Calcium and IL-6 regulate the anterograde trafficking and plasma membrane residence of the iron exporter ferroportin to modulate iron efflux.

Iron is an essential element for proper cell functioning, but unbalanced levels can cause cell death. Iron metabolism is controlled at the blood-tissue barriers provided by microvascular endothelial cells. Dysregulated iron metabolism at these barriers is a factor in both neurodegenerative and cardiovascular diseases. Mammalian iron efflux is mediated by the iron efflux transporter ferroportin (Fpn). Inflammation is a factor in many diseases and correlates with increased tissue iron accumulation. Evidence suggests treatment with interleukin 6 (IL-6) increases intracellular calcium levels and calcium is known to play an important role in protein trafficking. We have shown that calcium increases plasma membrane localization of the iron uptake proteins ZIP8 and ZIP14, but if and how calcium modulates Fpn trafficking is unknown. In this article, we examined the effects of IL-6 and calcium on Fpn localization to the plasma membrane. In HEK cells expressing a doxycycline-inducible GFP-tagged Fpn, calcium increased Fpn-GFP membrane presence by 2 h, while IL-6 increased membrane-localized Fpn-GFP by 3 h. Calcium pretreatment increased Fpn-GFP mediated 55Fe efflux from cells. Endoplasmic reticulum calcium stores were shown to be important for Fpn-GFP localization and iron efflux. Use of calmodulin pathway inhibitors showed that calcium signaling is important for IL-6-induced Fpn relocalization. Studies in brain microvascular endothelial cells in transwell culture demonstrated an initial increase in 55Fe flux with IL-6 that is reduced by 6 h coinciding with upregulation of hepcidin. Overall, this research details one pathway by which inflammatory signaling mediated by calcium can regulate iron metabolism, likely contributing to inflammatory disease mechanisms.

Causal effect of interleukin (IL)-6 on blood pressure and hypertension: A mendelian randomization study.

To examine whether circulating interleukin-6 (IL-6) levels (CirIL6) have a causal effect on blood pressure using Mendelian randomization (MR) methods. We used data from genome-wide association studies (GWAS) of European ancestry to obtain genetic instruments for circulating IL-6 levels and blood pressure measurements. We applied several robust MR methods to estimate the causal effects and to test for heterogeneity and pleiotropy. We found that circulating IL-6 had a significant positive causal effect on systolic blood pressure (SBP) and pulmonary arterial hypertension (PAH), but not on diastolic blood pressure (DBP) or hypertension. We found that as CirIL6 genetically increased, SBP increased using Inverse Variance Weighted (IVW) method (for ukb-b-20175, ß = 0.082 with SE = 0.032, P = 0.011; for ukb-a-360, ß = 0.075 with SE = 0.031, P = 0.014) and weighted median (WM) method (for ukb-b-20175, ß = 0.061 with SE = 0.022, P = 0.006; for ukb-a-360, ß = 0.065 with SE = 0.027, P = 0.014). Moreover, CirIL6 may be associated with an increased risk of PAH using WM method (odds ratio (OR) = 15.503, 95% CI, 1.025-234.525, P = 0.048), but not with IVW method. Our study provides novel evidence that circulating IL-6 has a causal role in the development of SBP and PAH, but not DBP or hypertension. These findings suggest that IL-6 may be a potential therapeutic target for preventing or treating cardiovascular diseases and metabolic disorders. However, more studies are needed to confirm the causal effects of IL-6 on blood pressure and to elucidate the underlying mechanisms and pathways.

Five-year follow-up of patients with difficult-to-treat rheumatoid arthritis.

OBJECTIVES: To elucidate the long-term outcomes of patients with difficult-to-treat rheumatoid arthritis (D2T RA). METHODS: We collected data on the clinical course of patients who had been identified as D2T RA in 2018 until 2023. We stratified the patients according to outcomes at the last visit: resolved D2T RA, persistent D2T RA, and mortality. We compared their clinical characteristics and investigated the predictive factors for the resolution of D2T RA or mortality. Furthermore, we investigated the impact of the causes of D2T RA identified in 2018, multidrug resistance, comorbidities, and socioeconomic factors on outcomes in 2023. RESULTS: Of 173 patients identified as D2T RA in 2018, 150 were included in the analysis. Among them, D2T RA was resolved in 67 (45%), 75 (50%) remained as D2T RA, and 8 (5%) died. Patients with resolved D2T RA were significantly younger at the latest visit (p= 0.02), had a higher proportion of treatment changes during five years (p= 0.002), and had a higher proportion of interleukin-6 receptor inhibitors use in 2023 (p= 0.04) than those in patients with persistent D2T RA or those who died. D2T RA resolved in 38% of patients with multidrug resistance, mainly with treatment changes. Rheumatic disease comorbidity index and glucocorticoid dose escalation were independent risk factors for mortality (odds ratio [OR], 3.50; p= 0.02 and OR, 31.9; p= 0.002, respectively). CONCLUSION: Further modifications in RA treatment are useful for resolving D2T RA. Multiple comorbidities and glucocorticoid use are associated with mortality.

Early changes in serum interleukin-6 levels in extremely premature newborns for detecting fetal inflammation.

BACKGROUND: Fetal inflammatory response syndrome (FIRS) is defined by elevated levels of inflammatory cytokines circulating in fetal blood, which may result in preterm morbidities. Serum interleukin-6 (IL-6) level has been reported to be a good indicator of FIRS; however, changes in IL-6 levels after birth remain to be elucidated. Herein, we characterized early changes in serum IL-6 levels in extremely premature newborns (EPNs, < 28 wks gestation), and then determined the cut-off values for detecting fetal inflammation at each postnatal epoch. METHODS: In this single-center study, 49 EPNs were retrospectively studied. Serum IL-6 measurements are routinely performed at delivery, 1-3, 6-12, and 24-36 h of life. Receiver operating characteristic (ROC) curve analyses were performed for detecting the presence of funisitis, the histologic counterpart of FIRS. RESULTS: Overall, serum IL-6 levels were significantly elevated at 1-3 (298 [31-4719] pg/mL) and 6-12 (29 [2-12,635] pg/mL) hours of life, then returned to at-delivery levels at 24-36 h of life. When comparing serum IL-6 levels at each postnatal epoch, the levels at delivery, 1-3, and 6-12 h of life were significantly higher in the EPNs with funisitis. Serum IL-6 cut-off values at delivery, 1-3, 6-12, and 24-36 h of life for the presence of funisitis were 20, 572, 290, and 13 pg/mL with area under ROCs of 0.75, 0.71, 0.68, and 0.53, respectively. CONCLUSIONS: Serum IL-6 levels in EPNs significantly increase early after birth, then decrease to at-delivery levels by 24-36 h of life. Therefore, postnatal age-dependent cut-off values of serum IL-6 might be considered for detecting fetal inflammation with confirmed funisitis.

Advancements in the study of IL-6 and its receptors in the pathogenesis of gout.

Gout is an autoinflammatory disease characterized by the deposition of monosodium urate crystals in or around the joints, primarily manifesting as inflammatory arthritis that recurs and resolves spontaneously. Interleukin-6 (IL-6) is a versatile cytokine with both anti-inflammatory and pro-inflammatory capabilities, linked to a variety of inflammatory diseases such as gouty arthritis, rheumatoid arthritis, inflammatory bowel disease, vasculitis, and several types of cancer. The rapid production of IL-6 during infections and tissue damage aids in host defense. However, excessive synthesis of IL-6 and dysregulation of its receptor signaling (IL-6R) might contribute to the pathology of diseases. Recent advancements in clinical and basic research, along with developments in animal models, have established the significant role of IL-6 and its receptors in the pathogenesis of gout, although the precise mechanisms remain to be fully elucidated. This review discusses the role of IL-6 and its receptors in gout progression and examines contemporary research on modulating IL-6 and its signaling pathways for treatment. It aims to provide insights into the pathogenesis of gout and to advance the development of targeted therapies for gout-related inflammation.

The association between changes in clinical pain severity and IL-6 reactivity among patients undergoing total knee Arthroplasty: The moderating role of change in insomnia.

Knee osteoarthritis (KOA) is linked to an enhanced release of interleukin-6 (IL-6). Increased levels of IL-6 are associated with greater pain and insomnia. While total knee arthroplasty (TKA) typically results in the reduction of pain, for a subgroup of patients, pain does not improve. Understanding patients' propensity to upregulate IL-6 may provide insight into variation in the clinical success of TKA for improving pain, and insomnia may play an important modulatory role. We investigated the association between pre- and post-surgical changes in clinical pain and IL-6 reactivity, and whether change in insomnia moderated this association. Patients (n = 39) with KOA came in-person before and 3-months after TKA. At both visits, patients completed validated measures of clinical pain and insomnia, as well as underwent quantitative sensory testing (QST). Blood samples were collected to analyze IL-expression both before and after QST procedures to assess changes in IL-6 in response to QST (IL-6 reactivity). Patients were categorized into two groups based on change in clinical pain from pre- to post-surgery: 1) pain decreased > 2 points (pain improved) and 2) pain did not decrease > 2 points (pain did not improve). Based on this definition, 49 % of patients had improved pain at 3-months. Among patients with improved pain, IL-6 reactivity significantly decreased from pre- to post-surgery, whereas there was no significant change in IL-6 reactivity among those whose pain did not improve. There was also a significant interaction between pain status and change in insomnia, such that among patients whose insomnia decreased over time, improved pain was significantly associated with a reduction in IL-6 reactivity. However, among patients whose insomnia increased over time, pain status and change in IL-6 reactivity were not significantly associated. Our findings suggest that the resolution of clinical pain after TKA may be associated with discernible alterations in pro-inflammatory responses that can be measured under controlled laboratory conditions, and this association may be moderated by perioperative changes in insomnia. Randomized controlled trials which carefully characterize the phenotypic features of patients are needed to understand how and for whom behavioral interventions may be beneficial in modulating inflammation, pain, and insomnia.

Effects of low-dose acetylsalicylic acid on the inflammatory response to experimental sleep restriction in healthy humans.

BACKGROUND: Sleep deficiencies, such as manifested in short sleep duration or insomnia symptoms, are known to increase the risk for multiple disease conditions involving immunopathology. Inflammation is hypothesized to be a mechanism through which deficient sleep acts as a risk factor for these conditions. Thus, one potential way to mitigate negative health consequences associated with deficient sleep is to target inflammation. Few interventional sleep studies investigated whether improving sleep affects inflammatory processes, but results suggest that complementary approaches may be necessary to target inflammation associated with sleep deficiencies. We investigated whether targeting inflammation through low-dose acetylsalicylic acid (ASA, i.e., aspirin) is able to blunt the inflammatory response to experimental sleep restriction. METHODS: 46 healthy participants (19F/27M, age range 19-63 years) were studied in a double-blind randomized placebo-controlled crossover trial with three protocols each consisting of a 14-day at-home monitoring phase followed by an 11-day (10-night) in-laboratory stay (sleep restriction/ASA, sleep restriction/placebo, control sleep/placebo). In the sleep restriction/ASA condition, participants took low-dose ASA (81 mg/day) daily in the evening (22:00) during the at-home phase and the subsequent in-laboratory stay. In the sleep restriction/placebo and control sleep/placebo conditions, participants took placebo daily. Each in-laboratory stay started with 2 nights with a sleep opportunity of 8 h/night (23:00-07:00) for adaptation and baseline measurements. Under the two sleep restriction conditions, participants were exposed to 5 nights of sleep restricted to a sleep opportunity of 4 h/night (03:00-07:00) followed by 3 nights of recovery sleep with a sleep opportunity of 8 h/night. Under the control sleep condition, participants had a sleep opportunity of 8 h/night throughout the in-laboratory stay. During each in-laboratory stay, participants had 3 days of intensive monitoring (at baseline, 5th day of sleep restriction/control sleep, and 2nd day of recovery sleep). Variables, including pro-inflammatory immune cell function, C-reactive protein (CRP), and actigraphy-estimated measures of sleep, were analyzed using generalized linear mixed models. RESULTS: Low-dose ASA administration reduced the interleukin (IL)-6 expression in LPS-stimulated monocytes (p<0.05 for condition*day) and reduced serum CRP levels (p<0.01 for condition) after 5 nights of sleep restriction compared to placebo administration in the sleep restriction condition. Low-dose ASA also reduced the amount of cyclooxygenase (COX)-1/COX-2 double positive cells among LPS-stimulated monocytes after 2 nights of recovery sleep following 5 nights of sleep restriction compared to placebo (p<0.05 for condition). Low-dose ASA further decreased wake after sleep onset (WASO) and increased sleep efficiency (SE) during the first 2 nights of recovery sleep (p<0.001 for condition and condition*day). Baseline comparisons revealed no differences between conditions for all of the investigated variables (p>0.05 for condition). CONCLUSION: This study shows that inflammatory responses to sleep restriction can be reduced by preemptive administration of low-dose ASA. This finding may open new therapeutic approaches to prevent or control inflammation and its consequences in those experiencing sleep deficiencies. TRIAL REGISTRATION: ClinicalTrials.gov NCT03377543.

Clinical chorioamnionitis at term: definition, pathogenesis, microbiology, diagnosis, and treatment.

Clinical chorioamnionitis, the most common infection-related diagnosis in labor and delivery units, is an antecedent of puerperal infection and neonatal sepsis. The condition is suspected when intrapartum fever is associated with two other maternal and fetal signs of local or systemic inflammation (eg, maternal tachycardia, uterine tenderness, maternal leukocytosis, malodorous vaginal discharge or amniotic fluid, and fetal tachycardia). Clinical chorioamnionitis is a syndrome caused by intraamniotic infection, sterile intraamniotic inflammation (inflammation without bacteria), or systemic maternal inflammation induced by epidural analgesia. In cases of uncertainty, a definitive diagnosis can be made by analyzing amniotic fluid with methods to detect bacteria (Gram stain, culture, or microbial nucleic acid) and inflammation (white blood cell count, glucose concentration, interleukin-6, interleukin-8, matrix metalloproteinase-8). The most common microorganisms are Ureaplasma species, and polymicrobial infections occur in 70% of cases. The fetal attack rate is low, and the rate of positive neonatal blood cultures ranges between 0.2% and 4%. Intrapartum antibiotic administration is the standard treatment to reduce neonatal sepsis. Treatment with ampicillin and gentamicin have been recommended by professional societies, although other antibiotic regimens, eg, cephalosporins, have been used. Given the importance of Ureaplasma species as a cause of intraamniotic infection, consideration needs to be given to the administration of antimicrobial agents effective against these microorganisms such as azithromycin or clarithromycin. We have used the combination of ceftriaxone, clarithromycin, and metronidazole, which has been shown to eradicate intraamniotic infection with microbiologic studies. Routine testing of neonates born to affected mothers for genital mycoplasmas could improve the detection of neonatal sepsis. Clinical chorioamnionitis is associated with decreased uterine activity, failure to progress in labor, and postpartum hemorrhage; however, clinical chorioamnionitis by itself is not an indication for cesarean delivery. Oxytocin is often administered for labor augmentation, and it is prudent to have uterotonic agents at hand to manage postpartum hemorrhage. Infants born to mothers with clinical chorioamnionitis near term are at risk for early-onset neonatal sepsis and for long-term disability such as cerebral palsy. A frontier is the noninvasive assessment of amniotic fluid to diagnose intraamniotic inflammation with a transcervical amniotic fluid collector and a rapid bedside test for IL-8 for patients with ruptured membranes. This approach promises to improve diagnostic accuracy and to provide a basis for antimicrobial administration.

Discovery of YS-1 as a cell line of gastric inflammatory cancer-associated fibroblasts.

BACKGROUND: Inflammatory cancer-associated fibroblasts (iCAFs) was first identified by co-culture of pancreatic stellate cells and tumor organoids. The key feature of iCAFs is IL-6high/αSMAlow. We examine this phenomenon in gastric cancer using two cell lines of gastric fibroblasts (HGF and YS-1). METHODS AND RESULTS: HGF or YS-1 were co-cultured with MKN7 (a gastric adenocarcinoma cell line) in Matrigel. IL-6 protein levels in the culture supernatant were measured by ELISA. The increased production of IL-6 was not observed in any of the combinations. Instead, the supernatant of YS-1 exhibited the higher levels of IL-6. YS-1 showed IL-6high/αSMA (ACTA2)low in real-time PCR, mRNA-seq and immunohistochemistry. In mRNA-seq, iCAFs-associated genes and signaling pathways were up-regulated in YS-1. No transition to myofibroblastic phenotype was observed by monolayer culture, or the exposure to sonic hedgehog (SHH) or TGF-ß. YS-1 conditioned medium induced changes of morphology and stem-ness/differentiation in NUGC-3 (a human gastric adenocarcinoma cell line) and UBE6T-15 (a human bone marrow-derived mesenchymal stem cell line). CONCLUSIONS: YS-1 is a stable cell line of gastric iCAFs. This discovery will promote further research on iCAFs for many researchers.

Macrophages regulate healing-associated fibroblasts in diabetic wound.

BACKGROUND: Recovery from a foot ulcer is compromised in a diabetic status, due to the impaired tissue microenvironment that consists of altered inflammation, angiogenesis and fibrosis. Phenotypic alterations in both macrophages and fibroblasts have been detected in the diabetic wound. Recently, a fibroblast subpopulation that expresses high matrix metalloproteinase 1 (MMP1), MMP3, MMP11 and Chitinase-3-Like Protein 1 (CHI3L1) was associated with a successful diabetic wound healing. However, it is not known whether these healing-associated fibroblasts are regulated by macrophages. METHODS AND RESULTS: We used bioinformatic tools to analyze selected public databases on normal and diabetic skin from patients, and identified genes significantly altered in diabetes. In a mouse model for diabetic wound healing, we detected not only a loss of the spatiotemporal changes in interleukin 1ß (IL1ß), IL6, IL10 and vascular endothelial growth factor A (VEGF-A) in wound macrophages, but also a compromised expression of MMP1, MMP3, MMP11, CHI3L1 and VEGF-A in healing-associated wound fibroblasts in a diabetic status. Co-culture with diabetic macrophages significantly reduced the expression of MMP1, MMP3, MMP11, CHI3L1 and VEGF-A in fibroblasts from non-diabetic wound. Co-culture with non-diabetic macrophages or diabetic macrophages supplied with IL6 significantly increased the expression of MMP1, MMP3, MMP11, CHI3L1 and VEGF-A in fibroblasts from diabetic wound. Moreover, macrophage-specific expression of IL6 significantly improved wound healing and angiogenesis in diabetic mice. CONCLUSIONS: Macrophages may induce the activation of wound-healing-associated fibroblasts, while the defective macrophages in diabetes may be corrected with IL6 treatment as a promising therapy for diabetic foot disease.

Effect of continuous positive airway pressure treatment on Th17/Treg imbalance in patients with obstructive sleep apnea and a preliminary study on its mechanism.

BACKGROUND: Obstructive sleep apnea (OSA) can be considered a chronic inflammatory disease that impacts all bodily systems, including the immune system. This study aims to assess the Th17/Treg pattern in patients with OSA and the effect of continuous positive airway pressure (CPAP) treatment. METHODS: OSA patients and healthy controls were recruited. OSA patients recommended for CPAP treatment were followed up for three months. Flow cytometry was employed to determine the proportion of Th17 and Treg cells. Real-time quantitative polymerase chain reaction (PCR) and western blotting were utilized to detect the mRNA and protein levels of receptor-related orphan receptor γt (RORγt) and forkhead/winged helix transcription factor (Foxp3), respectively, in peripheral blood mononuclear cells (PBMCs). Enzyme-linked immunosorbent assay (ELISA) was performed to measure the serum levels of interleukin-17 (IL-17), IL-6, transforming growth factor-ß1 (TGF-ß1), and hypoxia-induced factor-1α (HIF-1α). RESULTS: A total of 56 OSA patients and 40 healthy controls were recruited. The proportion of Th17 cells, Th17/Treg ratio, mRNA and protein levels of RORγt, and serum IL-17, IL-6, and HIF-1α levels were higher in OSA patients. Conversely, the proportion of Treg cells, mRNA and protein levels of Foxp3, and serum TGF-ß1 levels were decreased in OSA patients. The proportion of Th17 and Treg cells in OSA can be predicted by the apnea hypopnea index (AHI), IL-6, TGF-ß1 and, HIF-1α. 30 moderate-to-severe OSA patients were adherent to three-month CPAP treatment, with improved Th17/Treg imbalance, IL-17, IL-6, TGF-ß1, and HIF-1α levels compared to pre-treatment values. CONCLUSION: There was a Th17/Treg imbalance in OSA patients. The prediction of Th17 and Treg cell proportions in OSA can be facilitated by AHI, as well as serum IL-6, TGF-ß1, and HIF-1α levels. Furthermore, CPAP treatment can potentially improve the Th17/Treg imbalance and reduce proinflammatory cytokines in OSA patients.

Diagnostic and prognostic role of serum interleukin-6 and carotid ultrasonography to detect subclinical atherosclerosis in patients with RA and ANCA-associated vasculitis.

ANCA-associated vasculitis (AAV) can affect multiple organs with severe life-threatening manifestations. Disease monitoring is difficult due to a lack of defined biomarkers. We aimed to assess the diagnostic role of serum interleukin-6 and vascular ultrasonography in AAV and subclinical atherosclerosis. The study included 20 AAV patients and two control groups of 34 patients with rheumatoid arthritis (RA) and 35 healthy controls. The levels of Il-6, carotid intima-media thickness test (CIMT), atherosclerotic plaque, and degree of stenosis were investigated. A GRACE-risk score was calculated for AAV and RA patients. The AAV patients had elevated levels of IL-6 (115 ± 23.96) compared to the RA patients (91.25 ± 42.63) and the healthy controls (15.65 ± 3.30), p < 0.001. IL-6 showed a diagnostic accuracy of 73% in distinguishing AAV from RA patients (AUC = 0.730; 95% CI 0.591 to 0834). In the AAV group, CIMT was 1.09, above the upper reference value of 0.90, p < 0.001. The AAV patients had a higher median GRACE risk score, and 60% of them had a high risk of cardiovascular events as compared to 35% of the RA patients. Sonography of extracranial vessels and serum levels of IL-6 can be used in daily clinical practice to diagnose and monitor patients with AAV.

Long-Term Exposure of Cultured Astrocytes to High Glucose Impact on Their LPS-Induced Activation.

Diabetes mellitus is associated with various complications, mainly caused by the chronic exposure of the cells to high glucose (HG) concentrations. The effects of long-term HG exposure in vitro accompanied by lipopolysaccharide (LPS) application on astrocytes are relatively unknown. We used cell medium with normal (NG, 5.5 mM) or high glucose (HG, 25 mM) for rat astrocyte cultures and measured the release of NO, IL-6, ß-hexosaminidase and cell survival in response to LPS. We first demonstrated that HG long-term incubation of astrocytes increased the release of ß-hexosaminidase without decreasing MTT-detected cell survival, suggesting that there is no cell membrane damage or astrocyte death but could be lysosome exocytosis. Different from what was observed for NG, all LPS concentrations tested at HG resulted in an increase in IL-6, and this was detected for both 6 h and 48 h treatments. Interestingly, ß-hexosaminidase level increased after 48 h of LPS and only at HG. The NO release from astrocytes also increased with LPS application at HG but was less significant. These data endorsed the original hypothesis that long-term hyperglycemia increases proinflammatory activation of astrocytes, and ß-hexosaminidase could be a specific marker of excessive activation of astrocytes associated with exocytosis.

The Differential Effect of Senolytics on SASP Cytokine Secretion and Regulation of EMT by CAFs.

The tumor microenvironment (TME) plays an essential role in tumor progression and in modulating tumor response to anticancer therapy. Cellular senescence leads to a switch in the cell secretome, characterized by the senescence-associated secretory phenotype (SASP), which may regulate tumorigenesis. Senolytic therapy is considered a novel anticancer strategy that eliminates the deleterious effects of senescent cells in the TME. Here, we show that two different types of senolytic drugs, despite efficiently depleting senescent cells, have opposite effects on cancer-associated fibroblasts (CAFs) and their ability to regulate epithelial-mesenchymal transition (EMT). We found that senolytic drugs, navitoclax and the combination of dasatinib/quercetin, reduced the number of spontaneously senescent and TNF-induced senescent CAFs. Despite the depletion of senescent cells, the combination of dasatinib/quercetin versus navitoclax increased the secretion of the SASP pro-inflammatory cytokine IL-6. This differential effect correlated with the promotion of enhanced migration and EMT in MC38 colorectal cancer cells. Our results demonstrate that some senolytics may have side effects unrelated to their senolytic activity and may promote tumorigenesis. We argue for more careful and extensive studies of the effects of senolytics on various aspects of tumor progression and tumor resistance to therapy before the senolytic strategy is implemented in the clinic.

Preoperative Immune Cell Dysregulation Accompanies Ovarian Cancer Patients into the Postoperative Period.

Ovarian cancer (OC) poses a significant global health challenge with high mortality rates, emphasizing the need for improved treatment strategies. The immune system's role in OC progression and treatment response is increasingly recognized, particularly regarding peripheral blood mononuclear cells (PBMCs) and cytokine production. This study aimed to investigate PBMC subpopulations (T and B lymphocytes, natural killer cells, monocytes) and cytokine production, specifically interleukin-1 beta (IL-1ß), interleukin-4 (IL-4), interleukin-6 (IL-6), interleukin-10 (IL-10), interleukin-12 (IL-12), and tumor necrosis factor alpha (TNFα), in monocytes of OC patients both preoperatively and during the early postoperative period. Thirteen OC patients and 23 controls were enrolled. Preoperatively, OC patients exhibited changes in PBMC subpopulations, including decreased cytotoxic T cells, increased M2 monocytes, and the disbalance of monocyte cytokine production. These alterations persisted after surgery with subtle additional changes observed in PBMC subpopulations and cytokine expression in monocytes. Considering the pivotal role of these altered cells and cytokines in OC progression, our findings suggest that OC patients experience an enhanced pro-tumorigenic environment, which persists into the early postoperative period. These findings highlight the impact of surgery on the complex interaction between the immune system and OC progression. Further investigation is needed to clarify the underlying mechanisms during this early postoperative period, which may hold potential for interventions aimed at improving OC management.

Computer-aided prediction and design of IL-6 inducing peptides: IL-6 plays a crucial role in COVID-19.

Interleukin 6 (IL-6) is a pro-inflammatory cytokine that stimulates acute phase responses, hematopoiesis and specific immune reactions. Recently, it was found that the IL-6 plays a vital role in the progression of COVID-19, which is responsible for the high mortality rate. In order to facilitate the scientific community to fight against COVID-19, we have developed a method for predicting IL-6 inducing peptides/epitopes. The models were trained and tested on experimentally validated 365 IL-6 inducing and 2991 non-inducing peptides extracted from the immune epitope database. Initially, 9149 features of each peptide were computed using Pfeature, which were reduced to 186 features using the SVC-L1 technique. These features were ranked based on their classification ability, and the top 10 features were used for developing prediction models. A wide range of machine learning techniques has been deployed to develop models. Random Forest-based model achieves a maximum AUROC of 0.84 and 0.83 on training and independent validation dataset, respectively. We have also identified IL-6 inducing peptides in different proteins of SARS-CoV-2, using our best models to design vaccine against COVID-19. A web server named as IL-6Pred and a standalone package has been developed for predicting, designing and screening of IL-6 inducing peptides (https://webs.iiitd.edu.in/raghava/il6pred/).

Tocilizumab for the treatment of chronic antibody mediated rejection in kidney transplant recipients.

BACKGROUND: Chronic active antibody-mediated rejection (CAAMR) constitutes a dominant form of late allograft failure. Several treatment strategies directed at CAAMR have been attempted but proven ineffective at delaying kidney function decline or reducing donor-specific antibodies (DSA). We describe our single-center experience using tocilizumab in patients with CAAMR. METHODS: This is a retrospective analysis using electronic medical records. 38 kidney transplant recipients at Columbia University Irving Medical Center who had been prescribed tocilizumab and followed for at least 3 months between August 2013 through December 2019 were included. RESULTS: Tocilizumab use was associated with a decrease in the rate of estimated glomerular filtration rate (eGFR) decline in the 6 months following treatment initiation as compared to the 3 months before tocilizumab was initiated (difference between slopes before and after initiation of treatment = 2.6 mL/min/1.73 m2 (SE = .8, p = .002) per month for up to 6 months following Tocilizumab initiation). Allograft biopsies showed significant improvement in interstitial inflammation scores (score 1(0,1) to 0 (0,1), p = .03) while other histologic scores remained stable. There was no significant change in proteinuria or DSA titers post-treatment with tocilizumab. CONCLUSIONS: Treatment of CAAMR with tocilizumab was associated with a decrease in the rate of eGFR decline and a reduction in interstitial inflammation scores in patients with CAAMR.

The Physiological and Pathophysiological Role of IL-6/STAT3-Mediated Signal Transduction and STAT3 Binding Partners in Therapeutic Applications.

The interleukin 6 (IL-6) family of cytokines is defined by the usage of gp130, a common ß-receptor signaling subunit, which promotes a variety of signals. They induce many biological functions on many cell types, including immune and inflammatory cells. They also exhibit hormone-like features, which are involved in homeostatic processes. Signal transducer and activator of transcription 3 (STAT3) is a significant signaling molecule fundamental in regulating IL-6/gp130 and is highly implicated in pathological conditions; therefore, STAT3 activation is tightly regulated through various mechanisms and at multiple levels. There is a large amount of information about STAT3-interacting proteins, which positively or negatively regulate STAT3 activity. This review is focused on IL-6-mediated signal transduction and the introduction of novel STAT3-binding partners. The review will help develop new strategies for clinically controlling the functions of IL-6/STAT3.

Utility of Serum Interleukine-6 Level in Empty Nose Syndrome.

Objectives: Empty nose syndrome (ENS), a complication resulting from surgical procedures on turbinate tissue, is characterized by paradoxical nasal obstruction with wide nasal airways. Patients with ENS often also experience psychiatric symptoms, and psychiatric disorder detection remains dependent on subjective evaluation. Objective biomarkers for mental status assessment in patients with ENS are unestablished. This study aimed to evaluate the role of serum interleukin-6 (IL-6) levels in the mental status of patients with ENS. Methods: Overall, 35 patients with ENS who underwent endonasal submucosal implantation surgery were prospectively included in the study. The Sino-Nasal Outcome Test-25 (SNOT-25), Empty Nose Syndrome 6-item Questionnaire (ENS6Q), Beck Anxiety Inventory (BAI), and Beck Depression Inventory-II (BDI-II) were used to assess the physical and psychiatric symptoms of these patients preoperatively, and 3, 6, and 12 months postoperatively. Serum IL-6 levels were analyzed 1 day before surgery. Results: All subjective assessments significantly improved 3 months after surgery and plateaued at 12 months. Patients with higher serum preoperative IL-6 levels tended to experience more severe depression. Regression analysis showed that a preoperative serum IL-6 level > 1.985 pg/mL was significantly correlated with severe depression status in patients with ENS (odds ratio = 9.76, p = 0.020). Conclusions: ENS patients with higher preoperative serum IL-6 levels were more likely to have severe depressive burden. Since more suicidal thoughts or attempts were noted in these patients, timely treatment plan for patients with high levels of serum IL-6 is crucial and may consider psychotherapy after surgical treatment.

Effect of individualized PEEP titration by ultrasonography on perioperative pulmonary protection and postoperative cognitive function in patients with chronic obstructive pulmonary disease.

OBJECTIVE: To evaluate the effect of the individualized positive end-expiratory pressure (PEEP) lung protection ventilation strategy by combining driving pressure (ΔP) and pulmonary ultrasound (LUS)-based titration on lung function and postoperative cognitive function in patients with chronic obstructive pulmonary disease (COPD) during laparoscopic surgery. METHODS: A total of 108 patients with COPD undergoing laparoscopic gastrointestinal surgery under general anesthesia were included in this study. They were randomly divided into three groups (n = 36): traditional volume ventilation group (Group C), fixed PEEP 5 cmH2O group (Group P), and ΔP combined with LUS-based PEEP titration in the resuscitation room group (Group T). All three groups were given volume ventilation mode, I:E = 1:2; In group C, VT was 10 mL/kg and PEEP was 0 cmH2O; In groups P and T, VT was 6 mL/kg and PEEP was 5 cmH2O; After mechanical ventilation for 15 min in Group T, ΔP in combination with LUS was used to titrate PEEP. The oxygenation index (PaO2/FiO2), airway platform pressure (Pplat), dynamic lung compliance (Cdyn), Montreal Cognitive Assessment (MoCA), and venous interleukin-6(IL-6) were recorded at the corresponding time points, and the final PEEP value in Group T was recorded. RESULTS: The final PEEP value of Group T was (6.4 ± 1.2) cmH2O; Compared with groups C and P: PaO2/FiO2 and Cdyn in Group T were significantly increased (P < 0.05) and value of IL-6 was significantly decreased (P < 0.05) at the corresponding time points. Compared with group C, the MoCA score on day 7 after surgery in Group T was significantly higher (P < 0.05). CONCLUSION: Compared with the traditional ventilation strategy, the individualized ΔP combined with LUS-based PEEP titration in patients with COPD during the perioperative period of laparoscopic surgery can play a better role in lung protection and can improve postoperative cognitive function.