IL-8 Levels Research Articles

Variations in inflammatory regulators in male patients with chronic schizophrenia associated with psychopathology and cognitive deficits.

Immune dysregulation has been identified as a contributing factor in the pathophysiology of schizophrenia. This study aimed to investigate variations in specific immune regulators and their correlation with psychopathology and cognitive functions in male patients with chronic schizophrenia. Employing a cross-sectional design, this study included 72 male patients with chronic schizophrenia. The Positive and Negative Syndrome Scale (PANSS) and the Repeatable Battery for the Assessment of Neuropsychological Status were utilized to assess psychopathology and cognitive functions, respectively. Serum levels of interleukin (IL)-4, IL-10, IL-12p40, IL-13, and monocyte chemoattractant protein-1 (MCP-1) were measured. There were significantly increased levels of IL-4, IL-13, and MCP-1, alongside decreased levels of IL-10 in patients compared to controls (all P < 0.05). IL-4 levels showed a significant negative association with PANSS positive symptoms (beta=-0.222, P = 0.042). After controlling for antipsychotic medication, BMI, and smoking, this correlation was no longer significant (r=-0.232, P = 0.055). Additionally, positive correlations of IL-4 (beta = 0.297, P = 0.008), IL-13 (beta = 0.371, P = 0.001), and MCP-1 (beta = 0.280, P = 0.013) with language scores were observed. Increased levels of IL-4 (P = 0.044, OR = 1.994), IL-13 (P = 0.019, OR = 2.245), as well as IL-4 and MCP-1 interactions (P = 0.043, OR = 2.000) were positively associated with the risk of chronic schizophrenia, while lower levels of IL-10 (P = 0.003, OR = 0.2.867) were also linked to an increased risk. The identified associations between specific immune markers and the clinical and cognitive features of chronic schizophrenia in males underscored the potential immune-mediated mechanisms underlying schizophrenia.

Impact of antiplatelets, anticoagulants and cyclic nucleotide stimulators on neutrophil extracellular traps (NETs) and inflammatory markers during COVID-19.

While the association between coronavirus disease-19 (COVID-19) and neutrophils extracellular traps (NETs) is recognized, uncertainties remain regarding its precise onset, timing of resolution and target therapy. To assess changes in inflammatory and NET markers during the first week of COVID-19 hospitalization, and the association with disease severity. "In vitro" experiments investigated the effect of antiplatelets, anticoagulants, and cyclic nucleotide stimulators on NETs release. Prospective cohort study, changes in interleukin (IL)-6, IL-8, IL-17, TNF-α, RANTES, PF4, and citrullinated-H3 (citH3) levels within each outcome group was evaluated using ANOVA. Differences between moderately ill, critically ill, and non-survivors were determined using Kruskal-Wallis and logistic regression. Healthy neutrophils were stimulated with phorbol-12-myristate-13-acetate (PMA) or COVID-19 sera and treated with unfractionated heparin (UFH), low molecular weight heparin (LMWH), aspirin (ASA), ticagrelor, cinaciguat, sildenafil, and milrinone. The proportion of NETosis was assessed using IncuCyte Cell Imager. Of the 125 patients, 40.8% had moderate COVID-19, 40.8% had critical COVID-19 but recovered, and 18.4% died. From admission to hospitalization day 8, IL-6 levels decreased in moderately and critically ill, but not in non-survivors, while citH3 levels increased in critically ill and non-survivors. IL-6, IL-8, and TNF-α levels were associated with critical and fatal COVID-19. The release of NETs by neutrophils stimulated with PMA or COVID-19 sera was decreased in the presence of ASA, UFH, LMWH and cyclic nucleotide stimulators in a dose-dependent manner. In the first week of hospitalization, NET markers rose later than inflammatory markers in severe COVID-19 cases. Cyclic nucleotide stimulators, ASA and heparin may emerge as treatment approaches as they may modulate NETosis.

Pristimerin Alleviates DSS-Induced Colitis in Mice by Modulating Intestinal Barrier Function, Gut Microbiota Balance and Host Metabolism.

Pristimerin is a pentacyclic triterpenoid mainly derived from Celastraceae plants such as Maytenus ilicifolia, which has been traditionally used for the treatment of gastrointestinal disorders. Pharmacological studies have shown that pristimerin exhibited anti-inflammatory, antioxidant, anticancer and antibacterial activities. However, the potential mechanism of pristimerin for the treatment of ulcerative colitis (UC) remains elusive. In the present study, pristimerin could effectively inhibit the NO generation induced by LPS in RAW 264.7 cells and upregulate the decreased expression of tight junction proteins such as occludin and claudin-1. In vivo, oral administration of pristimerin (0.5 mg/kg and 1 mg/kg) could significantly relieve UC symptoms such as body weight loss, disease activity index, shortened colon length and colonic pathological damage. Meanwhile, pristimerin decreased the TNF-α, MPO and MDA levels and increased the levels of IL-10, IL-22, SOD activity, occludin and claudin-1 in colon tissues. Gut microbiota analysis of cecum contents revealed that pristimerin treatment effectively alleviated gut microbiota dysbiosis. Additionally, serum metabolomics showed that 33 potential biomarkers involving lipid and tryptophan metabolism were identified, which may account for the therapeutic effects of pristimerin on UC mice. In conclusion, our findings indicate that pristimerin attenuates UC symptoms in DSS-induced mice through modulating intestinal barrier integrity, gut microbiota composition, lipid and tryptophan metabolism.

Real-world predictors of dupilumab prescription in patients with chronic rhinosinusitis with nasal polyps.

Despite increasing dupilumab use for chronic rhinosinusitis with nasal polyps (CRSwNP), little is known about the factors influencing its use in real-world practice. We aimed to identify factors that may predict dupilumab prescription in CRSwNP patients who have undergone endoscopic sinus surgery (ESS). A single-institution, retrospective cohort study of patients who underwent ESS for CRSwNP between 2015 and 2023 was conducted. Demographics, comorbidities, 22-item sinonasal outcome test (SNOT-22) scores, and dupilumab prescription date were extracted from patient records. Intraoperative nasal mucus cytokine levels were measured using a multiplex bead assay. Univariate logistic regression analysis was performed to identify factors associated with dupilumab prescription, and multivariate logistic regression was used to adjust for surgery date. A total of 299 CRSwNP patients were included, including seventy (23.4%) who were prescribed dupilumab postoperatively. Patients were more likely to be prescribed dupilumab if they had asthma (odds ratio [OR] 2.304), aspirin-exacerbated respiratory disease (AERD, OR 3.375), elevated tissue eosinophils (OR 1.005), and higher 3-month postoperative SNOT-22 scores (OR 1.027). Patients prescribed dupilumab also had greater odds of having elevated mucus interleukin (IL)-5 (OR 1.128) and IL-13 (OR 1.213). When adjusting for surgery date, associated factors included: asthma (OR 2.444), AERD (OR 3.750), allergic rhinitis (OR 1.833), higher tissue eosinophils (OR 1.005), elevated 3-month SNOT-22 scores (OR 1.028), and higher IL-5 (OR 1.123) and IL-13 (OR 1.202) levels. Asthma, AERD, allergic rhinitis, and elevated tissue eosinophil, IL-5, and IL-13 levels are predictive of dupilumab prescription in CRSwNP patients. These may serve as clinical and inflammatory biomarkers and can aid in counseling patients about expected disease trajectory.

Hydrocortisone improves post-resuscitation myocardial dysfunction by inhibiting the NF-κB pathway.

Myocardial dysfunction is a major cause of early mortality after successful cardiopulmonary resuscitation (CPR) following cardiac arrest (CA). Following the return of spontaneous circulation, myocardial ischemia-reperfusion injury can activate the NF-κB pathway, leading to the transcription of inflammatory genes that impair myocardial function. While clinical studies show hydrocortisone (HC) improves outcomes in CA patients during CPR, its specific role in modulating the NF-κB pathway is unclear. In this study, we established an in vitro model by inducing hypoxia/reoxygenation (H/R) injury in H9C2 cardiomyocytes using Na2S2O4, followed by HC treatment. The results showed that HC treatment of H/R-injured cardiomyocytes promoted proliferation, inhibited apoptosis, and suppressed the NF-κB pathway, thereby reducing IL-6, IL-8, and TNF-α levels. Moreover, inhibition of the NF-κB pathway enhanced the proliferative capacity of H/R cardiomyocytes, decreased apoptosis rates, and reduced IL-6, IL-8, and TNF-α expression levels, with these effects being further amplified by HC treatment. These findings were further supported by in vivo experiments. In conclusion, our study suggests that HC may promote H/R cardiomyocyte proliferation, inhibit apoptosis, and alleviate inflammatory responses by suppressing the NF-κB pathway, providing new evidence to support its potential clinical application in CA management.

Abstract A034: Addressing the challenge of pre-analytical variables in circulating protein biomarker analysis for liquid biopsy

Abstract While liquid biopsy using plasma proteins is a promising avenue for early cancer detection, diagnosis, prognosis, and disease monitoring, the clinical translation of plasma proteomics has been limited due to the complexity of the proteome and the impact of pre-analytical variation on its integrity. In recent years, advancements in plasma proteomic technologies, such as Olink, have helped address the challenge of proteome complexity. However, challenges with pre- analytical variables have persisted. During blood collection and whole blood storage, ex vivo blood cell activation and lysis can occur, releasing proteins into the plasma and obscuring relevant in vivo abundances. This is especially true for cancer where many key biomarkers are expressed in white blood cells and platelets. To address these issues, Streck developed Protein Plus BCT, which stabilizes blood cells and minimizes plasma proteome changes following prolonged whole blood storage. To demonstrate its functionality and compatibility with Olink assays, blood was collected from 5 donors into EDTA, ACD-A, and Protein Plus BCT. Plasma was isolated at draw time (&amp;lt; 2 hours) and following 24, 72, and 120 hours of ambient whole blood storage using a double spin protocol (per Instructions for Use). Plasma samples were analyzed using an Olink Explore 384-plex panel. After just 24 hours of whole blood storage, plasma isolated from EDTA or ACD-A had 4.2 and 2.2 times more proteins that are significantly elevated in abundance relative to draw time, respectively, than plasma isolated from Protein Plus BCT. For the key cancer biomarker IL-8, which is associated with worse clinical outcomes and poor response to immunotherapy, Protein Plus BCT maintains draw-time levels such that the mean NPX difference relative to draw time never exceeds -0.18, or a 0.88-fold change for up to 120 hours. Comparatively, samples collected into EDTA and ACD-A show dramatic increases in IL-8 levels with mean NPX differences of 6.34 and 6.62, respectively, corresponding to 80.1- and 98.3-fold increases after 120 hours of whole blood storage. For Galectin-3, an inflammatory biomarker elevated in many cancer types (i.e., lung, breast, and ovarian), the mean NPX difference relative to draw time for samples drawn into EDTA is 1.46 after 24 hours and increases to 2.27 after 120 hours of whole blood storage (a 2.75-fold and 4.8-fold increase, respectively). In samples collected into Protein Plus BCT, the mean NPX difference, relative to draw time, for Galectin-3 never exceeds 0.05 (a 1.04-fold increase) even after 120 hours of whole blood storage. Taken together, these data suggest that Protein Plus BCT extends the storage of whole blood at ambient temperature without compromising the integrity of the sample or the proteomic results, providing researchers and assay developers valuable flexibility in the transport, storage, and processing of their samples. Protein Plus BCT is for Research Use Only. Not for use in diagnostic procedures. Protein Plus BCT should only be used for research or the development of new assays. Citation Format: Rachel M Miller, Jing Li. Addressing the challenge of pre-analytical variables in circulating protein biomarker analysis for liquid biopsy [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr A034.

Longitudinal Follow-up Reveals Peripheral Immunological Changes Upon Tick Bite in a-Gal-Sensitized Individuals.

α-Gal syndrome is characterized by specific IgE (sIgE) antibodies to the carbohydrate galactose-α-1,3-galactose (α-Gal) and delayed onset of allergic symptoms after ingestion of mammalian meat. While tick bites are assumed to mediate sensitization, the immune response to tick bites has not yet been investigated. To investigate the peripheral immune response to tick bites in humans over time. In a longitudinal cohort study, immunological reactions associated with tick bites (Ixodes species) were analyzed within 1 day (V1), 2 weeks (V2), 1 month (V3), and 3 months (V4) after the occurrence of a bite. sIgE, sIgG, and sIgG subclass levels, as well as 10 cytokines, were quantified. Deep immune phenotyping was performed using mass cytometry. A total of 4 controls and 10 patients were bitten by a tick and followed up over 3 months. None of the controls developed sIgE to α-Gal, and sIgE increased in all patients from V1 until V2/V3, as did IL-8 levels. We noted a significant increase in CD19+ B cells and B-cell subpopulations, as well as a decrease in γδ CD56+ T cells in patients between V0 and V1. At V1, frequencies of plasmacytoid dendritic cells (pDCs) and γδ CD56+ T cells were lower in patients than in controls. Our study provides evidence of significant changes in several immune cell populations in α-Gal sensitized patients, along with increased levels of IL-8 and sIgE. This is the first exploratory study to investigate longitudinal peripheral immune profiles in patients and controls bitten by ticks.

Effect of Epstein-Barr virus on macrophage M2/M1 migration and EphA2 expression in adverse drug reactions.

This study aims to investigate the effect of Epstein-Barr virus (EBV) reactivation or EBV reactivation with dexamethasone (DXM) in patients with adverse drug reactions (ADRs) through evaluating the levels of monocyte, macrophage M2/M1, and cytokines, and investigating whether expression of EBV receptor EphA2 could specifically influence EBV activation in ADRs. We performed a prospective longitudinal study to analyze the monocytes, macrophages, M2/M1 ratio, and cytokines, including interleukin (IL)-4, IL-13, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, IFN-β, C-X-C motif chemokine ligand (CXCL)9, and CXCL10, in patients with maculopapular exanthema (MPE) and Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), and control groups after disease onset. Skin biopsy samples from these patients were subjected to hematoxylin and eosin (H&E) staining to examine tissue architecture and inflammatory cell infiltration, as well as Epstein-Barr virus-encoded RNA (EBER) staining to detect the presence of EBV within the skin lesions. Peripheral blood mononuclear cells collected from these patients were co-cultured with EBV or EBV combined with DXM to assess the impact on monocytes, macrophages, the M2/M1 ratio, and the associated cytokine profile. Furthermore, we sought to identify which cytokines might be crucial in mediating the interaction between the M2/M1 ratio and EBV. EPhA2 expression was evaluated to determine its role in the reactivation of EBV and its correlation with increased viral load in MPE and SJS/TEN patients. Selective depletion of macrophages occurred during the acute stage of SJS/TEN, while a shift towards M2 macrophages was observed in MPE. Both IFN-β and CXCL9 levels were elevated in MPE and SJS/TEN. Additionally, our study demonstrated the presence of EBV in the skin lesions of SJS/TEN and MPE patients through H&E and EBER staining, confirming EBV's involvement in these conditions. Activation of EBV and EBV combined with DXM led to a shift from M1 to M2 macrophages, accompanied by increased levels of IL-4, IFN-γ, and CXCL9 in MPE and SJS/TEN, compared to healthy individuals. Specifically, EBV combined with DXM primarily drove IFN-γ and IL-4 expansions in MPE, while CXCL9 was predominantly elevated in SJS/TEN. The increased IL-4 levels were associated with the relative rise in EBV viral loads after EBV combined with DXM stimulation. Furthermore, EphA2 expression in monocytes was significantly higher in SJS/TEN and MPE patients compared to controls, with further increases on EBV stimulation. This elevation in EPhA2 correlated with increased EBV viral load, particularly in MPE and SJS/TEN patients. The gradual shift from M1 to M2 cell development observed during the clinical course of MPE and SJS/TEN is mediated by the predominance of EBV and EBV with DXM at the acute stage, leading to elevated IL-4, IFN-γ, and CXCL9 levels, which may exacerbate allergic reactions. The elevation in EPhA2 correlated with increased EBV viral load, particularly in MPE and SJS/TEN patients, suggesting that adverse drug reactions may induce EPhA2 expression, facilitating EBV replication and activation. EphA2 could thus serve as an indicator of EBV activation and a marker for assessing the risk of EBV in patients with adverse drug reactions.

Genetic association of missense (rs2919643), intergenic (rs2057178) and a 3'UTR (rs1009170) variant with tuberculosis: A replication study from India.

To investigate host genetic susceptibility to tuberculosis (TB), we conducted a replication study focussed on candidate SNPs, previously reported to be associated with TB. We examined nine candidate SNPs and genotyped them in an independent cohort of TB cases and household contacts from West Bengal, India. The association with TB was replicated for rs2919643 (Chr 18), rs2057178 (Chr 11) and rs1009170 (Chr 14). rs2919643-C (p = 8.81E-5) was a risk allele and rs2057178-A (p = 0.04188) was protective against TB in our population. Association of rs1009170; previously reported by us with TB was also replicated in the new set of samples (p = 0.0359). rs2919643 is a missense variant present in linkage disequilibrium with a TB associated synonymous SNP rs61104666. The risk genotype rs2919643-CC was associated with higher levels of plasma RANTES and IL5 in household contacts. rs2919643 is an eQTL for an immunosuppressive gene SIGLEC15 and autophagy related gene EPG5. rs2057178 is an eQTL for a pseudogene and present within weak enhancer marks in the lungs. The genomic locus around this SNP rs1009170 encompasses an active transcription factor peak in CD14+ monocytes and also serves as an eQTL for NDUFB1, ATXN3 and SLC24A4. TB cases with rs1009170-TT genotype showed lower expression of plasma RANTES compared to the heterozygote. All three associated SNPs have putative regulatory role in lungs and immune associated cells and organs which may be relevant to TB pathogenesis.

The Clinical and Molecular Response of Pyoderma Gangrenosum to Interleukin 23 Blockade: Result from a proof-of-concept open-label clinical trial.

Pyoderma Gangrenosum is a severe ulcerative disease with a great need for novel therapies. A major barrier to the development of novel therapies is a lack of understanding of disease pathogenesis. We present the results of a proof-of-concept open label clinical trial of IL-23p19 antagonism with Tildrakizumab ion Pyoderma Gangrenosum. Gene expression analysis identified pro-inflammatory genes associated with interferon responses and dendritic cell activity including IFI27, XBP1, SAA1 LGALS3 and STAT3 significantly downregulated in lesional tissue after 12 weeks of therapy. Immunohistochemistry confirmed reduction in IL-17A and IL-17 F positive cells as well as reduction in TNF-a, C5a and IL-1B positive cells in week 12 samples compared to baseline. Significant reduction in serum inflammation was observed via serum proteomics, with IL-8, IL-6, and CASP-8 levels reduced comparable to healthy controls at Week 12. Clinical outcomes demonstrated significant reduction in ulcer size, pain, itch and quality of life outcomes in line with the molecular findings. Differential expression of key inflammatory cytokines such as IL-8, CXCL5, PD-L1, SPP1 and MMP1 were observed in tissue and serum when stratified by clinical responders and non-responders. This data provides insights into the clinical relevance of alterations in molecular markers in pyoderma gangrenosum and the potential for the identification of clinically relevant biomarkers of disease activity.

DEPTOR attenuates asthma progression by suppressing endoplasmic reticulum stress through SOD1.

Endoplasmic reticulum (ER) stress has been shown to play a pivotal role in the pathogenesis of asthma. DEPTOR (DEP Domain Containing MTOR Interacting Protein) is an endogenous mTOR inhibitor that participates in various physiological processes such as cell growth, apoptosis, autophagy, and ER homeostasis. However, the role of DEPTOR in the pathogenesis of asthma is still unknown. In this study, an ovalbumin (OVA)-induced mice model and IL-13 induced 16HBE cells were used to evaluate the effect of DEPTOR on asthma. A decreased DEPTOR expression was shown in the lung tissues of OVA-mice and IL-13 induced 16HBE cells. Upregulation of DEPTOR attenuated airway goblet cell hyperplasia, inhibited mucus hypersecretion, decreased the expression of mucin MUC5AC, and suppressed the level of inflammatory factors IL-4 and IL-5, which were all induced by OVA treatment. The increased protein expression of ER stress markers GRP78, CHOP, unfolded protein response (UPR) related proteins, and apoptosis markers in OVA mice were also inhibited by DEPTOR overexpression. In IL-13 induced 16HBE cells, overexpression of DEPTOR decreased IL-4, IL-5, and MUC5AC levels, preventing ER stress response and UPR process. Furthermore, from the proteomics results, we identified that SOD1 (Cu/Zn Superoxide Dismutase 1) may be the downstream factor of DEPTOR. Similar to DEPTOR, upregulation of SOD1 alleviated asthma progression. Rescue experiments showed that SOD1 inhibition abrogates the remission effect of DEPTOR on ER stress in vitro. In conclusion, these data suggested that DEPTOR attenuates asthma progression by suppressing endoplasmic reticulum stress through SOD1.

Pathophysiology of De Novo Food Allergies After Solid Organ Transplant in Pediatric Patients.

De novo food allergy is a common phenomenon among pediatric solid organ recipients (8.5%-57%) when compared with the general population (0.45%-10%). Other associated disorders include non-IgE-mediated immune reactions and clinical predisposition to asthma and alterations in the oral mucosa. Originally, passive mechanisms (passive transfer of IgE and immune cells) were thought to be responsible for acute, transient cases of food allergies with a previous history of sensitization for a specific allergen in the donor. Recently proposed pathophysiological mechanisms to explain de novo allergies include TH2/B-cell imbalance, regulatory T-cell (Treg) disruption, gastrointestinal immaturity, and altered gastrointestinal permeability. Recent studies also suggest that immunosuppressive drugs, especially tacrolimus, promote naïve T-cell differentiation into TH2 cells, IgE-promoting cytokine production, decreased IL-5 and IL-10 levels, increased IgA levels, and Treg disruption. Such immunological interactions, in conjunction with altered intestinal permeability, intestinal immaturity in children, history of viral infection, and a personal history of allergies or eczema, are thought to explain most clinical cases of pediatric de novo food allergy after solid organ transplantation reported in the literature. A better understanding of the immunological mechanisms underpinning organ donors and recipients may unveil some of the caveats concerning therapeutic management and improve the quality of life of affected individuals.

Abstract 4134539: Hybrid Cardiomyocyte Targeting Peptide Down-regulates NF-κB Pathway in Human Cardiomyocytes

Introduction: Role of NF-κB driven inflammation leading to heart failure with preserved ejection fraction has received little attention. Our previous in vivo work with cardiac targeting peptide (CTP) in guinea pigs identified suppression of NF- κB pathway by CTP. In the current work we sought to further study the effects of a hybrid version of CTP (hCTP: amino acids at positions 3 and 11 substituted with D-amino acids) on TNF-α mediated NF-κB activation, as well as expression of its downstream inflammatory markers IL-1β and IL-8. Methods: Human cardiomyocytes (CMCs) were transfected using Lipofectamine 3000 with a reporter luciferase plasmid carrying an NF-κB promoter site upstream of the luciferase gene. Cells were treated with various concentrations of hCTP for 24 hours, followed by a TNF-α challenge (20ng/mL), addition of luciferin as substrate, and measurement of luminescence. Cell viability in response to above manipulations was assessed by FACS using live-dead stain. CMCs were treated as above, and cell culture supernatants analyzed for IL-8 levels using human ELISA kit. In another set of experiments, CMCs were transfected with NF-κB reporter plasmid, and after treatment for 24 hours with various concentrations of hCTP, incubated with 10nM angiotensin 2 (Ang2) and 100nM phenylephrine (PE) for 24hrs to assess levels of IL-1β in the cell culture media using an ELISA assay. Results: hCTP inhibited TNF-α mediated NF-κB activation with a dose-response curve, with maximum inhibition with hCTP seen at 10µM concentrations (p&lt;0.001). Treatment with hCTP inhibited the TNF-α induced IL-8 secretion with significant decreases seen even at the 1µM dose. Similarly, secretion of IL-1β production by CMCs in response to Ang2/PE stimulation was suppressed by hCTP even at the lowest tested dose (1µM; p&lt;0.5). Conclusions: Our data suggests that hCTP inhibited NF-κB pathway transcriptional activity in response to TNF-α stimulation in a dose-dependent fashion in human CMCs. Furthermore, treatment with hCTP inhibited TNF-α induced IL-8 and IL-1β secretion even at doses as low as 1µM. The ability of hCTP to efficiently targeting this inflammatory pathway suggests that it has therapeutic potential in the treatment of heart failure. Further in vivo studies are ongoing to test this hypothesis.

Effects of Nigella sativa on disease activity, T lymphocytes and inflammatory cytokine profiles in pediatric systemic lupus erythematosus: A randomized controlled trial

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with diverse manifestations, requiring long-term treatment that can have side effects, particularly in pediatric patients. Nigella sativa (NS) has shown potential for improving SLE symptoms due to its anti-inflammatory and immunomodulatory effects. The aim of this study was to investigate the immunomodulatory effect of N. sativa oil (NSO) on disease activity, T lymphocyte activity and inflammatory cytokine profiles in pediatric SLE patients. A randomized, double-blinded, placebo-controlled clinical trial was conducted at Saiful Anwar Hospital in Malang, Indonesia, from January 2022 to January 2023. Pediatric patients with SLE were randomly assigned to receive either one gram of NSO or a placebo containing starch in capsule form as adjunct therapy alongside their SLE primary treatment. Blood samples were collected before treatment and after eight weeks of daily capsules. Disease activity was assessed using the SLE Disease Activity Index 2000 (SLEDAI-2K); flow cytometry was used to identify T helper lymphocytes, and serum cytokine levels were measured using ELISA. The statistical analysis tests were performed to compare the outcomes between groups at baseline or after the treatment, and within-group comparisons before and after the study period, as appropriate. A total of 32 patients were included in the study. A significant decrease in the SLEDAI-2K score was observed at post-treatment in both the NSO and placebo groups (p&lt;0.001 and p=0.025, respectively). The percentage of T helper 17 (Th17) cells was significantly reduced in both the NSO and placebo groups post-treatment compared to pre-treatment (p=0.026 and p=0.034, respectively). Conversely, the post-treatment percentage of regulatory T (Treg) cells increased significantly in both groups. A significant reduction in interleukin (IL)-2 levels was observed in the NSO and placebo groups at post-treatment compared to pre-treatment (p=0.006 and p=0.046, respectively). Additionally, there were increases in IL-4 and IL-6 serum levels in both groups at post-treatment compared to pre-treatment (p&lt;0.05). This study highlights that although disease activity was not significantly different between NSO and placebo groups, NSO could affect the inflammatory cytokine profiles in pediatric SLE patients.

The Sexual Dimorphism of the Neuroimmune Response in the Brains of Taenia crassiceps-Infected Mice

Background: Helminth infections are associated with cognitive deficits, especially in school-age children. Deworming treatment in heavily infected children improves their short- and long-term memory recall. In mice, intraperitoneal helminth infection with Taenia crassiceps (T. crassiceps) shows sexual dimorphism in terms of the parasite load, immune response, hormone levels, and behavioral changes. We have previously shown poorer short-term memory performance and changes in the concentrations of cytokines and neurotransmitters in the hippocampus, which were replicated in this study. The molecular changes in other brain structures, such as those related to reproduction, are unknown. Methods: Male and female Balb/cAnN mice were chronically infected with T. crassiceps larvae. We determined the peritoneal parasite load and established the presence of cytokines and neurotransmitters in the hippocampus, olfactory bulb, and hypothalamus. Results: The parasite load was higher in female than male infected mice, as expected. In the hippocampus, the neurotransmitters norepinephrine and serotonin increased in males but decreased in females. In contrast, in the olfactory bulb and hypothalamus, the neurotransmitters assessed showed no statistical differences. The cytokine profiles were different in each brain structure. The TNF-α levels in the olfactory bulb and the IL-4 levels in the hippocampus of infected mice were dimorphic; IFN-γ was augmented in both male and female infected animals, although the increase was higher in infected males. Conclusions: The brain responds to peripheral infection with cytokine levels that vary from structure to structure. This could be a partial explanation for the dimorphic behavioral alterations associated with infection, it also demonstrates the synergic interaction between the immune, the endocrine, and the nervous systems.

Impact of IL-8 on survival after TARE in HCC: a comprehensive investigation and external validation from the SORAMIC trial.

In the treatment of hepatocellular carcinoma (HCC) with transarterial radioembolization (TARE), identifying reliable biomarkers for predicting survival outcomes remains a critical challenge. We aimed to address this gap by investigating the significance of serum cytokines associated with inflammation as potential biomarkers for the selection of patients for TARE. Our retrospective study involved 161 patients diagnosed with HCC who underwent Y90 radioembolization at our medical center between 2010 and 2020. Serum samples from a subset of 78 patients were retrospectively analyzed to determine the concentrations of pro-inflammatory cytokines. The results from the prospective SORAMIC trial were used for independent validation. With a median overall survival of 36 weeks (range 4-436), our study showed the strongest correlation between 12-week survival and IL-8 levels before treatment (p < 0.001), while other relevant interleukins, interferon-α2, INF-γ, TNF-α and MCP-1 were not associated with survival. IL-8 levels below the cut-off of 190 pg/mL were significantly associated with increased 12-week and 24-week survival, with hazard ratios of 19.01 (95% CI: 2.29-157.89) and 2.57 (95% CI: 1.05-6.31), respectively (p = 0.006 and p = 0.039, respectively). In the adjusted multivariate analysis, the 190 pg/mL cut-off for IL-8 remained independently associated with 12- (p = 0.011) and 24-week survival (p = 0.039). Similarly, the SORAMIC population showed a strong association between IL-8 levels and 36-week survival (p = 0.03). Our study emphasizes the pivotal role of IL-8 as a valuable parameter, demonstrating its potential for predicting treatment outcomes and assessing liver function in patients with HCC undergoing TARE. The robustness of these findings warrants further validation.

Amyloid beta-induced signalling in leptomeningeal cells and its impact on astrocyte response.

The pathological signature of Alzheimer's disease (AD) includes the accumulation of toxic protein aggregates, mainly consisting of amyloid beta (Aβ). Recent strides in fundamental research underscore the pivotal role of waste clearance mechanisms in the brain suggesting it may be an early indication of early onset AD. This study delves into the involvement of leptomeningeal cells (LMCs), crucial components forming integral barriers within the clearance system, in the context of AD. We examined the inflammatory cytokine responses of LMCs in the presence of Aβ, alongside assessments of LMC growth response, viability, oxidative stress, and changes in vimentin expression. The LMCs showed no changes in growth, viability, oxidative stress, or vimentin expression in the presence of Aβ, indicating that LMCs are less susceptible to Aβ damage compared to other CNS cells. However, LMCs exhibited a unique pro-inflammatory response to Aβ when compared to an LPS inflammatory control, showing an mRNA expression of pro-inflammatory cytokines such IL-6, IL-10 and IL-33 but no changes in IL-1α and IL-1β. Furthermore, LMCs influenced the astrocyte response to Aβ, as conditioned media from Aβ-treated LMCs was observed to downregulate somatic S100β in astrocytes. We also investigated whether the JAK/STAT3 pathway was involved in the Aβ response of the LMCs, as this pathway has been shown to be activated in astrocytes and neurons in the presence of Aβ. JAK/STAT3 activation was assessed through phosphorylated STAT3, revealing that JAK/STAT3 was not active in the cells when in the presence of Aβ. However, when JAK1 and JAK2 were inhibited, cytokine protein levels of IL7, IL10, IL15 and IL33 levels, which had shown alteration when LMCs were treated with Aβ, returned to base levels. This indicates that although JAK1/STAT3 and JAK2/STAT3 are not the direct pathway for Aβ response in LMCs, JAK1 and JAK2 may still play a role in regulating cytokine levels, potentially through indirect means or crosstalk. Overall, our findings reveal that LMCs are resilient to Aβ toxicity and suggest that JAK1/STAT3 and JAK2/STAT3 does not play a central role in the inflammatory response, providing new insights into the cellular mechanisms underlying AD.

IL-33/ST2 Signaling and its Correlation with Macrophage Heterogeneity and Clinicopathologic Features in Human Intrahepatic Cholangiocarcinoma.

IL-33/ST2 signaling plays crucial roles in the development and progression of various human malignancies. However, its significance in intrahepatic cholangiocarcinoma (ICC) still remains unclear. This study aimed to investigate the expression of IL-33/ST2 signaling and its correlations with macrophage heterogeneity and ICC patients' clinicopathologic features. The expression of different phenotype macrophage markers and IL-33/ST2 signalingrelated markers was detected. The correlation between L-33/ST2 signaling and different phenotype macrophage markers as well as ICC patients' clinicopathologic data was evaluated. Massive heterogeneous cancer cells and PAS-positive cells were observed in tumor tissues. CD68-positive cells accumulated in tumor tissues and expression of both M1 phenotype markers and M2 phenotype macrophage markers was higher in tumor samples than para-carcinoma samples. However, M2 phenotype macrophages represented the dominant macrophage population in ICC tissues. Plasma levels of IL-33, ST2, and MIF were evidently enhanced in ICC patients compared to healthy controls. IL-33/ST2 signaling-related markers exhibited a massive increase in tumor samples than para-carcinoma samples. IL-33 and ST2 expression in ICC tissues was positively associated with M1 and M2 phenotype macrophages. Plasma levels of IL-33, ST2, and MIF were correlated with the diameter of tumor lesions, lymph node metastasis, TNM stage, and tumor differentiation degree. Multivariate analysis demonstrated IL-33 expression to exhibit a correlation with the diameter of tumor lesions, lymph node metastasis, and TNM stage. Additionally, there was a relationship observed between ST2, MIF expression, and diameter of tumor lesions plus TNM stage. IL-33/ST2 signaling exhibited a positive relationship with macrophage heterogeneity in ICC tissues, and upregulated levels of IL-33, ST2, and MIF were associated with aggressive clinicopathologic characteristics. These findings may provide promising diagnostic biomarkers and potential therapeutic strategies for ICC patients targeting IL-33/ST2 signaling.

The association of maternal COVID-19-infection during pregnancy on the neonatal immune profile and associations with later diagnosis of neurodevelopmental disorders

Despite the prevalence and significant concern of COVID-19 in maternal and offspring health, little is known about the impact of COVID-19 during pregnancy on newborn immunity and neurodevelopment. This study aimed to examine 1) the relationship between maternal COVID-19 during pregnancy and newborn immune profiles and investigate the 2) associations between specific newborn immune profiles and the risk of subsequent diagnosis of a neurodevelopmental disorder (NDD) among children with prenatal exposure to COVID-19. Newborn dried bloodspots (NBS) from 545 children born at Kaiser Permanente Northern California between January 2020 and September 2021 (460 [223 males, 237 females] to COVID-19-infected [COVID + ] mothers; 85 [45 males, 40 females] to COVID-19-uninfected [COVID-] mothers) were used to profile newborn immune molecules via a 42-plex cytokine/chemokine assay. Among the 460 children born to COVID + mothers, 73 (47 males, 27 females) were later diagnosed with an NDD. In the first set of analyses examining the association between maternal COVID-19 infection during pregnancy and newborn immune profile, the results adjusted for covariates but uncorrected for multiple comparisons showed that newborns of COVID + mothers had significantly higher levels of IL-22 (est. = 0.16, 95 % Cl 0.01, 0.3, p = 0.04) and GM-CSF (estimate [est.] = 0.27, 95 % Cl 0.09, 0.46, p = 0.004) compared to newborns of COVID- mothers. These differences were no longer statistically significant after multiple comparison adjustments. In the second analysis exploring the association between newborn profile and later diagnosis of NDD among newborns born to COVID + mothers, the results adjusted for covariates revealed an association between higher neonatal levels of IL-22 (HR = 0.49, 95 % Cl 0.33, 0.75, p = 0.001) and lower risk of a later diagnosis of an NDD, which remained significant after multiple comparison adjustments (p = 0.04). Other neonatal cytokines/chemokines/growth factors such as sCD40L (HR = 0.7, 95 % Cl 0.57, 0.9, p = 0.009), IP-10 (HR = 0.46, 95 % Cl 0.25, 0.83, p = 0.009), MIG (HR = 0.52, 95 % Cl 0.3, 0.9, p = 0.02), FLT-3L (HR = 0.45, 95 % Cl 0.24, 0.83, p = 0.01), PDGF AB/BB (HR = 0.56, 95 % Cl 0.36, 0.99, p = 0.046), VEGF (HR = 0.57, 95 % Cl 0.34, 0.98, p = 0.04), and IL-4 (HR = 0.48, 95 % Cl 0.26, 0.93, p = 0.03) were no longer statistically significant after multiple comparison adjustments. Despite the imbalance between the number of COVID-19 exposed and unexposed newborns in this study cohort, our novel findings enhance our understanding of the potential impact of maternal COVID-19 infection during pregnancy on the developing neonatal immune system. Our findings highlight the role of immune molecules, beyond those considered to be pro-inflammatory, that may be crucial in maternal and newborn immunity against COVID-19 infection during pregnancy. Furthermore, our results suggest that reduced levels of neonatal immune molecules in newborns of COVID + mothers may be linked to an increased risk of a subsequent diagnosis of an NDD.

Guanxinning for Residual Inflammation of Stable Coronary Artery Disease: A Pilot Randomized Controlled Trial.

Despite statins and other medications central to atherosclerotic cardiovascular disease (ASCVD) secondary prevention, stable coronary artery disease (SCAD) patients remain at significant cardiovascular risk, partly due to residual inflammation risk (RIR). This study aims to assess if adding Guanxinning to standard ASCVD therapy further mitigates RIR in SCAD patients. In a prospective, randomized, single-blind endpoint design, 50 patients with SCAD who received ASCVD standardized treatment strategy were randomly assigned to either take Guanxinning tablets (4 tablets, thrice daily) or no Guanxinning tablets and were followed up for an average of 12weeks. The primary outcomes were changes in inflammation-related indicators, including interleukin-2 (IL-2), IL-4, IL-6, tumor necrosis factor-α (TNF-α), and high sensitivity C-reactive protein (hs-CRP). Compared with the control group, the intervention group showed significantly greater decreases in the levels of IL-2, IL-6, TNF-α, and hs-CRP (all P < 0.05). However, there was no significant difference in the IL-4 level between the two groups (P > 0.05). Compared with the control group, there were also significant improvements in endothelial function-related indicators (vascular endothelial growth factor (VEGF), nitric oxide (NO), and peroxisome proliferator-activated receptor-γ (PPAR-γ)), blood lipid profile (total cholesterol (Tch), low-density lipoprotein cholesterol (LDL-C)), and chest pain related scores (angina and Traditional Chinese medicine syndrome scores) in the intervention group (all P<0.05). There was no significant difference in the triglyceride (TG) and carotid intima-media thickness between the two groups (P<0.05). Compared to the control group, there was no significant difference in the white blood cell line, liver and kidney function, anemia, and bleeding in the intervention group (all P<0.05). The addition of Guanxinning tablets (4 tablets, thrice daily) to the standard treatment strategy for ASCVD was associated with a reduction in the RIR in patients with SCAD and demonstrated good safety.