Search Results (22,840)

This study explored the proteomic landscape of inflammatory protein dysregulation in ankylosing spondylitis (AS), a chronic inflammatory disorder primarily affecting the axial skeleton and strongly associated with the HLA-B27 allele, particularly the HLA-B2705 and HLA-B2704 subtypes prevalent in Chinese populations. Blood samples from HLA-B27-positive AS patients and normal controls (NC) were analyzed using the Olink Target 96 inflammation panel to profile 92 inflammatory proteins. HLA-B27 subtyping was performed via PCR-SSP. To identify key proteins and stratify AS subtypes, we employed machine learning classifiers, including LightGBM models coupled with SHAP value interpretation, alongside traditional statistical analyses. The proteomic analysis revealed significant dysregulation of pro-inflammatory cytokines, such as IL-6 and IL-17A, in AS patients compared to NC, with CXCL9 and NRTN identified as potential biomarkers associated with disease activity. The combination of LightGBM classifiers and traditional statistical methods demonstrated high accuracy in distinguishing AS from NC and effectively stratifying subtypes. These findings provide valuable insights into the inflammatory mechanisms underlying AS pathogenesis and highlight potential biomarkers and therapeutic targets for improving diagnosis and treatment strategies. Future studies with larger and more diverse cohorts, as well as longitudinal designs, are warranted to validate these biomarkers and elucidate their dynamic changes during disease progression. Full article

Inorganic polyphosphate (PolyP) is a high-molecular-weight polymer that plays multiple roles in regulating immune responses. However, the specific anti-inflammatory mechanisms of bacteria-derived PolyP are unclear. In the present study, PolyP was extracted from Lactobacillus plantarum (L. plantarum), and the chain length was estimated to be approximately 250 Pi residues. The immune regulatory functions of PolyP were investigated using a lipopolysaccharide (LPS)-induced RAW264.7 cell oxidative stress model, and dexamethasone was used as a positive control. The result revealed that both dexamethasone and PolyP were protective against oxidative stress by inhibiting macrophage M1 polarization and the production of several markers, such as nitric oxide (NO), reactive oxygen species (ROS), inducible nitric oxide synthase (iNOS), and cyclooxygenase (COX)-2. In addition, PolyP suppressed inflammation progression by regulating the production of several cytokines, such as interleukin (IL)-1β, interferon (INF)-γ, tumor necrosis factor (TNF)-α, and IL-6, and inhibited the expressions of inhibitory κB kinase (IKK) α, IKKβ, and extracellular regulated protein kinases 2 (ERK2). Conclusively, PolyP derived from L. plantarum has the ability to protect cells from oxidative stress damage by inhibiting M1 polarization in macrophages. These findings provide insights into the function of PolyP and offer support for the potential application of PolyP in immune-related diseases. Full article

Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by complex pathogenesis involving dysregulated immunity and gut microbiota imbalance, demanding innovative therapeutic strategies. This study investigates the synergistic therapeutic potential of pomegranate peel–hawthorn combinations and their active constituents (ellagic acid and maslinic acid) through an integrative approach combining network pharmacology, in vitro/in vivo experiments, and gut microbiota analysis. Network pharmacology identified 61 shared therapeutic targets (p < 0.05 for pathway enrichment) and revealed complementary mechanisms: pomegranate peel primarily modulated AGE-RAGE/PI3K-Akt pathways, while hawthorn targeted IL-17/NF-κB signaling. Experimental validation demonstrated potent synergistic anti-inflammatory effects (combination index < 1), with optimal combinations reducing nitric oxide production by 52.35% (herbal extracts, p < 0.05) and 74.4% (active monomers, p < 0.05). In DSS-induced UC mice, combinatorial therapies significantly suppressed pro-inflammatory cytokines (TNF-α: 204.78 vs. 446.52 pg/mL in UC group, p < 0.05; IL-6: 33.19 vs. 64.86 pg/mL, p < 0.05), restored colonic SOD activity (72.31 vs. 50.10 U/mg·prot in UC group, p < 0.01), and alleviated histopathological damage, outperforming monotherapeutics. Gut microbiota analysis revealed the recovery of α-diversity indices and normalized Bacteroidota/Bacillota ratios. Mechanistically, the combinations suppressed MAPK/NF-κB signaling cascades, reducing p-p38/p38 (p < 0.01 vs. UC group) and p-ERK1/2/ERK1/2 (p < 0.01 vs. UC group) phosphorylation. These findings establish that pomegranate peel–hawthorn formulations exert multi-modal therapeutic effects through the synergistic inhibition of pathways, mitigation of oxidative stress, and restoration of the microbiota, offering a scientifically validated approach for UC management rooted in traditional medicine principles. Full article

K. pneumoniae is a major cause of bovine mastitis worldwide, making it difficult to control due to its resistance to multiple drugs. L. paraplantarum has been explored as a promising new approach to fighting bovine mastitis. In this study, the probiotic potential and safety of L. paraplantarum SDN1.2, as well as its ex vivo and in vivo anti-inflammatory effects against K. pneumoniae-induced mastitis, were comprehensively investigated using bioinformatics analyses and experimental validation methods. The results revealed that L. paraplantarum SDN1.2 exhibits non-hemolytic activity, is not cytotoxic, lacks virulence genes (e.g., adhesion factors, toxins, and invasion factors) and antibiotic resistance genes (e.g., beta-lactamases and tetracycline resistance genes), as supported by whole-genome sequencing, and significantly inhibits the growth of K. pneumoniae, as evaluated by antimicrobial tests. Following further validation in vitro, L. paraplantarum SDN1.2 demonstrated the capability to inhibit the adhesion and invasion of K. pneumoniae to bMECs. In a mouse model of K. pneumoniae-induced mastitis, L. paraplantarum SDN1.2 reduced the extent of neutrophil infiltration and inflammatory lesions. Furthermore, L. paraplantarum SDN1.2 pretreatment significantly reduced myeloperoxidase (MPO) activity and the expression of inflammatory cytokines (IL-6, IL-1β, and TNF-a) in mouse mammary gland tissue. In K. pneumoniae-infected bMECs, L. paraplantarum SDN1.2 significantly lowered lactate dehydrogenase (LDH) levels and expression of inflammatory cytokines such as IL-6, IL-1β, and TNF-α. The results demonstrated that the newly isolated L. paraplantarum SDN1.2 from bovine sources exhibits promising characteristics as a safe probiotic for the alleviation of bovine mastitis due to its safety profile and anti-inflammatory and antibacterial properties. Full article

Background/Objectives: Diseases associated with inflammatory processes continue to grow steadily throughout the world. Unfortunately, prolonged use of drugs induces adverse effects ranging from hypersensitivity reactions to damage to the digestive system. These negative effects open the possibility of continuing the search for anti-inflammatory compounds with less toxicity. The aim of this research was to isolate and evaluate the anti-inflammatory activity of a mixture of two enantiomeric labdanes isolated from Gymnosperma glutinosum by in vivo, in vitro, and in silico methods. Methods: A brief description of the main methods or treatments applied. This can include any relevant preregistration or specimen information. The structure of the labdanes enantiomers was elucidated by X-ray crystallography and spectroscopies methods. The anti-inflammatory effect was evaluated on a mouse model of ear edema induced with 12-O-tetradecanoyl phorbol-13-acetate; the pro-inflammatory mediators, nitric oxide (NO) and interleukin (IL-6), were quantified on macrophages stimulated with lipopolysaccharide, and the interaction between labdanes and diana was studied by molecular docking. Results: We identified the chemical structures of two new labdane enantiomers: a-gymglu acid and b-ent-gymglu acid. The enantiomer mixture, named gymglu acid, diminished ear edema at doses of 1 and 2 mg/ear by 36.07% and 41.99%, respectively. A concentration of 155.16 µM of gymglu acid inhibited the production of NO by 78.06% and IL-6 by 71.04%. The in silico results suggest two routes by which these labdanes reduce inflammation: partial agonism toward the corticosteroid receptors and inhibition of nitric oxide synthases. Conclusions: These results show that the gymglu acid enantiomers have promising anti-inflammatory activity. Full article

Despite extensive efforts, no highly effective antiviral molecule exists for treating moderate and severe COVID-19. Nanotechnology has emerged as a promising approach for developing novel drug delivery systems to enhance antiviral efficacy. Among these, polymeric nanomicelles improve the solubility, bioavailability, and cellular uptake of therapeutic agents. In this study, Pluronic F127-based nanomicelles were developed and evaluated for their antiviral activity against SARS-CoV-2. The nanomicelles, formulated using the direct dissolution method, exhibited an average size of 37.4 ± 8.01 nm and a polydispersity index (PDI) of 0.427 ± 0.01. Their antiviral efficacy was assessed in SARS-CoV-2-infected Vero E6 and Calu-3 cell models, where treatment with a 1:2 dilution inhibited viral replication by more than 90%. Cytotoxicity assays confirmed the nanomicelles were non-toxic to both cell lines after 72 h. In SARS-CoV-2-infected Calu-3 cells (human type II pneumocyte model), treatment with Pluronic F127-based nanomicelles containing atazanavir (ATV) significantly reduced viral replication, even under high MOI (2) and after 48 h, while also preventing IL-6 upregulation. To investigate their mechanism, viral pretreatment with nanomicelles showed no inhibitory effect. However, pre-exposure of Calu-3 cells led to significant viral replication reduction (>85% and >75% for 1:2 and 1:4 dilutions, respectively), as confirmed by transmission electron microscopy. These findings highlight Pluronic F127-based nanomicelles as a promising nanotechnology-driven strategy against SARS-CoV-2, reinforcing their potential for future antiviral therapies. Full article

Background: Chronic inflammation increases morbidity in older adults and significantly impacts healthy ageing. Pomegranate extract (PE), rich in polyphenols, has been suggested to reduce inflammation and could prevent cardiovascular disease. However, there is limited research examining the potential of PE in disease prevention in ageing. Methods: A two-arm double-blind parallel trial was conducted, in which participants received either placebo capsules (maltodextrin) or pomegranate extract (740 mg) daily for 12 weeks. At baseline, week 6, and week 12, anthropometric measurements, blood pressure, and blood samples were collected. Serum inflammatory markers (IL-6, IL-1-α, IL1-β, IL-2, TNF-α, CRP and PAI-1), fasting blood glucose, and lipid levels were also measured. Results: A total of 86 participants met the eligibility criteria, with 76 completing the trial. A significant interaction between treatment and time was observed for the IL-6 (p = 0.02) and IL1-β (p = 0.05) levels, with both parameters significantly decreasing in the PE group. CRP and TNF-α showed a downward trend in the PE group, but it was not statistically significant (p > 0.05). Systolic blood pressure significantly decreased in the PE group (by 5.22 ± 1.26 mmHg (SE), p = 0.04), indicating potential clinical relevance, with diastolic blood pressure showing a similar downward trend (2.94 ± 1.08 mmHg (SE), p = 0.3). Despite being apparently healthy with no diagnosed diseases, a substantial number of participants exhibited elevated levels of inflammatory markers and systolic blood pressure. Conclusions: PE can lower inflammatory markers and blood pressure, which can be high in both normal-weight and overweight older adults, making it a cost-effective measure to promote healthy ageing. Further long-term studies are needed to address the limitations of this 3-month study, including the overrepresentation of normal-weight participants, and to gain a better understanding of the impact of weight on the above-mentioned outcomes. Full article

Probenecid has long been a versatile drug in pharmacological therapies, primarily known for blocking active tubular secretion in the kidney, affecting both endogenous substances like uric acid and exogenous ones like penicillin. Beyond its renal applications, probenecid has shown capabilities in crossing the blood–brain barrier and modulating the activity of various membrane channels and transporters. This compound has emerged as a potent antiviral agent, demonstrating efficacy against multiple viruses, including influenza, COVID-19, and RSV. Clinical trials with COVID-19 patients have confirmed its antiviral potential, sparking further investigation into its mechanisms of action. This study explores probenecid’s significant anti-inflammatory properties, focusing on its ability to inhibit inflammasome activation. Our study aims to unravel the anti-inflammatory effects of probenecid on the NLRP3 inflammasome and MAPK signaling pathways using murine macrophages as a relevant inflammation model. We reveal that probenecid treatment blocks JNK and ERK signaling without affecting p38 MAPK, suppressing NLRP3 inflammasome activation. Additionally, probenecid does not affect NFκB-directed protein expression, although it efficiently inhibits NLRP3 inflammasome outputs, e.g., IL-1β and pyroptosis. These results indicate probenecid’s potential therapeutic applications. Full article

This article explores systemic inflammatory response syndrome (SIRS), thromboinflammation, and septic shock in fetuses and neonates, offering a comprehensive examination of their pathophysiology, diagnostic criteria, and clinical implications. It identifies SIRS as an exaggerated response to external stress, disrupting the balance between inflammation and adaptive mechanisms, driven by cytokines such as TNF-α and IL-1. The fetal inflammatory response syndrome (FIRS), a subset of SIRS, is noted for its role in adverse neonatal outcomes, including organ damage, inflammation, and long-term developmental disorders. The article discusses the extensive effects of FIRS on critical systems, including the blood, lungs, central nervous system, and kidneys. It highlights the challenges in diagnosing and managing septic shock in neonates, focusing on the relationship between inflammation and the hemostatic system. Additionally, the paper points out recent advancements, such as the convergent model of coagulation and emerging biomarkers like microRNAs for early detection. Despite this progress, gaps remain in understanding the molecular mechanisms underlying these conditions and in developing effective therapeutic strategies. This highlights the necessity for targeted research to mitigate the morbidity and mortality associated with septic shock in neonates. Full article

Experimental autoimmune encephalomyelitis (EAE) is a preclinical animal model widely used to study multiple sclerosis (MS). Blood-based analytes, including cytokines and neural biomarkers are the predictors of neurodegeneration, disease activity, and disability in patients with MS. However, understudied confounding factors cause variation in reports on EAE across animal strains/studies, limiting the utility of these biomarkers for predicting disease activity. In this study, we investigated blood-based analyte profiles, including neural markers (NFL and GFAP) and cytokines (IL-6, IL-17, IL-12p70, IL-10, and TNF-α), in two clinically distinct EAE models: relapsing-remitting (RR)-EAE and chronic-EAE. Ultrasensitive single-molecule array technology (SIMOA, Quanterix) was used to profile the analytes in the blood plasma of mice at the acute, chronic, and progressive phases of disease. In both models, NFL was substantially increased during post-disease onset across all phases, with a pronounced increase observed in chronic-EAE. The leakage of GFAP into peripheral blood was also greater after disease onset in both EAE models, especially in the acute phase of chronic-EAE. Among all cytokines, only IL-10 had consistently lower levels in both EAE models throughout the course of disease. This study suggests NFL, GFAP, and IL-10 as potential translational predictors of disease activity in EAE, making them potential candidates as surrogate markers for the preclinical testing of therapeutic interventions in animal models of MS. Full article

Background/Objectives: Inflammatory sarcopenia, characterized by muscle weakness exacerbated by chronic systemic inflammation, has emerged as a critical factor in fall risk among older adults. While previous studies have examined sarcopenia and inflammation independently, few have investigated their combined impact on mobility impairments and fall susceptibility, particularly in immunocompromised individuals. This study aimed to assess the role of inflammatory sarcopenia in increasing fall risk by comparing functional performance, muscle strength, and inflammatory biomarkers across three groups: healthy older adults, individuals with non-inflammatory sarcopenia, and those with inflammatory sarcopenia. A secondary objective was to evaluate fall incidence in immunocompromised versus non-immunocompromised individuals. Methods: A prospective observational study was conducted on 250 adults aged ≥65 years, categorized based on inflammatory status and muscle health. Functional assessments included handgrip strength, the Timed Up and Go (TUG) test, and fall frequency analysis. Inflammatory status was determined by measuring C-reactive protein (CRP) and interleukin-6 (IL-6) levels. Multivariate regression models were used to identify predictors of fall risk. Results: Participants with inflammatory sarcopenia exhibited significantly higher CRP and IL-6 levels, greater muscle weakness, poorer mobility performance, and a fourfold increase in fall incidence compared to controls (p < 0.001). Immunocompromised individuals had nearly double the fall risk of their non-immunocompromised counterparts (p < 0.001). TUG test performance was the strongest fall predictor. Conclusions: Our findings highlight the importance of integrating fall prevention strategies that not only focus on muscle-strengthening programs but also include regular screening for inflammatory markers. Given the strong association between systemic inflammation, muscle weakness, and fall risk, identifying and managing chronic inflammation may play a crucial role in reducing mobility impairments and improving outcomes in older adults. Full article

This work aims to assess the intermolecular interaction of choline ionic liquids (ILs) (choline malonate ([Ch][Mal]), choline succinate ([Ch][Suc]), and choline valinate ([Ch][Val]) with two enzymes (lysozyme and α-chymotrypsin). We evaluated the state of the tertiary protein structure using circular dichroism (CD) spectrometry and quantified the binding parameters of the binding of the ionic liquids to the enzymes by fluorescence spectroscopy. The binding energies of the enzymes and the localization of ions on them were estimated using the molecular docking. We then analyzed the relationship between the enzymes’ thermostability and their tendency towards aggregation in the enzyme/ionic liquid systems. The obtained results were compared with previous data on albumins to identify similarities and differences between the behavior of enzymes and albumins in ionic liquid solutions. Despite the comparable values of the binding constants, the effect of ionic liquids on the thermostability of enzymes was the opposite of their effect on albumins. In addition, although these ionic liquids promoted aggregation in both enzymes and albumins, this effect was much more pronounced for albumins. Full article

Introduction: Recently, alpha-emitting radionuclides like astatine-211 have offered promising results in clinical development. Non-muscle-invasive bladder cancer (NMIBC) presents a need for novel therapies. One promising approach is radioimmunotherapy targeting Carbonic Anhydrase IX (CA-IX), which is supported by preclinical and clinical evidence. The aim of our preclinical and clinical studies was to evaluate the [²¹¹At]At-anti-CA-IX antibody (ATO-101™) for future use in NMIBC patient care. Methods: The anti-CA-IX antibody, girentuximab (TLX250), was labeled with lutetium-177 and astatine-211 for in vitro studies. Affinity constant measurements of [²¹¹At]At-girentuximab in RT-112 cells were taken, and toxicity evaluations were conducted in vitro and in healthy mice. Additionally, a clinical proof-of-concept study, PERTINENCE, that used [⁸⁹Zr]Zr-girentuximab for PET/CT imaging in bladder cancer patients was conducted. Results: The measurement of the affinity constant of [²¹¹At]At-girentuximab in RT112 cells revealed high binding affinity and significant cytotoxicity compared to [177Lu]Lu-girentuximab. Biodistribution studies in healthy mice indicated low systemic radioactivity uptake, and a bladder post-instillation examination showed no abnormalities in bladder mucosa, suggesting safety. In the PERTINENCE study, which involved patients with NMIBC tumors expressing CA-IX, [⁸⁹Zr]Zr-girentuximab PET/CT showed no extravesical leakage. Wall bladder uptake spots correlated with recurrence or inflammatory reaction. A dosimetric study suggested the potential efficacy and favorable safety profile of intravesical alpha therapy with the [²¹¹At]At-anti-CA-IX antibody (ATO-101™) in NMIBC treatment. Conclusion: Preclinical and clinical data demonstrate the promising therapeutic role of ²¹¹At-targeted alpha agents in NMIBC, and the [²¹¹At]At-anti-CA-IX antibody (ATO-101™) could fulfill this role. A phase I FIH clinical trial is in preparation, and results are expected within the next years. Ethical approval was obtained from the Ile de France III Review Board (21.05.10.47712). All patients signed a written informed consent form prior to participation in this study (2021-001709-61). Full article

Micro- and nanoplastics (MPs and NPs) are pervasive environmental pollutants detected in aquatic ecosystems, with emerging evidence suggesting their presence in airborne particles generated by water body motion. Inhalation exposure to airborne MPs and NPs remains understudied despite documented links between occupational exposure to these particles and adverse respiratory outcomes, including airway inflammation, oxidative stress, and chronic respiratory diseases. This study explored the effects of acute NP exposure on a fully differentiated 3D human airway epithelial model derived from 14 healthy donors. Airway epithelium was exposed to aerosolized 50 nm polystyrene NPs at concentrations ranging from 2.5 to 2500 µg/mL for three minutes per day over three days. Functional assays revealed no significant alterations in tissue integrity, cell survival, mucociliary clearance, or cilia beat frequency, suggesting intact epithelial function post-exposure. However, cytokine and chemokine profiling identified a significant five-fold increase in CCL3 (MIP-1α), a neutrophilic chemoattractant, in NP-exposed samples compared to controls. This was corroborated by increased neutrophil chemotaxis in response to conditioned media from NP-exposed tissues, indicating a pro-inflammatory neutrophilic response. Conversely, levels of interleukins (IL-21, IL-2, IL-15), CXCL10, and TGF-β were significantly reduced, suggesting immunomodulatory effects that may impair adaptive immune responses and tissue repair mechanisms. These findings demonstrate that short-term exposure to NP-containing aerosols induces a distinct pro-inflammatory response in airway epithelium, characterized by enhanced neutrophil recruitment and reduced secretion of key immune modulators. These findings underscore the potential for aerosolized NPs to induce oxidative and inflammatory stress, raising concerns about their long-term impact on respiratory health and redox regulation. Full article

Background: Agarwood has been widely used for the treatment of gastrointestinal diseases. Our research group has suggested that agarwood alcohol extracts (AAEs) provide good gastric mucosal protection. However, the exact mechanisms underlying this effect remain unclear. Objectives: This study aimed to investigate the ameliorative effect of agarwood chromone on gastric ulcers and its mechanism. Methods: Network pharmacology was used to predict the disease spectrum and key therapeutic targets of 2-(2-phenylethyl)chromone (CHR1) and 2-(2-(4-methoxyphenyI)ethyl)chromone (CHR2). Mice were orally administered CHR1 (20 and 40 mg/kg) and CHR2 (20 and 40 mg/kg) and the positive drug omeprazole as an enteric-coated capsule (OEC, 40 mg/kg) orally. After 7 days of pretreatment with the CHRs, gastric ulcers were induced using absolute ethanol (0.15 mL/10 g). The ulcer index, gastric histopathology, biochemical parameters, and inflammatory and apoptotic proteins were evaluated. Finally, binding of the core compounds to the key targets was verified via molecular docking and visualized. Results: The pharmacological results show that the CHRs reduced the gastric occurrence and ulcer inhibition rates by up to more than 70% in a dose-dependent manner. The CHRs decreased the levels of interleukin 6 (IL-6), interleukin 12 (IL-12), interleukin 18 (IL-18), and tumor necrosis factor α (TNF-α), and improved the severity of the pathological lesions in the gastric tissue. The expression of ATP-binding box transporter B1 (ABCB1), arachidonic acid-5-lipoxygenase (ALOX5), nuclear factor kappa B (NF-κB), cysteinyl aspartate specific proteinase 3 3 (Caspase3), and cysteinyl aspartate specific proteinase 9 (Caspase9) was inhibited, but the expression of B-cell lymphoma-2 (Bcl-2) was enhanced. The CHRs bound stably to the key targets via hydrogen bonding, van der Waals forces, etc. These results demonstrate that agarwood chromone compounds exert alleviative effects against the occurrence and development of gastric ulcers by inhibiting the NF-κB and caspase pathways. The CHRs have a therapeutic effect on gastric ulcers through anti-inflammation and anti-apoptosis mechanisms. Conclusions: This study suggests that agarwood may have a potential role in drug development and the prevention and treatment of gastrointestinal inflammation, and tumors. Full article