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Tumors can induce systemic disturbances in distant organs, leading to physiological changes that enhance host morbidity. In Drosophila cancer models, tumors have been known for decades to cause hypervolemic "bloating" of the abdominal cavity. Here we use allograft and transgenic tumors to show that hosts display fluid retention associated with autonomously defective secretory capacity of fly renal tubules, which function analogous to those of the human kidney. Excretion from these organs is blocked by abnormal cells that originate from inappropriate activation of normally quiescent renal stem cells (RSCs). Blockage is initiated by IL-6-like oncokines that perturb renal water-transporting cells and trigger a damage response in RSCs that proceeds pathologically. Thus, a chronic inflammatory state produced by the tumor causes paraneoplastic fluid dysregulation by altering cellular homeostasis of host renal units.

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.

Acute disseminated encephalomyelitis (ADEM) is one characteristic manifestation of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). A previously healthy man presented with retro-orbital headache and urinary retention 14 days after Tdap vaccination. Brain and spine MRI suggested a CNS demyelinating process. Despite treatment with IV steroids, he deteriorated, manifesting hemiparesis and later impaired consciousness, requiring intubation. A repeat brain MRI demonstrated new bilateral supratentorial lesions associated with venous sinus thrombosis, hemorrhage, and midline shift. Anti-MOG antibody was present at a high titer. CSF IL-6 protein was >2,000 times above the upper limits of normal. He improved after plasma exchange, then began monthly treatment alone with anti-IL-6 receptor antibody, tocilizumab, and has remained stable. This case highlights how adult-onset MOGAD, like childhood ADEM, can rapidly become life-threatening. The markedly elevated CSF IL-6 observed here supports consideration for evaluating CSF cytokines more broadly in patients with acute MOGAD.

Purpose: To compare the effectiveness of an interproximal brush, a water flosser, and dental floss in removing plaque and reducing inflammation around implant-supported crowns. Materials and Methods: A randomised controlled trial was conducted involving 45 participants with implant-supported single crowns. The participants were randomly assigned to three groups: interproximal brush, water flosser, and dental floss. Plaque index scores, gingival index scores, and interleukin-6 (IL-6) levels were assessed at baseline and after a two-week period. Statistical analysis was performed to compare the outcomes among the groups. Results: Following the second visit, improvements in plaque control were observed across all three interdental cleaning methods. The water flosser demonstrated a slight reduction in IL-6 levels (60.17 ± 3.07 vs 58.79 ± 4.04) compared to the initial visit, although this decrease was not statistically significant. Conversely, both the interdental brush and dental floss exhibited a slight increase in IL-6 levels at the second visit (60.73 ± 2.93 and 55.7 ± 10.64, respectively) compared to the mean at the first visit (58.38 ± 3.24 and 54.6 ± 2.22, respectively). Among the groups, only the interproximal brush demonstrated a statistically significant difference in IL-6 levels (p=0.008), while no statistically significant differences were observed in the dental floss and water flosser groups. Conclusion: Within the study’s limitations, our findings suggest that all three methods of interdental cleaning effectively improve plaque control and reduce gingival inflammation. However, using a water flosser appears to reduce inflammation more effectively, highlighting its potential advantage over the other two methods. Further research is needed to evaluate the long-term efficacy and impact of these methods on implant survival. [ABSTRACT FROM AUTHOR]

The Phenome-Wide Association Study (PheWAS) is increasingly used to broadly screen for potential treatment effects, e.g., IL6R variant as a proxy for IL6R antagonists. This approach offers an opportunity to address the limited power in clinical trials to study differential treatment effects across patient subgroups. However, limited methods exist to efficiently test for differences across subgroups in the thousands of multiple comparisons generated as part of a PheWAS. In this study, we developed an approach that maximizes the power to test for heterogeneous genotype-phenotype associations and applied this approach to an IL6R PheWAS among individuals of African (AFR) and European (EUR) ancestries. We identified 29 traits with differences in IL6R variant-phenotype associations, including a lower risk of type 2 diabetes in AFR (OR 0.96) vs EUR (OR 1.0, p-value for heterogeneity = 8.5 × 10-3), and higher white blood cell count (p-value for heterogeneity = 8.5 × 10-131). These data suggest a more salutary effect of IL6R blockade for T2D among individuals of AFR vs EUR ancestry and provide data to inform ongoing clinical trials targeting IL6 for an expanding number of conditions. Moreover, the method to test for heterogeneity of associations can be applied broadly to other large-scale genotype-phenotype screens in diverse populations.

BACKGROUND: Oxidized phospholipids play a key role in the atherogenic potential of lipoprotein(a) (Lp[a]); however, Lp(a) is a complex particle that warrants research into additional proinflammatory mediators. We hypothesized that additional Lp(a)-associated lipids contribute to the atherogenicity of Lp(a). METHODS: Untargeted lipidomics was performed on plasma and isolated lipoprotein fractions. The atherogenicity of the observed Lp(a)-associated lipids was tested ex vivo in primary human monocytes by RNA sequencing, ELISA, Western blot, and transendothelial migratory assays. Using immunofluorescence staining and single-cell RNA sequencing, the phenotype of macrophages was investigated in human atherosclerotic lesions. RESULTS: Compared with healthy individuals with low/normal Lp(a) levels (median, 7 mg/dL [18 nmol/L]; n=13), individuals with elevated Lp(a) levels (median, 87 mg/dL [218 nmol/L]; n=12) demonstrated an increase in lipid species, particularly diacylglycerols (DGs) and lysophosphatidic acid (LPA). DG and the LPA precursor lysophosphatidylcholine were enriched in the Lp(a) fraction. Ex vivo stimulation with DG(40:6) demonstrated a significant upregulation in proinflammatory pathways related to leukocyte migration, chemotaxis, NF-κB (nuclear factor kappa B) signaling, and cytokine production. Functional assessment showed a dose-dependent increase in the secretion of IL (interleukin)-6, IL-8, and IL-1β after DG(40:6) and DG(38:4) stimulation, which was, in part, mediated via the NLRP3 (NOD [nucleotide-binding oligomerization domain]-like receptor family pyrin domain containing 3) inflammasome. Conversely, LPA-stimulated monocytes did not exhibit an inflammatory phenotype. Furthermore, activation of monocytes by DGs and LPA increased their transendothelial migratory capacity. Human atherosclerotic plaques from patients with high Lp(a) levels demonstrated colocalization of Lp(a) with M1 macrophages, and an enrichment of CD68+IL-18+TLR4+ (toll-like receptor) TREM2+ (triggering receptor expressed on myeloid cells) resident macrophages and CD68+CASP1+ (caspase) IL-1B+SELL+ (selectin L) inflammatory macrophages compared with patients with low Lp(a). Finally, potent Lp(a)-lowering treatment (pelacarsen) resulted in a reduction in specific circulating DG lipid subspecies in patients with cardiovascular disease with elevated Lp(a) levels (median, 82 mg/dL [205 nmol/L]). CONCLUSIONS: Lp(a)-associated DGs and LPA have a potential role in Lp(a)-induced monocyte inflammation by increasing cytokine secretion and monocyte transendothelial migration. This DG-induced inflammation is, in part, NLRP3 inflammasome dependent.

BACKGROUND: Suicide is the second leading cause of death in 12- to 17-year-old adolescents in the USA. Research on biological mechanisms contributing to self-harm risk that could be targeted in treatment could help to prevent suicide and self-harm episodes. AIMS: We aimed to evaluate whether markers of inflammation, interleukin-6 (IL-6) and C-reactive protein (CRP), predict self-harm over 3 months within a sample selected for elevated suicide/self-harm risk at project entry. METHOD: Fifty-one adolescents aged 12-19 years selected for elevated suicide/self-harm risk completed three clinical interviews about suicide attempts and non-suicidal self-injury, 3 months apart. At baseline and 3 months, youth also provided blood samples, from which we assayed levels of IL-6 and CRP. RESULTS: Using generalised mixed models, we found that greater levels of IL-6 predicted more self-harm episodes (odds ratio [OR] = 3.3, 95% CI: 1.1, 10.0) and specifically, non-suicidal self-injury (OR = 3.5, 95% CI: 1.1, 11.2), over 3 months. CONCLUSIONS: The study findings increase our understanding of whether and how inflammation may be implicated in risk of self-harm. IL-6 may be a viable biological marker of short-term risk for self-harm.

BACKGROUND: In contrast to fine particles, less is known of the inflammatory and coagulation impacts of coarse particulate matter (PM10-2.5, particulate matter with aerodynamic diameter ≤10μm and>2.5μm). Toxicological research suggests that these pathways might be important processes by which PM10-2.5 impacts health, but there are relatively few epidemiological studies due to a lack of a national PM10-2.5 monitoring network. OBJECTIVES: We used new spatiotemporal exposure models to examine associations of both 1-y and 1-month average PM10-2.5 concentrations with markers of inflammation and coagulation. METHODS: We leveraged data from 7,071 Multi-Ethnic Study of Atherosclerosis and ancillary study participants 45-84 y of age who had repeated plasma measures of inflammatory and coagulation biomarkers. We estimated PM10-2.5 at participant addresses 1 y and 1 month before each of up to four exams (2000-2012) using spatiotemporal models that incorporated satellite, regulatory monitoring, and local geographic data and accounted for spatial correlation. We used random effects models to estimate associations with interleukin-6 (IL-6), C-reactive protein (CRP), fibrinogen, and D-dimer, controlling for potential confounders. RESULTS: Increases in PM10-2.5 were not associated with greater levels of inflammation or coagulation. A 10-μg/m3 increase in annual average PM10-2.5 was associated with a 2.5% decrease in CRP [95% confidence interval (CI): -5.5, 0.6]. We saw no association between annual average PM10-2.5 and the other markers (IL-6: -0.7%, 95% CI: -2.6, 1.2; fibrinogen: -0.3%, 95% CI: -0.9, 0.3; D-dimer: -0.2%, 95% CI: -2.6, 2.4). Associations consistently showed that a 10-μg/m3 increase in 1-month average PM10-2.5 was associated with reduced inflammation and coagulation, though none were distinguishable from no association (IL-6: -1.2%, 95% CI: -3.0 , 0.5; CRP: -2.5%, 95% CI: -5.3, 0.4; fibrinogen: -0.4%, 95% CI: -1.0, 0.1; D-dimer: -2.0%, 95% CI: -4.3, 0.3). DISCUSSION: We found no evidence that PM10-2.5 is associated with higher inflammation or coagulation levels. More research is needed to determine whether the inflammation and coagulation pathways are as important in explaining observed PM10-2.5 health impacts in humans as they have been shown to be in toxicology studies or whether PM10-2.5 might impact human health through alternative biological mechanisms. https://doi.org/10.1289/EHP12972.

This study examined the role that cytokines may have played in the beneficial outcomes found when outpatient individuals infected with SARS-CoV-2 were transfused with COVID-19 convalescent plasma (CCP) early in their infection. We found that the pro-inflammatory cytokine IL-6 decreased significantly faster in patients treated early with CCP. Participants with COVID-19 treated with CCP later in the infection did not have the same effect. This decrease in IL-6 levels after early CCP treatment suggests a possible role of inflammation in COVID-19 progression. The evidence of IL-6 involvement brings insight into the possible mechanisms involved in CCP treatment mitigating SARS-CoV-2 severity.

Considering the lack of consensus related to the impact of selective IL-6 receptor inhibition on bone remodeling and the scarcity of reports, especially on large bone defects, this study proposed to evaluate the biological impact of the selective inhibitor of interleukin-6 receptor (tocilizumab) in an experimental model of critical calvarial defect in rats. In this preclinical and in vivo study, 24 male Wistar rats were randomly divided into two groups (n=12/group): defect treated with collagen sponge (CG) and defect treated with collagen sponge associated with 2 mg/kg tocilizumab (TCZ). The defect in the parietal bone was created using an 8-mm diameter trephine drill. After 90 days, the animals were euthanized, and tissue samples (skull caps) were evaluated through micro-CT, histological, immunohistochemistry, cytokines, and RT-qPCR analyses. Tocilizumab reduced mononuclear inflammatory infiltration (P0.05). The bone cells (osteoblasts, osteoclasts, and osteocytes) in the defect area were similar in both groups (P>0.05). Tocilizumab reduced inflammatory cytokines, decreased osteogenic protein, and increased proteases in a critical bone defect in rats. Ninety days after the local application of tocilizumab in the cranial defect, we did not find a significant formation of bone tissue compared with a collagen sponge.

INTRODUCTION: IL6 signaling plays an important role in triggering labor and IL6 is an established biomarker of intrauterine infection/inflammation (IUI) driven preterm labor (PTL). The biology of IL6 during IUI at the maternal-fetal interface was investigated in samples from human subjects and non-human primates (NHP). METHODS: Pregnant women with histologic chorioamnionitis diagnosed by placenta histology were recruited (n=28 term, n=43 for preterm pregnancies from 26-36 completed weeks of gestation). IUI was induced in Rhesus macaque by intraamniotic injection of lipopolysachharide (LPS, n=23). IL1 signaling was blocked using Anakinra (human IL-1 receptor antagonist, n=13), and Tumor necrosis factor (TNF) signaling was blocked by anti TNF-antibody (Adalimumab n=14). The blockers were given before LPS. All animals including controls (intraamniotic injection of saline n=27), were delivered 16h after LPS/saline exposure at about 80% gestation. RESULTS: IUI induced a robust expression of IL6 mRNAs in the fetal membranes (chorion-amnion-decidua tissue) both in humans (term and preterm) and NHP. The major sources of IL6 mRNA expression were the amnion mesenchymal cells (AMC) and decidua stroma cells. Additionally, during IUI in the NHP, ADAM17 (a protease that cleaves membrane bound IL6 receptor (IL6R) to release a soluble form) and IL6R mRNA increased in the fetal membranes, and the ratio of IL6 and soluble forms of IL6R, gp130 increased in the amniotic fluid signifying upregulation of IL6 trans-signaling. Both IL1 and TNF blockade suppressed LPS-induced IL6 mRNAs in the AMC and variably decreased elements of IL6 trans-signaling. DISCUSSION: These data suggest that IL1 and TNF blockers may be useful anti-inflammatory agents via suppression of IL6 signaling at the maternal-fetal interface.

ObjectiveMany persons with opioid use disorders (OUDs) have HIV disease and experience clinically significant stress after they enroll in abstinence-based treatment and undergo medically assisted withdrawal. We examined whether opioid withdrawal affects virologic control, inflammatory markers, cognition, and mood in persons with an OUD and HIV, and explored whether measures of withdrawal stress, such as activation of the HPA axis, contribute to alterations in immune function, cognition, and mood.Method and participantsStudy participants were 53 persons with HIV who were admitted for OUD treatment at the City Addiction Hospital in Saint Petersburg, Russian Federation. Participants were examined at admission, at the anticipated peak of withdrawal 3 to 7 days after the last day of a clonidine-based withdrawal process lasting 7 to 14 days, and 3 to 4 weeks after completing withdrawal. At these times, participants received medical exams and were evaluated for symptoms of withdrawal, as well as cognition and mood. Viral load, plasma cortisol, DHEA sulfate ester (DHEA-S), interleukin-6 (IL-6), and soluble CD14 (sCD14) were determined. Multivariable models examined the relationships between markers of HPA activation and the other parameters over time.ResultsHPA activation as indexed by cortisol/DHEA-S ratio increased during withdrawal, as did markers of immune activation, IL-6 and sCD14. There were no significant associations between viral load and indicators of HPA activation. In longitudinal analyses, higher cortisol/DHEA sulfate was related to worse cognition overall, and more mood disturbance. Increase in IL-6 was associated with worse cognitive performance on a learning task. There were no significant associations with sCD14.ConclusionsWorsening of cognition and measures of mood disturbance during withdrawal were associated with activation of the HPA axis and some measures of inflammation. Whether repeated episodes of opioid withdrawal have a cumulative impact on long-term HIV outcomes and neurocognition is a topic for further investigation.

Background: Tocilizumab (TCZ), an interleukin-6 receptor antagonist, is approved for treating rheumatic diseases and has demonstrated efficacy in managing refractory non-infectious uveitis (NIU). This retrospective study aimed to investigate the long-term effects of TCZ on inflammation in the retinal and choroidal compartments in Birdshot NIU. Methods: Eight patients (16 eyes) received TCZ and were included in the analysis. The primary outcomes measured were inflammatory activity in the retina and choroid, assessed by fluorescein angiography (FA) and indocyanine green angiography (ICGA) using the Angiography Scoring for Uveitis Working Group at baseline, 6, 12, 24, and 36 months. Results: The mean follow-up time with TCZ treatment was 33 months. At baseline, the median FA score was 14 (quartiles: 10.25, 15.25), which significantly decreased over time (at 36 months: 8 (5.5, 11); p = 0.004). In contrast, the ICGA score significantly increased within the first year (median at baseline: 5 (4.75, 7.25); at 6 months: 7 (6, 9.25); at 12 months: 7 (6.5, 9.25); p = 0.002), but returned to baseline levels after two years (at 24 months: 5 (5, 6.5); at 36 months: 5.5 (4, 7.5)). Central retinal thickness (CRT) improved significantly after 6 months (median at baseline: 295 µm (275, 322); at 6 months: 275 µm (251, 308); p = 0.01). Conclusion: TCZ is effective in reducing retinal vasculitis and CRT in refractory Birdshot uveitis over time, but might be less effective in managing choroidal inflammation. Further studies are needed to determine the optimal treatment strategies for TCZ therapy in NIU. [ABSTRACT FROM AUTHOR]

The purposes of this study were 1) to investigate if cytokines were increased following a running road-race, and 2) to examine associations between cytokines and hyperthermia. Seventy-seven recreational runners participated in this study which occurred at the 7-mile race in the heat (ambient temperature, 25.0–26.7°C; %RH, 56.7–79.0 ± 5.0%). Before and following the race, blood draws were performed to measure circulating inflammatory cytokines. Core temperature was measured using an ingestible thermistor throughout the race. Core temperature was significantly higher at post-race (39.5 ± 0.7°C) than pre-race (36.9 ± 0.4°C, p < 0.001). IL-6, IL-8, and IL-10 significantly increased at post-race (IL-6, 48.0 ± 22.3 pg⋅ml−1; IL-8, 63.8 ± 23.9 pg⋅ml−1; IL-10, 29.2 ± 20.0 pg⋅ml−1) compared to pre-race (IL-6, 28.4 ± 13.6 pg⋅ml−1; IL-8, 53.2 ± 19.4 pg⋅ml−1; IL-10, 18.6 ± 11.9 pg⋅ml−1, p < 0.001). A greater increase in core temperature pre- to post-race was predicted by the faster finish time, a greater increase in IL-6, and greater body mass loss during the race (r2 = 0.298, p < 0.001). Small associations were found between IL-8 and core temperature at post-race (r = 0.255, p = 0.025). In conclusion, cytokines concentrations and core temperature increased following the race. Moreover, post-race hyperthermia is associated with increased IL-6, faster finish times, and higher body mass losses. [ABSTRACT FROM AUTHOR]

There is a growing interest in using fecal mRNA transcripts as biomarkers for non-invasive detection of colorectal cancer (CRC). The following study compares different RNA extraction and reverse transcription PCR (RT-PCR) methods for mRNA detection in stool and identifies a robust and sensitive protocol. A combination of the Stool total RNA purification kit (Norgen) and the Superscript III one-step RT-PCR kit (Invitrogen) provided high RNA purity and sensitive and consistent mRNA detection, making them well-suited candidates for large-scale studies. We tested the protocol by detecting the mRNA of several immune genes (CXCL1, IL8, IL1B, IL6, PTGS2, and SPP1) in 22 CRCs, 24 adenomatous polyps, and 22 control stool samples. All these inflammatory markers, except for CXCL1, showed a strong association with CRC. Cancer stool samples showed increased levels of IL1B, IL8, and PTGS2 transcripts compared to polyp and control groups. Thus, this work supports the potential use of fecal mRNA as biomarkers for CRC detection. [ABSTRACT FROM AUTHOR]

This study aimed to evaluate the prognostic significance of serum inflammatory factor levels in patients with acute ischemic stroke undergoing revascularization therapy.The study included 94 patients with acute ischemic stroke who underwent revascularization therapy at our hospital. The primary outcome was the modified Rankin scale (mRS) score assessed three months post-treatment. Patients were categorized into two groups: those with a poor prognosis (mRS score > 2) and those with a good prognosis (mRS score≤2). The patients were divided into two groups based on the type of revascularization treatment received: thrombus extraction or intravenous thrombolysis. Logistic regression analysis was used to identify independent risk factors associated with the prognosis of patients treated with recanalization for acute ischemic stroke.Among the 94 patients, 59 had a good prognosis, and 35 had a poor prognosis. At admission, the patients in the good prognosis group exhibited lower NIHSS scores, shorter hospital stays, fewer previous cardiac events, lower LDL levels, fasting glucose, IL-6, and TNF-a compared to those in the poor prognosis group (all P < 0.05). Logistic regression analysis identified TNF-a (odd ratio (OD), 1.623; 95% confidence interval (CI), 1.282–1.933; P = 0.035) and IL-6 (OD, 1.055; 95% CI, 1.024–1.088, P = 0.023) as independent risk factors for poor prognosis in patients after revascularization. Additionally, pre-hospital NIHSS scores, IL-6, and TNF-a levels were significantly lower in the good prognosis group compared to the poor prognosis group, with these differences being statistically significant.IL-6 and TNF-α may serve as prognostic markers for outcomes following revascularization therapy in patients with acute ischemic stroke, including those receiving intravenous thrombolysis. [ABSTRACT FROM AUTHOR]

Background and Aim Methods Results Conclusion Early predictors of morbidity after pancreaticoduodenectomy (PD) can guide tailored postoperative management. Preoperative inflammatory data in patients who underwent PD remained poorly studied in investigating the clinical significance of predicting postpancreatectomy acute pancreatitis (PPAP) and PPAP‐associated postoperative pancreatic fistula (POPF).The clinical data of 467 patients receiving PD between January 2020 and December 2022 were retrospectively reviewed. Preoperative inflammatory data were stratified according to PPAP, and independent risk factors were analyzed. Multivariate logistic regression and subgroup analyses were conducted to compare risk factors of PPAP‐associated POPF and non‐PPAP‐associated POPF.PPAP occurred in 17.6% of patients. The incidence of other complications increased following PPAP. Among the preoperative inflammatory factors, only interleukin‐6 (IL‐6) increased (P < 0.001), leading to a higher incidence of PPAP and POPF (P < 0.001; P = 0.002). The area under the curve of IL‐6 in predicting PPAP was 0.71 (0.65–0.77; P < 0.001). Abnormal preoperative IL‐6 levels (odds ratio [OR]: 5.01; P < 0.001), soft pancreatic texture (OR: 2.15; P = 0.007), and pathology (OR: 2.03; P = 0.012) were independent risk factors for PPAP. The subgroup analysis showed that increased IL‐6 (OR: 1.01; P = 0.006) and soft pancreatic texture (OR: 2.05; P = 0.033) resulted in a higher risk of PPAP‐associated POPF, while increased IL‐8 (OR: 1.01; P = 0.007), older age (OR: 1.05; P = 0.008), and higher body mass index (OR: 1.12; P = 0.021) correlated with non‐PPAP‐associated POPF.PPAP is common after PD; a high preoperative IL‐6 level can predict its occurrence, in addition to associated POPF, which could be due to a preoperative proinflammatory status. [ABSTRACT FROM AUTHOR]

Abstract1. Introduction2. Methods3. Results4. ConclusionThe study aimed to investigate the influence of interleukin (IL)-6 -174 G/C gene polymorphism on graft function (defined as estimated glomerular filtration rate, eGFR), as well as on the tacrolimus (Tac) pharmacokinetics during the five years after kidney transplantation.The study included 115 Caucasian kidney transplant recipients on Tac-based immunosuppression. The patients were followed between 6 and 60 post-transplantation months. Interleukin-6 and CYP3A5 genotyping were performed.Patients carrying the IL-6 -174GG genotype had lower eGFR values compared to the patients with the IL-6 -174GC and −174CC genotypes at the 12th, 48th and 60th post-transplantation months. The linear regression analysis indicated that eGFR at the 6th post-transplantation month and IL-6 -174 G/C polymorphism are independent predictors of eGFR values in the late post-transplantation period. The IL-6 -174GG genotype carriers had lower dose-adjusted trough concentration (C0/D) of Tac compared to the IL-6 C allele carriers during the entire observation period (except at the 24th month), while this effect was independent of the CYP3A5 genotype within three years post-transplantation.Interleukin-6 genotyping could be an additional tool to categorise patients towards the risk of graft deterioration in the long-term post-transplantation period. The IL-6 genotyping could be supportive in genotype-guided dosing of Tac. [ABSTRACT FROM AUTHOR]

Oncostatin M (OSM) is a unique Interleukin 6 (IL-6) family cytokine that plays pivotal roles in numerous biological events by signaling via two types of receptor complexes. While type I OSM receptor complex is formed by glycoprotein 130 (gp130) heterodimerization with Leukemia Inhibitory Factor receptor (LIFR), type II OSM receptor complex is composed of gp130 and OSM receptor (OSMR). OSM is an important contributor to multiple inflammatory diseases and cancers while OSM inhibition has been shown to be effective at reducing symptoms, making OSM an attractive therapeutic target. Using cryogenic electron microscopy (cryo-EM), we characterize full extracellular assemblies of human type I OSM receptor complex and mouse type II OSM receptor complex. The juxtamembrane domains of both complexes are situated in close proximity due to acute bends of the receptors. The rigid N-terminal extension of OSM contributes to gp130 binding and OSM signaling. Neither glycosylation nor pro-domain cleavage of OSM affects its activity. Mutagenesis identifies multiple OSM and OSMR residues crucial for complex formation and signaling. Our data reveal the structural basis for the assemblies of both type I and type II OSM receptor complexes and provide insights for modulation of OSM signaling in therapeutics. OSM is an IL-6 family cytokine that can signal via type I receptor complex (OSM/gp130/LIFR) or type I receptor complex (OSM/gp130/OSMR). Here, the authors report cryo-EM structures of the two types of OSM receptor complexes and provide insights for modulation of OSM signaling in therapeutics. [ABSTRACT FROM AUTHOR]

BACKGROUND: Previous studies have successfully constructed erythropoietin-overexpressed umbilical cord mesenchymal stem cells. It was found that the apoptosis of ischemic and hypoxic human neuroblastoma cell line (SH-SY5Y) was significantly reduced by erythropoietin-overexpressed umbilical cord mesenchymal stem cells. OBJECTIVE: To explore the possible neuroprotective mechanisms of erythropoietin-overexpressed umbilical cord mesenchymal stem cells against ischemic- hypoxic SH-SY5Y and their associated epigenetic mechanisms. METHODS: Oxygen-glucose deprivation was applied to ischemia-hypoxia-induced SH-SY5Y cell injury, and multifactorial assays were applied to detect the expression levels of inflammatory factors in the cells before and after hypoxia and co-culture, respectively, with mesenchymal stem cells, as well as lentiviral- transfected null-loaded plasmids of the negative control mesenchymal stem cells and erythropoietin-overexpressed umbilical cord mesenchymal stem cells. The expression levels of supernatant inflammatory factors were detected by multifactor assay after co-culture. Proteomics was used to detect the differentially expressed proteins of negative control mesenchymal stem cells and erythropoietin-overexpressed umbilical cord mesenchymal stem cells. Cleavage under targets and tagmentation sequencing was applied to detect genomic H3K4me2 modification, and joint analysis was conducted with RNA-sequencing. Lentiviral vector infection was applied to construct the stable knockdown of REST in SH-SY5Y cells. qRT-PCR and western blot assay were performed to detect the expression level of REST. The apoptosis was detected by flow cytometry after co-culture of oxygen-glucose deprivation treatment with erythropoietin- overexpressed umbilical cord mesenchymal stem cells. The expression difference of H3K36me3 group proteins was detected by western blot assay, and transcriptome sequencing was performed to analyze the differentially expressed genes. RESULTS AND CONCLUSION: (1) Compared with the control group, monocyte chemotactic protein 1, interleukin-6, interleukin-18, and interleukin-1 beta, interferon α2, and interleukin-23 levels significantly increased in the cerebrospinal fluid supernatant of patients with ischemic-hypoxic encephalopathy (P < 0.01). (2) After co-culturing SH-SY5Y cells with erythropoietin-overexpressed umbilical cord mesenchymal stem cells under ischemia and hypoxia, the expression levels of monocyte chemotactic protein 1 and interleukin-6 were significantly reduced. (3) Analysis of protein network interactions revealed significant downregulation of monocyte chemotactic protein 1, interleukin-6 related regulatory proteins CXCL1 and BGN. (4) Transcriptome sequencing analysis found that pro-inflammatory genes were down-regulated, and functional enrichment of histone modifications, and the expression of transcription factors REST and TET3 significantly up-regulated in the erythropoietin-overexpressed umbilical cord mesenchymal stem cell group compared with the negative control mesenchymal stem cell group. (5) Combined analysis of transcriptome sequencing and cleavage under targets and tagmentation revealed changes in epigenetic levels as well as significant activation of the promoter regions of transcription factors REST and TET3. (6) Stable knockdown REST in SH-SY5Y cells was successfully constructed; the transcript levels of REST mRNA and protein expression were both decreased. (7) After the REST knockdown SH-SY5Y cells were co-cultured with erythropoietin-overexpressed umbilical cord mesenchymal stem cells, apoptosis was significantly increased and H3K36me3 expression was significantly decreased. Transcriptome sequencing results showed that the expression of inflammation-related genes Aldh1l2 and Cth, as well as apoptosis-suppressor genes Mapk8ip1 and Sod2 was reduced at mRNA transcription level (P < 0.01). (8) It is concluded that erythropoietin-overexpressed umbilical cord mesenchymal stem cells activated the expression of REST and TET3 by altering the kurtosis of H3K4me2 and upregulated the modification level of H3K36me3, which in turn regulated the expression of inflammation-related genes Aldh1l2 and Cth, as well as apoptosis-suppressor genes Mapk8ip1 and Sod2, and facilitated neuronal survival. [ABSTRACT FROM AUTHOR]

Obstructive sleep apnea (OSA) is a common sleep disorder characterized by intermittent hypoxia (IH) and is associated with the occurrence and development of nonalcoholic fatty liver disease (NAFLD). However, the specific mechanism by which OSA induces NAFLD remains unclear. Therefore, effective interventions are lacking. This study aims to investigate the role and mechanism of ferroptosis in OSA‐related NAFLD using clinical data analyses, cell‐based molecular experiments, and animal experiments. Indicators of liver function, lipid accumulation, and ferroptosis are also examined. RNA‐seq, qPCR, western blotting, gene intervention, and E3 ligase prediction using UbiBrowser and co‐IP are used to explore the potential underlying mechanisms. The results show that ferroptosis increases in the liver tissues of patients with OSA. Chronic IH promotes NAFLD progression in mice and is alleviated by a ferroptosis inhibitor Fer‐1. The increased secretion of IL6 by macrophages can promote the expression of MARCH3 in hepatocytes under intermittent conditions, and subsequently promote the ubiquitination and degradation of GPX4 to regulate ferroptosis and lipid accumulation in hepatocytes. Hence, targeted inhibition of MARCH3 may alleviate IH‐induced ferroptosis and lipid accumulation in liver tissues and inhibit the progression of NAFLD. [ABSTRACT FROM AUTHOR]

Objective: Limited research exists on the use of electroconvulsive therapy (ECT) for adolescents with major depressive disorder (MDD). This study investigates the effects of ECT on inflammatory markers in adolescents aged 13-18 suffering from severe MDD, evaluating its efficacy in modulating cellular inflammatory markers and ameliorating depressive symptoms. Methods: A cohort of 38 adolescents with severe MDD received standard antidepressant therapy along with 6-8 ECT sessions spanning two weeks. A control group of 29 age-matched, healthy individuals was also assessed for comparative purposes. The investigation measured variations in depressive symptomatology and inflammatory marker levels (IL-1β, IL-6, IL-10) pre- and post-intervention. Results: Post-ECT, a substantial decrease in pro-inflammatory cytokines (IL-1β and IL-6) and an increase in the anti-inflammatory cytokine (IL-10) were noted. Participants who responded to the treatment showed a significant decline in HAMD-17 scores, which accentuates ECT's therapeutic potential. Comparative analysis indicated a significant correlation between post-treatment inflammatory marker alterations and clinical improvement, implying that shifts in inflammatory state might serve as predictors of treatment response. Moreover, the mitigation of depressive symptoms exhibited a moderate correlation with post-treatment decrements in IL-1β and IL-6 levels, underscoring MDD's intricacy and ECT's comprehensive impact. Conclusion: While initial inflammatory marker levels did not predict the response to ECT, the post-treatment measures appeared to be linked to clinical improvement. These findings suggest ECT's potential effectiveness in treating severe MDD in adolescents and point to the possible predictive value of inflammatory markers in therapeutic outcomes. The study contributes to our understanding of the biopsychosocial framework of MDD and indicates that ECT may be a viable treatment option for this population. [ABSTRACT FROM AUTHOR]

Aims: We evaluated the association of multiple thyroid parameters with the levels interleukin 6 (IL6) and interleukin 8 (IL8) in patients with euthyroid type 2 diabetes (T2D). Methods: A total of 166 adults with euthyroid T2D were examined. Serum IL6, IL8, triiodothyronine (FT3), free thyroxin (FT4), thyroid-stimulating hormone (TSH), five thyroid sensitivity indexes (FT3/FT4, TSH index [TSHI], thyrotroph T4 resistance index [TT4RI], thyroid feedback quantile-based index by FT3 [TFQIFT3], and TFQIFT4), and biochemical parameters were determined. Results: The median age was 64 years (IQR: 54.75,70) and the median duration of diabetes was 10 years (IQR: 3,18). Patients with high levels of IL6 (≥2.38 pg/mL) had lower levels of FT3 and TFQIFT3 (P <0.05). Patients with high levels of IL8 (≥18.1 pg/mL) had lower levels of TSH and higher levels of FT4 (P <0.05). IL6 was negatively correlated with FT3 (r=−0.359, P <0.001), TFQIFT3 (r=−0.273, P =0.009), and FT3/FT4 (r=−0.22, P =0.037). IL8 was negatively correlated with TSH (r=−0.256, P =0.01), TSHI (r=−0.226, P =0.033), and TT4RI (r=−0.244, P =0.021). Binary logistic regression analysis with multiple adjusted models showed that a high level of IL6 was negatively associated with FT3 (aOR: 0.529; 95%CI: 0.302, 0.926, P =0.026), and that a high level of IL8 was negatively associated with TSH (aOR: 0.343; 95%CI: 0.155, 0.759; P =0.008) and TT4RI (aOR: 0.398;95%CI: 0.191, 0.831; P= 0.014). Conclusion: Patients with euthyroid T2D who had lower levels of FT3 had significantly higher levels of IL6, and those with lower levels of TSH and TT4RI had significantly higher levels of IL8. [ABSTRACT FROM AUTHOR]

High-grade (HGOC) and low-grade ovarian carcinoma (LGOC) are distinct malignancies with different biological features, treatment paradigms, and life expectancies. However, differences in quality of life (QOL), sleep, and depressive symptoms have not been examined by grade, and neither have inflammatory profiles associated with these symptoms. We aim to characterize QOL and biomarkers by OC grade. Participants included patients with HGOC (N = 578) or LGOC (N = 85). Participants completed baseline assessments of psychosocial factors prior to primary surgery or neoadjuvant chemotherapy and contributed saliva for cortisol and blood for interleukin-6 (IL-6) quantification. Samples were collected intraoperatively to quantify tumor cortisol. General linear models were used to examine differences in biological and psychological variables by grade. At baseline, patients with LGOC reported less depression (p = 0.018) and sleep disturbances (p = 0.014), but no significant difference in depressive mood (p = 0.11) or QOL (p = 0.51) compared to patients with HGOC, adjusting for age and disease stage. There were trends towards lower tumor cortisol levels (p = 0.078) in LGOC compared to HGOC. One-year post-diagnosis, we found a significant improvement in QOL and fatigue, and a decrease in vegetative depression and IL-6 levels irrespective of grade. We present the first characterization of psychosocial experiences of patients with LGOC. Despite having a better disease prognosis, patients with LGOC were just as likely to have mood disturbances as those with HGOC. There was a trend towards differences in tumor cortisol by grade. Our findings highlight the need to address well-being in patients with both low- and high-grade ovarian malignancies. • Low-grade ovarian cancer patients report less vegetative depression than high-grade. • Both low- and high-grade patients report sleep disturbances that do not improve over time. • No difference in overall quality of life by grade at baseline or over time. • Trend towards lower tumor cortisol in low- versus high-grade patients. • No systematic differences in IL-6 or cortisol by grade were observed. [ABSTRACT FROM AUTHOR]

ABSTRACT Castleman Disease (CD) is a rare lymphoproliferative disorder that can be separated into two primary forms: Unicentric Castleman disease (UCD) and multicentric Castleman disease (MCD). UCD is localized, while MCD is systemic. Though UCD generally has a favorable prognosis following surgical resection, more aggressive forms of this disease have been identified, including cases associated with dendritic and spindle cell proliferation. Genetic analysis has deepened our understanding of UCD. Despite advancements in better understanding the pathophysiology of UCD, challenges persist in the diagnosis, management, and treatment due to its rarity and heterogeneity. Here, we review current knowledge on UCD, highlighting the epidemiology, clinical presentation, diagnostic criteria, and treatment options while emphasizing the need for further research and innovation in therapeutic strategies. [ABSTRACT FROM AUTHOR]

Acute liver injury (ALI) presents a challenging problem worldwide, prompting extensive research efforts. Cellular senescence has been found to be induced following ALI, and targeting cellular senescence has shown therapeutic potential. Therefore, understanding the expression of senescence-related genes in ALI can help to explore pathogenesis and treatment of this common disease. Carbon tetrachloride (CCl4) is commonly used to study ALI. Although polymerase chain reaction (PCR) is a convenient and economical molecular biology technique widely used in basic medicine, research on selecting suitable reference genes to obtain objective and reproducible PCR data is scarce. Moreover, evidence supporting the choice of reference genes for experimental studies of CCl4-induced ALI and hepatic senescence in mice is limited. In this study, we obtained murine livers at four time points (0, 12, 24, and 48 h) following CCl4 treatment. We used five algorithms (geNorm, BestKeeper, NormFinder, delta Ct, and RefFinder) to rank 12 candidate genes in real-time reverse-transcription quantitative PCR (RT-qPCR) experiments. Focusing on cellular senescence in this model, we adopted four senescence-associated secretory phenotype (SASP) genes (Il6, Il1b, Ccl2, and Ccl5) as target genes. Our results confirmed Gapdh and Tbp as suitable reference genes in murine CCl4-induced ALI models. Furthermore, we provide a table of published studies recommending reference genes for various liver disease models. This study provides a valuable reference for enhancing the reliability and reproducibility of ALI molecular findings. [ABSTRACT FROM AUTHOR]

Objective To analyze levels of pan-immune-inflammation value (PIV), interleukin-6 (IL-6), heparin-binding protein (HBP) and prealbumin (PAB) in patients with severe community-acquired pneumonia (CAP), and their values in evaluating the therapeutic effect at 72 h after admission. Methods According to the initial (72 h) treatment outcome, 120 patients with severe CAP (the severe group) were divided into the effective group (n=87) and the failed group (n=33). Meanwhile, 120 patients with non-severe CAP admitted in the same period were selected as the non-severe group. PIV, IL-6, HBP and PAB levels on the day after admission were compared between the severe group, the non-severe group, the failed group and the effective group. The value of above indicators in evaluating the condition of CAP and the therapeutic effect at 72 h after admission separately and in combination were analyzed using receiver operating characteristic (ROC) curves. Results Compared with the non-severe group, there were higher PIV, IL-6 and HBP levels, and lower PAB levels in the servere grouop (P < 0.05). ROC curves indicated that for evaluating severe CAP using a single indicator, the area under the curve (AUC) of PIV was the highest [0.830 (95%CI: 0.780-0.881)]. The AUC of PIV combined with IL-6, HBP and PAB for evaluating severe CAP was 0.929 (95%CI: 0.892-0.967), which was higher than that of evaluation using a single indicator (P < 0.05). Compared with the effective group, there were higher PIV, IL-6 and HBP levels, and lower PAB level in the failed group (P < 0.05). ROC curves indicated that for evaluating the therapeutic effect on severe CAP at 72 h after admission using a single indicator the AUC of PIV was the highest [0.777 (95%CI: 0.692-0.862)]. The AUC of PIV combined with IL-6, HBP and PAB for evaluating the therapeutic effect on severe CAP at 72 h after admission was 0.916 (95%CI: 0.846-0.986), which was higher than that of evaluation using a single indicator (P < 0.05). Conclusion Detection of PIV combined with IL-6, HBP and PAB has a good value in evaluating the condition of patients with CAP and the therapeutic effect on severe CAP at 72 h after admission. [ABSTRACT FROM AUTHOR]

Objective To investigate the protective effect and mechanism of ginsenoside Rg1 (G-Rg1) on interleukin6 (IL-6) -induced neuronal injury in rats by regulating Janus activated kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) signaling pathway. Methods After culture, rat hippocampal neurons were divided into the control group (normal culture), the IL-6 model group (50 µg/L IL-6 was used to treat rat hippocampal neurons for 18 h to simulate the inflammatory environment in brain), the G-Rg1 low dose (10 µmol/L) group and the G-Rg1 high dose (40 µmol/L) group. After 48 h of normal culture, the survival rate of hippocampal neurons was determined by MTT method. The total iron load of neurons was detected by spectrophotometry, and levels of ferroptosis markers glutathione (GSH) and glutathione peroxidase 4 (GPX4) were detected. The mRNA expression level of ferroportin 1 (FPN1) in hippocampal neurons was detected by qRTPCR. The expression of proteins related to the neuronal JAK/STAT3 signaling pathway was detected by Western blot assay. Results Compared with the CON group, the neuronal survival rate, GSH content, GPX4 content and FPN1 mRNA expression level were decreased in the IL-6 model group, and the total iron load, p-JAK and p-STAT3 protein expression levels were increased (P＜0.05). Compared with the IL-6 model group, the neuronal survival rate, GSH content, GPX4 content and FPN1 mRNA expression level were increased in the low-dose and high-dose G-Rg1 groups, and the total iron load, p-JAK and p-STAT3 protein expression levels were decreased (P＜0.05). Changes of the above indicators were more significant in the high-dose G-Rg1 group than those in the low-dose G-Rg1 group (P＜0.05). Conclusion The mechanism of G-Rg1 alleviating ferroptosis of hippocampal neurons in rats may be related to the inhibition of IL-6/JAK/STAT3 signaling pathway, up-regulation of FPN1 expression, and prevention of iron overload. [ABSTRACT FROM AUTHOR]

Background: There is an increase in the prevalence of intermittent post menstrual spotting in women with previous one or more cesarean section with no sufficient study about the association between cesarean scar defect, cesarean scar defect ultrasound measurement and post menstrual bleeding, so this study is conducted to assess this association. So, we aimed to evaluate the relationship between the caesarean scar defect ultrasound measurement and post menstrual spotting in women with previous Cesarean section. Methods: The current prospective cohort study was conducted in obstetrics and gynecology outpatient & fetal medicine unit at Zagazig University Hospital on 48 Patients, who had a previous caesarean section and complained of unexplained abnormal uterine bleeding. All patients were evaluated clinically as well as by transvaginal ultrasound. Cesarean scar niche assessed by transvaginal sonography (TVS) with measurement of niche dimensions (length, depth, width and residual myometrium thickness). Results: We found a significant positive correlation between menstrual duration, width, depth, and spotting, a significant negative correlation between residual myometrium thickness (RMT) and spotting, and a weak negative correlation between adjacent myometrial thickness (AMT) and spotting. There was a significant positive correlation between dysmenorrhea, dyspareunia, PID, subfertility, and spotting. A significant weekpositive correlation between dysuria and spotting and a significant negative correlation between menstrual regularity and spotting. Conclusions:Caesarean scar defect ultrasound measurements could be used for prediction of post-menstrual spotting. [ABSTRACT FROM AUTHOR]

Background: The immune system has been a hotspot for epilepsy researchers during the past decade. The outcome of this is an everincreasing body of knowledge about the role of several immunological variables in the development of epilepsy and seizures epileptogenesis. Methods: We carried out this case-control study in the Neurology Clinic and Neurology Department, Faculty of Medicine, Zagazig University Hospitals, on 224 persons categorized into two groups: 112 epileptics and 112 controls. Comprehensive evaluations were conducted on all patients, including electroencephalograms, brain MRIs, standard laboratory tests, as well as serum interleukin-6 (IL-6) levels that were assessed by an enzyme-linked immunosorbent assay (ELISA). Results: Patients with epilepsy had a significantly elevated serum IL-6 level compared to the control group (P<0.001). Astatistically significant difference was detected between drug-responsive and drug-non-responsive patients as regard IL-6, as the mean level of IL-6 was higher among drug-non-responsive patients (P=0.02). Also, IL-6 level was significantly higher among patients with generalized tonic-clonic seizures (P=0.02). The median level of IL-6 was significantly higher among patients who received polytherapy compared with those on monotherapy (P=0.001). Also, the median IL-6 level was significantly higher among patients who had generalized epileptiform activity compared with those who had partial-onset seizures(P=0.01). Conclusions: The correlation between serum IL-6 levels and epilepsy was statistically significant. Epileptic seizures could induce the production of IL-6, and a high concentration of IL-6 could be an obvious neurotoxic and pro convulsion factor. [ABSTRACT FROM AUTHOR]

Inflammation is critical in the development of acute liver failure (ALF). Peroxisome proliferator-activated receptor delta (PPARδ) regulates anti-inflammatory responses and is protective in several diseases such as obesity and cancer. However, the beneficial effects and underlying mechanisms of PPARδ agonist GW501516 in ALF remain unclear. This study investigated the molecular mechanisms underlying the anti-inflammatory effects of GW501516 in macrophages and assessed its protective potential against lipopolysaccharide (LPS)/galactosamine (GalN)-induced ALF. In vivo administration of GW501516 significantly reduced LPS/GalN-induced hepatotoxicity, as evidenced by lower mortality, decreased liver damage, and attenuated secretion of IL-1β, IL-6, and TNF-α. GW501516 treatment also decreased LPS-induced nitric oxide synthase 2 (NOS2) expression and nitric oxide (NO) production in RAW264.7 cells, an effect reversed by PPARδ siRNA. Additionally, GW501516 inhibited LPS-induced phosphorylation of p38 and c-Jun N-terminal kinase (JNK), suggesting that inactivation of these MAPKs contributes to its effects. The secretion of IL-6, TNF-α, and NF-κB DNA-binding activity were also suppressed by GW501516, while the nuclear translocation of the NF-κB p65 subunit was unaffected. In conclusion, our findings suggest that GW501516 exerts protective effects in ALF by inhibiting the production of inflammatory mediators. Therefore, GW501516 may act as a potential agent for developing anti-inflammatory therapies for ALF. [ABSTRACT FROM AUTHOR]

Background/Objectives: Severe clinical course and mortality from COVID-19 are mostly associated with increased concentrations of IL-6 and IL-10. Findings from clinical trials suggest that both statins and renin–angiotensin–aldosterone system inhibitors (RAASI) might have the potential to reduce unfavorable outcomes in patients with COVID-19. The aim of this study was to evaluate the effect of statins and RAASI on the cytokine concentrations in COVID-19 patients. Methods: SARS-CoV-2 infected patients were enrolled in this study, and demographic, clinical, and routine laboratory data were evaluated. Plasma cytokine levels were measured by multiplex assay. Results: COVID-19 patients with chronic cardiovascular diseases (CVD) had significantly lower median plasma IL-6 levels than COVID-19 patients with no co-morbidities (26 vs. 53 pg/mL, p = 0.021). COVID-19 patients with CVD who were taking statins had significantly lower median concentrations of IL-6 (21 vs. 44 pg/mL, p = 0.027), TNFα (21 vs. 39.5 pg/mL, p = 0.036), and IL-10 (19 vs. 25.5 pg/mL, p = 0.025) compared to COVID-19 patients with no CVD. In a binary logistic regression model, IL-6 was a significant variable, with an odds ratio value of 0.961 (95% CI 0.929–0.995). Regarding RAASI, only plasma IL-6 (22 vs. 44 pg/mL, p = 0.012) levels were found to be significantly lower in COVID-19 patients with CVD consuming these medications compared to patients who did not have any CVD. Conclusions: COVID-19 patients who had chronic cardiovascular co-morbidities and who were administered statins or RAASI had significantly lower concentrations of IL-6 than COVID-19 patients who did not have any co-morbidities. These findings suggest that the use of statins or RAASI may be of value in COVID-19 patients. [ABSTRACT FROM AUTHOR]

Background/Objectives: This retrospective study analyzed soluble urokinase plasminogen activator receptor (suPAR) plasma levels alongside routine inflammatory markers, including the neutrophil-to-lymphocyte count ratio, C-reactive protein (CRP), interleukin-6 (IL-6), procalcitonin (PCT), and D-dimers in COVID-19 patients hospitalized during the Omicron wave of the pandemic. Methods: We measured plasma suPAR levels using a suPARnostic® Quick Triage kit. We divided COVID-19 patients into two groups based on the severity of SARS-CoV-2 infection according to the National Institutes of Health (NIH) criteria. The logistic regression analysis tested the predictive value of the biomarkers. Results: We evaluated 160 consecutive COVID-19 patients hospitalized between January and August 2022. The cohort exhibited a high incidence of comorbidities, with an in-hospital mortality rate of 5.6%. Upon admission, the median suPAR plasma levels were not significantly different between patients with mild COVID-19 (n = 110) and those with moderate/severe disease (n = 50), with 7.25 ng/mL and 7.55 ng/mL, respectively. We observed significant differences (p < 0.01) between the groups for CRP and IL-6 levels that were higher in moderate/severe disease than in mild infection. Additionally, suPAR plasma levels were above the normal range (0–2.00 ng/mL) in all patients, with a significant positive correlation identified between suPAR levels and serum IL-6, PCT, and creatinine levels. Conclusions: These findings indicate that COVID-19 during the Omicron wave is strongly associated with elevated suPAR levels; however, these levels do not directly correlate with the severity of SARS-CoV-2 infection. [ABSTRACT FROM AUTHOR]

Ovarian torsion (OT) is a rare gynaecological emergency that requires a prompt diagnosis for optimal patient management. To determine whether there were any biomarkers suitable for the non-invasive detection of OT, two independent reviewers performed systematic searches of five literature databases (PubMed, Medline, Scopus, Cochrane, and CINAHL) from inception until October 1st, 2023. Following the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines, the search included patients with OT that had quantified biomarker expression with no age, geographical location, publication date, language, or setting restrictions. Articles were excluded if OT was found incidentally, was based on qualitative analyses, or were not primary research articles. Full texts of 23 selected articles were assessed for risk of bias and quality assurance using a modified Newcastle–Ottawa Scale (NOS) for clinical studies and SYRCLE's risk of bias tool for the assessment of pre-clinical (animal) studies. A total of 11 articles described studies on animals and all described serum biomarkers comparing results between OT versus a sham operation, a control group, or readings before and after OT. Ischaemia-modified albumhumin (IMA), serum D-dimer (s-DD), heat shock protein-70 (hsp-70), Pentraxin-3 (PTX3), and c-reactive protein (CRP) each showed the most promise, with p-values for the difference between OT and control groups achieving ≤ 0.001. In studies of humans, the biomarkers ranged from 16.4 to 92.3% sensitivity and 77–100% specificity. The most promising biomarkers for the early prediction of OT in patients included s-DD, interleukin-6 (IL-6), IMA, and tumour necrosis factor-alpha (TNF-α). Signal peptide, CUB domain, and EGF-like domain-containing 1 (SCUBE1) had a high specificity at 93.3%, second only to s-DD and a positive likelihood ratio (LR) > 10. IMA was the only other biomarker that also had a positive LR > 10, making it a promising diagnostic biomarker. The studies identified by this systematic literature review each analysed small patient groups but IMA, DD, and SCUBE1 nevertheless showed promise as serum biomarkers with a pooled LR > 10. However, further well-designed studies are needed to identify and evaluate individual markers or diagnostic panels to help clinicians manage this important organ-threatening condition. [ABSTRACT FROM AUTHOR]

Simple Summary: Cytokines are substances important in the regulation of the immune system. The cytokine interleukin-6 (IL-6) is important for the normal function of the immune system and also plays a pathogenic role in multiple diseases such as chronic inflammation, autoimmunity cancer, sepsis, and cardiovascular disease. A new immunoregulatory mechanism is described. Proteolytic degradation of serum albumin generates immunoregulatory neo-structures, one of which has the capacity to induce IL-6, Il-6-inducing factor, IL-6IF. The serum concentration of this factor is significantly increased in advanced stages of colon cancer and is associated with cancer-specific survival of the patients. IL-6IF is immunogenic, resulting in the production of autoantibodies with the capacity to inhibit IL-6IF-induced IL-6 synthesis. The specificity of these autoantibodies, using the single B-cell technique, enables the production of human monoclonal antibodies, which therapeutically can be used to specifically inhibit pathological IL-6 production, leaving IL-6 for the normal function of the immune system intact. Background: Interleukin-6 is dysregulated in multiple pathological conditions, e.g., cancer and inflammatory diseases. Aim: To investigate new mechanisms for the regulation of pathological IL-6 production. Methods: PBMCs (peripheral blood mononuclear cells) stimulated by cancer serum factors or specific peptides produce interleukin-6 (IL-6). Immunoregulatory albumin neo-structures and peptides were identified with 2D gel electrophoresis and MALDI-TOF-MS (matrix-assisted laser desorption/ionization time-of-flight mass spectrometry) analyses. Il-6 and albumin neo-structures were determined by ELISA (enzyme-linked immunosorbent assay). Results: Conformational changes in normal serum albumin by proteolytic degradation generates an IL-6-inducing neo-structure, IL-6-inducing factor (IL-6IF). This neo-structure is immunogenic which results in the production of autoantibodies. IL-6 production induced by IL-6IF and cancer patient sera is inhibited by specific antibodies. The serum concentration of IL-6IF is significantly higher in advanced cancer stages, and its presence is significantly correlated with the survival of the patients. Conclusions: A new mechanism for the induction IL-6 synthesis is presented. Based on this mechanism, the pathological IL-6 production related to enhanced proteolytic activity can be diagnosed and selectively inhibited by specific antibodies. Such antibodies were identified and purified. Thus, the neo-structure, inducing pathological IL-6 production, associated with a reduced survival of cancer patients, can be selectively removed by the therapeutic administration of antibodies leaving the function of IL-6 needed for the normal activity of the immune system intact. [ABSTRACT FROM AUTHOR]

Objectives: Maternal socioeconomic status (SES) is an important predictor of adverse birth outcomes and postnatal health across global populations. Chronic inflammation is implicated in cardiometabolic disease risk in high‐income contexts and is a potential pathway linking maternal adversity to offspring health trajectories. To clarify how socioeconomic inequality shapes pregnancy inflammation in middle‐income settings, we investigated SES as a predictor of inflammatory cytokines in late gestation in a sample from the Cebu Longitudinal Health Nutrition Survey in Cebu, Philippines. Methods: We used multiple regression to evaluate maternal SES, reflected in household assets, as a predictor of general inflammation (C‐reactive protein), inflammatory cytokines (interleukin‐6, interleukin‐10), and inflammatory balance (n = 407). Inflammatory markers were measured at 29.9 weeks gestation in dried blood spots, and a measure reflecting relative balance of IL6 and IL10 was calculated to capture pro‐ versus anti‐inflammatory skewed immune profiles. Results: Greater household assets significantly predicted lower IL6 concentration (p < 0.001), with a trend toward lower IL6 relative to IL10 (p = 0.084). C‐reactive protein and IL10 were not individually related to SES. Conclusions: The inverse relationship between SES and pregnancy inflammation in Cebu is consistent with results from high‐income settings. These findings further highlight the influence of socioeconomic conditions on immune regulation during pregnancy. Given the evidence that gestational inflammation impacts offspring fetal growth, our results suggest that social and economic effects on immune function may be an important pathway for the intergenerational transmission of health disparities. [ABSTRACT FROM AUTHOR]

Background: An increased intestinal permeability is a common feature in patients with diarrhoea-predominant irritable bowel syndrome (IBS-D). Probiotics have shown to improve IBS symptoms and might also affect intestinal barrier function. Aim: The aim of this study was to investigate the effects of a 6-week intervention with Limosilactobacillus reuteri ATCC PTA 6475 alone (single strain) or in combination with Limosilactobacillus reuteri DSM 17938 (dual strain) on gut barrier function, immune markers, and symptoms in IBS-D patients (ClinicalTrials.gov registration number: NCT03986476). Methods: 65 IBS-D patients were randomised into three groups (placebo, single strain, dual strain). Small and large intestinal permeability were assessed using a multi-sugar urinary recovery test. Blood, saliva, faecal samples, and several symptom scales were collected before, and after three and six weeks of intervention. Results: Small and large intestinal permeability as well as other markers of gut barrier function were not significantly affected by the probiotic interventions. Serum IL-6 levels showed a tendency to be reduced in the single strain group (descriptive p = 0.052). In addition, high-sensitivity C-reactive protein was significantly reduced in the dual strain group (p = 0.041). The participants in both treatment groups reported less gastrointestinal symptoms after three weeks, but this reached significance only in the dual strain group (total score: p = 0.032, pain subscore: p = 0.028). After six weeks, none of the assessed symptoms were significantly different from the placebo. Conclusion: The probiotic compounds investigated in this study did not seem to affect IBS-D patients' gut barrier function, but showed potential anti-inflammatory and symptom-improving properties, which need to be confirmed in larger study cohorts. [ABSTRACT FROM AUTHOR]

Background: Glioblastoma multiforme (GBM) is an aggressive tumor, difficult to treat pharmacologically because of the blood-brain barrier (BBB), which is rich in ATP-binding cassette (ABC) transporters and tight junction (TJ) proteins. The BBB is disrupted within GBM bulk, but it is competent in brain-adjacent-to-tumor areas, where eventual GBM foci can trigger tumor relapse. How GBM cells influence the permeability of BBB is poorly investigated. Methods: To clarify this point, we co-cultured human BBB models with 3 patient-derived GBM cells, after separating from each tumor the stem cell/neurosphere (SC/NS) and the differentiated/adherent cell (AC) components. Also, we set up cultures of BBB cells with the conditioned medium of NS or AC, enriched or depleted of IL-6. Extracellular cytokines were measured by protein arrays and ELISA. The intracellular signaling in BBB cells was measured by immunoblotting, in the presence of STAT3 pharmacological inhibitor or specific PROTAC. The competence of BBB was evaluated by permeability assays and TEER measurement. Results: The presence of GBM cells or their conditioned medium increased the permeability to doxorubicin, mitoxantrone and dextran-70, decreased TEER, down-regulated ABC transporters and TJ proteins at the transcriptional level. These effects were higher with AC or their medium than with NS. The secretome analysis identified IL-6 as significantly more produced by AC than by NS. Notably, AC-conditioned medium treated with an IL-6 neutralizing antibody reduced the BBB permeability to NS levels, while NS-conditioned medium enriched with IL-6 increased BBB permeability to AC levels. Mechanistically, IL-6 released by AC GBM cells activated STAT3 in BBB cells. In turn, STAT3 down-regulated ABC transporter and TJ expression, increased permeability and decreased TEER. The same effects were obtained in BBB cells treated with STA-21, a pharmacological inhibitor of STAT3, or with a PROTAC targeting STAT3. Conclusions: Our work demonstrates for the first time that the degree of GBM differentiation influences BBB permeability. The crosstalk between GBM cells that release IL-6 and BBB cells that respond by activating STAT3, controls the expression of ABC transporters and TJ proteins on BBB. These results may pave the way for novel therapeutic tools to tune BBB permeability and improve drug delivery to GBM. [ABSTRACT FROM AUTHOR]

To evaluate the levels of YKL40, IL-6(interleukin-6), IL-8(interleukin-8), IL-10(interleukin-10), TNF-α (tumor necrosis factor-α) in OSAS (obstructive sleep apnea syndrome)children and explore the mechanism of YKL40 promoting inflammatory factors overexpression in tonsils. qPCR and ELISA were used to identify the expression of YKL40, IL-6, IL-8, IL-10, and TNF-α in the tonsils of OSAS children. Primary tonsil lymphocytes (PTLCs) were cultured and recombinant human YKL40(rhYKL40)was used to stimulate PTLCs in different concentrations and at different time points. The activation of NF-κB in PTLCs was screened by western blotting. Relative mRNA of YKL40, IL-6, IL-8, TNF-α was over expressed in OSAS-derived tonsil tissue and the levels of YKL40, IL-6, IL-8, and TNF-α was increased in OSAS-derived protein supernatant of tonsil tissue.The relative mRNA expression of IL-6, IL-8 and TNF-α increased under the treatment of YKL40 (100 ng/mmol for 24 h). The phosphorylation of p65 in NF-κB pathway was stimulated in the process. The levels of YKL40, IL-6, IL-8, and TNF-α increases in OSAS children, and YKL40 promotes the overexpression of IL-6, IL-8 and TNF-α in PTLCs via NF-κB pathway. The result implements that inflammation may play an important role in the pathogenesis of OSAS in children. [ABSTRACT FROM AUTHOR]

Objectives: Juvenile scleroderma is a heterogeneous group of diseases associated with sclerotic skin lesions, grouped as juvenile systemic sclerosis and juvenile localized scleroderma. This study aims to measure the cytokine and chemokine levels involved in interferon (IFN) signalling in patients with juvenile scleroderma and determine their correlation with disease severity. Methods: Twenty-nine juvenile localized scleroderma, five juvenile systemic sclerosis, and nine healthy controls were included in the study. Cytokines and chemokines involved in IFN gene signalling (IL-1, IL-6, IL-8, IP-10, MCP1, TNF-α, CXCL-11, IFN-α, IFN-β, IFN-γ) and IFN-stimulated genes (ISGs), including IFI27, IFI44, ISIG15, IFIT1, OAS1, RSAD2, were measured by ELISA and RT-PCR method, respectively. Results: A significant increase in IFN-α, IFN-β, IFN-γ, TNF-α, IL-1, IL-6 IL-8, IP-10, and MCP1 levels was observed in patients with juvenile systemic sclerosis compared with the healthy control group. Furthermore, IFN-α and IP-10 were elevated in both juvenile localized scleroderma and juvenile systemic sclerosis compared to the healthy control group. IFN-γ and IFN-α positively correlated with LoSAI and LoSDI levels, respectively. According to PGA-A analysis, IFN-β, IFN-γ, TNF-α, IL-8, IP10, MCP1, and CXCL11 were significantly higher in active disease than in the inactive state in both groups. Conclusion: The results suggest that IFN signalling may be impaired in patients with juvenile scleroderma. Significant changes were observed in cytokines and genes related to IFN signalling, which may have a crucial role in monitoring disease activity. In addition, we have gained important insights into the possibility of using IFN-α and IFN-γ as biomarkers for monitoring juvenile scleroderma activity and damage. [ABSTRACT FROM AUTHOR]

Background: India currently accounts for a majority of global suicide deaths. Research in European ancestry has established that suicide mortality has a significant genetic component, and suggests that inflammation may play a crucial role in the pathophysiology of suicide. Inflammation is also highly relevant in regions of increased pollution exposure, such as the megacities of India. To address the existing gaps in genetic research on suicide and possible association with inflammatory biomarkers, we examined genetic polymorphism and clinical risk phenotypes in a population-based suicide-death cohort, India. Material and methods: Genotyping of IL-1β(rs16944) & (rs1143627), IL-4(rs2070874), IL-6(rs1800795) and IL-10(rs1800896) was done in 234 post-mortem suicide-death cases and 256 post-mortem controls (N = 490) using PCR RFLP method. Results: Our analyses identified three significant (p < 0.001) associations of cytokine variants with suicide death, including IL-1β(rs16944), OR = 0.627; IL-4(rs2070874), OR = 0.524; and IL-6(rs1800795), OR = 2.509. Cases were more likely female and were more likely to have a history of psychiatric illness, though rate of psychiatric illness was low in suicide cases(9%). Conclusion: Our genetic results are generally consistent with previous research on risk for depression and suicidal behaviour, and both genetic and phenotypic results provide new insights into risk factors that may contribute to suicide in India. [ABSTRACT FROM AUTHOR]

Traumatic spinal cord injuries (SCI) result in devastating impairment to an individual's functional ability. The pathophysiology of SCI is related to primary injury but further propagated by secondary reactions to injury, such as inflammation and oxidation. The inflammatory and oxidative cascades ultimately cause demyelination and Wallerian degeneration. Currently, no treatments are available to treat primary or secondary injury in SCI, but some studies have shown promising results by lessening secondary mechanisms of injury. Interleukins (ILs) have been described as key players in the inflammation cascade after neuronal injury; however, their role and possible inhibition in the context of acute traumatic SCIs have not been widely studied. Here, we review the relationship between SCI and IL-6 concentrations in the CSF and serum of individuals after traumatic SCIs. Furthermore, we explore the dual IL-6 signaling pathways and their relevance for future IL-6 targeted therapies in SCI. [ABSTRACT FROM AUTHOR]

• Bifidobacterium dentium reduces prenatal stress-induced reductions in gestational weight gain. • B. dentium has intergenerational effects on inflammation, reducing maternal CCL2 and offspring IL6. • Indole-3-propionic acid and kynurenic acid levels are increased in both dam and offspring by B. dentium. • Gestationally-administered B. dentium improves social behavior outcomes in adult offspring. Prenatal stress (PNS) profoundly impacts maternal and offspring health, with enduring effects including microbiome alterations, neuroinflammation, and behavioral disturbances such as reductions in social behavior. Converging lines of evidence from preclinical and clinical studies suggest that PNS disrupts tryptophan (Trp) metabolic pathways and reduces gut Bifidobacteria, a known beneficial bacterial genus that metabolizes Trp. Specifically, previous work from our lab demonstrated that human prenatal mood disorders in mothers are associated with reduced Bifidobacterium dentium in infants at 13 months. Given that Bifidobacterium has been positively associated with neurodevelopmental and other health benefits and is depleted by PNS, we hypothesized that supplementing PNS-exposed pregnant dams with B. dentium would ameliorate PNS-induced health deficits. We measured inflammatory outputs, Trp metabolite levels and enzymatic gene expression in dams and fetal offspring, and social behavior in adult offspring. We determined that B. dentium reduced maternal systemic inflammation and fetal offspring neuroinflammation, while modulating tryptophan metabolism and increasing kynurenic acid and indole-3-propionic acid intergenerationally. Additional health benefits were demonstrated by the abrogation of PNS-induced reductions in litter weight. Finally, offspring of the B. dentium cohort demonstrated increased sociability in males primarily and increased social novelty primarily in females. Together these data illustrate that B. dentium can orchestrate interrelated host immune, metabolic and behavioral outcomes during and after gestation for both dam and offspring and may be a candidate for prevention of the negative sequelae of stress. [ABSTRACT FROM AUTHOR]

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Background: CRP is a hepatic acute-phase reactant protein, which is primarily induced by the interleukin-6 action due to an inflammatory/infectious process. Precision is closeness of agreement between indications or measured quantity values obtained by replicate measurements on the same or similar objects under specified conditions. Precision goals should be stated as the maximum allowable imprecision, SD, and/or CV expressed as a percentage (% CV) at each analyte´s concentration to be tested. The aim of this study was to verify the two different manufacturers' claims on C-reactive protein (CRP) based on the Clinical and Laboratory Standards Institute (CLSI) EP 15-A3 document. Methods: To represent low, intermediate, and high level, 3 sera pools were prepared from remnant sera of patients. After the familiarization period of the operator, two runs per day (morning and afternoon) with ten replicates per run were performed for five days for each measurand concentrations. Original CRP kit of Beckman uses latex immunoturbidimetric assay (OSR 6299, Beckman) and novel kit practices enzymatic immunoturbidimetric assay (B21220, Bioanalytic) were utilized to measure CRP. For both kits, only one calibration was applied before the study in favor of daily internal control results within the eligible area. Results: The original kit failed at all levels, even if the upper verification limit was applied. Novel kit passed for the intermediate- and high-level claim of the manufacturers. The highest CV% was 5.24%, and the EFLM recommendation for CRP is 8.5% at the optimum level. Conclusions: Such experiments with expanded data should be performed with daily calibration to provide manufacturers' claim. Otherwise, it is hard to pass the precision verification. Studies are valuable in terms of demonstrating the reproducibility of the produced kits in end-user laboratories. [ABSTRACT FROM AUTHOR]

Retinal neovascularisation is a major cause of blindness in patients with proliferative diabetic retinopathy (PDR). It is mediated by the complex interaction between dysfunctional ganglion cells, microglia, and vascular endothelial cells. Notably, retinal microglia, the intrinsic immune cells of the retina, play a crucial role in the pathogenesis of retinopathy. In this study, we found that lysophosphatidylserines (LysoPS) released from injured ganglion cells induced microglial extracellular trap formation and retinal neovascularisation. Mechanistically, LysoPS activated the GPR34-PI3K-AKT-NINJ1 signalling axis by interacting with the GPR34 receptor on the microglia. This activation upregulated the expression of inflammatory cytokines, such as IL-6, IL-8, VEGFA, and FGF2, and facilitated retinal vascular endothelial cell angiogenesis. As a result, inhibition of the GPR34-PI3K-AKT-NINJ1 axis significantly decreased microglial extracellular trap formation and neovascularisation by suppressing LysoPS-induced microglial inflammatory responses, both in vitro and in vivo. This study reveals the crucial role of apoptotic ganglion cells in activating microglial inflammation in PDR, thereby enhancing our understanding of the pathogenesis of retinal neovascularisation. [ABSTRACT FROM AUTHOR]

Background: Pulmonary oedema is a feared and difficult to predict complication of severe malaria that can emerge after start of antimalarial treatment. Proinflammatory mediators are thought to play a central role in its pathogenesis. Methods: An exploratory study was conducted to evaluate the predictive capacity of biomarkers for development of clinical pulmonary oedema in patients with severe falciparum malaria at two hospitals in Bangladesh. Plasma concentrations of interleukin-6 (IL-6), IL-8, tumour necrosis factor (TNF), soluble Receptor of Advanced Glycation End-products (sRAGE), surfactant protein-D (SP-D), club cell secretory protein (CC16), and Krebs von den Lungen-6 (KL-6) on admission were compared with healthy controls. Correlations between these biomarker and plasma lactate and Plasmodium falciparum histidine-rich protein 2 (PfHRP2) levels were evaluated. Receiver Operating Characteristic (ROC) curves were constructed to assess the predictive capacity for clinical pulmonary oedema of the biomarkers of interest. Results: Of 106 screened patients with falciparum malaria, 56 were classified as having severe malaria with a mortality rate of 29%. Nine (16%) patients developed clinical pulmonary oedema after admission. Plasma levels of the biomarkers of interest were higher in patients compared to healthy controls. IL-6, IL-8, TNF, sRAGE, and CC16 levels correlated well with plasma PfHRP2 levels (rs = 0.39; P = 0.004, rs = 0.43; P = 0.001, rs = 0.54; P < 0.001, rs = 0.44; P < 0.001, rs = 0.43; P = 0.001, respectively). Furthermore, IL-6 and IL-8 levels correlated well with plasma lactate levels (rs = 0.37; P = 0.005, rs = 0.47; P < 0.001, respectively). None of the biomarkers of interest had predictive capacity for development of clinical pulmonary oedema. Conclusions: IL-6, IL-8, TNF, sRAGE, SP-D, CC16 and KL-6 cannot be used in predicting clinical pulmonary oedema in severe malaria patients. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusions Adolescents exposed to victimization are at an increased risk for a variety of adverse mental health outcomes, including depressive symptoms. Yet, the biological pathways underlying these associations remain poorly understood. Focusing on within‐person processes, we examined whether low‐grade systemic inflammation mediated the longitudinal associations between peer victimization and depressive symptoms in adolescence.207 adolescents (at baseline Mage = 12.69 years; SD = 0.49; 43.5% female) participated in a multi‐wave longitudinal study, with assessments repeated every 6 months over 1.5 years. At each assessment wave, participants self‐reported their peer victimization experiences and depressive symptoms. Dried blood spots were collected at each wave using a finger prick procedure to assay a key marker of low‐grade systemic inflammation, interkeukin‐6 (IL‐6). Data were analyzed using random‐intercept cross‐lagged panel models.The cross‐lagged paths from IL‐6 to depressive symptoms were significant across all models and waves (β12 = .13; β23 = .12; β34 = .08), indicating that when adolescents' levels of low‐grade systemic inflammation were above their person‐specific average, they reported increased levels of depressive symptoms in the subsequent months. However, no significant cross‐lagged within‐person associations emerged between peer victimization and either IL‐6 or depressive symptoms.The findings provide no evidence for the hypothesized mediating role of inflammation in the within‐person associations between peer victimization and depressive symptoms. Nevertheless, they extend prior research by indicating that elevated levels of low‐grade systemic inflammation predict the development of depressive symptoms in adolescence. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is an autoimmune disease characterised by persistent inflammation of the synovial joints as well as other tissues and organs. Left untreated, it can lead to joint damage, disability and even increased mortality. The disease is driven by inflammatory cytokines that contribute to the chronic inflammation seen in RA. Interleukin-6 (IL-6) is a key pathological cytokine and a target for treatments aiming to alleviate local and systemic inflammation. Despite advances in understanding RA and the introduction of new treatments, achieving sustained remission remains challenging. This review explores the role of IL-6 in RA pathogenesis, its potential as a treatment target and the significance of personalised medicine in RA management. IL-6 has a dual signalling mechanism, classical and trans-signalling, which influences various intracellular pathways. While several targeted therapies have emerged, no single mechanism-based therapy is universally effective due to the diversity and complexity of the disease. Different approaches to targeting IL-6 have been tested, including biologic blockade of receptors or ligands, and inhibition of IL-6 signalling. IL-6 receptor inhibitors have been validated as RA therapeutics, either alone or in combination with other treatments. Tocilizumab, the first approved IL-6 inhibitor, blocks both soluble and membrane-bound IL-6 receptors, reducing the inflammatory cascade. Clinical trials confirm the efficacy and safety of tocilizumab and its role as a treatment option for patients unresponsive to conventional therapies. The benefits of IL-6 inhibition extend beyond reduced joint inflammation to the amelioration of comorbidities like anaemia, cardiovascular disease, depression and osteoporosis. Tailoring treatment to patients' profiles and comorbidities is essential for optimal outcomes. A 'treat-to-profile' approach, focusing on a holistic view of the patient, could improve personalised medicine strategies. Biosimilars – lower-cost alternatives to biologics – further enhance the accessibility and cost-effectiveness of treatment. IL-6 inhibitors present a valuable treatment option for RA management, particularly for patients with specific comorbidities. Plain language summary: What have we learnt from the inhibition of IL-6 in RA and identifying the clinical opportunities for patient outcomes? Rheumatoid arthritis (RA) is a condition where joints become swollen and painful due to long-term (chronic) inflammation. If left untreated, it can cause severe joint damage, disability and even increase the risk of death. The disease is driven by cytokines, which are proteins in the body that help control the immune system and can cause inflammation. One important cytokine is interleukin-6 (IL-6), and scientists are studying ways to block its effects to help people with RA. This review looks at how IL-6 works in RA and how blocking it might help. Despite new treatments, it is still hard to fully control RA. Researchers are trying to find better ways to personalise treatments based on the symptoms of individual patients. One drug called tocilizumab stops IL-6 from working by attaching to its receptor. A receptor is a part of a cell that receives signals from substances like cytokines. When IL-6 attaches to its receptor, it triggers inflammation. Tocilizumab stops IL-6 from attaching to its receptor, reducing pain and inflammation in people with RA. This drug not only helps the joints but may also improve other problems like anaemia, heart disease and even depression that often come with RA. The review suggests that treating RA should involve looking at the person's overall health, not just the joints. IL-6 blockers might be particularly useful for patients with other health issues or for those who have not responded well to other treatments. Biosimilars, which are similar to the original IL-6 blocking drug but less expensive, have expanded the treatment options. Combining personalised treatments with more affordable options could help improve the lives of people with RA. Overall, IL-6 blockers seem to be a promising way to help people with RA, especially when used in a personalised approach that considers the whole person and their overall health. [ABSTRACT FROM AUTHOR]

IntroductionMethodsResultsConclusionsBiologic agents targeting interleukin-6 (IL-6) have gained attention as a promising treatment option for non-infectious uveitis (NIU) cases resistant to first-line therapies. IL-6 plays a pivotal role in the pathogenesis of uveitic conditions and its complications (i.e. macular edema and neovscularization). This review aims to assess the therapeutic potential of IL-6 inhibitors in managing NIU, especially focused in clinical outcomes, such as visual acuity and macular edema.Narrative review of studies evaluating the efficacy of IL-6 inhibitors in patients with NIU. Parameters assessed include control of inflammation, corticosteroid-sparing effects, visual acuity improvement, and reduction of macular edema.IL-6 inhibitors have demonstrated efficacy in controlling inflammation in 34% to 88% of cases and reducing corticosteroid dependence in approximately 55% of patients. Complete remission rates have been reported between 60% and 70%, with improvement in macular edema observed in 35.8% to 100% of cases. These results suggest that IL-6 inhibitors could be a therapeutic alternative for managing difficult cases of NIU.IL-6 inhibitors, including Tocilizumab and Sarilumab, have shown efficacy in controlling inflammation, improving visual outcomes, and reducing corticosteroid dependence in NIU. However, despite these promising results, further studies are needed to establish their long-term efficacy and safety. These therapies hold great potential for the future management of patients with uveitis. [ABSTRACT FROM AUTHOR]