IL-6 Gene Research Articles

Comparison of serum levels of IL-10 and IL-11 and mRNA expression of IL-10, IL-11, COX-2, BCL6, and ZEB Family in peripheral blood mononuclear cells (PBMC) of women with polycystic ovary syndrome and healthy individuals

BackgroundThe roles of IL-10, IL-11, COX-2, BCL6, ZEB1, and ZEB2 genes in the potential correlation between polycystic ovary syndrome (PCOS), inflammation, and cancer remain controversial. AimsThis study aimed to compare serum levels of IL-10 and IL-11 and gene expression of IL-10, IL-11, COX-2, BCL6, ZEB1, and ZEB2 in PBMCs of women with PCOS and healthy controls. MethodsA case-control study included 40 women with PCOS as the case group and 40 healthy women as controls. Group matching for age and BMI was performed. Serum levels of IL-10 and IL-11 were assessed using ELISA, while gene expression was measured using real-time PCR. Parameters were compared between groups, and correlations among gene expression and serum levels were explored. ResultsIn comparison to healthy women, women with PCOS exhibited a significant decrease in the expression of COX-2 and IL-10 genes (p<0.001), alongside a significant increase in ZEB2 gene expression (p<0.001). There were no significant differences observed in the expression of IL-11, BCL6, and ZEB1 genes. Furthermore, the serum level of IL-10 was significantly lower in women with PCOS compared to the control group (p<0.001), while no significant difference was found in IL-11 levels. Additionally, no significant correlations were identified between gene expression and serum levels. ConclusionIn women with PCOS, reduced IL-10 gene expression may indicate inflammation and serve as a diagnostic biomarker. However, conflicting findings on COX-2 expression complicate understanding. Elevated ZEB2 expression in PCOS women may lead to infertility, epithelial-mesenchymal transition, and aggressive phenotypes.

The effects of Artemisia Sieberi, Achillea Fragrantissima, and Olea Europaea leaves on the performance and physiological parameters in heat-stressed broiler chickens.

High temperatures have detrimental effects on the performance and physiology of broiler chickens. Medicinal plants have various biological activities and may enhance the heat resistance of chickens during heat waves. Therefore, this study aimed to explore the potential roles of using specific local medicinal plants to alleviate the negative impacts of heat stress (HS) in broilers. In this study, 180 day-old chicks were used to investigate the effects of HS and dietary indigenous medicinal plants on growth performance, antioxidant biomarkers, and intestinal health. The chicks were assigned to six groups (18 pens with 10 chicks per pen) with three replicates each. In the first group, the chicks were kept under thermoneutral conditions (CON) and fed a basal diet. The other five groups were exposed to recurrent heat stress and fed a basal diet (T1, HS group) or supplemented with Artemisia Sieberi (1.25 g/kg of feed; T2), Achillea Fragrantissima (15 g/kg of feed; T3), Olea europaea (10 g/kg of feed; T4), and all the previous additives (all-in-one) combined at the same dose levels mentioned above (T5). At 21 days of age, the chicks from each group were exposed to two phases of heat stress: phase 1 from days 21 to 34 (34 ± 1°C) followed by phase 2 from days 35 to 39 (37 ± 1°C). The results indicate that HS significantly increased rectal temperature and respiration rate in broiler chickens. Feed intake and body weight gain were improved in all supplemented groups, while the feed conversion ratio was decreased in response to the dietary inclusion of medicinal plants. Additionally, glutathione peroxidase and immunoglobulin G levels were increased in the T3, T4, and T5 groups compared to the other groups. HS induced significant upregulated in the mRNA levels of heat shock protein 70 and interleukin-8, while the mRNA of occludin was decreased. The T3, T4, and T5 showed significantly decreased expression of hepatic HSP70 and ileum IL-8 genes and increased ileum mRNA occludin levels relative to the CON and T1 groups. In conclusion, supplementation with these plants enhances growth performance and maintains intestinal health sustaining the productivity of broiler chickens under HS conditions.

Building a novel TRUCK by harnessing the endogenous IFN-gamma promoter for cytokine expression

Despite the remarkable success of CAR T therapy in hematological malignancies, its efficacy in solid tumors remains limited. Cytokine-engineered CAR T cells offer a promising avenue, yet their clinical translation is hindered by the risks associated with constitutive cytokine expression. In this proof-of-concept study, we leverage the endogenous IFN-γ promoter for transgenic IL-15 expression. We demonstrate that IFN-γ expression is tightly regulated by TCR signaling. By introducing IRES-IL15 into the 3’-UTR of the IFN-γ gene via HDR-mediated knock-in, we confirm that IL-15 expression can co-express with IFN-γ in an antigen-stimulation-dependent manner. Importantly, the insertion of transgenes does not compromise endogenous IFN-γ expression. In vitro and in vivo data demonstrate that IL-15 driven by the IFN-γ promoter dramatically improves CAR T cells' antitumor activity, suggesting the effectiveness of IL-15 expression. Lastly, as part of our efforts toward clinical translation, we have developed an innovative two-gene knock-in approach. This approach enables the simultaneous integration of CAR and IL-15 genes into TRAC and IFN-γ gene loci using a single AAV vector. CAR T cells engineered to express IL-15 using this approach demonstrate enhanced antitumor efficacy. Overall, our study underscores the feasibility of utilizing endogenous promoters for transgenic cytokines expression in CAR T cells.

Establishment of a human nasal epithelium model of histamine-induced inflammation to assess the activity of fexofenadine as an inverse agonist and its link to clinical benefit.

Fexofenadine (FEX) is an antihistamine that acts as an inverse agonist against histamine (HIS) receptor 1 (H1R), which mediates the allergic reaction. Inverse agonists may be more potent than neutral antagonists, as they bind the same receptor as the agonist (HIS) but stabilize the inactive form and induce an opposite pharmacological response, suppressing the basal activity of H1R and preventing HIS from binding. This study aims to establish and validate a model of HIS-induced inflammation based on fully reconstituted human nasal epithelial tissue to assess the activity of FEX as an inverse agonist in this model and explore its link to clinical benefit. The model was developed using nasal MucilAir™ (Epithelix) in vitro epithelium challenged by HIS. Two conditions were assessed in a side-by-side comparison: tissue was exposed to HIS + FEX with or without FEX pre-treatment (one-hour prior to HIS challenge). Tissue functionality, cytotoxicity, H1R gene expression, and inflammatory cytokines were assessed. HIS at 100µM induced significant 3.1-fold and 2.2-fold increases for inflammatory biomarkers interleukin (IL)-8 and IL-6, respectively (p < 0.0001), as well as rapid upregulation of H1R mRNA. Inflammatory biomarkers were inhibited by FEX and H1R expression was significantly reduced (p < 0.0001). FEX alone decreased H1R expression at all doses tested. With one-hour FEX pre-treatment, there was significantly higher downregulation of IL-8 (p < 0.05) and further downregulation of H1R expression and IL-6 versus without FEX pre-treatment; the effects of FEX were improved from 22% to 40%. A model of HIS-induced airway inflammation was established based on IL-8, IL-6 and H1R gene expression and was validated with FEX. FEX works as an inverse agonist, with a higher effect when used before+during versus only during the HIS challenge. Taking FEX before+during allergen exposure, or when symptoms first occur, may reduce basal activity and H1R gene expression, providing stronger protection against the worsening of symptoms upon allergen exposure.

Essential oils ameliorate the intestinal damages induced by nonylphenol exposure by modulating tryptophan metabolism and activating aryl hydrocarbon receptor via gut microbiota regulation

Nonylphenol (NP) is a ubiquitous endocrine disruptor that persists in the environment and can significantly contribute to serious health hazards, particularly intestinal barrier injury. Plant essential oils (EOs) have recently gained widespread interest due to their potential for improving intestinal health. However, the precise mechanism and protective effects of EOs ameliorating the intestinal damages induced by NP exposure remain unclear. To clarify the potential mechanism and protective impact of EOs against intestinal injury induced by NP, a total of 144 one-day-old male ducks were randomly allocated to four groups: CON (basal diet), EO (basal diet + 200 mg/kg EOs), NP (basal diet + 40 mg/kg NP), and NPEO (basal diet + 200 mg/kg EOs + 40 mg/kg NP). The data revealed that NP exposure significantly damaged intestinal barrier, as evidenced by a reduction in the levels of tight junction gene expression and an increase in intestinal permeability. Additionally, it disturbed gut microbiota, as well as interfered with tryptophan (Trp) metabolism. The NP-induced disorder of Trp metabolism restrained the activation of aryl hydrocarbon receptor (AhR) and resulted in decreased the expression levels of CYP1A1, IL-22, and STAT3 genes, which were alleviated after treatment with EOs. Taken together, NP exposure resulted in impairment of the intestinal barrier function, disruption of gut microbiota, and disturbances in Trp metabolism. Dietary EOs supplementation alleviated the intestinal barrier injury induced by NP through the Trp/AhR/IL-22 signaling pathway.

Effects of the commensal microbiota on spleen and mesenteric lymph node immune function: investigation in a germ-free piglet model.

Commensal microbial-host interaction is crucial for host metabolism, growth, development, and immunity. However, research on microbial-host immunity in large animal models has been limited. This study was conducted to investigate the effects of the commensal microbiota on immune function in two model groups: germ-free (GF) and specific-pathogen-free (SPF) piglets. The weight and organ index of the spleen of the GF piglet were larger than those in the SPF piglet (P < 0.05). The histological structure of the red pulp area and mean area of germinal centers were larger in the SPF piglet than in the GF piglet (P < 0.05), whereas the areas of staining of B cells and T cells in the spleen and mesenteric lymph nodes (MLNs) were lower in the GF piglet (P < 0.05). We identified immune-related genes in the spleen and MLNs using RNA sequencing, and used real-time quantitative PCR to analyze the expression of core genes identified in gene set enrichment analysis. The expression levels of genes in the transforming growth factor-β/SMAD3 signaling pathway, Toll-like receptor 2/MyD88/nuclear factor-κB signaling pathway, and pro-inflammatory factor genes IL-6 and TNF-α in the spleen and MLNs were higher in the SPF piglet and in splenic lymphocytes compared with those in the GF and control group, respectively, under treatment with acetic acid, propionic acid, butyric acid, lipopolysaccharide (LPS), or concanavalin A (ConA). The abundances of plasma cells, CD8++ T cells, follicular helper T cells, and resting natural killer cells in the spleen and MLNs were significantly greater in the SPF piglet than in the GF piglet (P < 0.05). In conclusion, the commensal microbiota influenced the immune tissue structure, abundances of immune cells, and expression of immune-related pathways, indicating the importance of the commensal microbiota for spleen and MLNs development and function. In our study, GF piglet was used as the research model, eliminating the interference of microbiota in the experiment, and providing a suitable and efficient large animal research model for exploring the mechanism of "microbial-host" interactions.

An Integrative Network Pharmacology and Bioinformatics Approach for Deciphering the Multi-target Effect of Nyctanthes arbortristis L. against COVID-19.

The COVID-19 pandemic represents a significant challenge across scientific, medical, and societal dimensions. The unpredictability of the disease progression, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), underscores the urgent need for identifying compounds that target multiple aspects of the virus to ensure swift and effective treatment. Nyctanthes arbortristis L., a delicate, perennial, deciduous shrub found across various Asian regions, has been recognized for its wide range of pharmacological benefits, including hepatoprotective, antimalarial, antibacterial, anti-inflammatory, antioxidant, and antiviral properties. Various in vitro studies revealed the therapeutic significance of Nyctanthes arbortristis against COVID-19. However, the exact molecular mechanism remains unclarified. In the present study, a network pharmacology approach was employed to uncover the active ingredients, their potential targets, and signaling pathways in Nyctanthes arbortristis for the treatment of COVID-19. In the framework of this study, we explored the active ingredient-target-pathway network and figured out that naringetol, ursolic acid, betasitosterol, and daucosterol decisively contributed to the development of COVID-19 by affecting IL6, MAPK3, and MDM2 genes. The results of molecular docking analysis indicated that Nyctanthes arbortristis exerted effective binding capacity in COVID-19. Further, we disclosed the targets, biological functions, and signaling pathways of Nyctanthes arbortristis in COVID-19. The analysis indicated that Nyctanthes arbortristis could help treat COVID-19 through the enhancement of immunologic functions, inhibition of inflammatory reactions and regulation of the cellular microenvironment. In short, the current study used a series of network pharmacologybased and computational analyses to understand and characterize the binding capacity, biological functions, pharmacological targets and therapeutic mechanisms of Nyctanthes arbortristis in COVID-19. However, the findings were not validated in actual COVID-19 patients, so further investigation is needed to confirm the potential use of Nyctanthes arbortristis for treating COVID-19.

Elucidating Korean meadowsweet (Filipendula glaberrima Nakai)-derived arabinogalactan protein-induced macrophage activation and its associated mechanism of action

This study aimed to confirm macrophage-stimulatory component from Korean meadowsweet (Filipendula glaberrima; FG) and characterize its compositional and structural properties. FG-CWH, prepared via cool-water extraction and ethanol precipitation, induced the highest secretion of NO (6.0–8.0 μM), TNF-α (8.7–9.5 ng/mL), and IL-6 (1.0–5.7 ng/mL) compared to other samples at 0.4–10 μg/mL in RAW 264.7 cells. Analytical results revealed that FG-CWH is a high-molecular-weight component with an average molecular weight of 220 kDa, constituting a polysaccharide-protein mixture. Chemical and enzymatic treatment of FG-CWH indicated its primary composition as arabinogalactan protein (AGP)-rich glycoprotein, with activity likely associated with the chemical and structural characteristics of AGP. FG-CWH treatment resulted in significant and concentration-dependent increases in iNOS (20.0–29.6 folds), TNFα (10.6–18.6 folds) and IL6 (10.9–155.6 folds) gene expression, as well as the secretion of NO (5.3–6.3 μM), TNF-α (35.4–44.3 ng/mL), and IL-6 (4.1–8.4 ng/mL) secretion, even at a reduced concentration range of 125–500 ng/mL, compared to the negative control group. Immunoblotting analysis indicated FG-CWH-induced macrophage stimulation significantly associated with the activation of MAPK (ERK, JNK, and p38) and NF-κB (p65 and IκBα). These findings can serve as valuable groundwork for developing FG-derived AGP as novel functional ingredients to enhance human immunity.

The Effect of Aerobic Exercise and Pistachio Soft Hull Extract on the Expression of the Il-6 and IL-1β Genes in the Soleus Muscle of Female Rats Fed a High-Fat Diet

Background: Obesity is considered the most important public health problem. Previous studies have confirmed that a high-fat diet (HFD) can cause the development of systemic and tissue inflammation due to the increase in pro-inflammatory markers. Objectives: This study aims to evaluate the effect of aerobic exercise and pistachio soft hull extract (PSHE) on inflammatory gene expression in the soleus muscle of rats fed a HFD. Methods: In an experimental trial, 30 female Wistar rats weighing between 180 and 200 grams were selected as subjects and randomly divided into five groups: Normal diet control, HFD control, HFD aerobic exercise, HFD-PSHE, and HFD aerobic exercise-PSHE. The aerobic exercise program consisted of four weeks of five weekly sessions of running on a treadmill at an intensity of 50 – 60% VO2max. Pistachio soft hull extract at a dose of 60 mg/kg was administered to the rats by gavage for four weeks, five times a week. Forty-eight hours after the last interventions, the rats were anesthetized, and the soleus muscle was removed to determine the expression of the IL-6 and IL-1β genes. Results: Induction of HFD significantly decreased IL-6 (P = 0.001) and increased IL-1β (P = 0.001) gene expression. IL-1β gene expression in the aerobic exercise (P = 0.001), PSHE (P = 0.003), and aerobic exercise-PSHE (P = 0.001) groups was significantly lower than in the HFD control group. Aerobic exercise (P = 0.002), PSHE (P = 0.002), and the combination of aerobic exercise and PSHE (P = 0.003) caused a significant increase in IL-6 gene expression compared to the HFD control group. Conclusions: High-fat diet promotes inflammation in skeletal muscle by increasing the expression of the IL-1β and IL-6 genes. Aerobic exercise, PSHE, and the combination of aerobic exercise and PSHE can exert their anti-inflammatory effects by reducing the expression of the IL-1β and IL-6 genes in skeletal muscle tissue.

Dynamic immune status analysis of peripheral blood mononuclear cells in patients with Klebsiella pneumoniae bloodstream infection sepsis using single-cell RNA sequencing.

Klebsiella pneumoniae is a common Gram-negative bacterium. Blood infection caused by K. pneumoniae is one of the most common causes of human sepsis, which seriously threatens the life of patients. The immune status of peripheral blood mononuclear cells (PBMCs) based on single-cell RNA sequencing (scRNA-seq) in acute stage and recovery stage of sepsis caused by K. pneumoniae bloodstream infection has not been studied. A total of 13 subjects were included in this study, 3 healthy controls, 7 patients with K. pneumoniae bloodstream infection in the acute stage (4 patients died), and 3 patients in the recovery stage. Peripheral blood of all patients was collected and PBMCs were isolated for scRNA-seq analysis. We studied the changes of PBMCs components, signaling pathways, differential genes, and cytokines in acute and recovery stages. During K. pneumoniae acute infection we observed a decrease in the proportion of T cells, most probably due to apoptosis and the function of T cell subtypes was disorder. The proportion of monocytes increased in acute stage. Although genes related to their phagocytosis function were upregulated, their antigen presentation capacity-associated genes were downregulated. The expression of IL-1β, IL-18, IFNGR1 and IFNGR2 genes was also increased in monocytes. The proportion of DCs was depleted during the acute stage and did not recover during sepsis recovery. DCs antigen presentation was weakened during the acute stage but recovered fast during the recovery stage. pDCs response to MCP-1 chemokine was weakened, they recovered it quickly during the recovery stage. B cells showed apoptosis both in the acute stage and recovery stage. Their response to complement was weakened, but their antigen presentation function was enhanced. The proportion of NK cells stable during all disease's stages, and the expression of IFN-γ gene was upregulated. The proportion of PBMCs and their immune functions undergo variations throughout the course of the disease, spanning from the acute stage to recovery. These findings provide new insights into the mechanism of PBMCs immune function during K. pneumoniae bloodstream infection sepsis and recovery and sets the basis for further understanding and treatment.

Immunogenic effects of enamel matrix derivative on human alveolar ridge mucosa-derived vascular endothelial cells under lipopolysaccharide stimulation.

Early peri-implant disease detection remains difficult. Enamel matrix derivative (EMD), which is used for periodontal tissue regeneration, promotes leukocyte chemotactic factor and adhesion molecule expression in vascular endothelial cells. We hypothesized that stimulating vascular endothelial cells with EMD would induce an inflammatory response in the peri-implant mucosa, enabling early peri-implant infection detection. To verify this hypothesis, we assessed the intercellular adhesion between human alveolar ridge mucosa-derived vascular endothelial cells (ARMEC) stimulated with lipopolysaccharide (LPS) and EMD and human periodontal ligament-derived vascular endothelial cells (PDLEC). Leukocyte chemotactic factors and cell adhesion molecules were investigated and we established an experimental model of peri-implant disease by stimulating ARMEC (representing the peri-implant mucosa) with Porphyromonas gingivalis-derived LPS. ARMEC and PDLEC were obtained from patients (n = 6) who visited the Nippon Dental University Niigata Hospital. The cells were divided into four subcategories, each cultured with: LPS (1µg/mL), EMD (100µg/mL), LPS + EMD, and pure medium. Cell viability, leukocyte chemotactic factor (interleukin-8: IL-8), adhesion molecules (intercellular adhesion molecule-1: ICAM-1), tight junction protein gene expression (zonula occludens-1: ZO-1 and Occludin), and transendothelial electrical resistance (TEER) was then determined. LPS reduced ARMEC viability, whereas simultaneous stimulation with EMD improved it. LPS and EMD stimulation enhanced IL-8 and ICAM-1 gene expression, suppressed TEER, and decreased ZO-1 and Occludin expression levels compared to that with stimulation with LPS alone. EMD stimulates leukocyte migration, increase vascular permeability, and trigger an immune response in the peri-implant mucosa, thus facilitating the early detection and treatment of peri-implant disease.

Assessment of the Anti-cancer Effects of Camel Milk Exosomes (CMEXOs) on Murine Colorectal Cancer Cell Line (CT-26).

Today, camel milk consumption in the Middle East is trendy because it is believed that it reduces the risk of cancer. Recently, studies have discovered that most of milk's beneficial effects are because of its nanoparticles, especially exosomes. The objective of the present research was to investigate the anti-cancer effects of camel milk exosomes (CMEXOs) in the murine colorectal cancer cell line (CT-26). Our findings verified the existence of exosomes measuring approximately 114.1±3.4 nm in diameter. Through MTT and migration assays, we established that CMEXOs exhibit dose-dependent anti-proliferative and anti-migration effects on the CT-26 cell line. Furthermore, our study showed that treatment with CMEXOs led to a reduction in TNF-α and IL-6 gene expression in CT-26 cells. While additional in vivo studies are required, our data demonstrate that CMEXOs have anti-proliferative and anti-migration effects on CT-26, possibly by influencing crucial genes within the inflammation pathway.

Prostacyclin synthase deficiency exacerbates systemic inflammatory responses in lipopolysaccharide-induced septic shock in mice.

Sepsis is a systemic inflammatory disorder characterized by life-threateningorgan dysfunction resulting from a dysregulated host response to infection. Prostacyclin (PGI2) is a bioactive lipid produced by PGI synthase (PGIS) and is known to play important roles in inflammatory reactions as well as cardiovascular regulation. However, little is known about the roles of PGIS and PGI2 in systemic inflammatory responses such as septic shock. Systemic inflammation was induced by intraperitoneal injection of 5mg/kg lipopolysaccharide (LPS) in wild type (WT) or PGIS knockout (KO) mice. Selexipag, a selective PGI2 receptor (IP) agonist, was administered 2h before LPS injection and again given every 12h for 3days. Intraperitoneal injection of LPS induced diarrhea, shivering and hypothermia. These symptoms were more severe in PGIS KO mice than in WT micqe. The expression of Tnf and Il6 genes was notably increased in PGIS KO mice. In contrast, over 95% of WT mice survived 72h after the administration of LPS, whereas all of the PGIS KO mice had succumbed by that time. The mortality rate of LPS-administrated PGIS KO mice was improved by selexipag administration. Our study suggests that PGIS-derived PGI2 negatively regulates LPS-induced symptoms via the IP receptor. PGIS-derived PGI2-IP signaling axis may be a new drug target for systemic inflammation in septic shock.

Cluster approach to identifying the 5-year prognosis of patients with chronic heart failure of ischemic etiology

BACKGROUND: The phenotypic and pathophysiological heterogeneity of patients with chronic heart failure increases the interest of researchers in grouping according to similar clinical and genetic characteristics based on cluster analysis. AIM: To identify phenotypic subgroups in a multivariate cohort of patients with chronic heart failure secondary to coronary artery disease using uncontrolled cluster analysis of clinical, instrumental and genetic components. MATERIAL AND METHODS: 470 patients with chronic heart failure of functional class I–IV, stable course, ischemic etiology of both sexes at the age of 66.4±10.4 years were examined. A clinical study was conducted, genotyping single nucleotide polymorphisms rs10927875 of the ZBTB17 gene, rs247616 of the CETP gene, rs1143634 of the IL-1β gene, rs1800629 of the TNF gene, rs1800795 of the IL-6 gene was carried out, and patient outcomes were assessed for 5 years. Quantitative data were presented as mean and standard deviation or median and interquartile range; categorical — as frequencies and percentages. Categorical intergroup differences were tested using the χ2 test, and quantitative differences were tested using the Student/Mann–Whitney test. Hierarchical clustering was carried out according to 44 demographic, clinical, genetic variables, time to event was analyzed by the Kaplan–Meier method, risk ratio — by Cox regression. Statistical processing was carried out in the R4.3.1 program. RESULTS: Two clusters of patients with heart failure were identified. Cluster 1 (66%) included older patients of both sexes, predominantly functional class III–IV chronic heart failure, with enlarged heart chambers, reduced left ventricular ejection fraction, higher heart rate, atrial fibrillation and left ventricular hypertrophy. In this cluster, more carriers of the GG genotype of the rs1800795 polymorphism of the IL-6 gene (p 0.001) and the CT genotype of the rs247616 polymorphism of the CETP gene (p=0.014) were identified. Cluster 2 (34%) was represented predominantly by younger women, with a higher metabolic index, a history of myocardial infarction and coronary intervention, smokers, and a larger proportion of the TT genotype of the rs247616 polymorphism of the CETP gene (p=0.029). CONCLUSION: 2 clusters of patients with chronic heart failure, characterized by a different set of 44 variables that determine the risk of death from all causes, were identified.

Structure-activity relationship studies of pyrogallol as a calcineurin/NFAT signaling suppressor

Previously, we have shown that pyrogallol alleviated nasal symptoms and suppressed IL-9 gene up-regulation in allergy model rats by inhibiting calcineurin/NFAT signaling. As pyrogallol has antioxidative activity, it may be responsible for inhibiting calcineurin/NFAT signaling-mediated IL-9 gene expression. However, the relationship between antioxidative activity and suppression of IL-9 gene expression has not been elucidated yet. Here, we conducted the structure-activity relationship studies of pyrogallol and its structurally related compounds to understand the mechanism of IL-9 gene suppression by pyrogallol. 2, 2-Diphenyl-1-picrylhydrazyl radical scavenging assay showed that the antioxidative activity of catechol, resorcinol, phloroglucinol, and gallic acid is 60.1%, 10.4%, 18.8%, and 113.5% of pyrogallol, respectively. Catechol, resorcinol, and phloroglucinol did not suppress NFAT dephosphorylation. Gallic acid suppressed dephosphorylation of NFAT. Gallic acid also suppressed ionomycin-induced up-regulation of IL-9 gene expression with the IC50 value of 82.6 μM. However, catechol, resorcinol and phloroglucinol showed no suppressive activity. In addition, using gallic acid-immobilized beads, we isolated and identified Poly(U)-binding-splicing factor 60 (PUF60) as a pyrogallol binding protein. These results suggest that the antioxidative activity of pyrogallol is not likely to be the mechanism of IL-9 gene suppression. Data also suggest that PUF60 is one of its target molecules responsible for the suppression of calcineurin/NFAT signaling by pyrogallol.

Microparticles incorporating dual apoptotic factors to inhibit inflammatory effects in macrophages

New approaches to treat autoimmune diseases are needed, and we can be inspired by mechanisms in immune tolerance to guide the design of these approaches. Efferocytosis, the process of phagocyte-mediated apoptotic cell (AC) disposal, represents a potent tolerogenic mechanism that we could draw inspiration from to restore immune tolerance to specific autoantigens. ACs engage multiple avenues of the immune response to redirect aberrant immune responses. Two such avenues are: phosphatidylserine on the outer leaflet of the cell and engaging the aryl hydrocarbon receptor (AhR) pathway. We incorporated these two avenues into one acetalated dextran (Ace-DEX) microparticle (MP) for evaluation in vitro. First phosphatidylserine (PS) was incorporated into Ace-DEX MPs and evaluated for cellular association and mediators of cell tolerance including IL-10 production and M2 associated gene expression when particles were cultured with peritoneal macrophages (PMacs). Further PS Ace-DEX MPs were evaluated as an agent to suppress LPS stimulated PMacs. Then, AhR agonist 2-(1′H-indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) was incorporated into Ace-DEX MPs and expression of M2 and IL-10 genes was evaluated in PMacs. Further the ITE and PS Ace-DEX MPs (PS/ITE MPs) were evaluated for suppression of T cell priming and Th1 polarization. Our results indicate that the PS/ITE-MPs stimulated anti-inflammatory cytokine expression and suppressed inflammation following LPS stimulation of PMacs. Moreover, PS/ITE MPs induced the anti-inflammatory enzyme IDO1 and suppressed macrophage-mediated T cell priming and Th1 polarization. These findings suggest that PS and ITE-loaded Ace-DEX MPs could be a promising therapeutic tool for suppressing inflammation.

Association of Interleukin-6 (rs1800795) and Interleukin-10 (rs1800896) Genetic Polymorphisms with the Outcome of COVID-19 Infection: A Single Center Study.

The corona virus disease-2019 (COVID-19) pandemic has affected most of the world with varying degrees of morbidity and mortality. The presence of genetic polymorphisms may be associated with the severity and outcome of COVID-19 infection. This work aimed to evaluate the genetic polymorphisms of interleukin (IL-6) and IL-10 genes with the outcome of COVID-19 infection. This cross-sectional study was conducted on 354 patients who were classified into moderate and severe cases (including alive and deceased cases). All individuals were genotyped for one SNP for IL-6 (rs1800795) and one SNP for IL10 (rs1800896) using allelic discrimination real-time PCR technique. In this study, 198 cases were moderate, and 156 cases were severe. The risk of allele carriage of the minor allele of IL-6 rs1800795 (C) was significantly higher among the severe group when compared with that of the moderate group (p < 0.0001), while there was a mild significant difference of same allele carriage among alive cases when compared to that of deceased one (p < 0.04). Furthermore, the risk of the C allele of IL-10 rs1800896 was significantly increased in severe cases when compared with the moderate group (p < 0.0001), while there was no significant difference of the risk of the C allele in deceased cases when compared with that of alive ones (p > 0.05). In conclusion, the C allele (rs1800795) of IL-6 and the C allele (rs1800896) of IL-10 were highly significant in severe cases than in moderate cases. The C allele carriage of IL-6 showed only a significant difference between alive and deceased patients and not with the C allele of IL-10.

Anti-Inflammatory Effect of Atorvastatin on Primary Human Endothelial Cells Incubated under Genotoxic Load.

The level of cytokine expression was measured in human coronary artery (HCAEC) and internal thoracic artery (HITAEC) endothelial cells exposed to 500 ng/ml alkylating mutagen mitomycin C (MMC) and 5 μM atorvastatin. It was found that treatment of MMC-exposed HCAEC with atorvastatin decreased secretion of macrophage migration inhibitory factor (MIF), IL-8, and IL8 gene expression, but increased the expression of SERPINE1 gene encoding the PAI-1 protein. In atorvastatin-treated HITAEC, the concentration of MIF protein and the expression of the IL8 and SERPINE1 genes were reduced. We can conclude that atorvastatin prevents proinflammatory activation of endothelial cells cultured under conditions of genotoxic load. However, the molecular mechanisms of this effect require further research.

Predicting the risk of developing vibration disease and vegetative-sensory polyneuropathy under vibration exposure using analysis of candidate gene polymorphism

In this study, we investigated the association of IL-6 (rs1800795), TNF-α (rs361525), IL-1β (rs16944), MMP-1 (rs1799750) and SOD2 (rs4880) gene polymorphisms with the risk of developing vibration disease (VD) and autonomic sensory polyneuropathy (ASPN). We examined 45 patients with VB, 10 patients with ASPN and 76 people who were not exposed to vibration in their professional activities. Polymorphic gene variants were determined using a real-time polymerase chain reaction. The polymorphic variant rs16944 of the IL-1β gene was established to carry both the G allele (p = 0.027) and the homozygous G/G genotype (p = 0.015) with elevated frequency in the group of patients with VD relative to the control group. Allele A of the rs361525 polymorphic variant of the TNF-α gene was more common in patients with ASPN as compared to controls, (p = 0.047). Statistically significant differences in polymorphic variants rs1800795 of the IL-6 gene, rs1799750 of the MMP-1 gene and rs4880 of the SOD2 gene were not found in both groups of patients as compared to the control group. However, when comparing groups of patients with each other, we established that the G allele of the polymorphic variant rs1800795 of the IL-6 gene was more often recorded in patients with ASPN (p = 0.032). The results obtained by examining the patients with VD and ASPN made it possible to establish that the rs361525 polymorphic variant of the TNF-α gene is associated with an elevated risk of developing ASPN, while carriers of the homozygous genotype G/G of the rs16944 polymorphic variant of the IL-1β gene have a high prognostic risk of developing VD. Polymorphic variants of the IL-1β and TNF-α genes can be considered probable molecular genetic predictors of VD and ASPN.

Прогнозирование риска развития вибрационной болезни и вегетативно-сенсорной полинейропатии при вибрационном воздействии с исполь-зованием анализа полиморфизма кандидатных генов

In this study, we investigated the association of IL-6 (rs1800795), TNF-α (rs361525), IL-1β (rs16944), MMP-1 (rs1799750) and SOD2 (rs4880) gene polymorphisms with the risk of developing vibration disease (VD) and autonomic sensory polyneuropathy (ASPN). We examined 45 patients with VB, 10 patients with ASPN and 76 people who were not exposed to vibration in their professional activities. Polymorphic gene variants were determined using a real-time polymerase chain reaction. The polymorphic variant rs16944 of the IL-1β gene was established to carry both the G allele (p = 0.027) and the homozygous G/G genotype (p = 0.015) with elevated frequency in the group of patients with VD relative to the control group. Allele A of the rs361525 polymorphic variant of the TNF-α gene was more common in patients with ASPN as compared to controls, (p = 0.047). Statistically significant differences in polymorphic variants rs1800795 of the IL-6 gene, rs1799750 of the MMP-1 gene and rs4880 of the SOD2 gene were not found in both groups of patients as compared to the control group. However, when comparing groups of patients with each other, we established that the G allele of the polymorphic variant rs1800795 of the IL-6 gene was more often recorded in patients with ASPN (p = 0.032). The results obtained by examining the patients with VD and ASPN made it possible to establish that the rs361525 polymorphic variant of the TNF-α gene is associated with an elevated risk of developing ASPN, while carriers of the homozygous genotype G/G of the rs16944 polymorphic variant of the IL-1β gene have a high prognostic risk of developing VD. Polymorphic variants of the IL-1β and TNF-α genes can be considered probable molecular genetic predictors of VD and ASPN.