Interleukin Research Articles

Cabozantinib-encapsulated and maytansine-conjugated high-density lipoprotein for immunotherapy in colorectal cancer

Advanced colorectal cancer (CRC) responds poorly to current adjuvant therapies, partially due to its immunosuppressive intestinal microenvironment. We found that myeloid-derived suppressor cells (MDSCs) were enriched in orthotopic tumors due to treatment-induced succinate release, which activated tuft cells and upregulated interleukin 25 (IL-25) and interleukin 13 (IL-13). We engineered a cabozantinib (Cabo)-encapsulated and maytansine (DM1)-conjugated synthetic high-density lipoprotein (ECCD-sHDL) to modulate the tumor microenvironment. DM1 induced immunogenic cell death and promoted the maturation of dendritic cells. Meanwhile, Cabo alleviated DM1-induced succinate release, preventing tuft cell activation, downregulating IL-25 and IL-13 secretion, and reducing intratumoral MDSC infiltration. ECCD-sHDL increased the densities of active cytotoxic T lymphocytes (CTLs) and M1 macrophages in the tumors, effectively inhibiting tumor growth and metastasis, thereby prolonging survival in murine CRC models. Our study sheds light on the mechanism of treatment-induced immunosuppression in orthotopic CRC and demonstrates that this combinatorial therapy could be an effective treatment for CRC.

Cimicifuga heracleifolia kom. Attenuates ulcerative colitis through the PI3K/AKT/NF-κB signaling pathway

Ethnopharmacological relevanceCimicifuga heracleifolia Kom. (C. heracleifolia) has demonstrated efficacy in treating gastrointestinal disorders, including splenasthenic diarrhea. Ulcerative colitis (UC), a chronic inflammatory bowel disease, shares similarities with splenasthenic diarrhea. However, the pharmacological effects of C. heracleifolia on UC and the underlying mechanisms remain unexplored. Aim of the studyThe present study investigates the therapeutic potential and mechanisms of C. heracleifolia in UC. MethodsInitially, network pharmacology analysis, encompassing ingredient screening, target prediction, protein-protein interaction (PPI) network analysis, and enrichment analysis, was employed to predict the mechanisms of C. heracleifolia. The findings were further validated using transcriptomics and functional assays in a dextran sulfate sodium (DSS)-induced UC model. Additionally, bioactive compounds were identified through surface plasmon resonance (SPR) analysis, molecular docking, and cell-based assays. ResultsA total of 52 ingredients of C. heracleifolia were screened, and 32 key targets were identified within a PPI network comprising 285 potential therapeutic targets. Enrichment analysis indicated that the anti-UC effects of C. heracleifolia are mediated through immune response modulation and the inhibition of inflammatory signaling pathways. In vivo experiments showed that C. heracleifolia mitigated histological damage in the colon, reduced the expression of phosphorylated Akt1, nuclear factor-kappa B (NF-κB) p65, and inhibitor of Kappa B kinase α/β (IKKα/β), suppressed the content of interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), and enhanced the expression of tight junction proteins. Moreover, cimigenoside, caffeic acid, and methyl caffeate were identified as the bioactive constituents responsible for the UC treatment effects of C. heracleifolia. ConclusionsIn summary, this study is the first to demonstrate that C. heracleifolia exerts therapeutic effects on UC by enhancing the intestinal mucosal barrier and inhibiting the phosphatidylinositol 3-kinase (PI3K)/AKT/NF-κB signaling pathway. These findings offer valuable insights into the clinical application of C. heracleifolia for UC management.

Spent brewer yeast glucan improves metabolic parameters and inflammatory markers reducing health risky changes imposed by the consumption of hypercaloric diet

β-glucans from yeasts are prebiotic health-promoting food ingredients able to boost immune response. An environmentally friendly source of yeast glucans is the spent brewer's yeast. This study investigated the effects of the administration of carboxymethyl glucan (CMG) (20 mg/kg, 12 weeks, orally), a derivative of the β-glucan from spent brewer's yeast, on food intake, weight gain, dyslipidemia, glucose intolerance, pro-inflammatory state, and hepatic steatosis of rats receiving a hypercaloric diet. The animals were divided into three groups: Normocaloric control (NCT); Hypercaloric diet and saline (HCT); and Hypercaloric diet and CMG (H-CMG). CMG administration could reduce rats' caloric value and food intake, reducing the index of adiposity (HCT:7.2±0.4% vs H-CMG:5.3±0.4% p < 0.05) and weight gain (HCT:111.1±3.8g vs H-CMG: 68.3±4.9g p < 0.05). Furthermore, it improved lipemic and glycemic profiles and lowered hepatic lipid accumulation. CMG decreased Monocyte Chemoattractant Protein (MCP)-1 (H-CT: 89.5±1.8 pg/mL vs H-CMG: 50.7±12.2 pg/mL p < 0.05), Interleukin (IL)-12 (H-CT: 206.0±14.0 pg/mL vs H-CMG:132.4±19.9 pg/mL, p < 0.05), and C-reactive protein (CRP) levels and increased IL-10 levels, decreasing the cardiovascular risk and pro-inflammatory state. Therefore, CMG has beneficial effects in preventing weight gain and, consequently, improves the metabolic profile in rats while consuming a hypercaloric diet. Findings indicate the spent brewer's yeast CMG can be a strategy to attenuate the risky metabolic changes related to the consumption of a hypercaloric diet.

Th2 and IL-17 responses inChlamydia pneumoniae-stimulated PBMC in asthmatic and non-asthmatic subjects

Abstract Background Chlamydia pneumoniae (C. pneumoniae) is a gram-negative intracellular bacterium that causes respiratory infections in humans, including asthmatic and non-asthmatic subjects. C. pneumoniae activates cells in vitro and produces cytokines that may contribute to the inflammatory responses observed in asthma. Different asthma endotypes are described, including Th2-high and Th2-low. Th2-low endotypes are characterized by IL-17 production and neutrophilic inflammation. The aim of this study was to investigate the role of C. pneumoniae in regulating Th2 versus Th17 responses in peripheral blood mononuclear (PBMC) from subjects with or without asthma. Methods PBM) (1×106/mL) from asthmatic (N=6) and non-asthmatic subjects (N=14) were infected +/- C. pneumoniae TW-183 at a multiplicity of infection (MOI) = 0.1, using dose responses (1:10, 1:100), and cultured 48 hrs. Cytokine responses (Interferon (IFN)-gamma, Interleukin (IL)-2, IL-4, IL-17 A/F) were measured in supernatants (ELISA). Results Comparison of cytokine responses (the mean differences in non-asthmatic versus asthmatic subjects) were significant for IFN gamma (unstimulated; P&amp;lt;0.0001), IL-2 (unstimulated and 1:100; P&amp;lt;0.0001, P=0.0002, respectively), IL-4 (unstimulated, 1:10, 1:100; P=0.0001, P&amp;lt;0.0001, P&amp;lt;0.0001, respectively) and IL-17 A/F (unstimulated, P&amp;lt;0.0001) (Wilcoxon signed-rank test). Cytokine levels were higher in asthmatic subjects for IFN-gamma (unstimulated,1:10, 1:100), IL-2 (unstimulated), and IL-17 A/F (unstimulated) compared with non-asthmatic subjects. However, IL-4 levels were higher in non-asthmatics (unstimulated, 1:10, 1:100). Conclusion Differences in Th2 and IL-17 cytokines responses in PBMC from subjects with and without asthma may indicate the involvement of cell-mediated immunity, while Th17 responses, which were increased in subjects with asthma at baseline, did not increase further in response to C. pneumoniae stimulation.

Influence of Donor-Specific Characteristics on Cytokine Responses in H3N2 Influenza A Virus Infection: New Insights from an Ex Vivo Model.

Influenza A virus (IAV) is known for causing seasonal epidemics ranging from flu to more severe outcomes like pneumonia, cytokine storms, and acute respiratory distress syndrome. The innate immune response and inflammasome activation play pivotal roles in sensing, preventing, and clearing the infection, as well as in the potential exacerbation of disease progression. This study examines the complex relationships between donor-specific characteristics and cytokine responses during H3N2 IAV infection using an ex vivo model. At 24 h post infection in 31 human lung explant tissue samples, key cytokines such as interleukin (IL)-6, IL-10, tumor necrosis factor-alpha (TNF-α), and interferon-gamma (IFN-γ) were upregulated. Interestingly, a history of lung cancer did not impact the acute immune response. However, cigarette smoking and programmed death-ligand 1 (PD-L1) expression on macrophages significantly increased IL-2 levels. Conversely, age inversely affected IL-4 levels, and diabetes mellitus negatively influenced IL-6 levels. Additionally, both diabetes mellitus and programmed cell death protein 1 (PD-1) expression on CD3+/CD4+ T cells negatively impacted TNF-α levels, while body mass index was inversely associated with IFN-γ production. Toll-like receptor 2 (TLR2) expression emerged as crucial in mediating acute innate and adaptive immune responses. These findings highlight the intricate interplay between individual physiological traits and immune responses during influenza infection, underscoring the importance of tailored and personalized approaches in IAV treatment and prevention.

Regulation of Airway Epithelial-Derived Alarmins in Asthma: Perspectives for Therapeutic Targets.

Asthma is a chronic respiratory condition predominantly driven by a type 2 immune response. Epithelial-derived alarmins such as thymic stromal lymphopoietin (TSLP), interleukin (IL)-33, and IL-25 orchestrate the activation of downstream Th2 cells and group 2 innate lymphoid cells (ILC2s), along with other immune effector cells. While these alarmins are produced in response to inhaled triggers, such as allergens, respiratory pathogens or particulate matter, disproportionate alarmin production by airway epithelial cells can lead to asthma exacerbations. With alarmins produced upstream of the type 2 inflammatory cascade, understanding the pathways by which these alarmins are regulated and expressed is critical to further explore new therapeutics for the treatment of asthmatic patients. This review emphasizes the critical role of airway epithelium and epithelial-derived alarmins in asthma pathogenesis and highlights the potential of targeting alarmins as a promising therapeutic to improve outcomes for asthma patients.

Myeloid-Specific JAK2 Contributes to Inflammation and Salt Sensitivity of Blood Pressure.

Salt sensitivity of blood pressure (SSBP), characterized by acute changes in blood pressure with changes in dietary sodium intake, is an independent risk factor for cardiovascular disease and mortality in people with and without hypertension. We previously found that elevated sodium concentration activates antigen-presenting cells (APCs), resulting in high blood pressure, but the mechanisms are unknown. Here, we hypothesized that APC-specific JAK2 (Janus kinase 2) through STAT3 (signal transducer and activator of transcription 3) and SMAD3 (small mothers against decapentaplegic homolog 3) contributes to SSBP. We performed bulk or single-cell transcriptomic analyses following in vitro monocytes exposed to high salt and in vivo high sodium treatment in humans using a rigorous salt-loading/depletion protocol to phenotype SSBP. We also used a myeloid cell-specific CD11c+ JAK2 knockout mouse model and measured blood pressure with radiotelemetry after N-omega-nitro-L-arginine-methyl ester and a high salt diet treatment. We used flow cytometry for immunophenotyping and measuring cytokine levels. Fluorescence in situ hybridization and immunohistochemistry were performed to spatially visualize the kidney's immune cells and cytokine levels. Echocardiography was performed to assess cardiac function. We found that high salt treatment upregulates gene expression of the JAK/STAT/SMAD pathway while downregulating inhibitors of this pathway, such as suppression of cytokine signaling and cytokine-inducible SH2, in human monocytes. Expression of the JAK2 pathway genes mirrored changes in blood pressure after salt loading and depletion in salt-sensitive but not salt-resistant humans. Ablation of JAK2, specifically in CD11c+ APCs, attenuated salt-induced hypertension in mice with SSBP. Mechanistically, we found that SMAD3 acted downstream of JAK2 and STAT3, leading to increased production of highly reactive isolevuglandins and proinflammatory cytokine IL (interleukin)-6 in renal APCs, which activate T cells and increase production of IL-17A, IL-6, and TNF-α (tumor necrosis factor-alpha). Our findings reveal the APC JAK2 signaling pathway as a potential target for the diagnosis and treatment of SSBP in humans.

Embryo-restricted responses to maternal IL-17A promote neurodevelopmental disorders in mouse offspring.

Prenatal imprinting to interleukin 17A (IL-17A) triggers behavioral disorders in offspring. However, reported models of maternal immune activation utilizing immunostimulants, lack specificity to elucidate the anatomical compartments of IL-17A's action and the distinct behavioral disturbances it causes. By combining transgenic IL-17A overexpression with maternal deficiency in its receptor, we established a novel model of prenatal imprinting to maternal IL-17A (acronym: PRIMA-17 model). This model allowed us to study prenatal imprinting established exclusively through embryo-restricted IL-17A responses. We demonstrated a transfer of transgenic IL-17A across the placental barrier, which triggered the development of selected behavioral deficits in mouse offspring. More specifically, embryonic responses to IL-17A resulted in communicative impairment in early-life measured by reduced numbers of nest retrieval calls. In adulthood, IL-17A-imprinted offspring displayed an increase in anxiety-like behavior. We advocate our PRIMA-17 model as a useful tool to study neurological deficits in mice.

Platelet-rich plasma ameliorates cartilage degradation in rat models of osteoarthritis via the OPG/RANKL/RANK system.

Osteoarthritis (OA) is one of the most common degenerative joint diseases in the elderly, which is featured by the degradation of articular cartilage. Recently, platelet-rich plasma (PRP) injection into the affected joint has become one biological therapy for OA treatment. The OPG/RANKL/ RANK signalling has been reported to mediate OA progression. Our study aimed to confirm whether PRP injection retards OA development through the regulation of the OPG/RANKL/RANK system. The OA rat models were induced by medial menisci resection combined with anterior cruciate ligament transection. Four weeks after surgery, OA-induced rats received intra- articular injection with 50 μL PRP once a week for 6 weeks. Rats were euthanised one week after the 6th injection. Rat knee joints were subjected to histopathological examination by haematoxylin- eosin (H&E) and safranin O staining. Osteoprotegerin (OPG), receptor activator of nuclear factor kappa B (RANK), and RANK ligand (RANKL) in the articular cartilage of rats were tested through immunofluorescence staining and western blotting. Serum interleukin-1β (IL-1β) and interleukin-6 (IL-6) levels were measured by enzyme-linked immunosorbent assay (ELISA). Matrix metalloproteinase- 13 (MMP-13), aggrecan, collagen α, IL-1β, IL-6, tumour necrosis factor-alpha (TNF-α), and nuclear factor kappa-B (NF-κB) mRNA and protein expression in rat articular cartilage were examined by real-time quantitative polymerase chain reaction (RT-qPCR) and western blotting, respectively. Intra-articular injections of PRP significantly improved the structural integrity of the articular cartilage and enhanced the synthesis of glycosaminoglycans. PRP reduced MMP-13 protein level but increased aggrecan and collagen α protein levels in articular cartilage of OA rats. OA-induced increase in serum IL-1β, IL-6, and TNF-α concentrations as well as increased MMP-13, and decreased collagen II mRNA levels were reversed by the administration of PRP. OA increased IL-1β, TNF-α, and NF-κB mRNA expression in rat articular cartilage whereas PRP administration ameliorated these changes. Moreover, in the articular tissue of OA-induced rats the increased OPG protein level was further elevated by PRP injections whereas the protein level of RANK did not change. The increase in the protein level of RANKL in OA-induced articular tissue was offset by PRP administration. PRP elevated OPG mRNA expression and the OPG/RANKL mRNA ratio, but reduced RANKL mRNA expression and the RANKL/RANK mRNA ratio in the articular tissue of OA-induced rats. PRP mitigates cartilage degradation and inflammation in experimental knee OA by regulating the OPG/RANKL/RANK signalling system.

PI3Kδ activation, IL6 overexpression, and CD37 loss cause resistance to naratuximab emtansine in lymphomas

AbstractCD37-directed antibody and cellular-based approaches have shown preclinical and promising early clinical activity. Naratuximab emtansine (Debio 1562; IMGN529) is an antibody-drug conjugate (ADC) incorporating an anti-CD37 monoclonal antibody conjugated to the maytansinoid DM1 as payload, with activity as a single agent and in combination with rituximab in patients with lymphoma. We studied naratuximab emtansine and its free payload in 54 lymphoma models, correlated its activity with CD37 expression, characterized 2 resistance mechanisms, and identified combination partners providing synergy. The activity, primarily cytotoxic, was more potent in B- than T-cell lymphoma cell lines. After prolonged exposure to the ADC, 1 diffuse large B-cell lymphoma (DLBCL) cell line developed resistance to the ADC due to the CD37 gene biallelic loss. After CD37 loss, we also observed upregulation of interleukin-6 (IL6) and related transcripts. Recombinant IL6 led to resistance. Anti-IL6 antibody tocilizumab improved the ADC’s cytotoxic activity in CD37+ cells. In a second model, resistance was sustained by a PIK3CD activating mutation, with increased sensitivity to PI3Kδ inhibition and a functional dependence switch from MCL1 to BCL2. Adding idelalisib or venetoclax overcame resistance in the resistant derivative and improved cytotoxic activity in the parental cells. In conclusion, targeting B-cell lymphoma with the naratuximab emtansine showed vigorous antitumor activity as a single agent, which was also observed in models bearing genetic lesions associated with inferior outcomes, such as MYC translocations and TP53 inactivation or R-CHOP (rituximab, cyclophosphamide, doxorubicin, Oncovin [vincristine], and prednisone) resistance. Resistant DLBCL models identified active combinations of naratuximab emtansine with drugs targeting IL6, PI3Kδ, and BCL2.

Mitigation of radiation-induced jejunum injuries in rats through modulation of the p53-miR34a axis using etoricoxib-loaded nanostructured lipid carriers

The most widely used cancer therapy is radiation therapy, but radiation damage to healthy tissues, particularly the gastrointestinal (GI) system, frequently reduces its effectiveness. This study investigates whether etoricoxib-loaded nanostructured lipid carriers (Et-NLC) could help shield the rat jejunum from radiation damage. Gamma irradiation (6 Gy) was used to damage the jejunum of Wistar albino rats, and then Et or Et-NLC (10 mg/kg b.w.) was administered orally for 14 days. It was found that the amounts of glutathione S-transferase (GST), superoxide dismutase (SOD), and nitric oxide (NO) decreased after irradiation but increased after Et-NLC therapy. Molecular analysis showed radiation-induced expression of microRNA-34a (miR34a), which may be involved in cellular stress response. Et-NLC treatments modulated the expression of miR34a, suggesting possible regulatory roles. Western blot analysis revealed changes in P53, interleukin-6 (IL-6), interleukin-10 (IL-10), tumor necrosis factor-alpha (TNF-α), and cyclooxygenase-2 (COX-2) levels. Et-NLC treatments decreased TNF-α, IL-6, IL-10, and COX-2 levels, indicating anti-inflammatory actions. DNA fragmentation analysis revealed a decrease in apoptotic activity after Et-NLC treatments. A histopathological examination confirmed that Et-NLC treatments had attenuated radiation damage, which had improved vascularization and reduced inflammation. The findings show that Et-NLC is more effective than Et-alone at reducing damage to the jejunum caused by radiation by controlling inflammation, oxidative stress, and apoptotic activity.

Effects of Ginseng Consumption on Cardiovascular HealthBiomarkers in Adults: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Ginseng, with various pharmacological activities, has received increasing attention to improve cardiovascular health (CVH). Therefore, this meta-analysis synthesized the effect of ginseng consumption on biomarkers of CVH in adults. A systematic search was performed in the databases of PubMed, Scopus, Web of Science, Embase, and the Cochrane Library through July 24, 2023 to screen out English-language randomized controlled trials (RCTs) evaluating the effects of ginseng consumption on body composition, blood pressure, vascular stiffness, lipid metabolism, glucose metabolism, insulin resistance, inflammatory cytokines, and adipocytokines in adults. The weighted mean difference (WMD) and 95% confidence interval (CI) were used to evaluate the overall effect size, and STATA 12.0 was used for comprehensive analysis. Forty-five studies were included in the meta-analysis. Ginseng consumption significantly reduced systolic blood pressure (SBP) (WMD = -2.57 mmHg, 95% CI = -4.99 to -0.14, p = 0.038), total cholesterol (TC) (WMD = -4.40 mg/dL, 95% CI = -8.67 to -0.132, p = 0.043), low density lipoprotein cholesterol (LDL-C) (WMD = -2.81 mg/dL, 95% CI = -4.89 to -0.72, p = 0.008), C-reactive protein (CRP) (WMD = -0.41 mg/L, 95% CI = -0.73 to -0.10, p = 0.010), and interleukin-6 (IL-6) (WMD = -2.82 pg./mL, 95% CI = -4.31 to -1.32, p < 0.001). Subgroup analyses suggested that supplementation with ginseng for less than 12 weeks significantly reduced SBP, but 12 weeks or more improved TC and CRP. Ginseng consumption on SBP, TC, and CRP seemed to be more effective on unhealthy participants. The meta-analysis showed that ginseng consumption might have the potential to improve SBP, TC, LDL-C, CRP, and IL-6. These findings suggest that ginseng is a potential candidate for the maintenance of CVH. However, our results had high heterogeneity. Future high-quality studies are needed to firmly establish the clinical efficacy of ginseng consumption.

Acetylcholine receptor-β inhibition by interleukin-6 in skeletal muscles contributes to modulating neuromuscular junction during aging

BackgroundAging-related strength decline contributes to physiological deterioration and is a good predictor of poor prognosis. However, the mechanisms underlying neuromuscular junction disorders affecting contraction in aging are not well described. We hypothesized that the autocrine effect of interleukin (IL)-6 secreted by skeletal muscle inhibits acetylcholine receptor (AChR) expression, potentially causing aging-related strength decline. Therefore, we investigated IL-6 and AChR β-subunit (AChR-β) expression in the muscles and sera of aging C57BL/6J mice and verified the effect of IL-6 on AChR-β expression.MethodsAnimal experiments, in vitro studies, bioinformatics, gene manipulation, dual luciferase reporter gene assays, and chromatin immunoprecipitation experiments were used to explore the role of the transcription cofactor peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC1α) and its interacting transcription factors in the IL-6-mediated regulation of AChR-β expression.ResultsIL-6 expression gradually increased during aging, inhibiting AChR-β expression, which was reversed by tocilizumab. Both tocilizumab and the PGC1α agonist reversed the inhibiting effect of IL-6 expression on AChR-β. Compared to inhibition of signal transducer and activator of transcription 3, extracellular signal-regulated kinases 1/2 (ERK1/2) inhibition suppressed the effects of IL-6 on AChR-β and PGC1α. In aging mouse muscles and myotubes, myocyte enhancer factor 2 C (MEF2C) was recruited by PGC1α, which directly binds to the AChR-β promoter to regulate its expression.ConclusionsThis study verifies AChR-β regulation by the IL-6/IL-6R-ERK1/2-PGC1α/MEF2C pathway. Hence, evaluating muscle secretion, myokines, and AChRs at an earlier stage to determine pathological progression is important. Moreover, developing intervention strategies for monitoring, maintaining, and improving muscle structure and function is necessary.

Metabolic-Associated Fatty Liver Disease: The Influence of Oxidative Stress, Inflammation, Mitochondrial Dysfunctions, and the Role of Polyphenols.

Metabolic-Associated Fatty Liver Disease (MAFLD) is a clinical-pathological scenario that occurs due to the accumulation of triglycerides in hepatocytes which is considered a significant cause of liver conditions and contributes to an increased risk of death worldwide. Even though the possible causes of MAFLD can involve the interaction of genetics, hormones, and nutrition, lifestyle (diet and sedentary lifestyle) is the most influential factor in developing this condition. Polyphenols comprise many natural chemical compounds that can be helpful in managing metabolic diseases. Therefore, the aim of this review was to investigate the impact of oxidative stress, inflammation, mitochondrial dysfunction, and the role of polyphenols in managing MAFLD. Some polyphenols can reverse part of the liver damage related to inflammation, oxidative stress, or mitochondrial dysfunction, and among them are anthocyanin, baicalin, catechin, curcumin, chlorogenic acid, didymin, epigallocatechin-3-gallate, luteolin, mangiferin, puerarin, punicalagin, resveratrol, and silymarin. These compounds have actions in reducing plasma liver enzymes, body mass index, waist circumference, adipose visceral indices, lipids, glycated hemoglobin, insulin resistance, and the HOMA index. They also reduce nuclear factor-KB (NF-KB), interleukin (IL)-1β, IL-6, tumor necrosis factor-α (TNF-α), blood pressure, liver fat content, steatosis index, and fibrosis. On the other hand, they can improve HDL-c, adiponectin levels, and fibrogenesis markers. These results show that polyphenols are promising in the prevention and treatment of MAFLD.

Inhalation of Microplastics Induces Inflammatory Injuries in Multiple Murine Organs via the Toll-like Receptor Pathway.

Previous studies have detected microplastics (MPs) in human biological samples, such as lungs, alveolar lavage fluid, and thrombus. However, whether MPs induce health effects after inhalation are unclear. In this study, fluorescent polystyrene microplastics (PS-MPs) were found in the thymus, spleen, testes, liver, kidneys, and brain on day 1 or day 3 after one intratracheal instillation. Furthermore, mice showed inflammation in multiple organs, manifested as obvious infiltration of neutrophils and macrophages, increased Toll-like receptors (TLRs), myeloid differentiation primary response protein 88 (MyD88) and nuclear factor-κB (NF-κB), as well as proinflammatory cytokines (tumor necrosis factor (TNF)-α and interleukin (IL)-1β) in the lungs, thymus, spleen, liver, and kidneys after four intratracheal instillations of PS-MPs at once every 2 weeks. Hepatic and renal function indexes were also increased. Subsequently, the inflammatory response in multiple murine organs was significantly alleviated by TLR2 and TLR4 inhibitors. Unexpectedly, we did not find any elevated secretion of monocyte chemotactic protein (MCP)-1 or TNF-α by RAW264.7 macrophages in vitro. Thus, PS-MPs induced inflammatory injuries in multiple murine organs via the TLRs/MyD88/NF-κB pathway in vivo, but not macrophages in vitro. These results may provide theoretical support for healthy protection against PS-MPs and their environmental risk assessment.

Efficacy and safety of the anti-IL1RAP antibody nadunolimab (CAN04) in combination with gemcitabine and nab-paclitaxel in patients with advanced/metastatic pancreatic cancer.

Interleukin (IL)-1 pathway upregulation is implicated in pancreatic ductal adenocarcinoma (PDAC) progression, therapy resistance, and survival. Nadunolimab is an IL-1 receptor accessory protein (IL1RAP)-targeting antibody with enhanced antibody-dependent cellular cytotoxicity that blocks IL-1α/IL-1β signaling. We investigated efficacy and safety of nadunolimab in PDAC, in combination with gemcitabine/nab-paclitaxel (GN). Patients with previously untreated locally advanced/metastatic PDAC received nadunolimab (1.0-7.5 mg/kg) every two weeks with standard GN. The primary objective was safety; secondary objectives were anti-tumor response, progression-free survival (PFS) and overall survival (OS). Correlations between serum and tumor biomarkers and clinical response were explored. 76 patients were enrolled, median age 63 years (range 43-89), 42% female, 97% with metastatic disease, 9% having received adjuvant chemotherapy. The most frequent Grade ≥3 adverse event was neutropenia (66%), typically during Cycle 1. Infusion-related reactions occurred in 29% (Grade 3, 3%). Only 1 of 76 patients had grade 3 or above peripheral neuropathy. No marked dose-dependent differences in safety or efficacy were observed between the four dose groups. Median OS overall was 13.2 months (95%CI 10.6-15.5) and 1-year survival was 58%. Median iPFS (iRECIST) was 7.2 months (95%CI 5.2-8.5). Treatment efficacy was higher in patients with high versus low tumor baseline IL1RAP expression (OS 14.2 vs 10.6 months, p=0.026). A reduction in serum IL-8 on treatment correlated with prolonged OS. Nadunolimab combined with GN shows promising efficacy and manageable safety in locally advanced/metastatic PDAC. Higher tumor baseline IL1RAP expression correlated with better outcome.

Assessing the causal relationship between CRP, IL-1α, IL-1β, and IL-6 levels and intervertebral disc degeneration: a two-sample Mendelian randomization study

Growing research has suggested an association between chronic inflammation and Intervertebral disc degeneration (IVDD), but whether there is a causal effect remains unknown. This study adopted two-sample Mendelian randomization (MR) approach to explore the etiological role of chronic inflammation in IVDD risk. Here, summary statistics for C-reactive protein (CRP), interleukin (IL)-1α\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\mathcal {\\alpha }$$\\end{document}, IL-1β\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\mathcal {\\beta }$$\\end{document}, IL-6 expression and IVDD were obtained from genome-wide association studies (GWAS) of European ancestry. MR analyses were conducted by using inverse variance weighted (IVW), Wald Ratio, weighted median, and MR-Egger method. Sensitivity analyses were conducted to assess the robustness of the results. The MR analyses suggested a lack of causal association of CRP, IL-6 , and IL-1α\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\mathcal {\\alpha }$$\\end{document} levels on IVDD (CRP-IVDD: odds ratio [OR] = 0.97, 95% confidence interval [CI] 0.86–1.09, P = 0.583; IL-6-IVDD: OR = 1.04, 95% CI 0.86–1.27, P = 0.679; IL-1α\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\mathcal {\\alpha }$$\\end{document}-IVDD: OR = 1.09, 95%CI 1.00–1.18, P = 0.058). However, there was a sign of a connection between genetically elevated IL-1β\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\mathcal {\\beta }$$\\end{document} levels and a decreased IVDD incidence (OR = 0.87, 95%CI 0.77–0.99, P = 0.03). Our findings suggest a connection between IL-1β\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\mathcal {\\beta }$$\\end{document} levels and the risk of IVDD. However, due to the support of only one SNP, heterogeneity and pleiotropy tests cannot be performed, the specific underlying mechanisms warrant further investigation.

EF24, a Curcumin Analog, Reverses Interleukin-18-Induced miR-30a or miR-342-Dependent TRAF3IP2 Expression, RECK Suppression, and the Proinflammatory Phenotype of Human Aortic Smooth Muscle Cells.

Curcumin, a polyphenolic compound derived from the widely used spice Curcuma longa, has shown anti-atherosclerotic effects in animal models and cultured vascular cells. Inflammation is a major contributor to atherosclerosis development and progression. We previously reported that the induction of the proinflammatory molecule TRAF3IP2 (TRAF3 Interacting Protein 2) or inhibition of the matrix metallopeptidase (MMP) regulator RECK (REversion Inducing Cysteine Rich Protein with Kazal Motifs) contributes to pro-oxidant, proinflammatory, pro-mitogenic and pro-migratory effects in response to external stimuli in vascular smooth muscle cells. Here we hypothesized that EF24, a curcumin analog with a better bioavailability and bioactivity profile, reverses interleukin (IL)-18-induced TRAF3IP2 induction, RECK suppression and the proinflammatory phenotype of primary human aortic smooth muscle cells (ASMC). The exposure of ASMC to functionally active recombinant human IL-18 (10 ng/mL) upregulated TRAF3IP2 mRNA and protein expression, but markedly suppressed RECK in a time-dependent manner. Further investigations revealed that IL-18 inhibited both miR-30a and miR-342 in a p38 MAPK- and JNK-dependent manner, and while miR-30a mimic blunted IL-18-induced TRAF3IP2 expression, miR-342 mimic restored RECK expression. Further, IL-18 induced ASMC migration, proliferation and proinflammatory phenotype switching, and these effects were attenuated by TRAF3IP2 silencing, and the forced expression of RECK or EF24. Together, these results suggest that the curcumin analog EF24, either alone or as an adjunctive therapy, has the potential to delay the development and progression of atherosclerosis and other vascular inflammatory and proliferative diseases by differentially regulating TRAF3IP2 and RECK expression in ASMC.

Expression profile of Toll-like receptors and cytokines in the cecal tonsil of chickens challenged with Eimeria tenella.

Chicken coccidiosis, caused by Eimeria spp., seriously affects the development of the poultry breeding industry. Currently, extensive studies of chicken coccidiosis are mostly focused on acquired immune responses, while information about the innate immune response of chicken coccidiosis is lacking. Toll-like receptor (TLR), the key molecule of the innate immune response, connects innate and adaptive immune responses and induces an immune response against various pathogen infections. Therefore, the quantitative real-time PCR was used to characterize the expression profile of chicken TLRs (chTLRs) and associated cytokines in the cecal tonsil of chickens infected with Eimeria tenella. The results showed that the expression of chTLR1a, chTLR2a, and chTLR5 was significantly upregulated at 3h post-infection, while chTLR1b, chTLR2b, chTLR3, chTLR7, chTLR15 and chTLR21 was significantly downregulated (p < 0.05). In addition, chTLR1a expression rapidly reached the peaked expression at 3h post-infection, while chTLR2b and chTLR15 peaked at 168h post-infection, and chTLR2a expression was highest among chTLRs, peaking at 48h post-infection (p < 0.05). For cytokines, interleukin (IL)-6 and tumor necrosis factor (TNF)-α peaked at 96h post-infection, IL-4 and IL-12 peaked at 144h post-infection, and interferon-γ expression was highest among cytokines at 120h post-infection. In addition, IL-12 and IL-17 were markedly upregulated at 6h post-infection (p < 0.05). These results provide insight into innate immune molecules during E. tenella infection in chickens and suggest that innate immune responses may mediate resistance to chicken coccidiosis.

The Role of Dicrocoelium dendriticum Egg Antigen in Colitis: A Molecular, Pathological and Serological Study in an Experimental Model of C57BL/6 Mice.

Inflammatory bowel disease (IBD) is a chronic and recurrent disease of the gastrointestinal tract that enhances the chance of developing colorectal cancer. Since standard treatments such as Mesalazine have limited effectiveness and are often accompanied by numerous side effects, the use of immune modulators derived from worms has been proposed as a new immunotherapy method for inflammatory diseases such as ulcerative colitis. The aim of this study is to investigate the protective effects of D. dendriticum egg antigen on DSS-induced colitis in C57BL/6 mice. D. dendriticum egg antigen was extracted and DSS (3.5%) was used to induce colitis in mice. Treatment and prophylaxis included intraperitoneal injections of D. dendriticum egg antigen. Histopathological indicators and the disease activity index (DAI), including weight loss, rectal bleeding, stool consistency, and rectal prolapse, were used to assess the severity of colitis. Real-time PCR measured the expression of transforming growth factor-β (TGF-β) and interleukin-17 (IL-17), while ELISA determined the concentration of these cytokines. Treatment with D. dendriticum egg antigen significantly improved the clinical symptoms and decreased the severity of DSS-induced colitis. Furthermore, D. dendriticum egg antigen increased the expression of TGF-β mRNA and reduced the expression of IL-17 mRNA, leading to a positive adjustment in the regulation of proteins and reduction of inflammatory proteins. As a result, the macroscopic, microscopic inflammation and activity index (DAI) of DSS-induced decreased. D. dendriticum egg antigen provides a promising new way to modulate the immune system and improve ulcerative colitis.