D5 p.i. in both heterozygous groups and the vacuole formation and pyknosis in ifnar1+/- mice. Moreover, CHIKV infection may also lead to cardiac fibrosis, as indicated by the upregulation of the expression of the Connective Tissue Growth Factor gene in the hearts of ifnar1+/- mice. In summary, our data suggest that the heterozygous ifnar1+/- and ifnag+/- mice are invaluable for studying pathogenesis and testing therapeutic interventions for CHIKV-caused cardiac diseases.

Diesel exhaust particulate (DEP) is widely recognized to weaken lung function and skin diseases. When the skin, which defends against external factors, is exposed to PM2.5, various chronic inflammatory diseases occur. When keratinocytes recognize harmful signals, they synthesize the NOD-like receptor protein 1 (NLRP1) inflammasome. DEP enhances NF-κB signaling and NLRP1 inflammasome expression through the interaction of TXNIP with NLRP1 in keratinocytes. Although many studies have reported the anti-inflammatory and antioxidant characteristics of Impressic acid (IPA), the umbrella consequences of IPA for PM2.5-influenced inflammasomes and the associated mechanisms remain unknown. Therefore, this study aimed to examine the protective function of IPA against inflammation in human keratinocytes. IPA attenuated the NLRP1 expression, caspase-1, IL-1β actuation, and NF-κB and IκB phosphorylation induction by DEP. IPA upregulated the Nrf2, HO-1, and NQO1 expression through CaMKKβ, AMPK, and GSK3β phosphorylation. Also, IPA led to the elevation of p62 and the degradation of the Keap1 protein. ML385 reversed the suppressive effect of IPA on the NLRP1 inflammasome, which was enhanced by DEP, and NAC counteracted the effect of ML385. These findings indicate that IPA can suppress inflammation induced by PM2.5 by expressing antioxidant enzymes through the Keap1/p62/Nrf2-signaling pathway in human keratinocytes.

Daemonorops draco Bl. extract and its active ingredients can remove blood stasis and promote muscle and wound healing and are widely used in skin health and other fields. Modern pharmacological studies have demonstrated that this extract exerts excellent anti-inflammatory effects beneficial for skin barrier repair. However, the mechanism of action and monomeric components of D. draco remain unclear. Seven active monomers (XJ-1 ~ XJ-7) were extracted and purified from D. draco. The successful construction of the HaCaT inflammation model was achieved through the detection of IL-1β and TNF-α expressions in UVB-irradiated HaCaT cells. Based on this cellular model, (2 S)-5-methoxy-6-methylflavan-7-ol (XJ-2) was determined to be the best-screened monomer. The effects of XJ-2 on the production of reactive oxygen species (ROS) and Ca2+ in HaCaT cells were investigated using fluorescent probes and flow cytometry, respectively. The impact of XJ-2 on the expression of crucial proteins within the NF-κB pathway was examined via immunofluorescence and western blotting. The expression levels of downstream inflammatory factors, namely IL-1β and TNF-α, were detected through PCR. The effects of XJ-2 on the expression of skin barrier-related factors filaggrin (FLG), aquaporin 3 (AQP-3), and claudin1 (CLDN1) were investigated using PCR, immunofluorescence, and western blotting. Based on these findings, we comprehensively examined the mechanisms underlying the anti-inflammatory and barrier repair effects of XJ-2. XJ-2 primarily protected the internal structure and function of the cells by inhibiting the mass production of ROS and Ca2+ inflow. XJ-2 exerts anti-inflammatory effects by regulating the key proteins of the NF-κB/IKKα pathway and reducing the expression of inflammatory factors. XJ-2 repairs skin barrier damage by regulating multiple factors. Compound XJ-2 from D. draco exerts excellent anti-inflammatory and barrier repair effects, possesses great potential for the treatment of skin diseases, and can be used as a dermatological drug to repair skin barrier damage.

The burden of chronic obstructive pulmonary disease (COPD) is increasing, especially for women in low-to-middle income countries. Biomarkers provide ever-increasing diagnostic precision for COPD and show promise for primary, secondary, and tertiary disease prevention. This review describes emerging applications for biomarkers in COPD, especially as they align with the Global Initiative for Chronic Obstructive Lung Disease (GOLD) emphasis on prevention, early diagnosis, and response to therapy. These biomarkers include blood eosinophils; IgE; C-reactive protein; fibrinogen; procalcitonin; interleukins 6, 8, and 33; tumor necrosis factor alpha; and soluble receptor for advanced glycated products (sRAGE). They have been used in various ways to identify COPD endotypes, predict exacerbations, predict mortality, and monitor the response to therapy. The fraction of exhaled nitric oxide (FENO) is increasingly studied in eosinophilic COPD endotypes and can be a diagnostic and predictive non-invasive biomarker. Imaging biomarkers, especially the quantitative computerized tomography (QCT) assessment of airway remolding, functional small airway disease, air trapping, lung function, and volume surrogates, all serve as non-invasive biomarkers for screening, early detection, and disease progression. Biomarkers facilitate all the phases of COPD care from detecting early airflow obstruction to predicting exacerbation and mortality. Biomarkers will be increasingly used as precise diagnostic tools to improve the COPD outcomes. The aim of this narrative review is to summarize the recent investigations in COPD biomarkers and their clinical applications.

Objectives: The oral cavity hosts one of the most complex microbial communities in the body. A disruption of the balance favors the growth of pathogenic species, contributing to oral diseases. The rise in microbial resistance has limited the effectiveness of conventional treatments, shifting the interest to natural product-based alternatives. Given its superior bioavailability and bioactivity in other models, this study investigates the antifungal potential of a novel curcumin derivative, PAC (3,5-bis(4-hydroxy-3-methoxybenzylidene)-N-methyl-4-piperidone), and studies its impact on host-pathogen dynamics and host defense mechanisms. Methods:Candida albicans was used as the model organism. Viability, growth kinetics, and colony formation were evaluated using optical density, agar culture, and MTT assay. Biofilm formation was assessed through electron microscopy and total sugar quantification. The morphological transition from hyphae to the less virulent blastospore was monitored using an optical microscope. The gene expression of adhesion factors and host defense markers was analyzed using RT-PCR. Results: PAC impairs C. albicans viability and reduces virulence by compromising biofilm formation and ensuring phenotypic transition to a blastospore form. Also, PAC controls C. albicans growth via necrosis/ROS pathways. As a result, PAC appears to repress host-pathogen interaction by downregulating SAPs, EAP1, and HWP1 adhesion genes, thus relieving the need to activate gingival epithelial cell defense mechanisms. This is highlighted by recording baseline levels of IL-6, IL-8, and IL-1β cytokines and antimicrobial β-defensin peptides in the presence of less virulent candida forms. Conclusions: PAC effectively reduces C. albicans virulence by limiting biofilm formation and adhesion while minimizing inflammatory responses. These findings support its potential as a promising therapeutic agent for infectious disease control.

The skin is a complex organ, containing an intricate network of immune cells that are crucial for host barrier function and defence against pathogens. Human papillomavirus (HPV) exclusively infects the skin, and its lifecycle is intimately associated with epithelial cell division and differentiation. There are over 450 HPV types, 12 of which are classified as carcinogenic. The primary focus of this review is the epithelial immune response to HPV infection of the cervix during the initial stages of infection, productive infection, and disease progression. During the early stages of infection, cells are HPV-positive; however, there are no attributable histological changes to the epithelium. The HPV-infected cells have the capacity for innate sensing and signalling through toll-like receptors in response to viral nucleic acids. However, HPV has evolved multiple mechanisms to evade the innate response. During productive infection, all viral antigens are expressed and there are visible histological changes to the epithelium, including koilocytosis. Disease regression is associated with Tbet positive cells in the infected epithelium and the presence of CD4 and CD8 T cells in the lamina propria. Disease progression is associated with the overexpression of the E6 and E7 oncoproteins after integration of viral genomes into the host chromosomal DNA. Histologically, the epithelium is less differentiated, and changes to cells include a higher nuclear-to-cytoplasmic ratio and an increased mitotic index. Immune changes associated with disease progression include increased numbers of cells expressing suppressor molecules, such as FoxP3, Blimp-1, and HMGB1, and myeloid cell infiltrates with an M2-like phenotype. This review highlights the gaps in the understanding of the immune response in HPV-positive cervical neoplasia, and in regression and progression of disease. This knowledge is critical for the development of effective immunotherapies that reliably cause HPV-positive cervical neoplasia to regress.

Non-alcoholic steatohepatitis (NASH) has emerged as a prevalent chronic liver disease with a huge unmet clinical need. A few studies have reported the beneficial effects of Poria cocos Wolf (P. cocos) extract on NASH mice, but the active components were still unknown. In this study we investigated the therapeutic effects of dehydrotrametenolic acid methyl ester (ZQS5029-1), a lanosterol-7,9(11)-diene triterpenes in P. cocos, in a high-fat diet plus CCl4 induced murine NASH model and a GAN diet induced ob/ob murine NASH model. The NASH mice were treated with ZQS5029-1 (75 mg·kg-1·d-1, i.g.) for 6 and 8 weeks, respectively. We showed that ZQS5029-1 treatment markedly relieved liver injury, inflammation and fibrosis in both the murine NASH models. We found that ZQS5029-1 treatment significantly suppressed hepatic NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome activation in both the NASH murine models, and blocked lipopolysaccharides (LPS)+adenosine 5'-triphosphate (ATP)/Nigericin-induced NLRP3 inflammasome activation in bone marrow-derived macrophages (BMDMs) and Kupffer cells in vitro. We demonstrated that ZQS5029-1 directly bound to the H236 residue of mouse Caspase-1, thereby inhibiting NLRP3 inflammasome activation. The effects of ZQS5029-1 on macrophage-hepatocyte/HSC crosstalk were analyzed using the supernatants from macrophages preconditioned with LPS + ATP introduced into hepatocytes and hepatic stellate cells (HSCs). We found that the conditioned medium from the BMDMs induced injury and death, as well as lipid accumulation in hepatocytes, and activation of HSCs; these effects were blocked by conditioned medium from BMDMs treated with ZQS5029-1. Moreover, the protective effects of ZQS5029-1 on hepatocytes and HSCs were eliminated by H236A-mutation of Caspase-1. We conclude that ZQS5029-1 is a promising lead compound for the treatment of NASH by inhibiting NLRP3 inflammasome activation through targeting Caspase-1 and regulating the macrophage-hepatocyte/HSC crosstalk.

Cold stress has important effects on the growth and production of broiler chickens. Glutamine (Gln) is a conditionally essential amino acid that plays an important role in promoting intestinal development and enhancing immune function. The aim of this study was to investigate the effects of Gln supplementation on the growth performance and health of cold-stressed prestarter broiler chicks.

A total of 375 1-day-old male SZ901 broilers were randomly divided into five groups (CON, CS, GLN1, GLN2, GLN3). Birds in the CON and CS groups were provided with normal drinking water, while the GLN1, GLN2 and GLN3 groups were provided with water supplemented with 0.4%, 0.8% and 1.2% Gln, respectively. At d7, birds in groups CS, GLN1, GLN2, and GLN3 were stressed at 12 ± 1 ℃ for 12 h. The results showed that cold stress significantly decreased the growth performance, serum antioxidant capacity and antibody concentrations, small intestine villus structure, and increased the gene expression of intestinal inflammatory factors of broiler chicks compared with the CON group (P < 0.05). Compared with the CS group, Gln supplementation exhibited increased growth performance, serum antioxidant capacity and antibody concentrations, gene expression levels of intestinal tight junction protein, villus height and villus height to crypt depth ratio (V/C) of small intestine, and decreased mRNA expression level of intestinal inflammatory factors (P < 0.05).

Gln supplementation ameliorated the impact of cold stress to a large extent as it promoted the development of the intestine and immune system and enhanced the antioxidant enzyme system in cold-stressed prestarter chicks.

Proinflammatory cytokines and enzymes responsible for tissue destruction are important in the development of periodontitis. This study compared salivary concentrations of interleukin-1 beta (IL-1β), matrix metalloproteinases (MMP-8), and (MMP-9) in individuals with and without periodontitis to evaluate their diagnostic utility as potential biomarkers.

A comprehensive search was performed across PubMed, Scopus, ScienceDirect, and Google Scholar, supplemented by manual searches in relevant journals up to January 2024. Eligibility criteria focused on human studies with defined diagnostic criteria for periodontitis and saliva samples analyzed for IL-1β, MMP-8, and MMP-9. Data were extracted to compare salivary levels of these markers between periodontitis patients and healthy controls. The Joanna Briggs Institute tool was used to evaluate the risk of bias and quality of the included studies. Statistical analysis employed a random effects model to calculate standardized mean differences and assess heterogeneity and publication bias.

The search yielded 122 articles, with 27 meeting the inclusion criteria. Fifteen percent of these studies presented a moderate risk of bias, while the remaining 85% exhibited a low risk of bias. The meta-analyses indicated significantly higher levels of IL-1β, MMP-8, and MMP-9 in the saliva of subjects with periodontitis compared to healthy individuals: IL-1β: Standardized Mean Difference (SMD) = 163.29 (95% CI = 104.64-221.95), p < 0.001; MMP-8: SMD = 282.22 (95% CI = 209.68-354.77), p < 0.001; MMP-9: SMD = 311.85 (95% CI = 179.64-444.05), p < 0.001.

Elevated salivary levels of IL-1β, MMP-8, and MMP-9 are linked to periodontitis.

The NLRP3 inflammasome plays a crucial role as a critical regulator of the immune response and has been implicated in the pathogenesis of numerous diseases. Peptides, known for their remarkable potency, selectivity, and low toxicity, have been extensively employed in disease treatment. Recent research has unveiled the potential of peptides in modulating the activity of the NLRP3 inflammasome. This review begins by examining the structure of the NLRP3 inflammasome, encompassing NLRP3, ASC, and Caspase-1, along with the three activation pathways: canonical, non-canonical, and alternative. Subsequently, we provide a comprehensive summary of peptide modulators targeting the NLRP3 inflammasome and elucidate their underlying mechanisms. The efficacy of these modulators has been validated through in vitro and in vivo experiments on NLRP3 inflammasome regulation. Furthermore, we conduct sequence alignment of the identified peptides and investigate their binding sites on the NLRP3 protein. This work is a foundational exploration for advancing peptides as potential therapeutic agents for NLRP3-related diseases.

Nanomedicines offer a means to overcome the limitations associated with traditional drug dosage formulations by affording drug protection, enhanced drug bioavailability, and targeted drug delivery to affected sites. Inflamed tissues possess unique microenvironmental characteristics (including excessive reactive oxygen species, low pH levels, and hypoxia) that stimuli-responsive nanoparticles can employ as triggers to support on-demand delivery, enhanced accumulation, controlled release, and activation of anti-inflammatory drugs. Stimuli-responsive nanomedicines respond to physicochemical and pathological factors associated with diseased tissues to improve the specificity of drug delivery, overcome multidrug resistance, ensure accurate diagnosis and precision therapy, and control drug release to improve efficacy and safety. Current stimuli-responsive nanoparticles react to intracellular/microenvironmental stimuli such as pH, redox, hypoxia, or specific enzymes and exogenous stimuli such as temperature, magnetic fields, light, and ultrasound via bioresponsive moieties. This review summarizes the general strategies employed to produce stimuli-responsive nanoparticles tailored for inflammatory diseases and all recent advances, reports their applications in drug delivery, and illustrates the progress made toward clinical translation.

Mitophagy is involved in acute myocardial infarction (AMI) process. However, the role of mitophagy-related genes (MRGs) in the AMI process is not well illustrated. We identified MRGs involved in AMI by bioinformatics analysis. The external datasets were employed for the validation of the MRGs, alongside the execution of cellular and animal experiments. Forty-five MRGs were detected, and machine learning identified the top four hub genes, namely ALDH2, ACSL1, IL1B, and GABARAPL1. Additionally, an external validation set was used to screen for three diagnostic markers (ACSL1, IL1B, and GABARAPL1) among these hub genes. Immune infiltration analysis revealed changes in the immune microenvironment among patients with AMI. Finally, the significant upregulation of ACSL1, IL1B, and GABARAPL1 in both cellular and animal models was confirmed. The occurrence of mitophagy was observed in the cell model through transmission electron microscopy (TEM). Our study demonstrated that ACSL1, IL1B, and GABARAPL1 possess potential biomarkers for AMI.

Pseudorabies virus (PRV) can infect most mammals and has caused significant economic losses in global pig production. The emergence of new mutants significantly reduces the protective effect of vaccination, indicating an urgent need for the development of specific therapeutic agents against PRV infection. In this study, we analyzed the changes in the cellular proteome after PRV infection in resveratrol-treated PK-15 cells using TMT quantitative proteomics combined with LC-MS/MS. The results identified the differential proteins osteopontin (iOPN) and interleukin-1 receptor accessory protein (IL-1RAP), which have significant biological implications. The regulation of OPN-IL-1β signaling by PRV infection was further studied through the OPN-ERK/JNK-IL-1β signaling axis. The transcriptional levels of OPN, C-JUN, IL-1RAP, and IL-1β, along with the protein levels of ERK, JNK, C-Jun, and their phosphorylated forms at 8, 12, and 16 h post-infection, were determined. The results showed that PRV infection inhibited the activation of this signaling axis, which was upregulated by resveratrol treatment. Down-regulation of OPN by siRNA increased PRV proliferation and inhibited the activation of the signaling axis, which was antagonized by resveratrol treatment. In PRV-infected mice, resveratrol treatment produced the same changes observed in vitro. The present study demonstrated that resveratrol can promote innate immune responses by regulating the OPN-ERK/JNK-IL-1β signaling axis, thereby activating host antiviral defenses against PRV infection. SIGNIFICANCE: Resveratrol targets the OPN-ERK/JNK-IL-1β axis to enhance innate immunity, offering a novel antiviral strategy against PRV infection. This study identifies OPN as a key regulator of host defense, linking ERK/JNK signaling to IL-1β-mediated antiviral responses. In vivo validation demonstrates resveratrol's therapeutic potential, reducing PRV replication and mortality in mice via immune pathway activation.

Electronic cigarettes ("e-cigarettes") are often marketed as smoking cessation tools and are used by smokers to reduce/quit cigarette smoking. The objective of this study was to assess the health effects of switching to e-cigarettes after long-term smoking in a mouse model and compare these effects with continued smoking, or quitting entirely. Adult BALB/c mice were whole-body exposed to mainstream cigarette smoke (2 h/day, 5 days/week) for 12 weeks prior to switching to flavoured e-cigarette aerosol (50:50 propylene glycol and glycerine) containing 18 mg/mL nicotine (2 h/day and 5 days/week), continuing cigarette smoking (2 h/day and 5 days/week), or quitting entirely for an additional 2 weeks. We then assessed a range of respiratory health outcomes including lung function and structure, pulmonary inflammation and changes in gene expression in the lung. Switching to e-cigarettes led to improvements in some aspects of respiratory health in mice compared with continued smoking, such as reduced neutrophilic inflammation in the lung. However, total cellular lung inflammation was still elevated and lung function was still impaired, in terms of airway responsiveness to methacholine, for e-cigarette use compared with quitting. Larger effects were typically seen in female mice compared to male. This study shows that switching to e-cigarettes after long-term cigarette smoking leads to improvements in some aspects of respiratory health, such as neutrophilic inflammation and the volume dependence of lung function compared with continued smoking. However, switching to e-cigarettes was not as effective as quitting smoking entirely.

Cytokine storm (CS) is a severe systemic inflammatory syndrome characterized by the excessive activation of immune cells and a significant increase in circulating levels of cytokines. This pathological process is implicated in the development of life-threatening conditions such as fulminant myocarditis (FM), acute respiratory distress syndrome (ARDS), primary or secondary hemophagocytic lymphohistiocytosis (HLH), cytokine release syndrome (CRS) associated with chimeric antigen receptor-modified T (CAR-T) therapy, and grade III to IV acute graft-versus-host disease following allogeneic hematopoietic stem cell transplantation. The significant involvement of the JAK-STAT pathway, Toll-like receptors, neutrophil extracellular traps, NLRP3 inflammasome, and other signaling pathways has been recognized in the pathogenesis of CS. Therapies targeting these pathways have been developed or are currently being investigated. While novel drugs have demonstrated promising therapeutic efficacy in mitigating CS, the overall mortality rate of CS resulting from underlying diseases remains high. In the clinical setting, the management of CS typically necessitates a multidisciplinary team strategy encompassing the removal of abnormal inflammatory or immune system activation, the preservation of vital organ function, the treatment of the underlying disease, and the provision of life supportive therapy. This review provides a comprehensive overview of the key signaling pathways and associated cytokines implicated in CS, elucidates the impact of dysregulated immune cell activation, and delineates the resultant organ injury associated with CS. In addition, we offer insights and current literature on the management of CS in cases of FM, ARDS, systemic inflammatory response syndrome, treatment-induced CRS, HLH, and other related conditions.

Vaccine formulations are a successful strategy against pathogen transmission because vaccine candidates induce effective and long-lasting memory immune responses (B and CD4+ T cells) at systemic and mucosal sites. Extracellular vesicles of lipoproteins, bioactive compounds from plants and invertebrates (sponges) encapsulated in liposomes, and glycoproteins can target these sites. The vaccine candidates developed can mimic microbial pathogens in a way that successfully links the innate and adaptive immune responses. In addition, vaccines plus adjuvants promote and maintain an inflammatory response. In this review, we aimed to identify the host-pathogen interface as a rich source of candidate targets for vaccine-induced protective and long-lasting memory immune responses.

The present study explored the immune response, milk production and health status of mastitis-infected lactating cows fed diets supplemented with Macleaya cordata extract.

Twenty-four Holstein and Jersey cows were equally assigned to two experimental groups: the first group was fed a control diet (control), and the second experimental group was fed a control diet plus Macleaya extract at 8 g/head/d (Macleaya). The experiment was conducted for 60 days. The daily milk yield was recorded, and the milk samples were analyzed for total solids, fat, protein, and lactose contents.

Blood samples were analyzed for different blood constituents, biochemical parameters, antioxidant capacity and immune indices. Compared with the control, the addition of Macleaya improved immune indices (p < 0.05). No significant differences (p > 0.05) were recorded between the two groups for different rumen liquor parameters, antioxidant capacities, milk yields or compositions. However, supplementing the diet with Macleaya significantly decreased SCC, SAA, and endotoxin.

This study suggested that supplementing the diets of lactating cows with Macleaya extract potentially improved their immune competence without adversely impacting their productive performance.

Acute myocardial necrosis activates the immune response and inflammatory processes. Although the initial response is helpful in restoring tissue injury, dysregulated and exacerbated inflammation contributes to the progression of cardiac remodeling. Inflammasomes play important roles in post-infarction inflammation. NALP1/NLRP1, NLRP 3, and NLRC4 are the best-known inflammasomes. NLRP3, which has received the most study in cardiovascular disease, has been linked to increased IL-1β (IL1B) production and caspase-1 activity, as well as impaired cardiac function. The role of NLRP1 and NLRC4 inflammasomes after acute myocardial infarction (MI) is poorly understood. We evaluated the expression of myocardial inflammasomes and inflammatory markers 72 h after MI in rats. Male Wistar rats were divided into Sham (n = 15) and MI (n = 16) groups. MI was induced by ligating the left anterior descending coronary artery. Infarct size was assessed by histology. Myocardial protein and gene expression was analyzed by Western blot and RT-qPCR, respectively. IL-1β (Il1b) concentrations in serum and heart macerate supernatant were evaluated by ELISA. Statistical analysis was performed using Student's t test. Rats with an MI size less than 30% of the total left ventricle (LV) area were excluded; infarct size was 46 ± 11% of the total LV area in MI. The interstitial collagen fraction was higher in MI. Nlrc4, caspase-1 (Casp1), and IL-1β (Il1b) protein expressions were higher in MI. Nlrp3, Nlrp1, ASC (Pycard), pro-caspase-1, and pro-IL-1β (Il1b) expressions did not differ between groups. Expression of the Nlrp3 and ASC (Pycard) genes, as well as myocardial and serum IL-1β (Il1b) concentrations, was higher in MI. Acute post-myocardial infarction inflammation is characterized by increased protein expression of Nlrc4, caspase-1, and interleukin-1β; increased gene expression of Nlrp3 and ASC (Pycard); and elevated serum and myocardial concentrations of interleukin-1β in combination with an increased myocardial collagen interstitial fraction.

Activated myofibroblasts deposit extracellular matrix material to facilitate rapid wound closure that can heal scarlessly during fetal development. However, adult myofibroblasts exhibit a relatively long life and persistent function, resulting in scarring. Thus, understanding how fetal and adult tissue regeneration differs may serve to identify factors that promote more optimal wound healing in adults with little or less scarring. We previously found that matricellular proteoglycan fibromodulin is one such factor promoting more optimal repair, but the underlying molecular and cellular mechanisms for these effects have not been fully elucidated. Here, we find that fibromodulin induces myofibroblast apoptosis after wound closure to reduce scarring in small and large animal models. Mechanistically, fibromodulin accelerates and prolongs the formation of the interleukin 1β-interleukin 1 receptor type 1-interleukin 1 receptor accessory protein ternary complex to increase the apoptosis of myofibroblasts and keloid- and hypertrophic scar-derived cells. As the persistence of myofibroblasts during tissue regeneration is a key cause of fibrosis in most organs, fibromodulin represents a promising, broad-spectrum anti-fibrotic therapeutic.

Inflammatory cytokines are fundamental mediators of the organismal response to injury, infection, or other harmful stimuli. To elucidate the early and mostly direct transcriptional signatures of inflammatory cytokines, we profiled all immunologic cell types by RNAseq after systemic exposure to IL1β, IL6, and TNFα. Our results revealed a significant overlap in the responses, with broad divergence between myeloid and lymphoid cells, but with very few cell-type-specific responses. Pathway and motif analysis identified several main controllers (NF-κB, IRF8, and PU.1), but the largest portion of the response appears to be mediated by MYC, which was also implicated in the response to γc cytokines. Indeed, inflammatory and γc cytokines elicited surprisingly similar responses (∼50% overlap in NK cells). Significant overlap with interferon-induced responses was observed, paradoxically in lymphoid but not myeloid cell types. These results point to a highly redundant cytokine network, with intertwined effects between disparate cytokines and cell types.

Cervical spondylosis is a prevalent ailment characterized by chronic wear and degenerative changes affecting the cervical spine, leading to various clinical syndromes such as axial neck pain, cervical myelopathy, and cervical radiculopathy. The pathophysiology of the development of cervical alterations is multifaceted, with alterations in the normal physiology and pathogenesis of intervertebral disc degeneration. The involvement of pro-inflammatory mediators, such as interleukin-1, tumor necrosis factor-α, interleukin-4, interleukin-6, and interleukin-10, in the pathological processes associated with intervertebral disc degeneration offers potential therapeutic targets. The review also introduces kinase inhibitors as potential treatments for cervical spondylosis. Protein kinase inhibitors, including mitogen-activated protein kinase (MAPK), Janus kinase (JAK), and spleen tyrosine kinase (SYK), are explored for their anti-inflammatory properties. The article discusses their potential in modulating inflammatory signaling cascades and presents them as attractive candidates for treating immune-mediated disorders. Inhibitors of Nuclear Factor-κB, p38 MAPK, Jun-N terminal kinase (JNK), and Extracellular signal-regulated kinase (ERK) have shown efficacy in suppressing inflammatory responses, offering potential avenues for intervention in this prevalent condition. Organogels are semi-solid materials formed by trapping an organic solvent within a three-dimensional cross-linked network. They hold considerable potential in drug delivery, especially in enhancing drug solubility, facilitating controlled release, and improving skin penetration. These properties of organogels can help treat or alleviate the symptoms of cervical spondylosis.

NOD-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) inflammasome, integral to innate immunity, has become a pivotal figure in the inflammatory cascade.

This article provides an overview of the NLRP3 inflammasome, reviewing its complicated structure, as well as the diverse signals that trigger its assembly. Furthermore, we explored the intricate relationship between the NLRP3 inflammasome and acute and chronic rejection in solid organ transplantation. Solid organ transplantation stands as a crucial medical intervention, yet its efficacy is challenged by immune-mediated complications, including acute rejection, ischemia-reperfusion injury, and chronic allograft rejection. We also investigated the encouraging potential of immunosuppressive therapies targeting NLRP3 signaling to alleviate inflammatory responses linked to transplantation.

In recent years, the NLRP3 inflammasome has garnered considerable attention owing to its critical functions spanning diverse fields. This study highlights the critical function of the NLRP3 inflammasome and presents insights, offering fresh perspectives on how its modulation might help to improve the outcomes among patients who undergo solid organ transplantations.

Endometritis in dairy cows significantly impacts their reproductive performance. However, its underlying mechanisms remain unclear. Hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit-alpha (HADHA) is known to regulate the occurrence of various diseases, but its role in bovine endometritis is poorly understood. In the present study, an in vitro bovine endometrial epithelial cells (BEECs) inflammation model was constructed to explore the effects of HADHA on inflammation, proliferation, and apoptosis. Functional analyses based on HADHA interference and overexpression revealed that it positively regulated the expression of IL-6, IL-8, and IL-1β in lipopolysaccharide (LPS)-induced BEECs, enhancing reactive oxygen species (ROS) production and promoting inflammation. Concurrently, HADHA decreased the expression of PCNA, CDK2, and CDK4, inhibited mitotic transition of BEECs from S to G2 phase, and negatively regulated BEEC proliferation. It also increased BAX and Caspase-3 expression while decreasing BCL2 expression, hence promoting BEECs apoptosis. Transcriptomic and metabolomic analyses indicated that HADHA modulated inflammation in BEECs by affecting pathways such as the TGF-beta signaling pathway, fatty acid metabolism, and p53 signaling. These findings provide novel insights into HADHA's role in bovine endometritis and reveal future research directions on its regulatory mechanisms.

This study aimed to investigate the therapeutic potential of scopoletin in ulcerative colitis, with a primary focus on its impact on crucial inflammatory pathways and immune responses. A male mouse model of DSS-induced colitis was employed with six distinct groups: a control group, a group subjected to DSS only, three groups treated with varying scopoletin doses, and the final group treated with dexamethasone. The investigation included an assessment of the effects of scopoletin on colitis symptoms, including alterations in body weight, Disease Activity Index (DAI), and histopathological changes in colonic tissue. Furthermore, this study scrutinized the influence of scopoletin on cytokine production, PPARγ and NF-κB expression, NLRP3 inflammasome, and the composition of intestinal bacteria. Scopoletin treatment yielded noteworthy improvements in DSS-induced colitis in mice, as evidenced by reduced weight loss and colonic shortening (p < 0.05, < 0.01, respectively). It effectively diminished TNF-α, IL-1β, and IL-12 cytokine levels (p < 0.01, p < 0.05), attenuated NLRP3 inflammasome activation and the associated cytokine release (p < 0.05, p < 0.01), and modulated the immune response by elevating PPARγ expression while suppressing NF-κB pathway activation (p < 0.05, p < 0.01). Additionally, scopoletin induced alterations in the gut microbiota composition, augmenting beneficial Lactobacillus and Bifidobacteria while reducing E. coli (p < 0.05). It also enhanced tight junction proteins, signifying an improvement in the intestinal barrier integrity (p < 0.05, < 0.01). Scopoletin is a promising therapeutic agent for managing ulcerative colitis, showing benefits that extend beyond mere anti-inflammatory actions to encompass regulatory effects on gut microbiota and restoration of intestinal integrity.

Inflammasomes are multi-protein complexes that detect pathogenic and damage-associated molecular patterns, activating caspase-1, pyroptosis, and the maturation of pro-inflammatory cytokines such as IL-1β and IL-18Within the tumor microenvironment, inflammasomes like NLRP3 play critical roles in cancer initiation, promotion, and progression. Their activation influences the crosstalk between innate and adaptive immunity by modulating immune cell recruitment, cytokine secretion, and T-cell differentiation. While inflammasomes can contribute to tumor growth and metastasis through chronic inflammation, their components also present novel therapeutic targets. Several inhibitors targeting inflammasome components- such as sensor proteins (e.g., NLRP3, AIM2), adaptor proteins (e.g., ASC), caspase-1, and downstream cytokines- are being explored to modulate inflammasome activity. These therapeutic strategies aim to modulate inflammasome activity to enhance anti-tumor immune responses and improve clinical outcomes. Understanding the role of inflammasomes in cancer immunity is crucial for developing interventions that effectively bridge innate and adaptive immune responses for better therapeutic outcomes.

Cardiovascular disease remains the leading global cause of mortality, largely driven by atherosclerosis, a chronic inflammatory condition characterized by lipid accumulation and immune-cell infiltration in arterial walls. Macrophages play a central role by forming foam cells and secreting pro-atherogenic cytokines, such as TNF-α, IFN-γ, and IL-1β, which destabilize atherosclerotic plaques, expanding the lipid core and increasing the risk of thrombosis and ischemia. Despite the significant health burden of subclinical atherosclerosis, few targeted therapies exist. Current treatments, including monoclonal antibodies, are limited by high costs and immunosuppressive side effects, underscoring the urgent need for alternative therapeutic strategies. In this study, we employed in silico drug repositioning to identify multitarget inhibitors against TNF-α, IFN-γ, and IL-1β, leveraging a virtual screening of 2750 FDA-approved drugs followed by molecular dynamics simulations to assess the stability of selected cytokine-ligand complexes. This computational approach provides structural insights into potential inhibitors. Additionally, we highlight nutraceutical options, such as fatty acids (oleic, linoleic and eicosapentaenoic acid), which exhibited strong and stable interactions with key cytokine targets. Our study suggests that these bioactive compounds could serve as effective new therapeutic approaches for atherosclerosis.

Chemotherapy-induced cognitive impairment, referred to as "chemobrain", is widely acknowledged as a significant adverse effect of cancer therapy. Paclitaxel, a chemotherapeutic drug, has been reported to cause cognitive impairment clinically and in animal models. However, the precise mechanisms are not fully understood. The current study explored the potential neuroprotective effect of lycopene in paclitaxel-induced cognitive impairment in mice and its potential underlying mechanisms. Mice were randomly allocated into six groups: control, paclitaxel-treated (10 mg/kg), lycopene-treated (5, 10, and 20 mg/kg) + paclitaxel, and lycopene alone-treated (20 mg/kg) groups. The effect of lycopene treatment on behavioral function and histological examination was assessed. Lycopene (20 mg/kg) was selected for additional investigation into the underlying mechanisms. Lycopene treatment counteracted paclitaxel-induced oxidative stress by reducing lipid peroxidation and enhancing catalase levels. Additionally, lycopene-treated mice demonstrated a significant elevation in nuclear factor erythroid 2-related factor 2 with no significant effect on hemeoxygenase-1. Moreover, paclitaxel administration elevated endoplasmic reticulum stress markers; glucose-regulated protein78, activating Transcription Factor 6, C/EBP homologous protein, and apoptosis marker annexin V which were significantly reduced by lycopene treatment. Furthermore, lycopene mitigated paclitaxel-induced neuroinflammation through the reduction of the levels of the NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome axis markers; nuclear factor-κB, NLRP3, caspase-1, interleukin-1β, and interleukin-18. Our study findings may provide new evidence that lycopene mitigates paclitaxel-induced cognitive impairment in mice by reversing oxidative stress, endoplasmic reticulum stress, and inflammatory mechanisms.