Elevated IL-6 Research Articles

Diminished salivary cortisol response to mental stress predict all-cause mortality in general population.

To characterize individuals with a diminished salivary cortisol response to mental stress, assess its association with all-cause mortality, and quantify the mediating effects of the most relevant and modifiable factors to identify potential target for prevention. Data from MIDUS II study with a 16-year follow-up, were used to categorize 1129 participants as responders or non-responders based on the existence of increase in salivary cortisol under mental stress. LASSO-logistics analysis identified the most relevant factors. Cox regression models and restricted cubic splines evaluated the prognostic impact. Further analyses examined the mediating effects of identified factors on prognosis. After employing Inverse Probability of Treatment Weighting to adjust for demographic differences between groups, individuals with diminished cortisol responses were found to have higher levels of depressive symptoms (p=0.050), increased inflammation (IL-6, 2.30 [1.41, 3.79] vs. 1.96[1.33, 3.31], p=0.011), and were less likely to regularly exercise (74.3% vs. 79.9%, p=0.030). IL-6 (OR: 1.25 [1.04, 1.52]，p=0.021) and regularly exercising (OR 0.71 [0.51, 0.97], p=0.032) emerged as significant modifiable factors in multivariate analysis. A notable prognostic association of diminished cortisol response with all-cause mortality (HR=1.33 [1.01-1.76], p=0.046) was observed, consistent across various subgroups and supported by non-linear model analysis. Approximately 13% of the mortality risk associated with diminished cortisol response was mediated by increased IL-6 levels (p=0.043). Diminished salivary cortisol response is linked to an increased risk of all-cause mortality, significantly mediated by elevated IL-6. This study offers a new perspective on prognostic prediction while highlighting potential avenues for intervention.

Protective Effect of Nerolidol on Paclitaxel-Induced Reproductive Toxicity in Rats: Oxidative Stress and Inflammation.

Paclitaxel (PAC), derived from Taxus brevifolia, is used to treat solid tumours but causes reproductive toxicity due to oxidative stress, affecting sperm quality and testicular tissue. Nerolidol (NRL), an antioxidant sesquiterpene alcohol, has not been studied for its potential to reduce PAC-induced reproductive damage. This study investigates NRL's ability to mitigate PAC-induced reproductive toxicity in rats. Forty healthy adult male Spraque Dawley rats were randomly divided into four equal groups (Control, PAC, NRL, PAC + NRL). PAC was given intraperitoneally at a dose of 2 mg/kg once a week for 4 weeks. NRL was given orally at a dose of 100 mg/kg/day for 4 weeks. Control group received PAC and NRL vehicles. After 4 weeks, testis tissue samples were collected, and parameters, including oxidants, antioxidants, sperm motility, density, abnormal spermatozoon ratios and cytokines, were measured. PAC administration increased oxidant levels and decreased antioxidant enzyme activities. Nerolidol mitigated these alterations significantly. Similarly, PAC elevated IL-1, IL-6, TNF-α levels and lowered IL-10 levels, these effects attenuated by nerolidol in the PAC + NRL group. In conclusion, it was determined that PAC induces reproductive toxicity through oxidative stress, and NRL demonstrates potential in ameliorating these effects through its antioxidant activity.

Astaxanthin Alleviates Lung Injury by Regulating Oxidative Stress, Inflammatory Response, P2X7 Receptor, NF-κB, Bcl-2, and Caspase-3 in LPS-Induced Endotoxemia.

Sepsis remains the leading cause of multiple-organ injury due to endotoxemia. Astaxanthin (ASTA), widely used in marine aquaculture, has an extraordinary potential for antioxidant and anti-inflammatory activity. Purinergic receptor (e.g., P2X7R) activation is a powerful signaling in the modulation of inflammation. The effect of ASTA was investigated on the regulation of oxidative stress, inflammatory response, apoptotic mediators, and P2X7R expression in the lung injury during lipopolysaccharide (LPS)-induced endotoxemia. Twenty-four rats were blocked into four groups as Control, LPS, ASTA, and LPS + ASTA. LPS was administered by intraperitoneal injection and ASTA by gavage. Blood and lung samples were taken 6 h after the administrations. The methods were ELISA, western blotting, histopathology, and immunohistochemistry. Sepsis was confirmed by the elevations of IL-1β, IL-6, IL-10, and TNF-α levels in bloodstream. Lung injury was determined by histopathological changes. There were increased P2X7R expression, malondialdehyde (MDA), IL-1β, TNF-α, nuclear factor kappa B (NF-κB), and Caspase-3 and decreased B-cell lymphoma 2 (Bcl-2) and glutathione (GSH) in the septic lung tissue (p < 0.05). ASTA treatment improved MDA, GSH, IL-1β, TNF-α, P2X7R, NF-κB, Caspase-3, and Bcl-2 levels and reduced P2X7R immunoreactivity and histological abnormalities in the lung (p < 0.05). The production of pro-inflammatory cytokines, oxidative stress, P2X7R expression, and apoptotic mediators in the lung is associated with LPS-induced endotoxemia. The ASTA administration appears to regulate the expressions of P2X7R, NF-κB, Bcl-2, and Caspase-3 improving the antioxidative and anti-inflammatory response of the lung tissue in sepsis, invivo.

DOP117 Innate lymphoid cells control colitis and intestinal fibrosis via cellular stress response in mice and human

Abstract Background Group 2 innate lymphoid cells (ILC2s) are increased in peripheral blood and intestinal samples from IBD patients and mice with colitis. ILC2s are major producers of type 2 cytokines including IL-5 and IL-13 and growth factor AREG that induce goblet cell hyperplasia and mitigate acute inflammation in the gut. On the other hand, prolonged or uncontrolled ILC2 activation may contribute to chronic inflammation and tissue fibrosis, although the role of ILC2s in stricturing/fibrostenotic Crohn’s disease (CD) has been unknown. In this study, we investigated the function of IRE1a-XBP1 pathway, a regulatory hub of cellular stress response, in colitis and fibrosis in mice and CD patients. Methods We generated conditional knockout Ire1aflo/floxIl5-Cre (Ire1aΔIl5) and Rag-/-Ire1aΔIl5 mice with Ire1a deleted in ILC2s. Dextran sodium sulfate (DSS)-induced and T-cell transfer colitis models were used. Human peripheral ILC2s were collected for flow cytometry and ex vivo stimulations. Results Mouse intestinal ILC2s express high level of Ire1a. The number of ILC2s increased in colon, small intestine (SI), and esophagus of Ire1aΔIl5 mice with elevated proliferation marker Ki67. Additionally, SI and colonic Ire1aΔIl5 ILC2s produced more IL-5, IL-13, and AREG after ex vivo stimulation with IL-33 or IL-25. Consistently, selective IRE1 inhibitor 4u8C enhanced production of IL-13, while selective IRE1 activator IXA4 suppressed IL-13 in sort-purified human ILC2s ex vivo (Figure 1). Bulk RNA-seq of SI Ire1aΔIl5 ILC2s showed reduced Rxrg and elevated fatty acid transport by pathway analysis, which may lead to the increased proliferation and cytokine production in Ire1aΔIl5 ILC2s. Upon DSS challenge, Ire1aΔIl5 mice exhibited milder signs of disease including weight loss, clinical scores as well as colon shortening and histology, which was accompanied by elevations in ILC2-derived cytokines and AREG as well as heightened goblet cell differentiation and mucin production. In contrast, upon adoptive T-cell transfer, Rag-/-Ire1aΔIl5 mice developed worsened chronic colitis and intestinal fibrosis, which was reversed by intraperitoneal injection of neutralizing antibody against IL-13 or AREG. Furthermore, CD patients with intestinal strictures expressed higher level of IL-13 in ILC2s in the blood (Figure 2). Conclusion IRE1a-XBP1 constrains cytokine production by intestinal ILC2s during inflammation. IRE1a deficiency in ILC2s protected against acute colitis with heightened type 2 cytokines and AREG; while loss of IRE1a exacerbated chronic colitis and fibrosis. The presence of CD strictures was associated with elevated IL-13 in peripheral ILC2s . We identified IRE1a and ILC2s as potential biomarkers and therapeutic targets for stricturing CD.

P1045 Treat-smart study: Leveraging individual inflammatory markers for personalized therapy in patients with IBD

Abstract Background Diverse patient responses to treatment challenge the management of inflammatory bowel disease (IBD). This study aims to evaluate if there are differences in the inflammatory mediators among IBD patients and the treatment outcome concerning these variations. Methods This study was conducted in the IBD clinic at AL-Rajhi Hospital, Assiut University. The concentrations of TNF-α and IL-12/23 (p40) were measured in IBD patients and healthy controls using enzyme-linked immunosorbent assay (ELISA) technique. In IBD patients, marker levels were assessed before and after induction of biological therapy to evaluate changes in their levels. Biological therapies were prescribed according to the treatment protocols of the funding entities (such as health insurance). The investigators did not know the levels of inflammatory markers at the time of treatment prescription. Results From May 23, 2023, to July 16, 2024,18 IBD patients were enrolled in this study. Half of the study population were males with a median age of 27 years. The cohort included 16 patients with Ulcerative Colitis and 2 with Crohn’s disease, as shown in table 1. Before enrollment, 9 patients had failed to achieve remission on conventional therapy, and 9 had also failed on both conventional and first-line biological therapies. The analysis of the inflammatory markers at baseline showed significant variation among patients. Third of the patients (6 out of 18) showed only elevation in the TNF- α, one patient had only elevated IL 12/23, and the rest had combined elevation of both markers. Among patients with TNF-α as the predominant pathway, remission was achieved in all patients given anti-TNF-α therapy (5 out of 6 patients). In contrast, one patient with IL12/23–dominant group failed to achieve remission after receiving Ustekinumab. In the same context, another patient with elevated IL-12/23 alone failed to respond after receiving anti-TNF-α treatment. Patients with elevated levels of both TNF-α and IL 12/23 (11 patients) exhibited mixed responses. Among those treated with anti-TNF-α, only 1 achieved remission, while 7 experienced treatment failure. Using Ustekinumab in this subgroup led to remission in only 1 out of 3 cases, as shown in figure 1. Conclusion These results showed that treatment response is significantly influenced by the predominant inflammatory pathway expressed in patients with IBD. Specifically, patients with TNF-α dominant pathway showed a high remission rate with anti-TNF-α therapy. Conversely, non-specific treatments were less effective, emphasizing the importance of targeted therapy. Patients with dual-marker elevation may have better responses by combo therapy or JAK inhibitors. These results may pave the way for tailored treatment for IBD patients.

DOP057 Early serum and faecal cytokines predict clinical outcomes in Acute Severe Ulcerative Colitis: results from PREDICT-UC

Abstract Background Acute severe ulcerative colitis (ASUC) is a medical emergency with variable outcomes. We aimed to evaluate whether early serum and faecal cytokine levels predict treatment response. Methods Serum and stool were collected from patients with ASUC. Steroid-refractory patients received infliximab (IFX, monoclonal antibody to tumour necrosis factor [TNF]) as part of PREDICT-UC (NCT02770040), a multi-centre randomised controlled trial that evaluated escalated infliximab (IFX) dosing.1 Specimens were collected at screening, and if steroid-refractory at days 1 and 3 post-IFX. Response to first IFX dose was assessed by day 7. Interleukin (IL)-6 and TNF levels were quantified using ELISA after clinical study conclusion. Results Within the cohort of 190 patients, 54 were steroid-responsive and 136 steroid-refractory and received IFX. Of the steroid-refractory patients, 85 (62.5%) were IFX responders and 51 (37.5%) were IFX non-responders. 17/136 (12.5%) patients underwent colectomy by 3 months. Steroid response At screening, serum IL-6 was higher in steroid non-responders compared to responders (10.5 pg/mL vs 3.5 pg/mL, P&amp;lt;0.001), whereas faecal IL-6 was similar in both groups (154.7 pg/mL vs 138 pg/mL, P=0.09). Faecal TNF at screening was higher in non-responders compared to responders (48.6 pg/mL vs 14.6 pg/mL, P=0.032). IFX response Serum IL-6 at was higher in IFX non-responders compared to responders at all timepoints (P&amp;lt;0.005); however, this finding was not observed with faecal IL-6. Whilst faecal TNF at screening, days 0 and 1 did not differ between IFX responders and non-responders, median day 3 faecal TNF was suppressed below detection limits (&amp;lt;1.56 pg/mL) in IFX responders compared to 4.4 pg/mL in non-responders (P=0.006, AUC=0.65). Colectomy by month 3 Higher serum IL-6 at screening (P=0.009, AUC=0.71) and day 1 (P=0.002, AUC=0.75) were associated with month 3 colectomy. Similarly, day 3 faecal IL-6 was higher in patients who required colectomy versus those who did not (159.0 pg/mL vs 110.7 pg/mL, P=0.02, AUC 0.69). Median faecal TNF at day 3 post-IFX was 6.3 pg/mL in patients who required colectomy but dropped below detection limit in those who avoided colectomy (P=0.004). Day 3 faecal TNF predicted colectomy (AUC=0.72) with a threshold of ≥7.07 pg/mL on Youden’s index having 50% sensitivity, 89.8% specificity, 43.8% PPV and 91.9% NPV. Conclusion Early serum and faecal cytokines predict outcomes in ASUC. Faecal TNF persistence 3 days after IFX is associated with non-response and colectomy, and might help identify patients who benefit from early IFX re-dosing. IL-6 elevation in non-responders suggests activation of an alternate immune pathway that may benefit from non-TNF-targeted therapy.

Exploring the Different Impacts of Ketamine on Neurotrophic Factors and Inflammatory Parameters in a Cecal Ligation and Puncture-Induced Sepsis Model.

Given ketamine's conflicting impacts on the central nervous system, investigating its effects within an inflammatory context becomes crucial. This study aimed to assess the impact of varying ketamine doses on neurotrophin and inflammatory cytokine levels within the brains of rats submitted to the sepsis model. Wistar rats were submitted to the cecal ligation and puncture (CLP) model of sepsis. Intraperitoneal ketamine injections (5, 15, or 25mg/kg) or saline were administered daily for seven days, thirty days post-CLP. Rats were euthanized thirty minutes following the last injection for analysis of IL-1β, IL-6, IL-10, TNF-α, BDNF, NGF, NT-3, and GDNF levels in the frontal cortex, hippocampus, and striatum. CLP-induced elevated IL-1𝛽, IL-6, IL-10, and TNF-α levels in the frontal cortex and hippocampus of rats, with reduced BDNF levels across all structures examined. Furthermore, reduced NGF and GDNF levels were observed solely in the hippocampus. Ketamine at 5mg/kg normalized CLP-induced alterations and, in Sham animals, increased BDNF and NGF levels in the frontal cortex and/or hippocampus. At 15mg/kg, ketamine elevated BDNF and NGF levels in Sham animals, while at 25mg/kg, it exacerbated the inflammatory response initiated by CLP. These findings suggest variable effects of ketamine within a context of systemic inflammation, emphasizing the importance of considering individual inflammatory backgrounds when utilizing ketamine.

Schistosoma japonicum cystatin has protective effects against "two-hit" sepsis in mice by regulating the inflammatory microenvironment.

To evaluate the protective effect of Schistosoma japonicum cystatin (rSj-Cystatin) in a mouse mode of "two-hit" sepsis. Sixty male C57BL/6 mice randomized equally into sham-operated group, protein group, "two-hit" modeling group, and protein intervention group. In the former two groups, the mice received an intraperitoneal injection of 100 μL PBS followed by exposure of the cecum and then by intraperitoneal injection of 100 μL PBS or 25 μg rSj-Cystatin 30 min later; In the latter two groups, 100 μL PBS containing LPS (5 mg/kg) was injected intraperitoneally 24 h before cecal ligation and puncture (CLP), and 100 μL PBS or 25 μg rSj-Cystatin were injected 30 min after CLP. At 12 h after rSj-Cystatin treatment, 6 mice from each group were sacrificed for detection of TNF-α, IL-6, IL-10, TGF-β, iNOS and Arg-1 in the serum, spleen, liver, lung and kidney tissues using ELISA, for examinations of liver, lung and kidney pathologies with HE staining, and for analysis of CD3+CD4+CD25+Foxp3+ T cell percentage in the spleen using flow cytometry. The remaining mice were observed for general condition and 72-h survival. The 72-h survival rates in the 4 groups were 100%, 100%, 0% and 20%, respectively, showing significant differences between the latter two groups. The mouse models of "two-hit" sepsis exhibited obvious tissue pathologies and significant elevations of TNF-α and IL-6 in both the serum and tissue homogenate, which were significantly ameliorated by rSj-Cystatin treatment. Treatment with rSj-Cystatin also increased IL-10 and TGF-β levels and spleen CD3+CD4+CD25+Foxp3+ T cell percentage. The septic mouse models also showed increased iNOS levels in all the detected tissues and a decreased Arg-1 level in the kidney, and these changes were obviously improved by rSj-Cystatin treatment. rSj-Cystatin has a protective effect against "two-hit" sepsis in mice by regulating the inflammatory microenvironment.

Protective immunity induced by a novel P1 adhesin C-terminal anchored mRNA vaccine against Mycoplasma pneumoniae infection in BALB/c mice.

Mycoplasma pneumoniae (Mp), a unique pathogen devoid of a cell wall, is naturally impervious to penicillin antibiotics. This bacterium is the causative agent of M. pneumoniae pneumonia, an acute pulmonary affliction marked by interstitial lung damage. Non-macrolide medications may have potential adverse effects on the developmental trajectory of children, thereby establishing macrolides as the preferred treatment for M. pneumoniae in pediatric patients. However, the emergence of macrolide-resistant and multidrug-resistant strains of M. pneumoniae presents significant challenges to clinical management and public health. Vaccines, particularly those based on mRNA technology, are regarded as a promising avenue for preventing and controlling M. pneumoniae infections due to their inherent safety, immunogenicity, and adaptability. Our research delves into the P1 adhesin of M. pneumoniae, a protein that binds to host cell receptors with its immunodominant epitopes located at the carboxyl terminus, known to provoke robust immune responses and pulmonary inflammation. We have developed an mRNA vaccine harnessing this dominant antigenic epitope and assessed its protective immunity in BALB/c mice against M. pneumoniae infection. The vaccine elicited potent humoral and cellular immune responses, effectively diminishing inflammation. It notably decreased IL-6 levels in the lungs of infected mice and concurrently elevated IL-4, IL-10, and IFN-γ levels post-immunization. The vaccine also reduced pathological changes in the lungs and the M. pneumoniae DNA copy numbers in the infected animals. Collectively, these findings underscore the mRNA vaccine's remarkable immunogenicity and protective potential against M. pneumoniae infections, offering valuable insights for the development of mRNA vaccines targeting mycoplasma infections.IMPORTANCEM. pneumoniae, a bacteria without a cell wall, is known for causing pneumonia and is resistant to penicillin. The increasing prevalence of macrolide-resistant strains has complicated treatment options, emphasizing the need for new strategies. Our research explores an mRNA vaccine candidate that targets the P1 adhesin of M. pneumoniae, a protein critical for the bacteria's interaction with host cells. In a mouse model, this vaccine has shown potential by inducing immune responses and suggesting a possible reduction in inflammation, as indicated by changes in cytokine levels and lung pathology. While further research is required, the vaccine's preliminary results hint at a potential new direction in managing mycoplasma infections, offering a promising avenue for future therapeutic development. This study contributes to the ongoing search for effective preventive measures against M. pneumoniae.

Clinical and laboratory characteristics of Sjögren's syndrome-associated autoimmune liver disease: a real-world, 10-year retrospective study.

To investigate the clinical and laboratory features of Sjögren's syndrome-associated autoimmune liver disease (SS-ALD) patients and identify potential risk and prognostic factors. SS patients with or without ALD, who visited Tongji Hospital between the years 2011 and 2021 and met the 2012 American College of Rheumatology (ACR) classification criteria for Sjögren's syndrome, were retrospectively enrolled. The clinical and laboratory data of the enrolled patients, including autoimmune antibodies, were collected and analyzed with principal component analysis, correlation analysis, LASSO regression, and Cox regression. A total of 117 SS-ALD patients were confirmed out of 568 SS patients. Compared to SS-non-ALD patients (n = 451), SS-ALD patients exhibited more severe involvement of the hepatic and hematologic systems, albeit with less pronounced typical SS symptoms. Disease activity was higher in SS-ALD patients, as indicated by elevated ESR, CRP, and IL-6 levels, particularly in the SS-overlap subgroup. Furthermore, SS-AIH patients without AIH-specific autoantibody testing or with negative testing results had higher AST and ALT levels than those who were autoantibody-positive. Our predictive model, incorporating IgG, IgM, AST, GGT, ALT, and C4, effectively identified ALD complications in SS patients, achieving an AUC of 0.924. Additionally, a grimmer prognosis was associated with higher baseline AST and ALT levels. SS-ALD patients often manifest with an insidious onset and atypical SS symptoms, yet frequently exhibit severe systemic involvement, intense inflammatory and immune responses, and a poor prognosis. To improve the clinical outcomes in SS-ALD patients, regular monitoring, early identification, and active treatment should be applied. Key Points • The study provided a detailed profile of clinical and laboratory features of SS-ALD and SS-non-ALD patients, contributing to a predictive model of ALD complications in SS patients • SS-ALD patients manifested with an insidious onset but exhibited severe systemic involvement, robust inflammatory and immune responses, and poor prognosis • SS-AIH patients without available testing for AIH-specific autoantibodies or with negative results demonstrated worse liver function, thus routine screening for autoimmune liver antibodies is recommended in SS patients • More severe baseline liver function status was associated with poorer therapeutic responses to routine medications, so early detection and timely intervention are essential for SS patients.

Caries experience and salivary interleukin-17 level in pre and postmenopausal women

Background: The oral tissues has been affected by menopause in the same way as the other human body systems. Aim of study: This study was set for estimating the experience of caries in correlation to the salivary interleukin-17 level in post-menopausal and pre-menopausal women. Materials and Methods: Females which aged (47-51) years old divided in to : First group (control group) contained forty five pre-menopausal females and the second group (study group) contained forty five post-menopause females and were examined for caries experience on the authority of WHO,(1997)).We'd collect the un stimulated saliva from all females to analyses salivary interleukin-17 level.. Results: In control group the pre-menopause; the mean value of Decayed Surfaces, Missed Surfaces and DMFS were lower than that of study group the post-menopause group with lower level of salivary interleukin-17. Conclusion: menopause influence female's dental health represented by higher dental caries severity which might be related to elevated IL-17 level among postmenopausal women. Further studies recommended with larger sample size with other salivary immune factors types measurement.

IL-8 promotes pyroptosis through ERK pathway and mediates glucocorticoid resistance in chronic rhinosinusitis with nasal polyps.

This study seeks to elucidate the role and molecular mechanisms of IL-8 in nasal epithelial cell pyroptosis and its impact on glucocorticoid (GC) resistance. We assessed the expression of pyroptosis-related biomarkers and IL-8 in tissues and human nasal epithelial cells (hNECs) from both control and nasal polyp patients using western blot. Their localization was determined through immunohistochemistry and immunofluorescence. Cell death and cytotoxicity assay, electron microscopy, ELISA, and immunofluorescence were utilized to investigate IL-8-induced pyroptosis and GC resistance in hNECs, alongside the examination of the involved signaling pathways via western blot and immunofluorescence. In a murine model, hematoxylin-eosin staining and immunohistochemistry clarified relationship between pyroptosis and GC resistance. IL-8 and pyroptotic biomarker expression were significantly higher in nasal polyp-derived tissues and hNECs compared to controls. IL-8 showed a positive correlation and co-localized with the pyroptotic biomarkers. IL-8 triggered pyroptosis in hNECs by activating the ERK signaling pathway, leading to increased IL-1β and IL-18 secretion. Moreover, IL-8-induced pyroptosis was found to contribute to GC resistance by affecting phosphorylation of GC receptor Ser211. Inhibition of pyroptotic proteins mitigated IL-8-induced GC resistance both in vitro and in vivo. Elevated IL-8 facilitates pyroptosis via the ERK signaling pathway and plays a significant role in GC resistance in nasal polyps.

Blood absolute lymphocyte count and trajectory are important in understanding severe COVID-19

BackgroundLow blood absolute lymphocyte count (ALC) may predict severe COVID-19 outcomes. Knowledge gaps remain regarding the relationship of ALC trajectory with clinical outcomes and factors associated with lymphopenia.MethodsOur post hoc analysis of the Therapeutics for Inpatients with COVID-19 platform trial utilized proportional hazards models to assess relationships between Day (D) 0 lymphopenia (ALC < 0.9 cells/uL), D0 severe lymphopenia (ALC < 0.5 cells/uL) or lymphopenia trajectory between D0 and D5 with mortality and secondary infections, and with sustained recovery using Fine-Gray models. Logistic regression was used to assess relationships between clinical variables and D0 lymphopenia or lymphopenia trajectory.ResultsD0 lymphopenia (1426/2579) and severe lymphopenia (636/2579) were associated with increased mortality (aHR 1.48; 1.08, 2.05, p = 0.016 and aHR 1.60; 1.20, 2.14, p = 0.001) and decreased recovery (aRRR 0.90; 0.82, 0.99, p = 0.033 and aRRR 0.78; 0.70, 0.87, p < 0.001 respectively). Trial participants with persistent D5 lymphopenia had increased mortality, and increased secondary infections, and participants with persistent or new lymphopenia had impaired recovery, as compared to participants with no lymphopenia. Persistent and new lymphopenia were associated with older age, male sex; prior immunosuppression, heart failure, aspirin use, and normal body mass index; biomarkers of organ damage (renal and lung), and ineffective immune response (elevated IL-6 and viral nucleocapsid antigen levels). Similar results were observed with severe lymphopenia.ConclusionsLymphopenia was predictive of severe COVID-19 outcomes, particularly when persistent or new during hospitalization. A better understanding of the underlying risk factors for lymphopenia will help illuminate disease pathogenesis and guide management strategies.

A novel technique of cryodenervation for murine vagus nerve: implications for acute lung inflammation

BackgroundNeuroimmune interaction is an underestimated mechanism for lung diseases, and cryoablation is a competitive advantageous technique than other non-pharmacologic interventions for peripheral nerve innervating the lung. However, a lack of cryodenervation model in laboratory rodents leads to the obscure mechanisms for techniques used in clinic.MethodHerein, we developed a novel practical method for mouse peripheral nerve cryoablation, named visualized and simple cryodenervation (VSCD). We first estimated the feasibility, safety and effectiveness of the technique via haematoxylin-eosin staining, histochemistry or immunofluorescence staining and immunoblotting assay. We then constructed the acute lung injury (ALI) model triggered by lipopolysaccharide (LPS) to verify the effect of VSCD in the resolution of pulmonary inflammation. Besides, the IL-10 knockout mice were also applied to explain the underlying mechanism of the protective activity of VSCD in ALI mice.ResultWe demonstrated that VSCD was able to induce a reliable and stable blockade of innervation, but reversible structural damage of mouse vagus nerve without detectable toxicity to lung tissues. Cholinergic parasympathetic nerve in the mouse lung coming from vagus nerve was activated at the initial stage (1 week) after VSCD, and blocked 3 weeks later. By use of the ALI mouse model, we found that VSCD effectively decreased pulmonary inflammation and tissue damage in the ALI mice. Moreover, the activated cholinergic anti-inflammatory pathway (CAP) and elevated IL-10 expression might explain the protective action of VSCD following LPS challenge.ConclusionThis study fills the gap in the cryoablation for mouse vagus nerve, thereby guiding the application of cryodenervation in clinical management of pulmonary diseases. It also offers evidence of anti-inflammatory potential of VSCD in ALI mouse model and opens therapeutic avenues for the intervention of acute lung inflammation.

Analysis of Immunometabolic Profiles in Patients With Chronic Drug-Induced Liver Injury and Validation in Mice to Reveal Potential Mechanisms.

The mechanism underlying chronic drug-induced liver injury (DILI) remains unclear. Immune activation is a common feature of DILI progression and is closely associated with metabolism. We explored the immunometabolic profile of chronic DILI and the potential mechanism of chronic DILI progression. Plasma and peripheral blood mononuclear cells from patients with chronic DILI were analyzed using multiplex immunoassays and untargeted metabolomics to reveal their immunometabolic profile. The effects and potential mechanisms of chronic DILI-related metabolite on acute or chronic liver injury induced by LPS or CCl4 in mice were investigated. Patients with chronic DILI exhibited elevated plasma IL-6, IL-12p70, IL-15 and reduced IL-10 levels. The percentage of IL-12+ monocytes was higher, while that of CD206+ monocytes, IL-10+ monocytes, Th2, Treg, and IL-10+ CD4+ T cells were lower in patients with chronic DILI compared to those with acute DILI. We identified the most significantly increased metabolite in patients with chronic DILI was cis-aconitic acid (CAA). Administration of CAA can attenuate liver injury in mice with acute liver injury induced by LPS or CCl4 and promote the spontaneous resolution of liver fibrosis in mice with chronic live injury induced by CCl4. The protective mechanism of CAA against liver injury is associated with the inhibition of hepatic macrophage infiltration and polarization, which is achieved by inhibiting the secretion of neutrophil-derived IL-33 and subsequent phosphorylation of GATA3. CAA, which is elevated in patients with chronic DILI, protects against liver injury by inhibiting hepatic macrophage infiltration and polarization through the suppression of the IL-33/GATA3 pathway, suggesting that CAA may serve as a potential target for regulating tissue repair in liver injury.

Smoking-induced shifts in salivary exosomal cytokines and amino acid profiles as potential early biomarkers for oral cancer.

Chronic smoking is an established risk factor for oral cancer (OC). The role of tobacco in oral squamous cell cancer (OSCC) emphasizes the need for non-invasive diagnostic approaches to identify early molecular alterations and improve patient outcomes. Salivary exosomes, which contain proteins, lipids, and nucleic acids, accessible and rich in biological content, making them interesting candidate biomarkers. Saliva samples were collected from non-smokers (n=20), smokers (n=20), and patients with oral cancer (n=20). Salivary exosomes were isolated and characterized using various techniques, including estimation of protein concentrations and amino acid profiling using High-Performance Liquid Chromatography (HPLC). Fourier Transform Infrared (FTIR) spectroscopy analyzed protein and amino acid peaks, while enzyme-linked immunosorbent assay (ELISA) measured pro-inflammatory cytokines IL-6 and IL-8. Elevated levels of salivary exosomal proteins (p=0.017), IL-6 (p=0.008), and IL-8 (p=0.0004), along with significant alterations in amino acid profiles, were observed in smokers compared with non-smokers. Additionally, protein (p=0.005) and IL-6 (p=0.004) levels were significantly elevated in oral cancer compared to non-smoker group. FTIR spectroscopy revealed distinct molecular fingerprints in exosomes, highlighting changes in protein and amino acid concentrations and indicating altered metabolism. This comparative cross-sectional study demonstrated that chronic smoking induces significant biochemical changes in salivary exosomes, establishing them as promising non-invasive biomarkers for early oral cancer detection. Elevated pro-inflammatory cytokines IL-6 and IL-8, along with altered amino acid profiles, may create pre-cancerous conditions. Notably, along with altered amino acid profiles, IL-6 levels progressively increase from smoking to oral cancer, highlighting its potential role in cancer progression.

The investigation of peripheral inflammatory and oxidative stress biomarkers in dementia with Lewy Bodies, compared with Alzheimer's Disease, and mild cognitive impairment.

Although inflammation and oxidative stress have been increasingly recognised as components of Alzheimer's disease (AD) and Parkinson's disease (PD) pathologies. Few studies have investigated peripheral inflammation, and none have examined oxidative stress in Dementia with Lewy bodies (DLB). The purpose of our study was to characterize and compare those biomarkers in DLB with those in AD and amnestic mild cognitive impairment (aMCI). Plasma samples were obtained from Chinese patients with DLB (n = 50), AD (n = 59), and aMCI (n = 30), and healthy controls (HCs) (n = 54). Peripheral inflammatory biomarkers, including interferon-gamma (IFN-γ), interleukins (IL-1β, IL-2, IL-4, IL-6, IL-10, IL-12p70, IL-17A), tumor necrosis factor-alpha (TNF-α), and C-reactive protein (CRP). Oxidative stress markers, such as superoxide dismutase (SOD), malondialdehyde (MDA), and glutathione peroxidase (GSH-Px), were also assessed. The findings revealed that DLB patients had higher IL-6 levels than AD and HCs and elevated IL-10 and IL-17A levels compared to HCs. In terms of oxidative stress, the levels of SOD were significantly lower and MDA were significantly higher in the DLB and AD compared with HCs. Significant positive correlations were found between Unified Parkinson's Disease Rating Scale (UPDRS) scores and CRP levels. Our study identifies a unique peripheral immune and oxidative stress profile in DLB, characterized by elevated IL-6, MDA, and reduced SOD levels, distinguishing it from AD. These findings, linked to α-synuclein (α-Syn) pathology, provide novel insights into DLB mechanisms and highlight potential biomarkers for disease monitoring, targeted therapies, and future clinical trials.

Comparative Analysis of Systemic Immune Responses and Metastatic Risks in Tumor Ablation: An Animal Study of Radiofrequency Ablation and Irreversible Electroporation with Immune Modulation.

This study aimed to compare systemic immune responses and metastatic effects induced by radiofrequency ablation (RFA) and irreversible electroporation (IRE) in murine tumor models. We assessed cytokine production, growth of treated and untreated metastatic tumors, and synergy with immune checkpoint inhibitors (ICIs). Hep55.1c murine hepatoma cells were implanted in C57BL/6N mice to establish primary tumors. In Experiment 1 (n = 50), RFA or IRE was applied to primary tumors, followed by CD8+ T cell depletion in some groups to assess anti-tumor immune responses. Experiment 2 (n = 45) tested RFA and IRE combined with anti-PD-1 therapy for enhanced abscopal effects. In Experiment 3 (n = 28), anti-IL-6 antibody was administered in IRE-treated mice to examine IL-6's role in secondary tumor growth. Tumor volumes and cytokine/chemokine levels were monitored. Both techniques induced significant CD8+ T cell-mediated anti-tumor responses, with abscopal effects observed in untreated secondary tumors. CD8+ T cell depletion abolished these effects, confirming their role in systemic tumor control. Anti-PD-1 therapy combination further suppressed secondary tumor growth. However, IRE uniquely elevated IL-6 and other inflammatory cytokines, unexpectedly accelerating secondary tumor growth. Administration of an anti-IL-6 antibody mitigated this effect, reducing secondary tumor progression. The results of this animal study indicate that both techniques promote systemic anti-tumor immunity, though IRE uniquely induces an inflammatory response that risks exacerbating micro-metastases through IL-6. Combining IRE with IL-6 blockade may offer a promising strategy for nonthermal tumor ablation therapies. Further studies are warranted to refine ablation-immune therapy combinations for optimal therapeutic outcomes.

Lipopolysaccharide preconditioning disrupts the behavioral and molecular response to restraint stress in male mice.

Major depressive disorder (MDD) is a complex neuropsychiatric disorder potentially influenced by factors such as stress and inflammation. Chronic stress can lead to maladaptive brain changes that may trigger immune hyperactivation, contributing to MDD's pathogenesis. While the involvement of inflammation in MDD is well established, the effects of inflammatory preconditioning in animals subsequently exposed to chronic stress remain unclear. This study aimed to investigate the impact of inflammatory preconditioning on behavioral, biochemical, and molecular changes in adult male Swiss mice subjected to chronic restraint stress (CRS). The mice received a single injection of lipopolysaccharide (LPS) 24 h before thefirst CRS and performed 6 h daily for 28 days. Behavioral tests were conducted 24 h after the last CRS, across 4 days, and euthanasia followed 24 h after the final tests. Results indicated that only the LPS + CRS group exhibited depressive- and anxiety-like behaviors, accompanied by demotivation and apathy. Biochemical and molecular analyses revealed anoxidative imbalance in the hippocampus, marked by elevated H2O2 levels and MPO activity. In the prefrontal cortex, theLPS + CRS group demonstrated a central inflammatory imbalance, with reduced IL-10 levels, increased Iba1 gene expression, and decreased Gfap and Bdnf gene expression. A trend toward elevated IL-17 levels was also observed at the peripheral level. These findings indicate that inflammatory preconditioning contributes significantly to behaviors phenotypically associated with MDD. Furthermore, the study suggests that these behavioral changes are linked to a dysfunctional immune response and impaired neuroplasticity.

Correlation Between Systemic Inflammation, Gut Microbiome Dysbiosis and Postoperative Complications After the Modified Whipple Procedure.

(1) Background: The modified Whipple procedure, or pylorus-preserving pancreaticoduodenectomy, is a complex surgical intervention used to treat pancreatic head tumors. While preserving digestive function, it is associated with significant perioperative risks. This study explores the clinical, immunological, and microbiome-related factors influencing postoperative complications, focusing on the interplay between patient comorbidities, systemic inflammation, and gut dysbiosis. (2) Methods: A retrospective analysis was conducted on 123 patients undergoing the modified Whipple procedure for pancreatic head tumors. Patients were categorized into two groups based on the occurrence of significant postoperative complications (Group A: with complications; Group B: without complications). Data on demographics, comorbidities, inflammatory markers (CRP, IL-6, procalcitonin), and gut microbiome composition were collected. Microbial diversity was evaluated using the Shannon Index, and logistic regression was performed to identify independent predictors of complications. (3) Results: Patients in Group A had a significantly higher prevalence of diabetes mellitus (43.1% vs. 20.8%; p = 0.02) and cardiovascular disease (35.3% vs. 13.9%; p = 0.01). Elevated inflammatory markers (CRP ≥ 40 mg/L, IL-6 ≥ 30 pg/mL, procalcitonin ≥ 0.5 ng/mL) were strongly associated with higher complication rates. Microbiome analysis indicated dysbiosis in Group A, with reduced Lactobacillus and Bifidobacterium levels, increased Enterobacteriaceae abundance, and a lower Shannon Index (<2). Patients exhibiting both dysbiosis and elevated inflammation had the highest complication rate (60%). Multivariate analysis identified diabetes, elevated IL-6, and dysbiosis as independent predictors of adverse outcomes. (4) Conclusions: Postoperative complications after the modified Whipple procedure are influenced by systemic inflammation and gut dysbiosis. A systematic preoperative assessment of microbiome health and inflammatory markers enables accurate risk stratification and personalized interventions, potentially reducing the incidence of complications and improving overall surgical outcomes.