Interleukin-6 Levels Research Articles

Interleukin-6 as a Pan-Cancer Prognostic Inflammatory Biomarker: A Population-Based Study and Comprehensive Bioinformatics Analysis.

Interleukin-6 (IL-6) is a central factor linking inflammation to cancer. This study aimed to provide a comprehensive assessment of the prognostic value of IL-6 and its immunotherapeutic features using a population-based pan-cancer analysis and comprehensive bioinformatic analysis. In the cohort study, 540 patients were included to explore the prognostic value of serum IL-6 levels in cancer. The differential expression of IL-6 and its association with survival and immune cell infiltration were investigated using the TCGA database. The SangerBox database was used to analyze the correlation between IL-6 expression and immune checkpoint (ICP), tumor mutation burden (TMB), and microsatellite instability (MSI) in cancer. Genomic changes in the IL-6 levels were studied using the c-BioPortal database. The IL-6 co-expression network was analyzed using the LinkedOmics database. Serum IL-6 is an independent prognostic factor for cancer, especially gastrointestinal cancers. Compared to other serum inflammatory markers, serum IL-6 is an optimal biomarker for cancer prognosis. A comprehensive bioinformatics analysis showed higher IL-6 expression in human cancers than in the paired normal tissues. The IL-6 expression is closely associated with prognosis, ICP, TMB, and MSI. In addition, it is also strongly correlated with tumor-infiltrating cells. IL-6 levels are significantly associated with the prognosis of stomach adenocarcinoma (STAD). The IL-6 co-expression network in STAD is mainly involved in regulating inflammatory pathways and cell communication. IL-6 is a potential prognostic and immune biomarker of cancer. Compared to other clinical inflammatory biomarkers, IL-6 demonstrates superior prognostic efficacy.

Dialysis and lyophilization of the mesenchymal stromal cell secretome for wound healing.

The clinical translation of mesenchymal stromal cell secretome (MSC-S) has been challenging owing to a lack of appropriate methods in downstream processing. Dialysis is an age-old method of protein purification by the exchange of small molecules through a semi-permeable membrane. In this study, we investigated the potential of three forms of umbilical cord-derived MSC secretome (UC-MSC-S)-native (S), dialyzed (DS), and lyophilized (LDS)-for wound healing applications. We dialyzed the UC-MSC-S using Slide-A-Lyzer G3 Dialysis Cassettes (20K MWCO) and then lyophilized it to obtain secretome powder. The DS fraction exhibited an 86.01-fold decrease compared with S, whereas LDS showed a 613.71-fold increase in the total protein concentration. Growth factor analysis revealed a significant decrease in the levels of interleukin-6 (IL-6; 54.44-fold), angiopoietin-1 (79.56-fold), angiopoietin-2 (51.76-fold), IL-8 (54.4-fold), platelet endothelial cell adhesion molecule-1 (PECAM-1; 63.25-fold), phosphatidylinositol glycan anchor biosynthesis class F (PIGF; 40.42-fold), vascular endothelial growth factor (VEGF; 39.64-fold), and tumor necrosis factor alpha (TNF-α; 24.62-fold) after dialysis as analyzed by the LEGEND plex multi-analyte flow assay kit on a FACS analyzer. Post-lyophilization, the levels of IL-6 (392.21-fold), angiopoietin-1 (823.04-fold), angiopoietin-2 (397.69-fold), IL-8 (584.83-fold), PECAM-1 (341.28-fold), PIGF (342.85-fold), VEGF (2209.42-fold), and TNF-α (194.4-fold) were enriched in LDS. The highest wound closure (64.07%) and a significant increase in angiogenesis were seen in DLS at the concentration of 1 µg/µL of protein by wound scratch and in ovo yolk sac membrane assay, respectively. Dialysis followed by lyophilization is a simple and cost-effective method to fractionate and enrich the bioactive components of MSC-S without compromising the bioactivity for tailor-made applications.

Elevated Serum IL-6 as a Negative Prognostic Biomarker in Glioblastoma: Integrating Bioinformatics and Clinical Validation.

Background: Glioblastoma multiforme (GBM) is the most lethal type of primary brain tumor, necessitating the discovery of reliable serum prognostic biomarkers. This study aimed to investigate the prognostic value of serum Interleukin-6 (IL-6) in GBM patients. Methods: Bioinformatics analysis via gene set enrichment analysis was conducted on The Cancer Genome Atlas RNA-seq data to explore the pathways enriched in samples with high IL-6 expression. The Tumor IMmune Estimation Resource database was used to analyze the association between IL-6 expression and immune cell infiltration. To validate the role of IL-6 in a clinical setting, a retrospective cohort study was conducted on newly diagnosed GBM patients. Serum IL-6 levels were repeatedly measured at key milestone time points, and their correlation with survival data was analyzed. Results: Bioinformatics analysis revealed that high IL-6 expression is associated with the activation of procancer pathways, that there is a positive correlation between IL-6 expression and immune cell infiltration in GBM. Between March 2021 and September 2023, 36 GBM patients and their serum IL-6 measurements at various time points were included in the clinical data analyses. Elevated serum IL-6 levels at baseline, with a cutoff of 7pg/mL, were identified in 11 patients (30.6%). In the multivariate analyses for overall survival (OS), elevated IL-6 was a significant risk factor (p = 0.048), along with unfavorable surgical resection (p = 0.039) and O6-methylguanine-DNA methyltransferase promotor unmethylation (p = 0.027). The median actuarial OS of the high initial IL-6 group was significantly shorter than that of the low initial IL-6 group (6.4 vs. 19.7 months, p < 0.001). However, IL-6 levels at other time points were not related to patient prognosis. Conclusion: Elevated IL-6 mRNA expression is correlated with the activation of procancer pathways, increased immune cell infiltration, and poor prognosis in GBM patients. In addition, elevated serum IL-6 at baseline is a negative prognostic factor confirmed in a clinical study. Serum IL-6 may be a potential prognostic biomarker enhancing the management of GBM.

Middle-aged females are resistant to LPS-induced learning deficits: Sex comparison

Preclinical data have repeatedly shown learning and memory disruption following administration of the bacterial endotoxin lipopolysaccharide (LPS). Normal aging is reported to enhance vulnerability to LPS-induced cognitive impairments. However, a limitation is the primary use of male subjects. Recent evidence indicates sex-related differences in vulnerability to LPS-induced cognitive deficits [1,2], with young females showing resilience. Whether middle-aged females are susceptible to LPS-induced cognitive impairment is unknown. The current experiment compared associative learning in young and middle-aged male and female C57BL/6J mice following a systemic LPS challenge. While LPS impaired acquisition of the two-way active avoidance conditioning task in adult and middle-aged males, females’ learning was unaffected. The sex difference in LPS-induced cognitive impairments appears unrelated to responsivity to LPS, as males and females mount a comparable sickness-like response. Additionally, relative to males, females produce higher brain levels of interleukin-6 (IL-6) and comparable splenic IL-6 levels following LPS. These data demonstrate that female resilience to LPS-induced learning deficits persists into middle age, whereas males are vulnerable as both young and middle-aged adults. Our findings confirm the importance of considering sex as a biological variable and extend the existing literature by evaluating sex-related responsivity to LPS in middle-aged males and females

Postoperative evaluation of interleukin-8 and C1q/TNF-related protein-12 in patients undergoing coronary artery bypass graft surgery.

Coronary artery bypass graft surgery is one of the most frequently performed surgeries worldwide. Coronary artery bypass graft surgery induces an inflammatory response. Interleukin-8 is a pro-inflammatory cytokine that plays a role in the pathogenesis of cardiovascular diseases. C1q/TNF-related protein-12 is implicated in mitigating inflammation and cardiomyocyte damage. This study aimed to compare interleukin-8 and C1q/TNF-related protein-12 levels before and 45 days after coronary artery bypass graft surgery. A total of 43 patients who underwent coronary artery bypass graft surgery were studied. Serum concentrations of interleukin-8 and C1q/TNF-related protein-12 were evaluated using the enzyme-linked immunosorbent assay method before and 45 days after the surgery. No significant differences were observed in interleukin-8 levels between pre- and post-coronary artery bypass graft surgery (p=0.077). However, serum levels of C1q/TNF-related protein-12 were found to be lower 45 days after coronary artery bypass graft surgery compared to pre-surgery levels (p<0.001). Moreover, changes in C1q/TNF-related protein-12 were not associated with diabetes, hypertension, and body mass index (p>0.05), but C1q/TNF-related protein-12 alterations were found to be associated with opium addiction. These findings suggest that the evaluation of C1q/TNF-related protein-12 can be beneficial for the late assessment of post-coronary artery bypass graft surgery inflammation. The reduction of C1q/TNF-related protein-12 levels might indicate increased levels of inflammation after surgery at this time point, which requires the assessment of further inflammatory factors to confirm this finding.

Therapeutic Potential of Combined 5% Lifitegrast and Tocopherol Eye Drops in Managing Inflammation and Oxidative Stress in Murine Dry Eye.

Background/Objectives: This study aimed to evaluate the therapeutic effects of combined 5% lifitegrast (LF) and tocopherol (TCP) eye drops in a murine experimental dry eye (EDE) model. Methods: Female C57BL/6 were divided into seven groups: untreated controls, EDE control, EDE + 0.05% cyclosporin A (CsA), EDE + tocopherol (TCP), EDE + 5% LF, EDE + 5% LF + TCP (once daily), and EDE + 5% LF + TCP (twice daily). Clinical parameters (tear volume, tear break-up time (TBUT), corneal fluorescein staining score (CFSS), tear film lipid layer grade (TFLLG)) were assessed on days 7 and 14. Goblet cell density in the conjunctiva, CD4+ IFN-γ+ T cells, interleukin levels, reactive oxygen species (ROS) levels, and corneal apoptotic cells were analyzed on day 14. Results: Monotherapy with 0.05% CsA and LF showed improvements in all clinical parameters compared to the EDE control (p < 0.05). Combination therapy groups demonstrated superior improvements in clinical parameters compared to the EDE control, 0.05% CsA, and 5% LF groups. CD4+ IFN-γ+ T cell percentages and ROS levels in the cornea and conjunctiva were markedly reduced in the combination groups compared with the 0.05% CsA and 5% LF groups (p < 0.01). Furthermore, corneal apoptotic cells significantly decreased in the combination groups compared to the 0.05% CsA and TCP groups (p < 0.05). Conclusions: Combined 5% LF and TCP eye drops improved tear film parameters and reduced inflammatory and oxidative stress markers. The combination therapy can mitigate ocular surface damage by managing inflammation and oxidative stress in dry eye.

Fruit Acid Inhibits UV-Induced Skin Aging via PI3K/Akt and NF-κB Pathway Inhibition.

Ultraviolet (UV) radiation-induced photoaging is a multifaceted biological process. Fruit acids have shown promise in combating photoaging. This study aims to investigate the mechanisms underlying the protective effects of fruit acids on UV-induced skin photoaging. Initially, we induced skin photoaging in rats through UV irradiation. Subsequently, the model group received glycolic acid treatment. The reparative effects of glycolic acid on skin tissue morphology and structure were assessed using Hematoxylin-eosin (HE) staining. The influence of glycolic acid on oxidative stress indicators (Superoxide Dismutase (SOD), Glutathione Peroxidase (GSH-Px), Malondialdehyde (MDA), Catalase (CAT)) and levels of cellular inflammatory factors (Interleukin-6 (IL-6), Tumor Necrosis Factor-alpha (TNF-α), IL-1β, Interferon-gamma (IFN-γ)) in photoaged skin was evaluated via Enzyme-Linked Immunosorbent Assay (ELISA). Additionally, alterations in collagen expression and levels of proteins associated with the Phosphoinositide 3-kinase/Protein Kinase B (PI3K/Akt) and Nuclear Factor kappa B (NF-κB) signaling pathways were determined through Western blot analysis. Compared to the model group, the fruit group exhibited a decrease in the thickness of the skin epidermal keratinization layer, an increase in dermal thickness, and more vigorous cortical secretion. Moreover, compared with the model group, the fruit group showed significant increases in SOD activity, CAT, GSH-Px, Collagen I, Collagen III, Collagen VII, and elastin. Conversely, levels of MDA, IL-6, IL-1β, IFN-γ, and TNF-α were lower in the fruit acid group than in the model group. Additionally, fruit acid treatment inhibited the phosphorylation levels of PI3K, Akt, and p65 induced by UV. Fruit acid demonstrates the ability to diminish the oxidative stress and inflammatory responses in skin photoaging rat models, thereby facilitating collagen recovery and ameliorating symptoms of skin photoaging. Its potential mechanism may entail the inhibition of the activation of the PI3K/Akt and NF-κB signaling pathways.

Effect of Vitamin D Supplementation on Serum Cytokines Level in Patients with Type 2 Diabetes Mellitus with and Without Foot Infection

Introduction: Diabetic foot infections (DFIs) are a common and serious complication in individuals with diabetes mellitus. Low levels of Vitamin D have been proposed as a risk factor for diabetic foot and may be associated with cytokine dysregulation. This study aimed to evaluate the effect of Vitamin D supplementation on circulating levels of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) in Type 2 diabetes mellitus (T2DM) patients with and without foot infections. Methods: T2DM patients with and without foot infections were enrolled as cases and controls. Both groups were supplemented with a total 300,000 IU oral dose of Vitamin D. Serum concentrations of 25 (OH) Vitamin D and cytokines (TNF-α, IL-6) were measured in both groups at baseline and follow-up using radioimmunoassay and enzyme-linked immunosorbent assay, respectively. Results: Serum concentrations of 25 (OH) Vitamin D significantly increased in both groups (cases: P &lt;0.0001; controls: P =0.012). The difference in mean (±standard deviation) levels of circulating serum inflammatory cytokines, TNF-α and IL-6, at baseline and follow-up was not significant in controls but was significant in cases (TNF-α: P =0.0001; IL-6: P =0.0026). Conclusion: Vitamin D supplementation, particularly a high dose (60,000 IU/week) for a short period (5 weeks), significantly reduces inflammatory cytokines TNF-α and IL-6 in patients with DFI, supporting its beneficial role in managing inflammation.

Serum Vitamin D Level Correlates Significantly With Leptin and Tumor Necrosis Factor-Alpha in Overweight Postmenopausal Women With Hypertension.

Association of serum vitamin D (vitD) with leptin (Lep) and tumor necrosis factor-alpha (TNF-α) is not precisely known in overweight hypertensive (OW-HT) postmenopausal (PMP) women. Hence, the present study was carried out to investigate the body mass index (BMI)-based correlation of serum vitD with Lep and TNF-α in OW-HT PMP women. Women subjects in their early PMP (n = 346, age: 51 - 60 years) categorized into three groups had main inclusion criteria of specified range of age, BMI and blood pressure (BP). Enzyme-linked immunosorbent assay (ELISA) and other kit methods were employed to investigate the role of various variables in three subject groups (normal weight normotensive (NW-NT, n = 116, BMI (kg/m2): 22 - 24.9), normal weight hypertensive (NW-HT, n = 115, BMI: 22 - 24.9) and OW-HT (n = 115, BMI: 25 - 29.9) PMP women). A significant negative linear correlation of vitD with serum Lep and TNF-α, and a significant positive linear correlation of BMI with Lep and TNF-α in OW-HT PMP women were obtained. Significantly higher levels of serum Lep, TNF-α and interleukin-6 (IL-6) were found in OW-HT PMP women, as compared to NW-HT PMP women. The present study suggests that decreased serum vitD levels correlate with the Lep and TNF-α in OW-HT PMP women. However, further studies may help understand the impact of vitD in cardiovascular events and the influencing factors in OW-HT PMP women.

Dapagliflozin inhibits ferroptosis to improve chronic heart failure by regulating Nrf2/HO-1/GPX4 signaling pathway.

To study the effect of Dapagliflozin on ferroptosis in rabbits with chronic heart failure and to reveal its possible mechanism. Nine healthy adult male New Zealand white rabbits were randomly divided into Sham group (only thorax opening was performed in Sham group, no ascending aorta circumferential ligation was performed), Heart failure group (HF group, ascending aorta circumferential ligation was performed in HF group to establish the animal model of heart failure), and Dapagliflozin group (DAPA group, after the rabbit chronic heart failure model was successfully made in DAPA group). Dapagliflozin was given by force-feeding method. Echocardiography was used to assess cardiac function, HE staining to evaluate pathological changes in the heart, Prussia blue staining to observe iron ions in myocardial tissue, and enzyme-linked immunosorbent assay (ELISA) to determine serum levels of the inflammatory factors interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) at the end of week 12 and/or the end of week 16. The oxidative stress related indexes of malondialdehyde (MDA), superoxide dismutase (SOD) and superoxide dismutase (GSH-Px) in serum were quantitatively analyzed by colorimetry. Protein expression levels of nuclear factor E2-related factor 2(Nrf2), heme oxygenase-1(HO-1), glutathione peroxidase 4(Gpx4) were detected by Western blot. In animals with chronic heart failure, Dapagliflozin improved cardiomyocyte hypertrophy, degeneration and necrosis. Dapagliflozin increased serum GSH-Px and SOD levels and decreased IL-1β, IL-6, TNF-α and MDA levels (P < 0.05) in a rabbit model of heart failure. Dapagliflozin also decreased cardiac iron ion levels and increased Nrf2, HO-1 and GPX4 protein expression. Dapagliflozin can improve heart failure by inhibiting oxidative stress and ferroptosis, and its mechanism may be related to the regulation of Nrf2/HO-1/GPX4 signaling pathway.

Curcumin exerts protective effects against valproic acid-induced testicular damage through modulating the JAK1/STAT-3/IL-6 signaling pathway in rats.

This experiment was carried out to investigate the protective effects of curcumin (CUR) on testicular damage induced by the valproic acid (VPA) administration. Male Wistar-Albino rats (n=28, 250-300 g) were randomly divided into four groups: Control (1 ml saline, oral), VPA (500 mg/kg, IP), CUR (200 mg/kg, oral), or VPA+CUR (500 mg/kg, VPA, IP plus 200 mg/kg CUR, oral). The treatments were applied for 14 days. Serum testosterone and testis [Janus kinases1 (JAK1), signal transducers and activators of transcription-3 (STAT-3), interleukin-6 (IL-6), malondialdehyde (MDA), tumor necrosis factor-alpha (TNF-α), interleukin-18 (IL-18), and nuclear factor (NF)-κB)] samples were collected for biochemical analyses. Semen samples were subjected to microscopy for spermatological parameters. Testis tissue was also analyzed for histopathological and immunohistochemical methods. The VPA administration caused a 37% decrease in serum testosterone concentration and 5.32, 9.51, 2.44, and 3.68-fold increases in testicular tissue JAK1, STAT-3, IL-6, and MDA levels, respectively. There were also 50, 52, and 72% reductions in sperm motility, sperm viability, and the mean testicular biopsy score, respectively, accompanied by considerable degenerative changes and necrosis in seminiferous tubules in the VPA group. There is also an immune-positive reaction for IL-18 and NF-κB in only Leydig cells. The CUR treatment may be beneficial in restoring testicular damage through antiinflammatory and anti-oxidant potential.

The Role of Key Molecules of Pyroptosis in Liver Damage of Rats With Exertional Heat Stroke.

Purpose: This study is aimed at investigating the role of key molecular elements involved in pyroptosis in liver injury caused by exertional heat stroke (EHS). Methods: We established a model of EHS-induced liver injury in Sprague-Dawley rats, with a control group (receiving no treatment) for comparison and 12 rats in each group. Alanine transaminase (ALT) and aspartate transaminase (AST) levels in the blood were detected. Interleukin-1 beta (IL-1β) and interleukin-18 (IL-18) levels were assessed using enzyme-linked immunosorbent assays (ELISA). Pathological changes in liver tissue were examined by hematoxylin and eosin (H&E) staining. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were used to detect mRNA and protein expression levels of Caspase-1 and Gasdermin D. Results: Compared to the control group, the liver tissue of the EHS group showed congestion in hepatic sinusoids, hepatocyte edema, eosinophilic changes, necrosis, and infiltration of inflammatory cells. ALT and AST levels in the EHS group were significantly higher than those in the control group (p < 0.05). The mRNA expressions of Caspase-1, Gasdermin D, IL-1β, and IL-18 were significantly increased in the EHS group compared to the control group (p < 0.001). The protein expressions of Caspase-1, cleaved Caspase-1, Gasdermin D, and cleaved Gasdermin D were significantly increased in the EHS group. Conclusion: These findings indicated that hepatic pyroptosis plays an important role in EHS-induced liver injury.

Synergistic toxicity of nanoplastics and Helicobacter pylori on digestive system in mice.

Nanoplastics, in combination with pathogenic microorganisms or toxic substances, have been shown to induce oxidative stress and disrupt energy and lipid metabolism, posing significant health risks. This study evaluated the toxic effects of co-exposure to nanoplastics and Helicobacter pylori on the digestive system of mice. Transmission electron microscopy confirmed the accumulation of AuPS-NPs (Au-core polystyrene nanoplastics) in the stomach, colon, and liver, while hematoxylin and eosin staining revealed dose-dependent pathological damage in these tissues. Enzyme-linked immunosorbent assays quantified interleukin-6 (IL-6), malondialdehyde (MDA), triglyceride (TG), and lactate dehydrogenase (LDH) levels, which significantly increased in co-exposure groups compared to single-exposure groups (P < 0.05). After 28 days, the 100 mg/L H. pylori-AuPS-NPs group showed the highest levels of IL-6 (172.91 ± 1.51 pg/mL in the stomach, 188.31 ± 1.49 pg/mL in the colon, and 174.85 ± 0.26 pg/mL in the liver) and MDA (13.49 ± 0.16 nmol/mg in the stomach, 14.39 ± 0.20 nmol/mg in the colon, and 15.61 ± 0.63 nmol/mg in the liver). These increases, accompanied by elevated TG and LDH levels, suggest aggravated inflammation, oxidative stress, and metabolic disruption. Accumulation analysis showed that while AuPS-NPs content significantly increased over time and with higher concentrations, co-exposure with H. pylori reduced nanoparticle accumulation in gastric and intestinal tissues. These results indicate that co-exposure exacerbates tissue damage, inflammation, oxidative stress, and metabolic disruptions while modulating nanoparticle accumulation. These findings highlight the synergistic toxic effects of nanoplastics and H. pylori, underscoring the importance of understanding combined exposure risks for public health.

Curcumin Regulates Microglia Polarization to Alleviate Ischemic Stroke by Targeting microRNA-205-5p/Kruppel-Like Factor 2 (KLF2)/Activating Transcription Factor 2 (ATF2) Axis.

Ischemic stroke (IS) often causes fearful sequela, even death. Curcumin was beneficial to IS, but its underlying molecular mechanism is unclear. Mice were subjected to middle cerebral artery occlusion (MCAO) surgery, and BV-2 cells were treated with oxygen-glucose deprivation/reoxygenation (OGD/R) induction to establish IS models invivo and invitro. Abundance of genes and proteins was determined using quantitative real-time polymerase chain reaction (RT-qPCR), immunofluorescence (IF), and western blot. Interleukin-1β (IL-1β), interleukin-6 (IL-6), and interleukin-10 (IL-10) levels were analyzed using enzyme-linked immunosorbent assay (ELISA). Modified neurological severity score (mNSS), corner test, foot fault test, adhesive removal test, and 2,3,5-triphenyltetrazolium chloride (TTC) staining were applied to evaluate the brain injury of mice. The correlation between miR-205-5p and Kruppel-like factor 2 (KLF2) was affirmed using dual luciferase reporter assay. Our results revealed that curcumin alleviated brain damage in MCAO mice through driving microglia M2 polarization. Of note, curcumin resulted in decreased miR-205-5p expression in MCAO mice. miR-205-5p knockdown resulted in promoted microglia M2 polarization in OGD/R conditions and achieved similar results to curcumin treatment in MCAO mice. Moreover, curcumin played a promoting role in microglia M2 polarization under OGD/R conditions, while miR-205-5p overexpression or KLF2 knockdown abolished these effects. On the mechanism, miR-205-5p was a target of curcumin, and miR-205-5p further interacted with KLF2 to inhibit activating transcription factor 2 (ATF2) expression. miR-205-5p, decreased by curcumin, suppressed microglia M2 polarization to worsen IS injury through the mediating KLF2/ATF2 axis.

Regulation of Concanavalin A-induced Immune Hepatitis in Mice by Dihydromyricetin at the M1/M2 Type Macrophage Level.

Autoimmune hepatitis (AIH) is an autoimmune disease accompanied by an autoimmune inflammatory response that often leads to severe liver damage. In addition, it may further lead to complications such as liver fibrosis, cirrhosis and liver failure. Dihydromyricetin (DHM) possesses various pharmacological properties, such as being anti-inflammatory, antioxidant, and antibacterial. In this experiment, we investigated the effect of DHM on autoimmune hepatitis mice based on the level of M1/M2 type macrophages. An autoimmune hepatitis mouse model was established by the administration of DHM followed by tail vein injection of Concanavalin A (Con A). Liver tissues were examined for pathological and morphological changes. Interleukin-1β (IL-1β), interleukin-10 (IL-10), interleukin-6 (IL-6), and interleukin-4 (IL-4) levels in liver tissues were assessed. Serum hepatic function indexes were measured, including alanine aminotransferase (ALT), aspartate transaminase (AST), and lactatedehydrogenase (LDH). Oxidative stress indexes, malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and Nitric oxide (NO), were quantified. Additionally, tumor necrosis factor-α (TNF-α) and nuclear factor kappa-B (NF-κB) p65 mRNA and protein expression polarization were determined. The presence of M1/M2-type macrophages was also investigated. Compared to the model group, mice in the DHM group exhibited a significant reduction in serum hepatic function indexes (p < 0.05). Liver tissues from the DHM group showed a noteworthy decrease in MDA and NO levels, along with a significant increase in SOD and GSH-Px levels (p < 0.05). Furthermore, in the liver tissues of mice from the DHM group, there was a notable reduction in the count of M1-type macrophages and a considerable elevation in the M2-type macrophages (p < 0.05). IL-1β and IL-6 expression levels exhibited a significant decrease, whereas IL-10 and IL-4 levels displayed a significant increase (p < 0.05). Additionally, both TNF-α and NF-κB p65 mRNA levels and protein expression experienced a noteworthy decrease (p < 0.05). DHM mitigates the inflammatory response in AIH mice by reducing oxidative stress and modulating macrophage polarization and the TNF-α/NF-κB pathway.

IL-8 Downregulation Mediates the Beneficial Effects of Infection-Induced Fever on Breast Cancer Prognosis.

Previous studies have reported that infection-induced fever is associated with improved breast cancer prognosis, potentially through the modulation of cytokines. However, the key cytokines and the underlying mechanisms through which fever exerts its anti-tumor effects remain unclear. A total of 794 breast cancer patients were recruited between 2008 and 2017, with follow-up extending until October 31st, 2023. Infection-induced fever was assessed using questionnaires, while a multiplex assay evaluated a panel of 27 cytokines. The mediation effects of various cytokines were analyzed through model-based causal mediation analysis. Additionally, we explored modifications to these mediation effect by examining interactions among the cytokines themselves as well as their interactions with infection-induced fever. Bioinformatic analyses were conducted to elucidate the biological pathways mediating infection-induced fever. The relationship between infection-induced fever and improved breast cancer prognosis was mediated by a decrease in interleukin-8 (IL-8) levels. Furthermore, our findings revealed that the downregulation of IL-8, which mediates the beneficial effects of fever, was antagonized by IL-2, IL12p70 and IL-7. By intersecting the biological pathways influenced by IL-8, alongside those affected by IL-2, IL12p70, or IL-7, we found that these latter cytokines antagonized the mediation effects of IL-8 via regulating critical pathways such as neutrophil degranulation, extracellular matrix organization and asparagine N-linked glycosylation. Infection-induced fever may improve breast cancer prognosis through IL-8 downregulation and the mediation mechanisms may be involved in neutrophil degranulation, extracellular matrix organization and asparagine N-linked glycosylation. Such findings not only provide valuable insights into effectively managing febrile responses for breast cancer patients, but also underscore the therapeutic potential of cytokines in breast cancer patients.

Effect of decitabine on PD-L2 methylation in whole blood of iodine-induced autoimmune thyroiditis rats.

Excessive iodine intake can induce autoimmune thyroiditis (AIT), and the methylation of programmed death receptor 2 (PD-L2) may be involved in the development of iodine-induced AIT. Here, we investigated the immune role of methylation of the susceptibility gene PD-L2 in the occurrence of iodine-induced AIT using the DNA methyltransferase inhibitor Decitabine (Dec) in an experimental autoimmune thyroiditis (EAT) rat model. After injecting Dec intraperitoneally into EAT rats, we performed arsenic-cerium catalytic spectrophotometry, pathological hematoxylin and eosin staining, enzyme-linked immunosorbent assay, quantitative methylation-specific polymerase chain reaction (qMSP), and quantitative real-time polymerase chain reaction (qPCR) to determine the relevant indices. The results showed that compared with the control group, the urinary iodine, thyroid lymphocyte infiltration, thyroglobulin antibody (TgAb), interferon (IFN-γ), and interleukin (IL-23) levels of the EAT rats were significantly increased. The PD-L2 methylation levels were significantly decreased in EAT rats compared to control rats, and the mRNA expression of the PD-L2 was significantly increased. Following Dec intervention, the methylation level of the PD-L2 in rats increased and interferon and interleukin-23 levels decreased, albeit not significantly. However, the mRNA expression of PD-L2 decreased significantly after Dec intervention, and the thyroid function of EAT rats also showed a gradual improvement trend. In summary, hypomethylation of PD-L2 is closely related to the development of iodine-induced AIT. Pro-inflammatory cellular factors are also involved in iodine-induced AIT progression. Although Dec shows promise in the treatment of AIT, further evaluation of its safety is necessary.

Genetic predisposition to high circulating levels of interleukin 6 and risk for Alzheimer's disease. Discovery and replication.

Aging is accompanied by immune dysregulation, which has been implicated in Alzheimer's disease (AD) pathogenesis. Individuals who are genetically predisposed to elevated levels of proinflammatory mediators might be at increased risk for AD. To investigate whether genetic propensity for higher circulating levels of interleukin 6 (IL-6) is associated with AD risk. We analyzed data from the Hellenic Longitudinal Investigation of Aging and Diet (HELIAD). Mean follow-up was 2.9 (SD, 0.8) years. Baseline assessment was from 11/2009 to 11/2016, and cognitive follow-up from 01/2013 to 07/2019. Associations of interest were also examined in the UK Biobank (UKB) for replication purposes (mean follow-up was 12.9 (SD, 2.4) years; baseline assessment was from 12/2006 to 10/2010). Population-based study. The HELIAD sample included 622 participants ≥65 years of age without baseline dementia or amnestic mild cognitive impairment (aMCI-the prodromal stage of AD). The UKB sample included 142,637 participants ≥60 years of age without prevalent dementia. Genetic predisposition to elevated circulating levels of IL-6 was estimated using a polygenic risk score (PRS), calculated based on the summary statistics of a current GWAS meta-analysis. AD and MCI diagnoses were based on standard clinical criteria [HELIAD], or hospital records and death registry data [UKB]. Associations with AD or aMCI incidence [HELIAD] and AD incidence [UKB] were examined with Cox regression models. In HELIAD, mean age was 73.4 (SD, 5.0) years; 363 (58%) women. An increase in IL-6 PRS by 1 standard deviation unit (SDU) was associated with up to a 43% increase in the risk for incident AD/aMCI (HRGWAS significance threshold of 0.01, 1.43 [95%CI, 1.14 - 1.80]). In UKBB, mean age was 64.2 (SD, 2.8) years; 73,707 (52%) women. A 1 SDU increase in IL-6 PRS was associated with up to an 8% increase in the risk for incident AD (HRGWAS significance threshold of 0.2, 1.08 [95%CI, 1.04 - 1.12]). Genetic predisposition to higher circulating levels of IL-6 was associated with an increased risk for AD, supporting the role of IL-6-related pathways in AD pathogenesis, and suggesting that genetic predisposition to proinflammatory states might trigger or accelerate AD-related neuropathology.

High BMP7 Expression May Worsen Airway Disease in COPD by Altering Epithelial Cell Behavior.

Airway disease is the main pathological basis of chronic obstructive pulmonary disease (COPD), but the underlying mechanisms are unknown. Bone morphogenetic protein-7 (BMP7) is a multi-functional growth factor that belongs to the transforming growth factor superfamily, which affects the regulation of proliferation, differentiation, and apoptosis. Previous research has shown that BMP7 is highly expressed in the airway epithelia of patients with COPD, but its role in airway disease has not been fully elucidated. A lung tissue cohort and a sputum cohort were included in the study. BMP7 expression in the airway epithelium and the BMP7 level in sputum supernatants were detected. Human primary bronchial epithelial cells (HPBECs) were isolated by bronchoscopy from healthy individuals. The functional consequences of adding recombinant human BMP7 or BMP7 overexpression to HPBECs were explored. BMP7 expression in bronchial epithelial cells of patients with COPD was significantly higher than that in smoking and nonsmoking controls. The expression of BMP7 in the bronchial epithelia of patients with COPD was negatively correlated with the airway counts measured by quantitative computed tomography, positively correlated with airway wall thickness, and negatively correlated with FEV1. The BMP7 level in the induced sputum of patients with COPD was higher than that in controls, and was related to the levels of interleukin-6 (IL-6), IL-8, and IL-1β. The addition of rhBMP7 (100 ng/mL) inhibited the proliferation of HPBECs and promoted squamous metaplasia and inhibit ciliated cell differentiation in human bronchial epithelial cells. BMP7 overexpression promotes apoptosis in human bronchial epithelial cells, through regulating MKK7/JNK2 signaling pathway and activating the caspase-3 pathway. High expression of BMP7 in the bronchial epithelia may play a crucial role in airway disease of COPD through inhibiting proliferation and promoting abnormal differentiation and excessive apoptosis of human bronchial epithelial cells.

Patient-reported symptom burden and circulating cytokines undergoing chemotherapy: a pilot study in patients with ovarian cancer.

To analyze the fluctuations of patient-reported outcomes (PROs) and their relationships with cytokines in the peripheral blood of patients undergoing chemotherapy for ovarian cancer (OC). PROs burden was prospectively measured by the M.D. Anderson Symptom Inventory-Ovarian Cancer (MDASI-OC) at baseline before chemotherapy, on a daily basis during and post-chemotherapy days (PCD) 7, 14, and 20. Cytokines were collected at baseline, days prior to hospital discharge and PCD 20. Pearson correlation was used to explore the associations between PROs and cytokines levels in peripheral blood. The top 8 rated symptoms were compared between the neoadjuvant chemotherapy (NACT) group (n=20) and the postoperative adjuvant chemotherapy (PAC) group (n=7). Before chemotherapy, the mean scores of fatigue and lack of appetite in the NACT group were higher than those in the PAC group. After chemotherapy, pain, nausea, vomiting, disturbed sleep, lack of appetite, and constipation increased to peak during PCD 2-6; while, fatigue and numbness or tingling remained at high levels over PCD 2-13. By PCD 20, disturbed sleep and fatigue showed a significant increase in mean scores, particularly in the NACT group; while, other symptom scores decreased and returned to baseline levels. Additionally, the longitudinal fluctuations in pain, fatigue, and lack of appetite were positively associated with circulating levels of interleukin-6 and interferon gamma (p<0.05). MDASI-OC was feasible and adaptable for demonstrating the fluctuations of symptom burden throughout chemotherapy course. Moreover, symptoms changing along with cytokines levels could provide clues for exploring mechanism underlying biochemical etiology.