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Purpose: To evaluate the effect of interleukin-6 (IL-6) inhibitor (tocilizumab) on bacterial infection-associated bone resorption around implants during osseointegration in rabbits. Materials and Methods: At total of 24 male, 9-monthold New Zealand white rabbits were included, and their two mandibular anterior teeth were extracted. Three months after extraction, 24 one-piece Dentium implants (Ø 2.5 mm, intraosseous length of 12 mm) were inserted in the anterior mandible, and the rabbits were divided into four groups (n = 6 per group). Different treatment methods were used in each group: blank control group (BC); only silk ligation (negative control [NC]); silk ligation and injection with minocycline hydrochloride ointment (positive control [PC]); and silk ligation and injection with tocilizumab at 8 mg/kg via the auricle vein (experimental [EP]). Eight weeks later, the animals were sacrificed, and samples were collected and then analyzed using microcomputed tomography (microCT) scanning, immunohistochemical analysis, and histologic analysis. Results: From the microCT measurement, the ratio of the bone volume to the total volume (BV/TV) in the EP group was 67.00% ± 2.72%, which was higher than that in the other three groups (58.85% ± 2.43% in the BC group, 55.72% ± 2.48% in the PC group, and 36.52% ± 3.02% in the NC group). From immunohistochemical analysis, the expression of IL-6 was found to be higher in the NC group than in the BC, PC, and EP groups, but there was no statistical difference between these three groups. Furthermore, the RANKL (receptor activator of nuclear factor-κB ligand) expression was the lowest in the EP group, followed by the BC group, the PC group, and the NC group, which had the highest expression; there was no difference between the NC and PC groups. Upon histologic analysis, significant new bone was found on the implant surfaces in the EP group, sparse and less new bone could be seen in the BC and PC groups, and the most serious bone resorption occurred in the NC group. Conclusions: Tocilizumab, an inhibitor of IL-6, has a certain effect in preventing bone loss around implants caused by bacterial infection during the osseointegration period. [ABSTRACT FROM AUTHOR]

Inflammation appears to be a critical mechanism in the development of alcohol use disorder (AUD) and a consequence of chronic alcohol use. The potential anti-inflammatory properties of cannabis may modulate the proinflammatory effects of alcohol. This study sought to extend previous work investigating the relationship between alcohol consumption, cannabis use and circulating interleukin (IL)-6 levels in a sample with AUD. One hundred and thirty-three individuals with an AUD provided blood samples to assess IL-6 and answered questions regarding alcohol and cannabis use. An ordinary least squares multiple regression analysis was conducted to assess the effect of alcohol and cannabis use on IL-6. A moderation analysis examined cannabis use as a potential moderator of the relationship between alcohol use and circulating IL-6 levels. Alcohol use was predictive of higher log IL-6 levels (standardized β = 0.16, p = 0.03), while cannabis use was not predictive of log IL-6 levels (p = 0.36). Days of cannabis use moderated the relationship between alcohol use and IL-6 levels, such that the relationship between alcohol use and IL-6 levels was only significant in individuals with AUD without recent cannabis use. This study extends previous work to a clinical sample with an AUD and underscores the importance of considering cannabis use in studies on alcohol use and inflammation. This study also indicates the need for in-depth analyses on cannabinoids and inflammation and the interaction between cannabinoids and alcohol use on inflammation.

In this experimental investigation, male college students (N = 56; Mage = 19.95 years) who did not yet know how to juggle were randomly assigned to a 30-min instructional juggling session with either a caring, task-involving climate or an ego-involving climate. An inflammatory response to psychosocial stress was assessed via salivary interleukin-6 prior to (t = 0) and following (t = +30, +45, +60 min) the session. Surveys were utilized to examine positive and negative affect prior to the session and affect, psychological needs, challenge and threat appraisals, and perceived ability to juggle following the session. This is the first investigation to show that ego-involving climates can trigger inflammation, along with maladaptive psychological responses. Participants in the caring, task-involving climate responded with greater psychological need satisfaction, resource evaluations, positive affect, and perceived juggling ability. This research suggests there may be important physiological consequences to ego-involving climates, in addition to concerning cognitive, affective, and behavioral responses. [ABSTRACT FROM AUTHOR]

Unraveling the multisymptomatic Gulf War Illness (GWI) pathology and finding an effective cure have eluded researchers for decades. The chronic symptom persistence and limitations for studying the etiologies in mouse models that differ significantly from those in humans pose challenges for drug discovery and finding effective therapeutic regimens. The GWI exposome differs significantly in the study cohorts, and the above makes it difficult to recreate a model closely resembling the GWI symptom pathology. We have used a double engraftment strategy for reconstituting a human immune system coupled with human microbiome transfer to create a humanized-mouse model for GWI. Using whole-genome shotgun sequencing and blood immune cytokine enzyme linked immunosorbent assay (ELISA), we show that our double humanized mice treated with Gulf War (GW) chemicals show significantly altered gut microbiomes, similar to those reported in a Veteran cohort of GWI. The results also showed similar cytokine profiles, such as increased levels of IL-1β, IL-6, and TNF R-1, in the double humanized model, as found previously in a human cohort. Further, a novel GWI Veteran fecal microbiota transfer was used to create a second alternative model that closely resembled the microbiome and immune-system-associated pathology of a GWI Veteran. A GWI Veteran microbiota transplant in humanized mice showed a human microbiome reconstitution and a systemic inflammatory pathology, as reflected by increases in interleukins 1β, 6, 8 (IL-1β, IL-6, IL-8), tumor necrosis factor receptor 1 (TNF R-1), and endotoxemia. In conclusion, though preliminary, we report a novel in vivo model with a human microbiome reconstitution and an engrafted human immune phenotype that may help to better understand gut-immune interactions in GWI.

Background: The Interleukin-6 (IL-6)-signal transducer and activator of transcription 3 (STAT3) pathway, along with the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, are critical contributors to neuroinflammation in Alzheimer's disease (AD). Although previous research outside the context of AD has indicated that the IL-6-STAT3 pathway may regulate the cGAS-STING pathway, the exact molecular mechanisms through which IL-6-STAT3 influences cGAS-STING in AD are still not well understood. Methods: The activation of the IL-6-STAT3 and cGAS-STING pathways in the hippocampus of 5×FAD and WT mice was analyzed using WB and qRT-PCR. To explore the effects of IL-6 deficiency, Il6+/− mice were crossed with 5×FAD mice, and the subsequent impact on hippocampal STAT3 pathway activity, cGAS-STING pathway activation, amyloid pathology, neuroinflammation, and cognitive function was evaluated through WB, qRT-PCR, immunohistochemistry, ThS staining, ELISA, and behavioral tests. The regulatory role of STAT3 in the transcription of the Cgas and Sting genes was further validated using ChIP-seq and ChIP-qPCR on hippocampal tissue from 5×FAD and Il6−/−: 5×FAD mice. Additionally, in the BV2 microglial cell line, the impact of STAT3 activation on the transcriptional regulation of Cgas and Sting genes, as well as the production of inflammatory mediators, was examined through WB and qRT-PCR. Results: We observed marked activation of the IL-6-STAT3 and cGAS-STING pathways in the hippocampus of AD mice, which was attenuated in the absence of IL-6. IL-6 deficiency reduced beta-amyloid deposition and neuroinflammation in the hippocampus of AD mice, contributing to cognitive improvements. Further analysis revealed that STAT3 directly regulates the transcription of both the Cgas and Sting genes. These findings suggest a potential mechanism involving the STAT3-cGAS-STING pathway, wherein IL-6 deficiency mitigates neuroinflammation in AD mice by modulating this pathway. Conclusion: These findings indicate that the STAT3-cGAS-STING pathway is critical in mediating neuroinflammation associated with AD and may represent a potential therapeutic target for modulating this inflammatory process in AD. [ABSTRACT FROM AUTHOR]

Inflammation underlies many conditions causing excess morbidity and mortality among people with HIV (PWH). A handful of single-trait epigenome-wide association studies (EWAS) have suggested that inflammation is associated with DNA methylation (DNAm) among PWH. Multi-trait EWAS may further improve statistical power and reveal pathways in common between different inflammatory markers. We conducted single-trait EWAS of three inflammatory markers (soluble CD14, D-dimers and interleukin-6) in the Veterans Aging Cohort Study (n = 920). The study population was all male PWH with an average age of 51 years, and 82.3% self-reported as Black. We then applied two multi-trait EWAS methods—CPASSOC and OmniTest—to combine single-trait EWAS results. CPASSOC and OmniTest identified 189 and 157 inflammation-associated DNAm sites, respectively, of which 112 overlapped. Among the identified sites, 56% were not significant in any single-trait EWAS. Top sites were mapped to inflammation-related genes including IFITM1, PARP9 and STAT1. These genes were significantly enriched in pathways such as "type I interferon signaling" and "immune response to virus." We demonstrate that multi-trait EWAS can improve the discovery of inflammation-associated DNAm sites, genes and pathways. These DNAm sites might hold the key to addressing persistent inflammation in PWH. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID-19) risk factors for hospitalization and mortality have been reported to be older age, comorbidities, and vaccination status. However, its clinical course and the risk of hospitalization and mortality in patients who received home health care for their predisposing status and diseases remain unclear. This study aimed to determine the characteristics and outcomes of these patients after being infected with the Omicron variant of COVID-19. This retrospective study included 33 patients diagnosed with COVID-19 after we initiated home health care. We classified the patients into 2 groups, that is, hospitalization (n = 7) and non-hospitalization (n = 26), and non-survival (n = 6) and survival (n = 27) and compared their backgrounds. COVID-19 severity was an affecting factor in hospitalization and survival. The nursing care environments and low daily life activities also affected hospitalization but not survival. The proportion of patients with terminal malignancies (50.0% vs 3.7%, p =.017) and the Charlson Comorbidity Index (5.0 vs 2.0, p =.096) were higher in the non-survival than in the survival group. Some patients had urinary tract infections and persistent weight and appetite loss (post COVID-19 syndrome), regardless of this improvement. Serum IL-6 levels were higher in patients with post COVID-19 syndrome than those without symptoms. Optimizing the nursing care environment is essential to continue home health care and lower the hospitalization rate even with SARS-CoV-2 infection. Post COVID-19 syndrome, such as appetite and weight loss, are associated with IL-6-induced inflammation. [ABSTRACT FROM AUTHOR]

• Human iPSC neural progenitor cells (NPC) only respond to IL-6 by trans -signalling. • Microglia-secreted sIL6Ra levels insufficient to induce NPC IL-6 trans -signalling. • NPC display marginal transcriptional responses to IL-6 in co-culture with microglia. • There are clear and replicable effects of IL-6 on the microglial transcriptome. • Future work should explore the role of IL-6 cis- and trans -signalling in microglia. Elevated interleukin (IL-)6 levels during prenatal development have been linked to increased risk for neurodevelopmental disorders (NDD) in the offspring, but the mechanism remains unclear. Human-induced pluripotent stem cell (hiPSC) models offer a valuable tool to study the effects of IL-6 on features relevant for human neurodevelopment in vitro. We previously reported that hiPSC-derived microglia-like cells (MGLs) respond to IL-6, but neural progenitor cells (NPCs) in monoculture do not. Therefore, we investigated whether co-culturing hiPSC-derived MGLs with NPCs would trigger a cellular response to IL-6 stimulation via secreted factors from the MGLs. Using N=4 donor lines without psychiatric diagnosis, we first confirmed that NPCs can respond to IL-6 through trans -signalling when recombinant IL-6Ra is present, and that this response is dose-dependent. MGLs secreted soluble IL-6R, but at lower levels than found in vivo and below that needed to activate trans -signalling in NPCs. Whilst transcriptomic and secretome analysis confirmed that MGLs undergo substantial transcriptomic changes after IL-6 exposure and subsequently secrete a cytokine milieu, NPCs in co-culture with MGLs exhibited a minimal transcriptional response. Furthermore, there were no significant cell fate-acquisition changes when differentiated into post-mitotic cultures, nor alterations in synaptic densities in mature neurons. These findings highlight the need to investigate if trans -IL-6 signalling to NPCs is a relevant disease mechanism linking prenatal IL-6 exposure to increased risk for psychiatric disorders. Moreover, our findings underscore the importance of establishing more complex in vitro human models with diverse cell types, which may show cell-specific responses to microglia-released cytokines to fully understand how IL-6 exposure may influence human neurodevelopment. [ABSTRACT FROM AUTHOR]

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Introduction: Sepsis is a complex clinical syndrome characterized by a heterogenous host immune response. Historically, static protein and transcriptomic metrics have been employed to describe the underlying biology. Here, we tested the hypothesis that ex vivo functional TNF expression as well as an immunologic endotype based on both IFNg and TNF expression could be used to model clinical outcomes in sepsis patients. Methods: This prospective, observational study of patient samples collected from the SPIES consortium included patients at five health systems enrolled over 17 months, with 46 healthy control patients, 68 ICU patients without sepsis, and 107 ICU patients with sepsis. Whole blood was collected on day 1, 4, and 7 of ICU admission. Outcomes included in-hospital and 180-day mortality and nonfavorable discharge disposition defined by skilled nursing facility, long-term acute care facility, or hospice. Whole blood ELISpot assays were conducted to quantify TNF expression [stimulated by lipopolysaccharide (LPS)] and IFNg expression (stimulated by anti-CD3/CD28 mAb), which were then used for assignment to one of four subgroups including an 'immunocompetent', 'immunosuppressed endotype', and two 'mixed' endotypes. Results: Whole blood TNF spot-forming units were significantly increased in septic and CINS patients on days 4 and 7 compared to healthy subjects. In contrast, TNF expression per cell on days 1, 4, and 7 was significantly lower in both septic and critically ill non-septic (CINS) patients compared to healthy subjects. Early increases in total TNF expression were associated with favorable discharge disposition and lower in-hospital mortality. 'Immunocompetent' endotype patients on day 1 had a higher proportion of favorable to nonfavorable discharges compared to the 'immunosuppressed' endotype. Similarly, 'immunocompetent' endotype patients on day 4 had a higher in-hospital survival compared to the 'immunosuppressed' endotype patients. Finally, among septic patients, decreased total TNF and IFNg expression were associated with 180- day mortality. Conclusions: Increased ex vivo whole blood TNF expression is associated with improved clinical outcomes. Further, the early 'immunocompetent' endotype is associated with favorable discharge and improved in-hospital and 180-day survival. The ability to functionally stratify septic patients based on blood cell function ex vivo may allow for identification of future immune modulating therapies. [ABSTRACT FROM AUTHOR]

Corrosive esophageal burn (CEB) is a disease with high mortality and morbidity rates. The aim of this study was to determine the efficacy of castor oil, in preventing stricture development at the experimental CEB model. In addition to studying standard histopathological damage data, neopterin, IL-33, and ST-2 proteins were also studied for the first time. Fifty Wistar-Albino rats were divided into randomized 5 groups. [Sham group (G1) (n:10), Control group (G2) (n:10), Early Stage Topical Application group (G3)(n:10), Late Stage Topical Application group (G4) (n:10), Oral Application group (G5) (n:10)]. Weight measurement, esophageal length, histopathological damage score (HDS) and total stenosis score (TSS), tissue caspase-3 and VEGF staining, tissue hydroxyproline (HYP), blood TNF-alpha, IL-6, IL-33, Neopterin, and ST-2 levels were measured. In the castor oil application groups, weight gain was observed, the acute phase reaction decreased, submucosal/tunica muscularis fibrosis (TMF) and muscularis mucosal damage (MMD) were reduced, and TSS and HDS decreased. While no significant difference was detected in the ST-2 protein, which was used for the first time in this study model, a significant increase in neopterin protein was observed in the application groups. Results indicate the nutritional contribution of castor oil, as well as its tissue healing and esophageal stricture-preventing efficacy at histopathological and immune-histochemical levels. [ABSTRACT FROM AUTHOR]

Aim: An ineffective immune response resulting from dysregulation of cytokine production might encourage viral persistence and cause chronic viral hepatitis to worsen. This study examined the relationship between alterations in interleukin-6 (IL-6) levels and the IL-6 − 174 G > C (rs1800795) polymorphism, as well as how this polymorphism affects the development and progression of chronic hepatitis brought on by hepatitis B (HBV) and hepatitis C (HCV) into hepatocellular carcinoma (HCC). Patients and methods: Whole blood samples from 126 Egyptian patients with HCC (111 with HCV and 15 with HBV), as well as 126 age- and sex-matched healthy individuals, were used to extract DNA. Using PCR-based allele-specific amplification (ASA), the existence of the IL-6 G-174C polymorphism was investigated. Additionally, each participant's serum IL-6 levels were determined using an enzyme-linked immunosorbent assay (ELISA). Results: The primary observations revealed that HCC patients had greater serum levels of IL-6 compared to the control groups (p < 0.001). Patients with the variant (CG and GG) genotype in the HCC group were found to have more disease severity indicated by higher levels of alpha-fetoprotein (AFP) and a higher ascites grade, as well as increased inflammatory activity as defined by higher levels of IL-6 and C-reactive protein (CRP) (p < 0.001 for both) in comparison to patients with the wild-type (CC) genotype (p < 0.001 and p = 0.002, respectively). Conclusion: The rs1800795 SNP in the IL-6 gene was associated with increased inflammatory activity and high levels of IL-6, indicating that this SNP may play a role in the development of HCC in Egyptian patients with chronic viral hepatitis. [ABSTRACT FROM AUTHOR]

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

Psychotic and mood disorders are discussed as part of the same continuum. The potential role of immune dysregulation in defining their clinical presentations, however, remains unclear. Differences in TNF-α, IL-6 and TGF-β levels were investigated in 143 patients with schizophrenia (SCH = 63) and bipolar disorder (BD = 80), in remission. Cytokines were evaluated against the dimensional assessment of psychosis and affective symptoms using the schizo-bipolar scale, together with the severity of the same symptom domains measured by the brief psychiatric rating scale (BPRS). Lower TGF-β was associated with more lifetime episodes, family risk for psychosis, and more severe mood and psychotic symptoms in all patients. BPRS Affect symptoms domain correlated with lower TGF-β levels in BD, and higher TGF-β levels in SCH patients. Using moderated mediation analysis, TGF-β was a relevant predictor only in the setting of non-categorical symptom distribution, with familial risk for psychosis confirmed as a significant moderator. Severity of BPRS Affect symptoms domain was an independent predictor of inclination towards the psychosis spectrum. The underlying immune dysregulation may be shared by the disorders, rather than a unique characteristic of each, having significant implications for our understanding of the continuum vs. categorical approach to psychosis and mood disorders. [ABSTRACT FROM AUTHOR]

Vigorous research confirmed the anti‐inflammatory, antioxidant, and antidementia effects of apigenin (Api). The present study evaluated the beneficial impacts of Api administration on behaviour, brain‐derived neurotrophic factor (BDNF), Interleukin 6 (IL‐6), oxidative stress, and inflammation induced by social isolation (SI) stress in rats. For this purpose, rats underwent a 28‐day SI period followed by a 4‐week oral Api treatment (50 mg/kg/day, PO). On Day 56, behaviour tests were performed, including an elevated plus maze (EPM), Morris water maze (MWM), and three‐chamber social tests. The oxidative stress markers, IL‐6, and BDNF levels were measured in the hippocampus. Our results showed that SI stress caused an increase in anxiety and a decrease in spatial memory, sociability, and social preference index. In addition, SI stress increased hippocampal levels of IL‐6 and malondialdehyde (MDA) content, whereas it reduced the hippocampal BDNF level and superoxide dismutase (SOD) activities. Our study indicated that Api attenuates anxiety and causes improvements in spatial memory and social interaction. These desirable effects of Api might be related to amelioration in the BDNF level, IL‐6, and oxidative stress biomarkers in the hippocampus. [ABSTRACT FROM AUTHOR]

Targeting the interleukin-6 (IL-6)/glycoprotein 130 (GP130) signaling pathway holds significant promise for cancer therapy given its essential role in the survival and progression of various cancer types. We have identified that bazedoxifene (BZA), a Food and Drug Administration (FDA)-approved drug used for the prevention of postmenopausal osteoporosis, when combined with conjugated estrogens in Duavee, also has a novel function as an inhibitor of IL-6/GP130 interaction. BZA is currently under investigation for its potential anticancer therapeutic function through the inhibition of the IL-6/GP130 pathway. Numerous studies have highlighted the efficacy of BZA (monotherapy or combined with other chemotherapy drugs) in impeding progression across multiple cancers. In this review, we mainly focus on the anticancer activity of BZA and the underlying anticancer mechanism through inhibition of the IL-6/GP130 pathway, aiming to provide valuable insights for the design and execution of further research and the potential repositioning of BZA in oncological clinical trials. [ABSTRACT FROM AUTHOR]

Objective: To investigate correlation between neutrophil lymphocyte ratio (NLR), IL-6 and lymphocyte subsets and prognosis of viral pneumonia complicated with acute respiratory distress syndrome (ARDS). Methods: A total of 98 patients with viral pneumonia complicated with ARDS admitted to Xinxiang Central Hospital/the Fourth Clinical College from May 2017 to June 2019 were selected, NLR, IL-6 and lymphocyte subsets expressions in patients with different severity were analyzed. Correlation between NLR, IL-6 and lymphocyte subsets levels in prognosis of viral pneumonia complicated with ARDS was analyzed by Pearson correlation. Logistc regression was used to analyze prognostic risk factors of viral pneumonia complicated with ARDS. Results: With aggravation of viral pneumonia complicated with ARDS, NLR and IL-6 levels were significantly increased (P<0.05), while CD3+T, CD4+T and CD19+T cells levels were significantly decreased (P<0.05). Pearson correlation analysis results showed that NLR and IL-6 were positively correlated with prognosis of viral pneumonia complicated with ARDS (P<0.05), while CD3+T, CD4+T, CD19+T and CD8+T cells were negatively correlated with prognosis of ARDS with viral pneumonia (P<0.05). Multivariate Logistic analysis showed that NLR, IL-6, CD3+T and CD19+T cells were risk factors for viral pneumonia complicated with ARDS (P<0.05). Conclusion: Serum NLR, IL-6, CD3+T and CD19+T cells are closely related to severity and prognosis of patients with viral pneumonia complicated with ARDS. [ABSTRACT FROM AUTHOR]

Objective: Meat processing is among the most extensive industries globally. However, data on the effects of occupational exposure on the pulmonary health of slaughterhouse workers is limited. Ascertaining the impact of the slaughterhouse atmosphere on the breathing habits of laborers exposed to it and the inflammatory markers associated with it was the aim of the current investigation. Methods: A cross-sectional study was performed on 82 non-smoker subjects of 41 male workers working in one of the major slaughterhouses in Cairo, Egypt, matched to 41 controls of administrative personnel. An elaborate questionnaire encompassing medical and occupational history was administered to each participant in the research. General and local systemic examinations and ventilatory function tests were carried out, and serum levels of interleukin 6 (IL-6) and high-sensitivity C-reactive protein (hsCRP) were measured. Results: Respiratory symptoms were more prevalent with a statistically significant decline in ventilatory function parameters (FVC%, FEV1%, FEV1/FVC, FEF 25%, FEF 50%, FEF 75%, and PEF%) among the exposed group compared to those of control. In addition, there was a significantly higher serum level of inflammatory markers (IL-6 and hsCRP) among the exposed group compared to the control group, with a negative correlation with ventilatory functions. Moreover, there was a positive association between levels of serum IL-6 and hsCRP and the age and duration of employment of workers. Conclusion: There was a notable increase in the prevalence of respiratory disorders and inflammatory markers among slaughterhouse workers. Additionally, there was a substantial decrease in ventilatory function parameters, which could be attributed to the bioaerosols they encountered in the workplace. [ABSTRACT FROM AUTHOR]

Low-grade inflammation (LGI) represents a key driver of type 2 diabetes (T2D) and its associated cardiovascular diseases (CVDs). Indeed, inflammatory markers such as hs-CRP and IL-6 predict the development of T2D and its complications, suggesting that LGI already increases before T2D diagnosis and remains elevated even after treatment. Overnutrition, unhealthy diets, physical inactivity, obesity, and aging are all recognized triggers of LGI, promoting insulin resistance and sustaining the pathogenesis of T2D. Once developed, and even before frank appearance, people with T2D undergo a pathological metabolic remodeling, with an alteration of multiple CVD risk factors, i.e., glycemia, lipids, blood pressure, and renal function. In turn, such variables foster a range of inflammatory pathways and mechanisms, e.g., immune cell stimulation, the accrual of senescent cells, long-lasting epigenetic changes, and trained immunity, which are held to chronically fuel LGI at the systemic and tissue levels. Targeting of CVD risk factors partially ameliorates LGI. However, some long-lasting inflammatory pathways are unaffected by common therapies, and LGI burden is still increased in many T2D patients, a phenomenon possibly underlying the residual inflammatory risk (i.e., having hs-CRP > 2 mg/dL despite optimal LDL cholesterol control). On the other hand, selected disease-modifying drugs, e.g., GLP-1RA, seem to also act on the pathogenesis of T2D, curbing the inflammatory trajectory of the disease and possibly preventing it if introduced early. In addition, selected trials demonstrated the potential of canonical anti-inflammatory therapies in reducing the rate of CVDs in patients with this condition or at high risk for it, many of whom had T2D. Since colchicine, an inhibitor of immune cell activation, is now approved for the prevention of CVDs, it might be worth exploring a possible therapeutic paradigm to identify subjects with T2D and an increased LGI burden to treat them with this drug. Upcoming studies will reveal whether disease-modifying drugs reverse early T2D by suppressing sources of LGI and whether colchicine has a broad benefit in people with this condition. [ABSTRACT FROM AUTHOR]

Context: Adipose-derived mesenchymal stem cells (ADMSCs) are progenitor cells that shape the tissue's biological properties. Objective: To examine the adipocytes differentiated from the ADMSCs of lean and obese individuals with/without a metabolic syndrome (MetSx) cytokine secretory profile, as to date, little is known on this topic. Methods: Interleukin, chemokine and growth factor levels in the culture medium were determined using the Human Cytokine kit. Results: We observed a characteristic secretory fingerprint displayed by the cells from the MetSx group and identified a set of putative markers (IL-1β, IL-6, IL-7, IL-10, IL-12, IL-13, VEGF, FGF, GM-CSF, TNF-α, IFN-γ) of the condition. Surprisingly, the concentrations of most of the molecules (except for IL-6, IFN-γ, IP-10, VEGF) decreased when compared with the cells from the lean group. We postulate that the difference stemmed from the fact that in vivo cytokines were mostly secreted by the activated monocytes/macrophages and not adipocytes per se. This may also suggest that the aforementioned upregulated cytokines (IL-6, IFN-γ, IP-10, VEGF) might have been the ones that attracted monocytes and triggered the vicious cycle of tissue inflammation. Conclusions: Our study indicated that the adipocytes newly derived from the ADMSCs of obese patients with metabolic syndrome displayed a secretory fingerprint that may be characteristic to the early stages of the condition. [ABSTRACT FROM AUTHOR]

Background and Aim: Primary biliary cholangitis (PBC) is an autoimmune‐mediated cholestatic liver disease that can progress to biliary cirrhosis and liver‐related death. The associations between baseline myostatin levels and clinical outcomes in PBC patients are unknown. We aimed to clarify the influence of myostatin levels on the clinical outcomes of PBC patients. Methods: A total of 119 PBC patients were analyzed in this study. Myostatin levels were measured in stored sera before ursodeoxycholic acid treatment, and their associations with the clinical features and prognosis of PBC patients were analyzed. We analyzed the correlation between serum myostatin and chemokines/cytokines. Results: Serum myostatin was significantly lower in PBC patients (2343 pg/mL) than in healthy controls (4059 pg/mL, P < 0.001). The prevalence of patients with low myostatin levels increased according to the severity of histological fibrosis. The serum myostatin concentration was negatively correlated with the IL‐6 and leucine‐rich α2 glycoprotein levels, but the chemokine concentration was not correlated with the myostatin concentration. Low myostatin in PBC patients was associated with shorter survival without liver‐related complications (hazard ratio [HR], 3.598; 95% confidence interval [CI], 1.27–10.1; P = 0.015) and shorter transplant‐free survival (HR, 3.129; 95% CI, 1.02–9.56; P = 0.045) independent of pretreatment GLOBE score. Patients with both high pretreatment GLOBE scores and low myostatin levels had poor prognoses (log–rank test: P < 0.001). Conclusions: A low serum myostatin concentration at diagnosis was associated with poor clinical outcomes. Assessment of circulating myostatin levels may improve the prediction of outcomes in patients with PBC. [ABSTRACT FROM AUTHOR]

Cysteine cathepsins are lysosomal proteases subject to dynamic regulation within antigen‐presenting cells during the immune response and associated diseases. To investigate the regulation of cathepsin X, a carboxy‐mono‐exopeptidase, during maturation of dendritic cells (DCs), we exposed immortalized mouse DCs to various Toll‐like receptor agonists. Using a cathepsin X‐selective activity‐based probe, sCy5‐Nle‐SY, we observed a significant increase in cathepsin X activation upon TLR‐9 agonism with CpG, and to a lesser extent with Pam3 (TLR1/2), FSL‐1 (TLR2/6) and LPS (TLR4). Despite clear maturation of DCs in response to Poly I:C (TLR3), cathepsin X activity was only slightly increased by this agonist, suggesting differential regulation of cathepsin X downstream of TLR activation. We demonstrated that cathepsin X was upregulated at the transcriptional level in response to CpG. This occurred at late time points and was not dampened by NF‐κB inhibition. Factors secreted from CpG‐treated cells were able to provoke cathepsin X upregulation when applied to naïve cells. Among these factors was IL‐6, which on its own was sufficient to induce transcriptional upregulation and activation of cathepsin X. IL‐6 is highly secreted by DCs in response to CpG but much less so in response to poly I:C, and inhibition of the IL‐6 receptor subunit glycoprotein 130 prevented CpG‐mediated cathepsin X upregulation. Collectively, these results demonstrate that cathepsin X is differentially transcribed during DC maturation in response to diverse stimuli, and that secreted IL‐6 is critical for its dynamic regulation. [ABSTRACT FROM AUTHOR]

Active polysaccharides from plants are broadly applied in the food and health industry. The purpose of this study is to identify a new plant active polysaccharide and to investigate its role in modulating spatial memory. Ultrasonics and DEAE-52 chromatography were used to separate and purify the plant active polysaccharide (PAP). Mice were exposed to 100 ppm of lead acetate from birth to 7 weeks old to establish the memory impairment model. PAPs with concentrations of 200 or 400 ppm were fed to the subject mice each day after weaning in a spatiotemporally separated fashion. At the end of the intervention, mice were examined using the Morris water maze test, microbiome sequencing, cytokine profiling and protein analysis. The derived active polysaccharide was constituted by β-anomeric carbon, indicating a new form of PAP. The PAP significantly ameliorates the memory impairment caused by postnatal lead exposure, as evidenced by the preferred coverage of the test mouse in the hidden platform, demonstrating salient neuroregulatory activity. In terms of the gut microbiome in response to PAP treatment, it was found that the 400 ppm PAP reversed the gut dysbiosis, producing a comparable structure to the intact animals, represented by the relative abundance of Firmicutes and Muribaculum, Desulfovibrio, etc. For cytokines, the PAP reversed the plasma levels of IL-6, suggesting an anti-inflammatory trend in the context of proinflammation caused by lead invasion. By injecting an IL-6 antagonist, Tocilizumab, into the deficient mice, the spatial memory was significantly repaired, which demonstrates the central roles of IL-6 in mediating the positive effect of the PAP. Finally, a histone modification mark, H3K27me3, was found to be potent in responding to the signals conveyed by the PAP. The PAP could improve the memory deficits by remodeling the gut–brain axis centered at the microbiota and IL-6, which is regarded as an important cytokine-modulating brain activity. This is an intriguing instance linking neuromodulation with the active polysaccharide, shedding light on the innovative applications of plant polysaccharides due to the scarcity of similar phenotypic connections. [ABSTRACT FROM AUTHOR]

Corosolic acid (CA) is a well-known natural pentacyclic triterpene found in numerous therapeutic plants that can exhibit many bioactivities including anti-inflammatory and anti-tumor actions. The current investigation explores the chemoprotective roles of CA against azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) in rats. Thirty Sprague Dawley rats were grouped in 5 cages; Group A, normal control rats inoculated subcutaneously (sc) with two doses of normal saline and fed orally on 10% tween 20; Groups B-E received two doses (sc) of azoxymethane in two weeks and treated with either 10% tween 20 (group B) or two intraperitoneal injections of 35 mg/kg 5-fluorouracil each week for one month (group C), while group D and E treated with 30 and 60 mg/kg, respectively, for 2 months. The toxicity results showed lack of any behavioral abnormalities or mortality in rats ingested with up-to 500 mg/kg of CA. The present AOM induction caused a significant initiation of ACF characterized by an increased number, larger in size, and well-matured tissue clusters in cancer controls. AOM inoculation created a bizarrely elongated nucleus, and strained cells, and significantly lowered the submucosal glands in colon tissues of cancer controls compared to 5-FU or CA-treated rats. CA treatment led to significant suppression of ACF incidence, which could be mediated by its modulatory effects on the immunohistochemical proteins (pro-apoptotic (Bax) and reduced PCNA protein expressions in colon tissues). Moreover, CA-treated rats had improved oxidative stress-mediated cytotoxicity indicated by increased endogenous antioxidants (SOD and CAT) and reduced lipid peroxidation indicators (MDA). In addition, CA ingestion (30 and 60 mg/kg) suppressed the inflammatory cascades, indicated by decreased serum TNF-α and IL-6 cytokines and increased anti-inflammatory (IL-10) cytokines consequently preventing further tumor development. CA treatment maintained liver and kidney functions in rats exposed to AOM cytotoxicity. CA could be a viable alternative for the treatment of oxidative-related human disorders including ACF. [ABSTRACT FROM AUTHOR]

Cryptococcus neoformans (Cn) is an opportunistic encapsulated fungal pathogen that causes life-threatening meningoencephalitis in immunosuppressed individuals. Since IL-6 is important for blood-brain barrier support and its deficiency has been shown to facilitate Cn brain invasion, we investigated the impact of IL-6 on systemic Cn infection in vivo, focusing on central nervous system (CNS) colonization and glial responses, specifically microglia and astrocytes. IL-6 knock-out (IL-6−/−) mice showed faster mortality than C57BL/6 (Wild-type) and IL-6−/− supplemented with recombinant IL-6 (rIL-6; 40 pg/g/day) mice. Despite showing early lung inflammation but no major histological differences in pulmonary cryptococcosis progression among the experimental groups, IL-6−/− mice had significantly higher blood and brain tissue fungal burden at 7-days post infection. Exposure of cryptococci to rIL-6 in vitro increased capsule growth. In addition, IL-6−/− brains were characterized by an increased dystrophic microglia number during Cn infection, which are associated with neurodegeneration and senescence. In contrast, the brains of IL-6-producing or -supplemented mice displayed high numbers of activated and phagocytic microglia, which are related to a stronger anti-cryptococcal response or tissue repair. Likewise, culture of rIL-6 with microglia-like cells promoted high fungal phagocytosis and killing, whereas IL-6 silencing in microglia decreased fungal phagocytosis. Lastly, astrogliosis was high and moderate in infected brains removed from Wild-type and IL-6−/− supplemented with rIL-6 animals, respectively, while minimal astrogliosis was observed in IL-6−/− tissue, highlighting the potential of astrocytes in containing and combating cryptococcal infection. Our findings suggest a critical role for IL-6 in Cn CNS dissemination, neurocryptococcosis development, and host defense. [ABSTRACT FROM AUTHOR]

Introduction: NK cells are dysfunctional in myasthenia gravis (MG), but the mechanism is unclear. This study aims to measure associations and underlying mechanisms between the NK cells and the development of MG. Methods: Twenty healthy controls (HCs) and 53 MG patients who did not receive glucocorticoids and immunosuppressants were collected. According to the Myasthenia Gravis Foundation of America (MGFA) classification, MG patients were categorized into MGFA I group (n = 18) and MGFA II-IV group (n = 35). Flow cytometry, cell sorting, ELISA, mRNA-sequencing, RT-qPCR, western blot, and cell culture experiments were performed to evaluate the regulatory mechanism of exhausted NK cells. Results: Peripheral NK cells in MGFA II-IV patients exhibit exhausted phenotypes than HCs, marked by the dramatic loss of total NK cells, CD56dimCD16-NK cells, elevated PD1 expression, reduced NKG2D expression, impaired cytotoxic activity (perforin, granzyme B, CD107a) and cytokine secretion (IFN-g). Plasma IL-6 and IL-21 are elevated in MG patients and mainly derived from the aberrant expansion of monocytes and Tfh cells, respectively. IL-6/IL-21 cooperatively induced NKcell exhausted signature via upregulating SOCS2 and inhibiting the phosphorylation of STAT5. SOCS2 siRNA and IL-2 supplement attenuated the IL-6/IL-21-mediated alteration of NK-cell phenotypes and function. Discussion: Inhibition of IL-6/IL-21/SOCS2/STAT5 pathway and recovery of NKcell ability to inhibit autoimmunity may be a new direction in the treatment of MG. [ABSTRACT FROM AUTHOR]

Background: The association between cytokines in peripheral blood and clinical symptoms of multiple system atrophy (MSA) has been explored in only a few studies with small sample size, and the results were obviously controversial. Otherwise, no studies have explored the diagnostic value of serum cytokines in MSA. Methods: Serum cytokines, including interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor alpha (TNF-a), were measured in 125 MSA patients and 98 healthy controls (HCs). Correlations of these serum cytokines with clinical variables were analyzed in MSA patients. Diagnostic value of cytokines for MSA was plotted by receiver operating curves. Results: No significant differences were found in sex and age between the MSA group and the HCs. TNF-a in MSA patients were significantly higher than those in HCs (area under the curve (AUC) 0.768), while IL-6 and IL-8 were not. Only Hamilton Anxiety Scale (HAMA) has a positive correlation between with TNF-a in MSA patients with age and age at onset as covariates. Serum IL-6 was associated with HAMA, Hamilton Depression Scale (HAMD), the Unified MSA Rating Scale I (UMSARS I) scores, the UMSARS IV and the Instrumental Activity of Daily Living scores. However, IL-8 was not associated with all clinical variables in MSA patients. Regression analysis showed that HAMA and age at onset were significantly associated with TNF-a, and only HAMA was mild related with IL-6 levels in MSA patients. Conclusion: Serum TNF-a and IL-6 levels in MSA patients may be associated with anxiety symptom; however, only TNF-a was shown to be a useful tool in distinguishing between MSA and HCs. [ABSTRACT FROM AUTHOR]

Myocarditis is a major cause of heart failure and death, particularly in young individuals. Current treatments are mainly symptomatic, but emerging therapies focus on targeting inflammation and fibrosis pathways. Natural bioactive compounds like flavonoids and phenolic acids show promising anti-inflammatory and antioxidant properties. Corticosteroids are frequently employed in the treatment of autoimmune myocarditis and appear to lower mortality rates compared to conventional therapies for heart failure. This study aims to explore the effects of Mangiferin on pro-inflammatory cytokine levels, nitro-oxidative stress markers, histopathological alterations, and cardiac function in experimental myosin-induced autoimmune myocarditis. The effects were compared to Prednisone, used as a reference anti-inflammatory compound, and Trolox, used as a reference antioxidant. The study involved 30 male Wistar–Bratislava rats, which were randomly divided into five groups: a negative control group (C−), a positive control group with induced myocarditis using a porcine myosin solution (C+), three groups with induced myocarditis receiving Mangiferin (M), Prednisone (P), or Trolox (T) as treatment. Cardiac function was evaluated using echocardiography. Biochemical measurements of nitro-oxidative stress and inflammatory markers were conducted. Finally, histopathological changes were assessed. At echocardiography, the evaluation of the untreated myocarditis group showed a trend toward decreased left ventricular ejection fraction (LVEF) but was not statistically significant, while all treated groups showed some improvement in LVEF and left ventricular fraction shortening (LVFS). Significant changes were seen in the Mangiferin group, with lower end-diastolic left ventricular posterior wall (LVPWd) by day 21 compared to the Trolox group (p < 0.001). In the first week of the experiment, levels of interleukins (IL)-1β, IL-6, and tumour necrosis factor (TNF)-α were significantly higher in the myosin group compared to the negative control group (p < 0.001, p < 0.001, p < 0.01), indicating the progression of inflammation in this group. Treatment with Mangiferin, Prednisone, and Trolox caused a significant reduction in IL-1β compared to the positive control group (p < 0.001). Notably, Mangiferin resulted in a superior reduction in IL-1β compared to Prednisone (p < 0.05) and Trolox (p < 0.05). Furthermore, Mangiferin treatment led to a statistically significant increase in total oxidative capacity (TAC) (p < 0.001) and a significant reduction in nitric oxide (NOx) levels (p < 0.001) compared to the negative control group. Furthermore, when compared to the Prednisone-treated group, Mangiferin significantly reduced NOx levels (p < 0.001) and increased TAC levels (p < 0.001). Mangiferin treatment significantly lowered creatine kinase (CK) and aspartate aminotransferase (AST) levels on day 7 (p < 0.001 and p < 0.01, respectively) and reduced CK levels on day 21 (p < 0.01) compared to the untreated group. In the nontreated group, the histological findings at the end of the experiment were consistent with myocarditis. In the group treated with Mangiferin, only one case exhibited mild inflammatory infiltrates, represented by mononucleated leukocytes admixed with few neutrophils, with the severity graded as mild. Statistically significant correlations between the grades (0 vs. 1–2) and the study groups have been highlighted (p < 0.005). This study demonstrated Mangiferin's cardioprotective effects in autoimmune myocarditis, showing reduced oxidative stress and inflammation. Mangiferin appears promising as a treatment for acute myocarditis, but further research is needed to compare its efficacy with other treatments like Trolox and Prednisone. [ABSTRACT FROM AUTHOR]

T-cell acute lymphoblastic leukemia is an aggressive neoplasia due to hyper-proliferation of lymphoid progenitors and lacking a definitive cure to date. Notch-activating mutations are the most common in driving disease onset and progression, often in combination with sustained activity of NF-κB. Myeloid-derived suppressor cells represent a mixed population of immature progenitors exerting suppression of anti-cancer immune responses in the tumor microenvironment of many malignancies. We recently reported that in a transgenic murine model of Notch3-dependent T-cell acute lymphoblastic leukemia there is an accumulation of myeloid-derived suppressor cells, dependent on both Notch signaling deregulation and IL-6 production inside tumor T-cells. However, possible interaction between NF-κB and Notch in this context remains unexplored. Interestingly, we also reported that Notch3 transgenic and NF-κB1/p50 deleted double mutant mice display massive myeloproliferation. Here, we demonstrated that the absence of the p50 subunit in these mice dramatically enhances the induction and suppressive function of myeloid-derived suppressor cells. This runs in parallel with an impressive increase in IL-6 concentration in the peripheral blood serum, depending on IL-6 hyper-production by tumor T-cells from double mutant mice. Mechanistically, IL-6 increase relies on loss of the negative control exerted by the p50 subunit on the IL-6 promoter. Our results reveal the Notch/NF-κB cross-talk in regulating myeloid-derived suppressor cell biology in T-cell leukemia, highlighting the need to consider carefully the pleiotropic effects of NF-κB-based therapy on the tumor microenvironment. [ABSTRACT FROM AUTHOR]

Despite effective antiretroviral therapy (ART), 15-30% of people with HIV experience poor CD4+ T-cell recovery, termed immunologic non-responders (INR). This study aims to evaluate whether pre-ART plasma levels of interleukin-6 (IL-6), interferon gamma-induced protein-10 (IP-10), macrophage inflammatory protein-1-β (MIP-1β), and/or pentraxin-3 (PTX-3) could predict subsequent immunologic recovery. Seventy-four participants were enrolled and classified as INR and immunologic responders (IR) based on CD4+/CD8+ ratio increase over 24 months after starting ART. The results showed no significant differences in cytokine levels between INR and IR. Therefore, IL-6, IP-10, MIP-1β, and PTX-3 were unsuitable as predictive markers of poor immune recovery. [ABSTRACT FROM AUTHOR]

Introduction: COVID-19 is a significant cause of morbidity and mortality. It is crucial to identify biomarkers that can aid in predicting patients' prognosis and mortality. This study evaluated the relationship between galectin-3 (Gal-3), interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) levels and the prognosis and mortality of COVID-19 patients. Methodology: The study included 69 COVID-19 patients (32 outpatients, 37 inpatients) and 19 healthy controls. Gal-3, IL-1, IL-6, and TNF-α levels in serum samples were measured using an ELISA test. Results: In a comparison between the patient and healthy control groups, it was observed that the patient group had significantly higher levels of Gal-3, IL-6, and TNF-α. Comparison between the outpatient and inpatient groups revealed that the hospitalized patient group had significantly higher levels of IL-6 and TNF-α, while the Gal-3 levels were lower in this group. In the analysis of subgroups to assess disease severity, critical COVID-19 patients exhibited elevated levels of Gal-3 and IL-6 compared to those with severe COVID-19. Moreover, Gal-3 and IL-6 were identified as having predictive value for mortality in hospitalized patients, while both IL-6 and TNF-α demonstrated diagnostic accuracy across all patient groups. Conclusions: The study results indicate that the levels of IL-6 TNF-α play a crucial role in determining the hospitalization and mortality of COVID-19 patients. Additionally, it was observed that Gal-3 and IL-6 levels can be utilized to assess the severity of the disease and predict mortality in patients who require hospitalization. [ABSTRACT FROM AUTHOR]

The effect of chronic overcrowding on the social behavior of adult male Wistar rats was studied. From postnatal day 30 (P30) to P180, the rats lived under standard (STND) or overcrowded (CRWD) conditions. Starting from P100, rat behavior was studied in the social preference and tube dominance tests, and aggressive behavior was investigated in the resident-intruder test. After decapitation of rats on P180, amygdala, dorsal hippocampus, ventromedial hypothalamus, and medial prefrontal cortex were collected and analyzed for expression of the IL-1β, TNF, TGF-β1, and IL-6 mRNAs by quantitative polymerase chain reaction. Compared to the STND group, rats from the CRWD group demonstrated shorter interaction time with a social object in the social preference test. They also had more wins in the tube test and initiated more attacks in the resident-intruder test. Expression of the IL1β gene in the hippocampus and medial prefrontal cortex and of the TGFβ1 gene in the hippocampus, amygdala, and prefrontal cortex was increased in the CRWD group. The stress induced by overcrowding increased social dominance and aggressiveness and decreased social motivation in rats. The changes in the social behavior of CRWD rats were accompanied by upregulation of expression of genes for the proinflammatory cytokine IL-1β and the anti-inflammatory cytokine TGF-β1 in a number of brain structures, which can be considered as manifestations of neuroinflammation and compensatory processes, respectively. [ABSTRACT FROM AUTHOR]

Myokines released by exercise are identified as factors that can influence a person's health and wellbeing. While myokine secretion in response to an acute bout of endurance and resistance-type exercise has been examined, the influence of resistance-exercise training on myokines at rest is less well established. Therefore, this study was designed to evaluate a panel of myokines at rest following a 12-week resistance-exercise training program in younger and older males. Participants (n = 15) completed a 12-week progressive resistance-exercise training program supervised by a certified fitness professional. The training protocol targeted all major muscle groups of the upper and lower body. Resting blood samples were collected before and after completion of the training program to determine concentrations of apelin, fibroblast growth factor-21 (FGF-21), interleukin (IL)-4, IL-6, IL-7, IL-15, leukemia inhibitory factor (LIF), and irisin. Two-way repeated ANOVAs were used to compare variables between time-points and age groups. There was a main effect of time found for apelin (p = 0.003) and IL-15 (p < 0.001), while no main effects for group or time were found for the other myokines (all p > 0.05). Age group × training status interactions were found for IL-6 (p = 0.04) and irisin (p = 0.014) without pairwise differences for IL-6 (p > 0.05), and younger males had higher concentrations of irisin compared to older males post-training (p = 0.036). Overall, the 12-week resistance-exercise training program significantly increased apelin and IL-15 over time but did not change the other resting myokine concentrations for the younger or older males. However, the higher concentration of irisin in younger versus older males post-training suggests a potential explanation for the anabolic resistance observed with aging. [ABSTRACT FROM AUTHOR]

A severe consequence of SARS-CoV-2 infection that manifests as systemic inflammation and multi-organ involvement is called Multisystem Inflammatory Syndrome in Children (MIS-C). This review examines the possible relationship between gut barrier integrity, the microbiome, dysregulation of interleukin 6 (IL-6) signaling, and MIS-C. Clinical and biochemical features of MIS-C are comparable to those of other hyper-inflammatory syndromes, suggesting a dysregulated immune response. One possible explanation for the systemic inflammation seen in MIS-C patients is the SARS-CoV-2-induced dysregulation of the IL-6 signaling pathway. In addition, new data suggest a reciprocal link between gut barrier integrity and IL-6. SARS-CoV-2 exhibits bacteriophage-like behavior, highlighting the role of bacteria as a reservoir for the virus and emphasizing the importance of understanding the bacteriophagic mechanism of the virus in fecal–oral transmission. The increased translocation of viral products and bacterial toxins may result from disrupting the intestinal barrier and cause systemic inflammation. On the other hand, systemic inflammation can weaken the integrity of the intestinal barrier, which feeds back into the loop of immunological dysregulation. In the context of MIS-C, understanding the interaction between SARS-CoV-2 infection, IL-6, and gut barrier integrity may shed light on the etiology of the disease and guide treatment options. Since children with gut dysbiosis may be more susceptible to MIS-C, it is critical to reinforce their microbiome through probiotics supplementation, and plant-fiber-rich diets (prebiotics). Early antibiotic treatment and the use of zonulin antagonists should also be considered. [ABSTRACT FROM AUTHOR]

Background: Currently, creating more effector T cells and augmenting their functions is a focal point in pancreatic ductal adenocarcinoma (PDAC) treatment research. T cell immunoglobulin domain and mucin domain molecule 4 (TIM‐4), known for promoting cancer progression in various malignancies, is implicated in the suppressive immune microenvironment of tumors. Analyzing of the role of TIM‐4 in the immune regulation of PDAC can offer novel insights for immune therapy. Methods: We analyzed the TIM‐4 expression in tumor specimens from PDAC patients. Meanwhile, multiple fluorescent immunohistochemical staining was used to study the distribution characteristics of TIM‐4, and through tissue microarrays, we explored its correlation with patient prognosis. The influence of TIM‐4 overexpression on cell function was analyzed using RNA‐seq. Flow cytometry and ELISA were used for verification. Finally, the relationship between TIM‐4 and T lymphocytes was analyzed by tissue microarray, and the impacts of TIM‐4 on T cell subsets were observed by cell coculture technology and a mouse pancreatic cancer in situ model. Results: In PDAC, TIM‐4 is mainly expressed in tumor cells and negatively correlated with patient prognosis. TIM‐4 influences the differentiation of Treg by inhibiting IL‐6 secretion in pancreatic cancer cells and facilitates the proliferation of pancreatic cancer in mice. Additionally, the mechanism may be through the CD8+ effector T cells (CD8+Tc). Conclusion: TIM‐4 has the potential to be an immunotherapeutic target or to improve the efficacy of chemotherapy for PDAC. [ABSTRACT FROM AUTHOR]

Massage therapy increases muscle blood flow and heat, relieving pain, improving immune function, and increasing vagal activity. The mechanisms are unclear. Muscles release cytokines and other peptides called myokines. These myokines exert their effects on different tissues and organs in para-, auto-, and endocrine fashion. The aim of this intervention study was to investigate if massage therapy affects circulating myokine levels. A total of 46 healthy, normal-weight subjects (15 men) aged 18–35 were recruited. Forty-five minutes of massage Swedish therapy was applied to the back and hamstrings. Blood samples via cannula were taken at the baseline, during the massage (30 min), end of the massage (45 min), and 30 min and 1 h after the massage. Interleukin 6 (IL-6) and insulin-like growth factor 1 (IGF-1) were measured as surrogate markers by ELISAs. There was a significant increase in IL-6 from 1.09 pg/mL to 1.85 pg/mL over time (Wilks' Lambda Value 0.545, p < 0.000; repeated measures ANOVA). Pair-wise comparisons showed a significant increase after 1 h of massage. No significant increase was observed in IGF-1 levels. The change in myokine levels was not correlated with muscle mass (p = 0.16, 0.74). The increase in IL-6 suggests that there might be anti-inflammatory effects, affecting glucose and lipid metabolism pathways via IL-6 signaling to muscles, fat tissue, and the liver. [ABSTRACT FROM AUTHOR]

Simple Summary: Understanding the inflammatory interplay between cancer and COVID-19 infection is essential for improving patient care. Our study bridges a vital knowledge gap by exploring how a pre-existing tumor-induced inflammatory state can exacerbate the inflammatory response to COVID-19, adversely impacting COVID-19 outcomes. We introduce the FLARE score, a robust predictor derived from circulating inflammatory markers, that provides clinicians a practical tool for early identification of patients with cancer at higher risk of severe COVID-19 complications who might benefit most from immediate and intensive treatment strategies. Additionally, our study also underscore the role of immature neutrophils in the progression of COVID-19 in patients with cancer, advocating for further investigation into how these cells contribute to both cancer and COVID-19 disease. Purpose: Inflammation and neutrophils play a central role in both COVID-19 disease and cancer. We aimed to assess the impact of pre-existing tumor-related inflammation on COVID-19 outcomes in patients with cancer and to elucidate the role of circulating neutrophil subpopulations. Methods: We conducted a multicenter retrospective analysis of 524 patients with cancer and SARS-CoV-2 infection, assessing the relationship between clinical outcomes and circulating inflammatory biomarkers collected before and during COVID-19 infection. Additionally, a single-center prospective cohort study provided data for an exploratory analysis, assessing the immunophenotype of circulating neutrophils and inflammatory cytokines. The primary endpoints were 30-day mortality and the severity of COVID-19 disease. Results: Prior to COVID-19, 25% of patients with cancer exhibited elevated dNLR, which increased to 55% at the time of COVID-19 diagnosis. We developed the FLARE score, incorporating both tumor- and infection-induced inflammation, which categorized patients into four prognostic groups. The poor prognostic group had a 30-day mortality rate of 68%, significantly higher than the 23% in the favorable group (p < 0.0001). This score proved to be an independent predictor of early mortality. This prospective analysis revealed a shift towards immature forms of neutrophils and higher IL-6 levels in patients with cancer and severe COVID-19 infection. Conclusions: A pre-existing tumor-induced pro-inflammatory state significantly impacts COVID-19 outcomes in patients with cancer. The FLARE score, derived from circulating inflammatory markers, emerges as an easy-to-use, globally accessible, effective tool for clinicians to identify patients with cancer at heightened risk of severe COVID-19 complications and early mortality who might benefit most from immediate and intensive treatment strategies. Furthermore, our findings underscore the significance of immature neutrophils in the progression of COVID-19 in patients with cancer, advocating for further investigation into how these cells contribute to both cancer and COVID-19 disease. [ABSTRACT FROM AUTHOR]

Atractylis flava Desf. (AF) is common plant that is widely used for its anti- inflammatory and antioxidant properties. The purpose of this study was, therefore, to evaluate the cytotoxic effect and the molecular basis of antioxidant and anti-inflammatory effects of the ethyl acetate extract (AFEAE) obtained from the whole plant A. flava. This was accomplished through the use of NR8383 alveolar rat macrophage cells. Cultures of alveolar rat macrophage cells were treated with AFEAE (25–800 μg/mL), and cell viability was determined via WST-1 and LDH tests. In turn, the gene expression levels of nuclear factor κB (NF-κB), tumor necrosis factor-alpha (TNFα), interleukin 1 beta (IL1-β), interleukin 6 (IL-6), mitochondrial dynamin like GTPase (OPA1), Succinate dehydrogenase complex subunit A (SDHA) and neutrophil cytosolic factor 1 (NCF1) were assessed by applying RT-qPCR. The results show that ethyl acetate extracts of A. flava have non-cytotoxic effects, and the gene expression analysis demonstrates that AFEAF extracts generate significant downregulation of NF-κB, TNFα, IL-1 β, IL-6, NCF1, OPA1 and SDHA, compared to untreated cells. This study reveals that Atractylis flava ethyl acetate extract administration may be considered as a potential therapeutic strategy for inflammatory related diseases. [ABSTRACT FROM AUTHOR]

Purpose: Searching for quick determinable biomarkers with high sensitivity and specificity is necessary to improve and optimise the early diagnosis of periprosthetic elbow infection (PEI). Therefore, this study's objective was to evaluate the diagnostic value of synovial fluid interleukin-6 (IL-6) levels for diagnosing PEI in total elbow arthroplasty. Method: Twelve prospective enrolled patients underwent total elbow arthroplasty revision surgery, during which synovial fluid was obtained. Between the initial implantation and the revision procedure were 33.5 ± 41 months (range, 2–144 months). Synovial fluid was collected for immediate IL-6 analysis parallel to the revision surgery. Furthermore, microbiological samples were obtained and analysed. Two groups were defined based on the microbiological results: non-infection and infection group. The ability of synovial fluid IL-6 analysis to predict infection status was explored using receiver operating characteristic curves and further statistical analysis. Results: Synovial fluid IL-6 analysis had a good diagnostic accuracy of 83% for PEI with an area under the curve of 0,79 and an ideal cutoff value (determined using Youden's criterion) of 15244 pg/mL. Discussion: This is the first study to clinically evaluate IL-6 as a diagnostical marker for periprosthetic joint infection (PJI) in total elbow arthroplasty. Our results suggest a good accuracy and high sensitivity for IL-6 to identify a PEI. The analysis of IL-6 can improve surgical decision-making regarding managing total elbow arthroplasty in terms of one- or two-staged revision. Conclusion: IL-6 can play an important role in the perioperative differentiation of infected and non-infected situations. [ABSTRACT FROM AUTHOR]

A chronic microbial infection that is mediated by the host's immune system is the cause of periodontal disease. As the world's population grows, phytotherapy is a therapeutic strategy that makes use of a renewable resource that can provide less costly medicines. This study aimed to investigate the therapeutic effects of eugenol administration on periodontitis by examining the effects of eugenol at different doses biochemically, histopathologically, and radiologically in rats with experimental periodontitis. Thirty-two Sprague Dawley male rats were divided into four groups: 1. the healthy control group (CG), 2. The experimental periodontitis group (PG), 3. The experimental periodontitis+10 mg/kg eugenol group (EG10), and 4. the experimental periodontitis+20 mg/kg eugenol group (EG20). Alveolar bone loss was measured using micro-CT imaging. The TNF-α, IL-6, leptin, asprosin, and apelin levels were analyzed in the serum samples of rats. Histological and immunohistochemical analyses were performed. The data were analyzed statistically. The serum TNF-α, IL-6, leptin, asprosin, and apelin levels were found to be statistically significantly lower in the eugenol-applied groups (EG10 and EG20) than in the PG (p < 0.05). There was a statistically significant difference in the TNF-α, IL-6, leptin, asprosin, and apelin levels between the EG10 and EG20 (p < 0.05). In the measurements made using micro-CT imaging, alveolar bone loss was found to be at the lowest FR1 level, and in histopathological analysis, the least inflammation was observed in the EG20. It was concluded that the application of 20 mg/kg eugenol in rats with experimental periodontitis was a safe dose, was beneficial in alleviating bone loss, and had a positive effect on the healing process. [Display omitted] • Eugenol reduced TNF-α, IL-6, leptin, asprosin and apelin levels. • Histologically, it was found that eugenol decreased inflammation in periodontitis. • Eugenol was observed to improve alveolar bone loss in periodontitis. [ABSTRACT FROM AUTHOR]

Interleukin-6 (IL-6) plays a crucial role in various cellular functions, including innate and adaptive immune responses. Dysregulated expression of IL-6 is associated with hyperinflammation and chronic inflammatory diseases. In this study, we aimed to identify the enhancer regions responsible for robust Il6 mRNA expression in murine macrophages. Through comprehensive genome-wide ChIP- and ATAC-seq analyses, we identified two distinct clusters, termed E1 and E2 regions, located at −144 to −163 kb relative to the Il6 transcription start site in lipopolysaccharide (LPS)-activated murine macrophages. These clusters exhibited an accumulation of histone modification marks (H3K27ac and H3K4me1), as well as open chromatin, and were found to contain binding sites for the transcription factors PU.1, NF-κB, C/EBPβ, and JunB. Upregulation of non-coding RNA (ncRNA) transcripts from the E1 and E2 regions was observed upon LPS stimulation, and repression of these ncRNAs resulted in abrogation of Il6 expression. Additionally, deletion of either E1 or E2 region significantly impaired Il6 expression, while CRISPR/dCas9 activation-mediated recruitment of the co-activator p300 to the E1 and E2 regions facilitated Il6 expression. Collectively, our findings suggest that the E1 and E2 regions serve as putative enhancers for Il6 expression. [ABSTRACT FROM AUTHOR]

Aim: This study aimed to investigate the associations between single nucleotide polymorphisms (SNPs) of IL-6 (-174G/C), microRNA146a (rs2910164C/G) and MALAT1 (rs619586A/G) and susceptibility to rheumatoid arthritis (RA) in Egyptians. Methods: SNPs were genotyped in 101 RA patients and 104 controls. Expression levels were evaluated either by Enzyme-linked immunosorbent assay (ELISA) for IL-6 or quantitative real-time PCR (qRT-PCR) for miR-146a and MALAT1. Results:IL-6–174 GC (OR = 3.422) genotype, IL-6–174 C allele (OR = 2.565), miR-146a (rs2910164) CG (OR = 2.190) and MALAT1 (rs619586) AA (OR = 4.125) genotypes and A allele (OR = 6.122) could be considered as risk factors for RA. An increase in the expression of IL-6, miR-146a and MALAT1 was detected in RA patients, which was independent of any SNP. Conclusion: SNPs of IL-6, miR-146a and MALAT1were linked to RA predisposition in Egyptians. Plain Language Summary Rheumatoid arthritis (RA) is a chronic joint disorder with overexpression of inflammatory mediators. There is increasing evidence that epigenetic changes could play a prominent role in RA pathogenesis. This study was designated to explore the associations between genetic mutation of inflammatory cytokines (Interleukin (IL-6) and epigenetic modulators (miR-146a and MALAT1) and susceptibility to RA. Increased production of IL-6, miR-146a and MALAT1 is a remarkable event in RA patients. We provide evidence that certain genotypes could be used as risk factors for the disease. Our data suggest that detecting certain mutations is quite important in disease prediction. Special concern has to be directed to those persons harboring definite genotypes to achieve better clinical manipulation of patients at risk. Tweetable Abstract This study demonstrated an elevation in IL-6, miR-146a and MALAT1 in RA patients. Moreover, we found that susceptibility to RA is associated with IL-6 (rs1800795) GC, miR-146a (rs2910164) CG and MALAT1 (rs619586) AA genotypes. Article highlights IL-6 (-174G/C), miR-146a (rs2910164C/G) and MALAT1 (rs619586A/G) SNPs were thought to be associated with RA risk. This study aimed to investigate this association with RA in Egyptians. in 101 RA patients and 104 controls. IL-6 (-174G/C) was genotyped utilizing MS-PCR, miR-146a (rs2910164 C/G) and MALAT1 (rs619586 A/G) was genotyped using RFLP-PCR. Expression levels were evaluated either by ELISA for IL-6 or qRT-PCR for miR-146a and MALAT1. The statistical analysis showed that IL-6–174GC genotype, C allele and miR-146a (rs2910164) CG genotype were significantly increased in patients versus controls (p < 0.01, p < 0.05, p < 0.01; respectively). Patients showed a significant reduction in IL-6–174GG (p < 0.05), miR-146a (rs2910164) CC genotypes (p < 0.05) and MALAT1(rs619586) G allele (p < 0.05) compared with controls. The genotypes of IL-6–174GC, miR-146a rs2910164 CG and MALAT1 rs619586AA could all be considered risk factors for RA. CGA haplotype was significantly increased (p < 0.01) in patients than in healthy ones. A significant elevation of IL-6, miR-146a and MALAT1 expression levels was detected in RA patients (p < 0.001, p < 0.05 and p < 0.001, respectively). miR-146a was positively correlated with MALAT1 (r = 0.326, p < 0.05) in RA patients. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is a neoplastic condition resulting from the uncontrolled expansion of B-cell-derived plasma cells. The importance of angiogenesis in MM development has also been demonstrated. Extracellular vesicles (EVs) have vital functions in interactions between neighboring cells, such as angiogenesis. The objective of this in vitro study was to examine the transfection and angiogenesis effects of MM-EVs on endothelial cells (ECs) upon treatment with Tetrahydroisoquinoline (THIQ) as a bioactive organic compound derivative from isoquinoline. Following treatment of multiple myeloma cells (U266) with THIQ, MM-EVs were harvested and transmigrated to human umbilical vein endothelial cells (HUVEC) in a co-culture model. EVs transmigration was traced by flow cytometry. Correspondingly, the expression of angiogenic genes and/or proteins in U266 cells and HUVECs was measured by RT-PCR and ELISA methods. Likewise, the proliferation and migration of HUVECs treated with THIQ-treated MM-EVs were visualized and estimated by performing both tube formation and scratch wound healing methods. Surprisingly, the anti-angiogenic effect of THIQ-treated MM-EVs was evident by the decreased expression of CD34, VEGFR2, and IL-6 at the mRNA and/or protein levels after internalization of MM-EVs in HUVEC. Finally, tube formation and scratch wound healing experiments showed inhibition of HUVEC cell proliferation and migration by THIQ-treated MM-EVs compared to control MM-EVs. MM-EVs derived from THIQ-treated myeloma cells (U266) inhibited angiogenesis in HUVECs. This phenomenon is coordinated by the internalized THIQ-treated MM-EVs in HUVECs, and ultimately the reduction of angiogenic factors and inhibition of tube formation and scratch wound healing. [ABSTRACT FROM AUTHOR]

Summary: Purpose: Multiple Myeloma (MM) is considered an incurable, biologically heterogeneous disease of the plasma cells. The clinical data on the association between stress and the molecular mechanism of stress hormone receptor expression and its relationship with IL‑6 signaling pathway have not yet proposed a clear answer in MM. This study aims to explore the effect of isoproterenol and propranolol, which are beta-adrenergic agonists and antagonists, respectively on suppressor of cytokine signaling (SOCS) and IL-6/gp130 signaling in MM cell lines. Material and methods: Four different MM cell lines (KMM‑1, RPMI 8226, LP‑1, and L363) were treated with isoproterenol and propranolol. Optimal dosages of isoproterenol and propranolol were determined, and the mRNA expression levels of IL‑6, gp130, and SOCS‑1 were examined using qRT-PCR. Results: The analysis of our results indicated that propranolol, as a β-adrenoreceptor antagonist, could increase MM cell death and ameliorate IL‑6 and its receptor gp130 in addition to up-regulate SOCS‑1 gene expression. On the other hand, isoproterenol, as a β-adrenoreceptor agonist, could provoke MM cell viability and IL‑6 expression. Conclusions: β‑adrenergic signaling seems to affect cell viability through targeting IL-6/gp130 and SOCS‑1 signaling in MM, underscoring the importance of further studies on stress hormones and IL‑6 suppressors as potent candidates for MM therapy. [ABSTRACT FROM AUTHOR]

Castleman disease (CD) is a benign lymphoproliferative disease causing severe systemic inflammation. Interleukin-6 (IL-6) is a major pathogenesis of multicentric CD (MCD), but only 30–60% of patients respond to IL-6 inhibitors. Novel agents for IL-6 inhibitor-refractory cases are needed. Clinical data and samples are being collected on a large scale and the clinical, pathological, and pathogenetic aspects are being elucidated. The pathological and clinical classification of CD is outlined. Focusing on idiopathic MCD (iMCD), this review identifies therapeutic targets and summarizes currently recommended drugs and promising therapeutic candidates. The pathogenesis of MCD has been implicated in the activation of the Janus kinase (JAK)-transcriptional signaling activator (STAT) 3 pathway and the phosphatidylinositol 3-kinase (PI3K)/Akt/mechanical target of rapamycin (mTOR) signaling pathway. iMCD-TAFRO (thrombocytopenia, anasarca, fever/elevated CRP, reticulin myelofibrosis/renal dysfunction, organ enlargement) is resistant to IL-6 inhibitors, and cyclosporine and mTOR inhibitors are sometimes effective. JAK inhibitors and mTOR inhibitors may be therapeutic agents for iMCD. Recently, we have shown that peripheral helper T (Tph) cell abnormalities are at the core of iMCD pathogenesis. Therapies targeting chemokine (C-X-C motif) ligand 13 (CXCL13) produced by Tph cells and blocking the Tph-CXCL13-B cell pathway may satisfy unmet need in refractory cases. [ABSTRACT FROM AUTHOR]

The pathogenesis of schizophrenia begins in early neurodevelopment and leads to excitatory-inhibitory imbalance. It is therefore essential that preclinical models used to understand disease, select drug targets and evaluate novel therapeutics encompass similar neurochemical deficits. One approach to improved preclinical modelling incorporates dual-hit neurodevelopmental insults, like neonatal administration of phencyclidine (PCP, to disrupt development of glutamatergic circuitry) then post-weaning isolation (Iso, to mimic adolescent social stress). We recently showed that male Lister-hooded rats exposed to PCP-Iso exhibit reduced hippocampal expression of the GABA interneuron marker calbindin. The current study expanded on this by investigating changes to additional populations of GABAergic interneurons in frontal cortical and hippocampal tissue from the same animals (by immunohistochemistry) as well as levels of GABA itself (via ELISA). Because inflammatory changes are also implicated in schizophrenia, we performed additional immunohistochemical evaluations of Iba-1 positive microglia as well as ELISA analysis of IL-6 in the same brain regions. Single-hit isolation-reared and dual-hit PCP-Iso rats both showed reduced parvalbumin immunoreactivity in the prelimbic/infralimbic region of the frontal cortex. However, this was more widespread in PCP-Iso, extending to the medial/ventral and lateral/dorsolateral orbitofrontal cortices. Loss of GABAergic markers was accompanied by increased microglial activation in the medial/ventral orbitofrontal cortices of PCP-Iso, together with frontal cortical IL-6 elevations not seen following single-hit isolation rearing. These findings enhance the face validity of PCP-Iso, and we advocate the use of this preclinical model for future evaluation of novel therapeutics—especially those designed to normalise excitatory-inhibitory imbalance or reduce neuroinflammation. [ABSTRACT FROM AUTHOR]

Recent single-cell RNA-sequencing analysis of rheumatoid arthritis (RA) synovial tissues revealed the heterogeneity of RA synovial fibroblasts (SFs) with distinct functions such as high IL-6 production. The molecular mechanisms responsible for high IL-6 production will become a promising drug target of RASFs to treat RA. In this study, we performed siRNA screening of 65 transcription factors (TFs) differentially expressed among RASF subsets to identify TFs involved in IL-6 production. The siRNA screening identified 7 TFs including ARID5B, a RA risk gene, that affected IL-6 production. Both long and short isoforms of ARID5B were expressed and negatively regulated by TNF-α in RASFs. The siRNA knockdown and lentiviral overexpression of long and short isoforms of ARID5B revealed that the long isoform suppressed IL-6 production stimulated with TNF-α. eQTL analysis using 58 SFs demonstrated that RA risk allele, rs10821944, in intron 4 of the ARID5B gene had a trend of eQTL effects to the expression of long isoform of ARID5B in SFs treated with TNF-α. ARID5B was found to be a negative modulator of IL-6 production in RASFs. The RA risk allele of ARID5B intron may cause high IL-6 production, suggesting that ARID5B will become a promising drug target to treat RA. [ABSTRACT FROM AUTHOR]

Lung tumor-promoting environmental exposures and γherpesvirus infections are associated with Type 17 inflammation. To test the effect of γherpesvirus infection in promoting lung tumorigenesis, we infected mutant K-Ras-expressing (K-RasLA1) mice with the murine γherpesvirus MHV68 via oropharyngeal aspiration. After 7 weeks, the infected mice displayed a more than 2-fold increase in lung tumors relative to their K-RasLA1 uninfected littermates. Assessment of cytokines in the lung revealed that expression of Type 17 cytokines (Il-6, Cxcl1, Csf3) peaked at day 7 post-infection. These observations correlated with the post-infection appearance of known immune mediators of tumor promotion via IL-17A in the lungs of tumor-bearing mice. Surprisingly, Cd84, an immune cell marker mRNA, did not increase in MHV68-infected wild-type mice lacking lung tumors. Csf3 and Cxcl1 protein levels increased more in the lungs of infected K-RasLA1 mice relative to infected wild-type littermates. Flow cytometric and transcriptomic analyses indicated that the infected K-RasLA1 mice had increased Ly6Gdim/Ly6Chi immune cells in the lung relative to levels seen in uninfected control K-RasLA1 mice. Selective methylation of adenosines (m6A modification) in immune-cell-enriched mRNAs appeared to correlate with inflammatory infiltrates in the lung. These observations implicate γherpesvirus infection in lung tumor promotion and selective accumulation of immune cells in the lung that appears to be associated with m6A modification of mRNAs in those cells. [ABSTRACT FROM AUTHOR]

Abstract Inflammation underlies many conditions causing excess morbidity and mortality among people with HIV (PWH). A handful of single-trait epigenome-wide association studies (EWAS) have suggested that inflammation is associated with DNA methylation (DNAm) among PWH. Multi-trait EWAS may further improve statistical power and reveal pathways in common between different inflammatory markers. We conducted single-trait EWAS of three inflammatory markers (soluble CD14, D-dimers and interleukin-6) in the Veterans Aging Cohort Study (n = 920). The study population was all male PWH with an average age of 51 years, and 82.3% self-reported as Black. We then applied two multi-trait EWAS methods—CPASSOC and OmniTest—to combine single-trait EWAS results. CPASSOC and OmniTest identified 189 and 157 inflammation-associated DNAm sites, respectively, of which 112 overlapped. Among the identified sites, 56% were not significant in any single-trait EWAS. Top sites were mapped to inflammation-related genes including IFITM1, PARP9 and STAT1. These genes were significantly enriched in pathways such as “type I interferon signaling” and “immune response to virus.” We demonstrate that multi-trait EWAS can improve the discovery of inflammation-associated DNAm sites, genes and pathways. These DNAm sites might hold the key to addressing persistent inflammation in PWH.

Abstract Background The Interleukin-6 (IL-6)-signal transducer and activator of transcription 3 (STAT3) pathway, along with the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, are critical contributors to neuroinflammation in Alzheimer’s disease (AD). Although previous research outside the context of AD has indicated that the IL-6-STAT3 pathway may regulate the cGAS-STING pathway, the exact molecular mechanisms through which IL-6-STAT3 influences cGAS-STING in AD are still not well understood. Methods The activation of the IL-6-STAT3 and cGAS-STING pathways in the hippocampus of 5×FAD and WT mice was analyzed using WB and qRT-PCR. To explore the effects of IL-6 deficiency, Il6 +/− mice were crossed with 5×FAD mice, and the subsequent impact on hippocampal STAT3 pathway activity, cGAS-STING pathway activation, amyloid pathology, neuroinflammation, and cognitive function was evaluated through WB, qRT-PCR, immunohistochemistry, ThS staining, ELISA, and behavioral tests. The regulatory role of STAT3 in the transcription of the Cgas and Sting genes was further validated using ChIP-seq and ChIP-qPCR on hippocampal tissue from 5×FAD and Il6 −/− : 5×FAD mice. Additionally, in the BV2 microglial cell line, the impact of STAT3 activation on the transcriptional regulation of Cgas and Sting genes, as well as the production of inflammatory mediators, was examined through WB and qRT-PCR. Results We observed marked activation of the IL-6-STAT3 and cGAS-STING pathways in the hippocampus of AD mice, which was attenuated in the absence of IL-6. IL-6 deficiency reduced beta-amyloid deposition and neuroinflammation in the hippocampus of AD mice, contributing to cognitive improvements. Further analysis revealed that STAT3 directly regulates the transcription of both the Cgas and Sting genes. These findings suggest a potential mechanism involving the STAT3-cGAS-STING pathway, wherein IL-6 deficiency mitigates neuroinflammation in AD mice by modulating this pathway. Conclusion These findings indicate that the STAT3-cGAS-STING pathway is critical in mediating neuroinflammation associated with AD and may represent a potential therapeutic target for modulating this inflammatory process in AD.