Inflammatory Mediators Research Articles

Unmasking culprits: novel analysis identifies complement factors as potential therapeutic targets to mitigate inflammation during children's heart surgery

BackgroundCardiopulmonary bypass (CPB) causes systemic inflammation during pediatric cardiac surgery, which can contribute to post-operative organ dysfunction and prolonged recovery. This study aims to identify key inflammatory mediators related to this clinically significant immunologic response.MethodsPediatric patients were enrolled in a single-arm prospective clinical study (NCT05154864) and received standard cardiac operation, CPB and subzero-balance ultrafiltration. Arterial samples were taken before CPB initiation and immediately after weaning, and concentrations of 33 inflammatory mediators were assayed. A principal component analysis with hierarchical clustering (PCA-HCPC) included inflammatory mediator concentrations measured at the end of CPB, validated peak post-operative clinical scores, ventilation time and intensive care length of stay. Mahalanobis distance assessed statistical differences between clusters. Spearman’s correlation described the linear relationship between mediator concentrations at the end of CPB and intensive care length of stay. Results are median (IQR).ResultsForty consecutive patients were enrolled; the majority were male (58%), age of 7.3 (1.7–39.0) months and weight of 6.7 (4.6–14.9) kg. The PCA-HCPC revealed activated complement factors along with all peak clinical scores and prolonged intensive care requirements in the same cluster. Cytokine, chemokine, and leukocyte adhesion molecule concentrations were found in two other distinct clusters (Mahalanobis distance = 16.5; p = 0.004 and Mahalanobis distance = 17.4; p = 5.8 × 10–4). Mediator concentrations of C2 (Rho = 0.50; p = 0.001), C3 (Rho = 0.58; p = 1.1 × 10–4), C3b (Rho = 0.47; p = 0.002), C5 (Rho = 0.48; p = 0.002) and C5a (Rho = 0.63; 1.7 × 10–5) showed linear correlations with intensive care unit length of stay.ConclusionsActivated complement factors, but not pro-inflammatory cytokines or chemokines, were most related to cardiopulmonary dysfunction and prolonged recovery in this novel analysis. Investigation of therapies that inhibit complement to dampen CPB-associated inflammation and enhance recovery after pediatric cardiac surgery is warranted.Trial Registration ClinicalTrials.gov, NCT05154864

Comparison of Airway Inflammation Characteristics Detected by Lower Exhaled Nitric Oxide in Cough Variant Asthma, Non-Asthmatic Eosinophilic Bronchitis, and Classic Asthma

Objective To investigate the inflammatory profiles of non-asthmatic eosinophilic bronchitis (NAEB), cough variant asthma (CVA), and classic asthma (CA) using fractional exhaled nitric oxide (FeNO) analysis to identify their unique inflammatory phenotypes. Methods This study involved cough patients newly diagnosed, corticosteroid-naïve with CVA (n = 68), NAEB (n = 53), and CA (n = 49). FeNO measurements at exhalation flow rates of 50 mL/s (FeNO50) and 200 mL/s (FeNO200) were conducted. The concentration of alveolar nitric oxide (CaNO) was calculated using a two-compartment model. Inflammatory mediators in induced sputum were also analyzed across the groups. Results Significant differences in FeNO50, FeNO200, and CaNO levels were observed among the three groups (all P < 0.001). Compared to NAEB, CVA patients demonstrated significantly higher FeNO50 levels (27.5 [interquartile range, IQR: 12.0 - 33.0] ppb vs. 16.0 [IQR: 12.5 - 22.0] ppb; P = 0.008) but lower CaNO levels (2.6 [IQR: 1.0 - 4.3] ppb vs. 3.7 [IQR: 2.3 - 6.1] ppb; P = 0.009). CA exhibited the highest levels of FeNO50, FeNO200, and CaNO compared to both NAEB and CVA (all P < 0.01). In CVA, FeNO50 positively correlated with sputum eosinophils, IL-4, and LTC4, whereas NAEB showed elevated CaNO levels with higher sputum eosinophils, IL-5, and PGE2 (all P < 0.05). Conclusions Inflammation predominantly affects the central airways in CVA and the peripheral airways in NAEB, with a more uniform distribution across the airway in CA. These discrepancies in airway inflammation may suggest distinct cough mechanisms in CVA, NAEB, and CA.

Bortezomib induces Rho-dependent hyperpermeability of endothelial cells synergistically with inflammatory mediators

BackgroundBortezomib (BTZ), a selective 26 S proteasome inhibitor, is clinically useful in treating multiple myeloma and mantle cell lymphoma. BTZ exerts its antitumor effect by suppressing nuclear factor-B in myeloma cells, promoting endothelial cell apoptosis, and inhibiting angiogenesis. Despite its success, pulmonary complications, such as capillary leak syndrome of the vascular hyperpermeability type, were reported prior to its approval. Although the incidence of these complications has decreased with the use of steroids, the underlying mechanism remains unclear. This study aims to investigate how BTZ influences endothelial cell permeability.MethodsWe examined the impact of BTZ on vascular endothelial cells, focusing on its effects on RhoA and RhoC proteins. Stress fiber formation, a known indicator of increased permeability, was assessed through the Rho/ROCK pathway.ResultsBTZ was found to elevate the protein levels of RhoA and RhoC in vascular endothelial cells, leading to stress fiber formation via the Rho/ROCK pathway. This process resulted in enhanced vascular permeability in a Rho-dependent manner. Furthermore, the stress fiber formation induced by BTZ had synergistic effects with the inflammatory mediator histamine.ConclusionsOur findings suggest that BTZ accumulates RhoA and RhoC proteins in endothelial cells, amplifying the inflammatory mediator-induced increase in the active GTP-bound state of Rho, thereby exaggerating vascular permeability during pulmonary inflammation. This study provides novel insights into the molecular mechanism underlying the pulmonary complications of BTZ, suggesting that BTZ may enhance inflammatory responses in pulmonary endothelial cells by increasing RhoA and RhoC protein levels.

High cumulative glucocorticoid dose is associated with increased levels of inflammation-related mediators in active rheumatoid arthritis

IntroductionGlucocorticoids (GCs) are widely used as a treatment for rheumatoid arthritis (RA), leading to high cumulative doses in long-term treated patients. The impact of a high cumulative GC dose on the systemic inflammatory response in RA remains poorly understood.MethodsWe investigated long-treated patients with RA (n = 72, median disease duration 14 years) through blood counts and the serum levels of 92 inflammation-related proteins, and disease activity was assessed using the Simple Disease Activity Index (SDAI). Patients were grouped based on the cumulative GC dose, with a cut-off value of 20 g (low/high, n = 49/23).Results and discussionPatients with a high cumulative GC dose within the active RA group had elevated serum levels in 23 inflammation-related proteins compared with patients with a low dose (cytokines/soluble receptors: CCL3, CCL20, CCL25, IL-8, CXCL9, IL-17A, IL-17C, IL-18, sIL-18R1, IL-10, sIL-10RB, OSM and sOPG; growth factors: sTGFα and sHGF; other inflammatory mediators: caspase 8, STAMBP, sCDCP1, sirtuin 2, 4E-BP1, sCD40, uPA and axin-1; pcorr &amp;lt; 0.05). In non-active RA, the high and low GC groups did not differ in analysed serum protein levels. Moreover, patients with active RA with a high GC dose had an increased white blood cell count, increased neutrophil–lymphocyte and platelet–lymphocyte ratios and a decreased lymphocyte–monocyte ratio compared with the low dose group (p &amp;lt; 0.05). This is the first study to report elevated serum levels in inflammation-related proteins and deregulated blood counts in patients with active RA with a high cumulative GC dose. The elevated systemic inflammation highlights the importance of improving care for patients receiving high cumulative GC doses.

Cannabichromene as a Novel Inhibitor of Th2 Cytokine and JAK/STAT Pathway Activation in Atopic Dermatitis Models

Cannabichromene (CBC) is one of the main cannabinoids found in the cannabis plant, and although less well known than tetrahydrocannabinol (THC) and cannabidiol (CBD), it is gaining attention for its potential therapeutic benefits. To date, CBC’s known mechanisms of action include anti-inflammatory, analgesic, antidepressant, antimicrobial, neuroprotective, and anti-acne effects through TRP channel activation and the inhibition of inflammatory pathways, suggesting that it may have therapeutic potential in the treatment of inflammatory skin diseases, such as atopic dermatitis (AD), but its exact mechanism of action remains unclear. Therefore, in this study, we investigated the effects of CBC on Th2 cytokines along with the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathways involved in AD pathogenesis. We used a 2,4-Dinitrochlorobenzene (DNCB)-induced BALB/c mouse model to topically administer CBC (0.1 mg/kg or 1 mg/kg). The results showed that skin lesion severity, ear thickness, epithelial thickness of dorsal and ear skin, and mast cell infiltration were significantly reduced in the 0.1 mg/kg CBC-treated group compared with the DNCB-treated group (p &lt; 0.001). In addition, real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis showed a significant decrease in the mRNA expression of Th2 cytokines (TSLP, IL-4, IL-13) and inflammatory mediators (IFN-γ, IL-1β, IL-6, IL-17, IL-18, and IL-33) (p &lt; 0.05). Western blot analysis also revealed a significant decrease in JAK1, JAK2, STAT1, STAT2, STAT3, and STAT6 protein expression (p &lt; 0.05). These results suggest that CBC is a promising candidate for the treatment of AD and demonstrates the potential to alleviate AD symptoms by suppressing the Th2 immune response.

Integrating bioinformatics and machine learning to unravel shared mechanisms and biomarkers in chronic obstructive pulmonary disease and type 2 diabetes.

Chronic obstructive pulmonary disease (COPD) and type 2 diabetes mellitus (T2DM) are on the rise. While there is evidence of a link between the two diseases, the pathophysiological mechanisms they share are not fully understood. In this study, the co-expressed genes of COPD and T2DM in Gene Expression Omnibus database were identified by bioinformatics method, and the functional enrichment analysis was performed. Machine learning algorithms were used to identify biomarkers. The diagnostic value of these biomarkers was assessed by receiver operating characteristic analysis, and their relationship to immune cells was investigated by immunoinfiltration analysis. Finally, real-time quantitative polymerase chain reaction was performed. A total of five overlapping genes were obtained, focusing on pathways associated with insulin resistance and inflammatory mediators. The machine learning method identified three biomarkers: matrix metalloproteinase 9, laminin α4, and differentially expressed in normal cells and neoplasia domain containing 4 C, all of which were shown to have high diagnostic values by receiver operating characteristic analysis. Immunoinfiltration analysis showed that it was associated with a variety of immune cells. In addition, the real-time quantitative polymerase chain reaction results confirmed agreement with our bioinformatics analysis. Our study sheds light on the common pathogenesis and biomarkers of both diseases, and these findings have potential implications for the development of new diagnostic and treatment strategies for COPD and T2DM. Key message What is already known on this topic? Chronic obstructive pulmonary disease (COPD) and type 2 diabetes mellitus (T2DM) often coexist as comorbidities. However, the exact mechanistic link between the two diseases remains complex, multifactorial, and not fully understood. What this study adds? Three biomarkers, including matrix metalloproteinase, laminin α4, and differentially expressed in normal cells and neoplasia domain containing 4 C, were identified as key co-expression hub genes in COPD and T2DM. How this study might affect research, practice or policy? Future studies may benefit from incorporating a larger sample set to further explore and validate the diagnostic and therapeutic effects of these core genes.

Deficiency of neutrophil gelatinase-associated lipocalin elicits Hemophilia-like bleeding and clotting disorder.

Coagulation is related to inflammation, but the key pathway, especially innate immune system and coagulation regulation, is not well understood and need to be further explored. Here, we demonstrated that neutrophil gelatinase-associated lipocalin (NGAL), an innate immune inflammatory mediator, is upregulated in thrombosis patients. Furthermore, it contributes to the initiation and amplification of coagulation, hemostasis, and thrombosis. This occurs by enhancing tissue factor expression on the cell surface, potentiating various clotting factors such as thrombin, kallikrein, FXIa, and FVIIa, promoting thrombin-induced platelet aggregation, and inhibiting antithrombin. NGAL knockout led to strikingly prolonged clot reaction time and kinetic time in thromboelastography analysis, along with reduced thrombus generation angle and lower thrombus maximum amplitude, which were in line with remarkably prolonged activated partial thromboplastin time and prothrombin time. In several mouse hemostasis and thrombosis models, NGAL overexpression or intravenous administration promoted coagulation and hemostasis and aggravated thrombosis whereas NGAL knockout or treatment with anti-NGAL monoclonal antibody significantly prolonged bleeding time and alleviated thrombus formation. Notably, NGAL knockout prolonged mouse tail bleeding time or artery occlusion time to over 40 or 60 min, respectively, resembling uncontrollable bleeding and clotting disorder seen in Hemophilia mice. Furthermore, anti-NGAL monoclonal antibody treatment markedly reduced the formation of blood clots in inflammation-induced thrombosis models. Collectively, these findings unveil a previously unidentified role of NGAL in the processes of coagulation, hemostasis, and thrombosis, as well as the crosstalk between innate immunity, inflammation, and coagulation. Thus, modulating NGAL levels could potentially help balance thrombotic and hemorrhagic risks.

Molecular Mechanisms of Rett Syndrome: Emphasizing the Roles of Monoamine, Immunity, and Mitochondrial Dysfunction

Rett syndrome (RTT), which predominantly affects females, arises in most cases from mutations in the Methyl-CpG-binding Protein-2 (MECP2) gene. When MeCP2 is impaired, it disrupts the regulation of numerous genes, causing the production of dysfunctional proteins associated with various multi-systemic issues in RTT. In this review, we explore the current insights into molecular signaling related to monoamines, immune response, and mitochondrial function, and their implications for the pathophysiology of RTT. Research has shown that monoamines—such as dopamine, norepinephrine, epinephrine, serotonin, and histamine—exhibit alterations in RTT, contributing to a range of neurological symptoms. Furthermore, the immune system in RTT individuals demonstrates dysfunction through the abnormal activity of microglia, macrophages, lymphocytes, and non-immune cells, leading to the atypical release of inflammatory mediators and disruptions in the NF-κB signaling pathway. Moreover, mitochondria, essential for energy production and calcium storage, also show dysfunction in this condition. The delicate balance of producing and scavenging reactive oxygen species—termed redox balance—is disrupted in RTT. Targeting these molecular pathways presents a promising avenue for developing effective therapies.

Understanding and Using Animal Models of Hepatotoxicity.

Hepatotoxicity is a critical health hazard, primarily contributing to the increased incidence of deaths globally. The liver is one of the major and extremely vital organs of the human body. Autoimmune diseases, viruses, exposure to toxicants such as carcinogens, and changes in eating habits can all cause liver problems, among other things. Free radical generation, together with raised enzyme levels including SGOT, SGPT, and total bilirubin, are among the pathological changes set off by liver injury. Hepatotoxicity causes changes in cells, such as eosinophilic cytoplasm, nuclear pyknosis, fatty degeneration, too many liver lesions, and hepatic centrilobular necrosis due to lipid peroxidation. Researchers have used animal models to investigate liver diseases and toxicities. Drugs such as azathioprine, alcoholism, paracetamol intoxication, and anti-tuberculosis drugs are some of the most common causes of liver toxicity. These toxins cause calcium ions (Ca2+), reactive oxygen species (ROS), and inflammatory mediators to be released inside cells. This activates immune cells like NK cells, NKT cells, and Kupffer cells. These signaling pathways also play roles in hepatotoxicity. Due to its pathogenesis, no effective drug is currently available for hepatotoxicity due to a lack of understanding related to the signaling factors involved in it. The paper primarily examines different experimental models of hepatotoxicity, including non-invasive and invasive methods, as well as genetic models. As such, these models are crucial tools in advancing our understanding of hepatotoxicity, thus paving the way for new therapeutic interventions.

SNHG15 is involved in the progression of atherosclerosis through targeted regulation of miR-370-3p and bioinformatics analysis

IntroductionThis study aimed to explore the expression of SNHG15 in atherosclerotic population and further evaluate the regulatory mechanism of SNHG15 in AS.Material and methodsqRT-PCR was used to detect the level of SNHG15 in serum samples. An in vitro cell model was constructed using 50 µg/ml ox-LDL-induced VSMCs. Transwell, CCK-8 assay and ELISA were used to detect the migration, proliferation, phenotypic transformation, and inflammatory reaction of the cell model. The interaction between SNHG15 and miR-370-3p was verified by the luciferase reporter gene. Pearson analysis was used to assess the correlation between SNHG15 and miR-370-3p. The target genes of miR-370-3p and their functions were evaluated by bioinformatics analysis.ResultsThe expression of SNHG15 in the AS group and ox-LDL-induced VSMCs group were upregulated (p &lt; 0.001), while miR-370-3p was decreased (p &lt; 0.001). In vitro studies showed that inhibition of SNHG15 can obviously weaken the proliferation, migration, phenotypic transformation, and inflammation of VSMCs induced by ox-LDL (p &lt; 0.01). Bioinformatics and luciferase reporter gene confirmed that miR-370-3p was the downstream target gene of SNHG15. Pearson correlation coefficient revealed that miR-370-3p was negatively regulated by SNHG15 (r = –0.6998, p &lt; 0.001). Bioinformatics analysis indicated that miR-370-3p had 160 potential target genes, whose functions were mainly related to cell cycle and cell adhesion, and were mainly concentrated in the MAPK signaling pathway. Further analysis showed that the downstream target gene of miR-370-3p was FOXO1.ConclusionsSNHG15 mediated cell proliferation, migration, phenotypic transformation, and inflammation response via inhibiting miR-370-3p in ox-LDL-induced VSMCs.

Inflammatory mediator contributes to leptin resistance and obesity in craniopharyngioma.

Obesity presents a significant challenge in managing patients with craniopharyngioma (CP). Cyst fluid (CF), rich in inflammatory mediators, is implicated in CP-related obesity, though the precise mechanism remains unclear. This study investigated the impact of CF or C-X-C motif chemokine ligand-1 (CXCL1) injections on body weight, Lee index, plasma lipid profiles, hepatic lipid accumulation, leptin levels, NF-κB pathway, the suppressor of cytokine signaling 3 (SOCS3) expression, and leptin sensitivity in rats. Bioinformatics was employed to identify differentially expressed genes (DEGs) between CF/CXCL1-treated and control SY5Y cells, as well as to confirm enriched pathways. Western blotting was used for experimental validation, including the effects of sodium salicylate (SS) on leptin sensitivity in SY5Y cells. Injecting CF or CXCL1 into the brain, without hypothalamic damage, led to increased body weight, Lee index, and hepatic lipid accumulation in rats, alongside elevated fasting blood glucose, triglycerides, and total cholesterol, while high-density lipoprotein cholesterol levels decreased. Additionally, CF and CXCL1 could induce elevated leptin levels, a higher leptin-to-body weight ratio, and resistance to exogenous leptin by activating the NF-κB pathway and upregulating the expression of SOCS3 in rats. Further validation confirmed that CF and CXCL1 suppress leptin signaling by activating the NF-κB pathway and upregulating SOCS3. Moreover, SS mitigated the inhibitory effects of CF or CXCL1 on leptin signaling, preserving leptin sensitivity in SY5Y cells. These results highlight the obesogenic role of CF and CXCL1, offering insights into the development of morbid obesity through inflammatory factor-mediated leptin resistance, independent of hypothalamic damage. SS may serve as a promising therapeutic approach for CP-associated obesity, though additional clinical studies are necessary to confirm its efficacy.

Evaluation of the covariation between leukotriene B4, prostaglandin E2, and hematologic inflammatory parameters in a canine pentylenetetrazole-induced seizure model

BackgroundSeizures can cause as well as result from neuroinflammation. This study was performed to identify the hematologic inflammatory parameters (HIPs) and inflammatory mediators that change after a single seizure in a canine pentylenetetrazole (PTZ)-induced seizure model.MethodsFive healthy Beagle dogs were used in this study. A 3% solution of PTZ was infused until the occurrence of generalized convulsion. Two separate experiments were conducted to observe changes in HIPs over short and long time periods. Blood sampling time points were divided into two periods as follows: short period (baseline, 30, 60, 90, and 120 min after seizure induction) and long period (baseline, 2, 6, 12, 24, and 48 h after seizure induction). The HIPs were calculated, and the serum prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) concentrations were estimated using enzyme-linked immunosorbent assay.ResultsSignificant changes (p &amp;lt; 0.05) in various HIPs were observed at different time point as follows: neutrophil × monocyte (90 min), neutrophil-to-lymphocyte ratio (60, 90, and 120 min), lymphocyte to monocyte ratio (60 min, 90 min, 120 min, 2 h, 12 h, and 24 h), platelet-to-albumin ratio (90 min), lymphocyte percentage × serum albumin concentration (LA; 60 min, 90 min, 120 min, 2 h), and neutrophil × platelet (6 h). LTB4 concentrations were significantly increased (p &amp;lt; 0.05) at 60 and 90 min, and 2, 6, and 48 h after seizure induction. PGE2 was significantly increased only 6 h after seizure induction (p &amp;lt; 0.05). LA was one of the HIPs that demonstrated a correlation with LTB4 concentration and showed significant changes that could be observed for a long-period (p &amp;lt; 0.05, r = −0.4194).ConclusionThe LA was the only HIP that reflected seizure-associated neuroinflammation. The 5-lipoxygenase pathway might be related to seizure-associated neuroinflammation.

Elevated IL-6 Expression in Autologous Adipose-Derived Stem Cells Regulates RANKL Mediated Inflammation in Osteoarthritis

Interleukin-6 (IL-6) expression in mesenchymal stem cells (MSCs) has been shown to play a pivotal role in modulating cartilage regeneration and immune responses, particularly in the context of diseases that involve both degenerative processes and inflammation, such as osteoarthritis (OA). However, the precise mechanism through which IL-6 and other immune-regulatory factors influence the therapeutic efficacy of autologous adipose-derived stem cells (ASCs) transplantation in OA treatment remains to be fully elucidated. This study aims to investigate the relationship between IL-6 expression in autologous ASCs isolated from OA patients and their impact on immune modulation, particularly focusing on the regulation of Receptor Activator of Nuclear factor Kappa-Β Ligand (RANKL), a key mediator of immune-driven cartilage degradation in OA. Autologous ASCs were isolated from the stromal vascular fraction (SVF) of adipose tissue obtained from 22 OA patients. The isolated ASCs were cultured and characterized using reverse transcription polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA), and flow cytometry to the phenotype and immune regulatory factors of MSCs. Based on IL-6 expression levels, ASCs were divided into high and low IL-6 expression groups. These groups were then co-cultured with activated peripheral blood mononuclear cells (PBMCs) to evaluate their immune-modulatory capacity, including the induction of regulatory T cells, inhibition of immune cell proliferation, and regulation of key cytokines, such as interferon-gamma (IFN-γ). Additionally, RANKL expression, a critical factor in osteoclastogenesis and cartilage degradation, was assessed in both ASC groups. High IL-6-expressing ASCs demonstrated a significantly greater capacity to inhibit immune cell proliferation and IFN-γ production compared to their low IL-6-expressing counterparts under co-culture conditions. Moreover, the group of ASCs with high IL-6 expression showed a marked reduction in RANKL expression, suggesting enhanced potential to control osteoclast activity and subsequent cartilage defect in OA. Conclusion: Autologous ASCs with elevated IL-6 expression exhibit enhanced immunomodulatory properties, particularly in regulating over-activated immune response and reducing osteoclastogenesis through RANKL suppression. These findings indicate that selecting ASCs based on IL-6 expression could enhance the therapeutic efficacy of ASC-based treatments for OA by mitigating immune-driven joint inflammation and cartilage degradation, potentially slowing disease progression.

Association Between Peripheral Blood Regulatory T Cell Content with Inflammatory Stress Response and Immune Response in Children with Sepsis.

The study aims to analyze the correlation between Regulatory T(Treg) Cells and inflammatory stress response and immune response in sepsis patients. Sixty sepsis patients admitted between January 2021 and June 2023 were selected as the subjects and included in the observation group. During the same period, 80 healthy children who underwent physical examinations in the hospital were included in the control group. The Treg content, inflammatory mediators, and immune response biochemical indicators of two groups are compared. The Pearson correlation analysis verifies the correlation between Treg content and inflammatory stress response, and immune response. Treg content in the observation group exceeded that found in the control group (P < 0.05). Among the relevant biochemical indicators, Tumor Necrosis Factor-α (TNF-α), Interleukin-1β (IL-1β), Interleukin-6 (IL-6), Procalcitonin (PCT), and Hypersensitive C-reactive protein (hs-CRP) exceeded that found in healthy children (P < 0.05). The immunoglobulin IgA, IgM, and IgG in healthy children were below respective values in the control group (P < 0.05). The Pearson correlation data demonstrated that the peripheral blood Treg content in children with sepsis was positively related to inflammatory mediator indicators. It was negatively related with the immunoglobulin IgA, IgM, and IgG. In summary, when the Treg content in the peripheral blood of sepsis patients increases, it directly affects the body's inflammatory stress response and immune function.

REGγ-mediated Barrier Disruption and NF-κB Activation Aggravates Intestinal Inflammation in Necrotizing Enterocolitis.

Necrotizing enterocolitis (NEC) stands as the most prevalent and severe gastrointestinal ailment affecting premature newborns, particularly those with extremely low birth weights. Intestinal barrier dysfunction emerges as a crucial factor in NEC's pathogenesis. REGγ predominantly manifests in the intestinal epithelium and has shown to regulate experimental colitis. However, the potential correlation between REGγ and NEC remains ambiguous. This study reveals that REGγ is notably overexpressed in both human and murine NEC samples. REGγ-deficient mice displayed improvements in intestinal mucosal inflammation and reduced NEC severity. Additionally, REGγ deficiency notably lowered the expression of phosphorylated transcription factor p65 and inflammatory factors in intestinal epithelial cells of NEC-afflicted mice. REGγ exacerbates the local inflammation by triggering the degradation of IκBɛ, a negative regulator of NFκB. Clinically, REGγ and p65 expression levels exhibit a positive correlation in NEC specimens. Moreover, pre-treatment of mice with a p65 inhibitor effectively suppressed the expression of inflammatory mediators and alleviated REGγ-mediated NEC development. These findings underscore that abnormal upregulation of REGγ triggers NEC development by enhancing NF-κB activity and exacerbating epithelial barrier dysfunction. Thus, novel therapeutic approaches targeting REGγ inhibition may offer enhanced treatment for NEC.

Современные представления о моногенных аутовоспалительных заболеваниях

Autoinflammatory diseases (AIDs) are a group of rare disorders characterized by recurrent episodes of inflammation with neither infectious nor autoimmune nor neoplastic trigger. The AIDs pathogenesis is based on mutations in genes that lead to uncontrolled and excessive production of proinflammatory cytokines. Authors represent current views on the pathogenesis, clinical manifestations, diagnosis and treatment of the most studied monogenic AIDs. New therapeutic approaches based on targeted blockade of key inflammatory mediators are described as well.

Lentiviral Injection of Inter-α-Trypsin Inhibitor Heavy Chain 4 Promotes Female Spinal Cord Injury Mice Recuperation by Diminishing Peripheral and Central Inflammation.

Inter-alpha-trypsin inhibitor heavy chain H4 (ITIH4) acts as a mediator of inflammation and extracellular matrix stabilization. The current study intended to delve into the impact of ITIH4 on locomotor performance, nerve injury, neuroinflammation, systemic inflammation, and the downstream pathway in spinal cord injury (SCI) mice. Overexpression lentivirus of ITIH4 (LV-ITIH4) and negative control lentivirus (LV-NC) were intravenously injected into adult C57BL/6 mice on 7days before SCI surgery. All mice were euthanized on day 28 after SCI surgery, and their blood samples and spinal cord tissues were collected. Decreased relative gene expression and protein levels of ITIH4 were observed in SCI mice. LV-ITIH4 improved the locomotor performance compared to LV-NC in SCI mice. In spinal cord of SCI mice, LV-ITIH4 reduced apoptosis and increased survival of neurons compared to LV-NC. By comparison with LV-NC, LV-ITIH4 also reduced relative gene expressions of interleukin (IL)-6 and tumor necrosis factor-α in spinal cord of SCI mice. Moreover, LV-ITIH4 reduced microglia M1 polarization compared with LV-NC in spinal cord of SCI mice. In the serum, LV-ITIH4 decreased the protein levels of IL-6 and IL-1β compared to LV-NC in SCI mice. LV-ITIH4 also inhibited the nuclear factor kappa-B (NF-κB) pathway compared to LV-NC in spinal cord of SCI mice. ITIH4 enhances locomotor performance in SCI mice, and it inhibits nerve injury, neuroinflammation, systemic inflammation, and the NF-κB pathway in SCI mice.

Combined bisoprolol and trimetazidine ameliorate arsenic trioxide -induced acute myocardial injury in rats: targeting PI3K/GSK-3β/Nrf2/HO-1 and NF-κB/iNOS signaling pathways, inflammatory mediators and apoptosis

Background Arsenic-trioxide (ATO) is an effective therapy for acute promyelocytic leukemia. Unfortunately, its utility is hindered by the risk of myocardial injury. Both bisoprolol (BIS) and trimetazidine (TMZ) have various pharmacological features, including anti-oxidant, anti-inflammatory, and anti-apoptotic properties. Aim The cardioprotective effects of BIS and TMZ were studied, and their mechanistic role in ameliorating ATO-induced myocardial injury. Materials and Methods Forty male Wistar rats were randomly allotted into five groups as follows: normal control group (received normal saline, orally), ATO group (7.5 mg/kg, orally), BIS (8 mg/kg, orally), TMZ (60 mg/kg, orally), and finally combination group (BIS+TMZ+ATO). Following 21 days, samples of serum and cardiac tissues were obtained to perform biochemical, molecular, and histopathological investigations. Results The present study showed that ATO caused myocardial injury evidenced by changes in serum biomarkers (Aspatate aminotransferase, alanine aminotransferase, alkaline phosphatase, lactate dehydrogenase, creatine kinase-MB, and cardiac troponin-1), electrolyte imbalance, and lipid profiles alongside histopathologic changes. In addition, ATO administration significantly elevated malondialdehyde, nicotinamide adenine dinucleotide phosphate hydrogen oxidase, myloperoxidase, total nitrite, inducible nitric oxide synthase, tumor necrosis factor-alpha, interleukin-1β, interleukin-6, 8-Hydroxy-2’-deoxyguanosine, nuclear factor NF-kappa-B p65 subunit, glycogen synthase kinase-3 beta, and caspase-3 expression contemporaneously with down-regulation of reduced glutathione, glutathione peroxidase, superoxide dismutase, catalase, heme oxygenase 1, nuclear factor erythroid 2–related factor 2, phosphatidylinositol-3 kinase, p-PI3K, and Bcl-2 expression. Interestingly, pretreatment with BIS and TMZ significantly reversed the detrimental effects of ATO-induced myocardial injury at both cellular and molecular levels. Otherwise, combining the two drugs displayed more enhancement than each drug alone. Conclusion The present research depicted that BIS and TMZ have the potential to protect the heart and provide therapeutic benefits by preventing acute heart injury induced by ATO. This is achieved by reversing the redox-sensitive pathway, reducing inflammation, and inhibiting apoptosis.

Quercetin alleviates ulcerative colitis through inhibiting CXCL8-CXCR1/2 axis: a network and transcriptome analysis

IntroductionUlcerative colitis (UC) is a chronic inflammatory condition of the intestinal tract in which mucosal healing is a crucial measure of therapeutic efficacy. Quercetin, a flavonoid prevalent in various foods and traditional Chinese medicines, exhibits notable pharmacological properties, including antioxidant and anti-inflammatory activities. Consequently, it warrants investigation to determine its potential therapeutic effects on UC. The objective of this study was to investigate the effects and underlying mechanisms of quercetin in a murine model of UC.MethodsA comprehensive approach integrating network predictions with transcriptomic analyses was employed to identify the potential targets and enriched pathways associated with quercetin in UC. Subsequently, the effects of quercetin on pathological morphology, inflammatory mediators, and mucosal barrier-associated proteins, as well as the identified potential targets and enriched pathways, were systematically investigated in a murine model of dextran sulfate sodium (DSS)-induced UC.ResultsNetwork analyses identified CXCL8 and its receptors, CXCR1 and CXCR2, as primary target genes for therapeutic intervention in UC. Further validation through transcriptomic analysis and immunofluorescence staining demonstrated significant upregulation of the CXCL8-CXCR1/2 axis in the intestinal tissues of patients with UC. Experimental investigations in animal models have shown that quercetin markedly alleviates DSS-induced symptoms in mice. This effect includes the restoration of colonic crypt architecture, normalization of goblet cell structure and density, reduction of inflammatory cell infiltration, and decreased concentrations of inflammatory mediators. Quercetin enhanced the expression of tight junction (TJ) proteins, including ZO-1, MUC2 (Mucin 2), and occludin, thereby preserving the integrity of the intestinal mucosal barrier. Additionally, it significantly diminished the levels of IL-17A, NF-κB, CXCL8, CXCR1, and CXCR2 in the colonic tissues of mice with UC.DiscussionThe ameliorative effects of quercetin on colon tissue damage in DSS-induced UC mice were significant, possibly due to its ability to inhibit the CXCL8-CXCR1/2 signaling axis. These findings provide a solid foundation for the clinical application and pharmaceutical advancement of quercetin.

Treatment of cancer-associated fibroblast-like cells with celecoxib enhances the anti-cancer T helper 1/Treg responses in breast cancer.

Tumor inflammation, as one of the hallmarks of cancer, has been the target for anti-cancer treatments. Celecoxib is a selective inhibitor of the enzyme cycloxygenase-2 (COX-2) and inhibits the production of PGE2, which is an important mediator of tumor inflammation produced by cancer cells and cells of the tumor microenvironment. In this study, we aimed at inhibiting COX-2 using celecoxib, expressed in cancer-associated fibroblast (CAF)-like cells isolated from breast cancer and evaluated the alterations in their cytokine profile and gene expression. CAF-like cells were isolated by explant culture from 13 breast cancer tissues. Simultaneously, peripheral blood mononuclear cells (PBMCs) were isolated from patients' blood. CAF-like cells were treated with 10µM of celecoxib and expression of genes COX-2, smooth muscle actin-alpha (α-SMA), and production of prostaglandin E2 (PGE2), Interleukin 10 (IL10), and transforming growth factor beta1 (TGF-β1) was evaluated. Next, PBMCs were co-cultured with celecoxib-treated CAF-like cells and the expression of genes T-bet, Foxp3, GATA-3; production of cytokines IFN-ɣ, IL-10, IL-4, TGF-β1, and the mediator PGE2 were assessed by real-time-PCR and ELISA, respectively. Isolated CAF-like cells showed expression of fibroblast activation protein (FAP). Treatment with celecoxib was able to efficiently reduce the production of PGE2 and the expression of α-SMA in isolated CAF-like cells. Furthermore, PBMCs in co-culture with these cells showed enhanced Th1 phenotype including T-bet and IFNγ expression and decreased the phenotypical markers of regulatory T cells such as FoxP3 and IL-10 and TGF-β1 production. Our study shows the important role of COX-2 in CAFs by promoting immune suppression. Our results suggested that high expression of COX-2 in CAFs may serve as a new therapeutic, targeting CAFs in enhancing immune responses in breast cancer treatment.