Cytokine Homeostasis Research Articles

Colonization of microbiota derived from Macaca fascicularis, Bama miniature pigs, beagle dogs, and C57BL/6J mice alleviates DSS-induced colitis in germ-free mice.

Fecal microbiota transplantation (FMT) is an innovative and promising treatment for inflammatory bowel disease (IBD), which is related to the capability of FMT to supply functional microorganisms to improve recipient gut health. Numerous studies have highlighted considerable variability in the efficacy of FMT interventions for IBD. Several factors, including the composition of the donor microorganisms, significantly affect the efficacy of FMT in the treatment of IBD. Consequently, identifying the functional microorganisms in the donor is crucial for enhancing the efficacy of FMT. To explore potential common anti-inflammatory bacteria with therapeutic implications for IBD, germ-free (GF) BALB/c mice were pre-colonized with fecal microbiota obtained from diverse donors, including Macaca fascicularis (MCC_FMT), Bama miniature pigs (BP_FMT), beagle dogs (BD_FMT), and C57BL/6 J mice (Mice_FMT). Subsequently, mice were treated with dextran sodium sulfate (DSS). As expected, the symptoms of colitis were alleviated by MCC_FMT, BP_FMT, BD_FMT, and Mice_FMT, as demonstrated by the prevention of an elevated disease activity index in mice. Additionally, the utilization of distinct donors protected the intestinal barrier and contributed to the regulation of cytokine homeostasis. Metagenomic sequencing data showed that the microbial community structure and dominant species were significantly different among the four groups, which may be linked to variations in the anti-inflammatory efficacy observed in the respective groups. Notably, Lactobacillus reuteri and Flavonifractor plautii were consistently present in all four groups. L. reuteri exhibited a significant negative correlation with IL-1β, and animal studies further confirmed its efficacy in alleviating IBD, suggesting the presence of common functional bacteria across different donors that exert anti-inflammatory effects. This study provides essential foundational data for the potential clinical applications of FMT.IMPORTANCEDespite variations in efficacy observed among donors, numerous studies have underscored the potential of fecal microbiota transplantation (FMT) for managing inflammatory bowel disease (IBD), indicating the presence of shared anti-IBD bacterial species. In the present study, the collective anti-inflammatory efficacy observed across all four donor groups prompted the identification of two common bacterial species using metagenomics. A significant negative correlation between Lactobacillus reuteri and IL-1β was revealed. Furthermore, mice gavaged with L. reuteri successfully managed the colitis challenge induced by dextran sodium sulfate (DSS), suggesting that L. reuteri may act as an efficacious bacterium mediating shared anti-inflammatory effects among variable donors. This finding highlights the utilization of variable donors to screen FMT core bacteria, which may be a novel strategy for developing FMT applications.

Role of fingolimod in acute respiratory distress syndrome.

Objective: Sphingosine 1 Phosphate (S1P) is a key regulator of inflammation, angiogenesis, vessel permeability, and immune processes, acting through S1P receptors. Fingolimod (FTY720), an S1P receptor analog Fingolimod, was initially approved for multiple sclerosis treatment and has shown potential for application in infectious and inflammatory disorders, including COVID-19. Study Design: Comprehensive Literature Review. Setting: Northwest School of Medicine. Period: 1st March 2023 to 3rd July 2023. Methods: Examining S1P pathways, S1P receptor analogs, and their potential in treating inflammatory and infectious disorders, particularly COVID-19, utilizing Fingolimod. Results: S1P analogs have demonstrated therapeutic benefits in autoimmune diseases. In COVID-19, these analogs modulate the inflammatory response, reduce tissue damage, and promote viral clearance. Fingolimod, in particular, affects S1PR1, S1PR4, and S1PR5, blunting the inflammatory response and mitigating lung tissue injury. Early administration may prevent excessive inflammation without interfering with viral clearance. Potential risks include disturbance of cytokine homeostasis and delayed administration. Limited human studies and concerns about off-target effects need addressing. Conclusion: Fingolimod shows promise in treating COVID-19 by reducing inflammation and lung damage. Further research is needed to address limitations and ensure safety for clinical application. Sphingosine 1 Phosphate (S1P) plays a key role in regulating inflammation and immune responses, with Fingolimod being a potential treatment option.

Autoimmune Responses and Therapeutic Interventions for Systemic Lupus Erythematosus: A Comprehensive Review.

Systemic Lupus Erythematosus (SLE) or Lupus is a multifactorial autoimmune disease of multiorgan malfunctioning of extremely heterogeneous and unclear etiology that affects multiple organs and physiological systems. Some racial groups and women of childbearing age are more susceptible to SLE pathogenesis. Impressive progress has been made towards a better understanding of different immune components contributing to SLE pathogenesis. Recent investigations have uncovered the detailed mechanisms of inflammatory responses and organ damage. Various environmental factors, pathogens, and toxicants, including ultraviolet light, drugs, viral pathogens, gut microbiome metabolites, and sex hormones trigger the onset of SLE pathogenesis in genetically susceptible individuals and result in the disruption of immune homeostasis of cytokines, macrophages, T cells, and B cells. Diagnosis and clinical investigations of SLE remain challenging due to its clinical heterogeneity and hitherto only a few approved antimalarials, glucocorticoids, immunosuppressants, and some nonsteroidal anti-inflammatory drugs (NSAIDs) are available for treatment. However, the adverse effects of renal and neuropsychiatric lupus and late diagnosis make therapy challenging. Additionally, SLE is also linked to an increased risk of cardiovascular diseases due to inflammatory responses and the risk of infection from immunosuppressive treatment. Due to the diversity of symptoms and treatment-resistant diseases, SLE management remains a challenging issue. Nevertheless, the use of next-generation therapeutics with stem cell and gene therapy may bring better outcomes to SLE treatment in the future. This review highlights the autoimmune responses as well as potential therapeutic interventions for SLE particularly focusing on the recent therapeutic advancements and challenges.

Fecal bacteria-free filtrate transplantation is proved as an effective way for the recovery of radiation-induced individuals in mice.

Ionizing radiation can cause intestinal microecological dysbiosis, resulting in changes in the composition and function of gut microbiota. Altered gut microbiota is closely related to the development and progression of radiation-induced intestinal damage. Although microbiota-oriented therapeutic options such as fecal microbiota transplantation (FMT) have shown some efficacy in treating radiation toxicity, safety concerns endure. Therefore, fecal bacteria-free filtrate transplantation (FFT), which has the potential to become a possible alternative therapy, is well worth investigating. Herein, we performed FFT in a mouse model of radiation exposure and monitored its effects on radiation damage phenotypes, gut microbiota, and metabolomic profiles to assess the effectiveness of FFT as an alternative therapy to FMT safety concerns. FFT treatment conferred radioprotection against radiation-induced toxicity, representing as better intestinal integrity, robust proinflammatory and anti-inflammatory cytokines homeostasis, and accompanied by significant shifts in gut microbiome. The bacterial compartment of recipients following FFT was characterized by an enrichment of radioprotective microorganisms (members of family Lachnospiraceae). Furthermore, metabolome data revealed increased levels of microbially generated short-chain fatty acids (SCFAs) in the feces of FFT mice. FFT improves radiation-induced intestinal microecological dysbiosis by reshaping intestinal mucosal barrier function, gut microbiota configurations, and host metabolic profiles, highlighting FFT regimen as a promising safe alternative therapy for FMT is effective in the treatment of radiation intestinal injury.

27-hydroxycholesterol causes cognitive deficits by disturbing Th17/Treg balance and the related immune responses in mild cognitive impairment patients and C57BL/6J mice

BackgroundCognitive impairment is associated with dysregulated immune responses. Emerging evidence indicates that Th17 cells and their characteristic cytokine-IL-17 are receiving growing interest in the pathogenesis of cognitive decline. Here, we focus on the involvement of Th17 cells in mild cognitive impairment (MCI) and the possible mechanism of cholesterol metabolite-27-hydroxycholesterol (27-OHC).Methods100 individuals were recruited into the nested case–control study who completed cognition assessment and the detection of oxysterols and Th17-related cytokines in serum. In addition, mice were treated with 27-OHC and inhibitors of RORγt and Foxp3 (Th17 and Treg transcription factors), and the factors involved in Th17/Treg balance and amyloidosis were detected.ResultsOur results showed there was enhanced 27-OHC level in serum of MCI individuals. The Th17-related cytokines homeostasis was altered, manifested as increased IL-17A, IL-12p70, IL-23, GM-CSF, MIP-3α and TNF-α but decreased IL-13, IL-28A and TGF-β1. Further, in vivo experiments showed that 27-OHC induced higher immunogenicity, which increased Th17 proportion but decreased Treg cells in peripheral blood mononuclear cells (PBMCs); Th17 proportions in hippocampus, and IL-17A level in serum and brain were also higher than control mice. The fluorescence intensity of amyloid-β (Aβ) and the precursor of amyloid A amyloidosis–serum amyloid A (SAA) was increased in the brain of 27-OHC-treated mice, and worse learning and memory performance was supported by water maze test results. While by inhibiting RORγt in 27-OHC-loaded mice, Th17 proportions in both PBMCs and hippocampus were reduced, and expressions of IL-17A and TGF-β1 were down- and up-regulated, respectively, along with a decreased amyloidosis in brain and improved learning and memory decline.ConclusionsAltogether, our results demonstrate that excessive 27-OHC aggravates the amyloidosis and leads to cognitive deficits by regulating RORγt and disturbing Th17/Treg balance.

Treatment Outcomes and Prognostic Factors with Lenalidomide, Bortezomib, and Dexamethasone (RVd) Alone Versus Rvd Plus Autologous Stem Cell Transplantation (ASCT) in African American (AA) Patients (Pts) with Newly Diagnosed Multiple Myeloma (NDMM) in the Determination Phase 3 Trial

Background AA pts with NDMM have equal or longer overall survival (OS) vs White pts when treatment access is equal (Fillmore, Blood 2019; Dong, Blood Cancer J 2022). DETERMINATION included one of the largest cohorts of AA pts in prospective NDMM trials (n=132/722, 18.3%). The overall progression-free survival (PFS) difference (RVd-alone vs RVd+ASCT; median 46.2 vs 67.5 months [mos]; hazard ratio [HR] 1.53) was not seen in AA pts (HR 1.07; Richardson, N Engl J Med 2022). Multivariable PFS analyses, overall and by arm, showed that prognostic factors may vary according to treatment received, potentially indicating differences in MM pathobiology; PFS in AA vs White pts was longer with RVd-alone (HR 0.58) but similar with RVd+ASCT (HR 0.95) (Hassoun, EBMT 2023). We build upon this prior work with new analyses to explore outcomes with RVd-alone vs RVd+ASCT in AA and White pts. Methods Pts aged 18-65 y received RVd (3 cycles), stem cell mobilization, then 5 more RVd cycles (RVd-alone: n=357; 66 AA, 268 White) or ASCT and 2 more RVd cycles (RVd+ASCT: n=365; 66 AA, 272 White), and then R maintenance. We analyzed PFS (primary endpoint) by race, with exploration of potentially confounding effects of body mass index (BMI) and sex. Treatment exposure, response, event-free survival (EFS; events: progressive disease [PD], death, non-protocol therapy [NPT]), OS, and safety by race were evaluated. Exploratory genomic analyses in a subset of pts assessed frequency of Duffy-null genotype, a common variant in AA pts associated with lower circulating neutrophil count without increased infection risk that may have a key role in cytokine homeostasis (Jinna, Cells 2022). Results AA pts were younger and more commonly female than White pts, as seen in the GRIFFIN study (Nooka, Blood Cancer J 2022), with higher rates of ECOG PS >0, BMI ≥30, LDH >ULN, and low hemoglobin (panel A). Of 153 samples tested to date, 13 (8.5%) were Duffy-null: 11/17 (64.7%) AA and 2/136 (1.5%) non-AA pts. Median treatment duration from randomization (cycle 2) in AA and White pts, respectively, was 27.5 and 28.7 mos (RVd-alone) vs 36.1 and 36.2 mos (RVd+ASCT); 16% of AA and 13% of White pts discontinued within the first 3 RVd cycles due to adverse events (AEs; 5%/3% of AA/White pts), pt/investigator decision (5%/6%), PD (3%/3%), death (2%/<1%), or other reasons (2%/1%). In the 79%/86% of AA/White pts (RVd+ASCT) who underwent ASCT on study, transplant parameters were similar. 77%/83% of AA/White pts on the RVd-alone arm and 74%/80% on RVd+ASCT started R maintenance; median duration was 43.3/35.8 mos and 45.2/40.4 mos, respectively. In AA/White pts, median % of cycles with mean R dose >10 mg was 78%/88% (RVd-alone) and 83%/58% (RVd+ASCT). At data cut-off, of pts who started maintenance, 35%/25% of AA/White pts on the RVd-alone arm and 35%/29% on the RVd+ASCT arm were ongoing, and 65%/75% and 65%/71% had discontinued (including 37%/57% and 33%/37% due to PD), respectively. AE data are shown in panel B. Odds of achieving ≥CR were greater with RVd-alone vs RVd+ASCT in AA pts and were lower for AA vs White pts on the RVd+ASCT arm (panel B). Median PFS (RVd-alone vs RVd+ASCT) was not reached (NR) vs 61.4 mos (HR 1.07) in AA pts and 44.3 vs 67.2 mos (HR 1.67) in White pts. PFS with RVd-alone vs RVd+ASCT was longer in AA pts with BMI ≥30 (median NR vs 58.6 mos, HR 0.74), but shorter in AA pts with BMI <30 (66.4 mos vs NR, HR 1.86) and White pts with BMI <30 (45.3 vs 82.3 mos, HR 1.78) or ≥30 (41.1 vs 64.4 mos, HR 1.58). The PFS with RVd-alone vs RVd+ASCT was similar in male (HR 1.28) and female (HR 0.90) AA pts but shorter in male (HR 1.47) and female (HR 1.85) White pts. With RVd-alone vs RVd+ASCT, median EFS was 47.7 vs 48.2 mos (HR 0.99) in AA pts and 31.7 vs 46.7 mos (HR 1.30) in White pts; 5-y OS was 83.2% vs 78.7% (HR 0.99) in AA pts and 77.1% vs 80.3% (HR 1.08) in White pts. Among AA/White pts off study treatment, 64%/77% had received NPT; 27%/28% (RVd-alone arm) had received ASCT as NPT. Conclusions Our analyses suggest that PFS, EFS, and OS were similar with RVd-alone and RVd+ASCT in AA pts on this study. Importantly, while outcomes with RVd+ASCT were similar in AA and White pts, exploratory analyses suggest AA pts with high BMI and female AA pts may derive more PFS benefit from RVd-alone. Rates of starting maintenance/NPT use were lower in AA vs White pts, but maintenance duration proved longer in AA pts, with similar rates of grade ≥3 hematologic AEs, including neutropenia; analyses of outcomes by Duffy status are ongoing and will be presented.

Green tea polyphenols alleviate β-conglycinin-induced anaphylaxis by modulating gut microbiota in rats

Heretofore, there are no effective therapeutic interventions for food allergies induced by β-conglycinin, an major allergen in soybean. The objective of this study was to explore the alleviating effect and underlying mechanism of green tea polyphenols (GTPs) on β-conglycinin-induced anaphylaxis. Twenty-one-day-old weaned BN rats were sensitized by gavage of β-conglycin and then given drinking water containing 1% GTPs. The results showed that β-conglcyinin sensitized rats had increased serum IgE levels and IL-4 level in spleen cell culture supernatant compared with the control group. However, total IgE, β-conglycin-specific IgE and IL-4 levels were significantly decreased by GTPs, suggesting that it weakened Th2-type immune response and restored cytokine homeostasis. The impact of GTPs on gut microbiota mainly focused on the changes in specific microbes, characterized by a significant increase of Bacteroides and other beneficial bacteria, which would contribute to the recovery of gastrointestinal allergies. This study is the first to demonstrate that GTPs, as good immunomodulator, played an important role in alleviating soybean protein allergy, which were associated with the alterations in gut microbiota. These results contribute to the development and application of green tea and provided an effective nutritional therapy strategy for the prevention and treatment of allergic diseases caused by soybean allergens.

Evaluation of Serum Ghrelin and Leptin Levels in Patients with Celiac Disease, Type1Diabetes Mellitus and Rheumatoid Arthritis

Ghrelin and leptin are two hormones that possess multiple functions, including appetite regulation, maintenance of the tissue homeostasis and regulation of proinflammatory cytokines. A few studies on serum ghrelin and leptin levels in autoimmune diseases have exhibited conflicting results. Therefore, the present study aimed to investigate the relationship between the two energy balance hormones and autoimmune diseases. Serum ghrelin and leptin levels were assessed in 94 adult patients, 61 females and 33 males, with various autoimmune diseases (celiac disease, type 1 diabetes mellitus and rheumatoid arthritis) as well as in 35 healthy people as controls, using commercially available ELISA kits. Statistically important distinctions (P < 0.05) were found between the patients and controls with regard to serum ghrelin and leptin levels. Moreover, females had higher mean serum ghrelin and leptin levels than males. On the other hand, serum ghrelin level was positively correlated with serum leptin levels (r = 0.399, P < 0.05) in the RA group. Whereas no significant correlation (P > 0.05) was found between serum ghrelin and leptin levels in both CD and T1DM groups. As well as the correlation of the diseases biomarkers (tissue transglutaminase antibodies, anti-tTG; glutamic acid decarboxylase antibodies, anti-GAD; and cyclic citrullinated peptide antibodies, anti-CCP) with ghrelin/leptin levels revealed that anti-CCP was the only marker that significantly (P < 0.05) associated with ghrelin and leptin in patients with RA. The current study indicates a linkage between the immune system and metabolic hormones depending on response to different autoimmune conditions. Additional studies are required to understand whether changes in ghrelin-leptin levels influence the emergence of autoimmune diseases or vice versa.

Whole intestinal microbiota transplantation is more effective than fecal microbiota transplantation in reducing the susceptibility of DSS-induced germ-free mice colitis.

Fecal microbiota transplantation (FMT) is an emerging and effective therapy for the treatment of inflammatory bowel disease (IBD). Previous studies have reported that compared with FMT, whole intestinal microbiota transplantation (WIMT) can more precisely replicate the community structure and reduce the inflammatory response of the host. However, it remains unclear whether WIMT is more effective in alleviating IBD. To examine the efficacy of WIMT and FMT in the intervention of IBD, GF (Germ-free) BALB/c mice were pre-colonized with whole intestinal microbiota or fecal microbiota before being treated with dextran sodium sulfate (DSS). As expected, the symptoms of colitis were alleviated by both WIMT and FMT, as demonstrated by the prevention of body weight loss and decreased the Disease activity index and histological scores in mice. However, WIMT's anti-inflammatory effect was superior to that of FMT. In addition, the inflammatory markers myeloperoxidase (MPO) and eosinophil peroxidase were dramatically downregulated by WIMT and FMT. Furthermore, the use of two different types of donors facilitated the regulation of cytokine homeostasis in colitis mice; the level of the pro-inflammatory cytokine IL-1β in the WIMT group was significantly lower than that in the FMT group, while the level of the anti-inflammatory factor IL-10 was significantly higher than that in the FMT group. Both groups showed enhanced expression of occludin to protect the intestinal barrier in comparison with the DSS group, and the WIMT group demonstrated considerably increased levels of ZO-1. The sequencing results showed that the WIMT group was highly enriched in Bifidobacterium, whereas the FMT group was significantly enriched in Lactobacillus and Ochrobactrum. Correlation analysis revealed that Bifidobacterium was negatively correlated with TNF-α, whereas Ochrobactrum was positively correlated with MPO and negatively correlated with IL-10, which might be related to different efficacies. Functional prediction using PICRUSt2 revealed that the FMT group was considerably enriched in the L-arginine biosynthesis I and L-arginine biosynthesis IV pathway, whereas the WIMT group was enriched in the L-lysine fermentation to acetate and butanoate pathway. In conclusion, the symptoms of colitis were subsided to varying degrees by the two different types of donors, with the WIMT group being more effective than the FMT group. This study provides new information on clinical interventions for IBD.

CLEC18A Impairs Phagocytosis by Reducing FcγRIIA Expression and Arresting Autophagosome-Lysosome Fusion.

Mixed cryoglobulinemia (MC) is a hepatitis C virus (HCV)-related extrahepatic manifestation that is characterized by the abnormal presence of immune complexes (ICs). This may be due to the reduced uptake and clearance of ICs. The C-type lectin member 18A (CLEC18A) is a secretory protein that is expressed abundantly in hepatocytes. We previously observed that CLEC18A increased significantly in the phagocytes and sera of patients with HCV, particularly those with MC. Herein, we explored the biological functions of CLEC18A in the MC syndrome development of patients with HCV by using an in vitro cell-based assay with quantitative reverse transcription-PCR, immunoblotting, immunofluorescence, flow cytometry, and enzyme-linked immunosorbent assays. HCV infection or Toll-like receptor 3/7/8 activation could induce CLEC18A expression in Huh7.5 cells. Upregulated CLEC18A interacts with Rab5 and Rab7 and enhances type I/III interferon production to inhibit HCV replication in hepatocytes. However, overexpressed CLEC18A suppressed phagocytic activity in phagocytes. Significantly decreased levels of the Fc gamma receptor (FcγR) IIA were found in the neutrophils of HCV patients, particularly in those with MC (P < 0.005). We demonstrated that CLEC18A could inhibit FcγRIIA expression in a dose-dependent manner through the production of NOX-2-dependent reactive oxygen species to impair the uptake of ICs. Additionally, CLEC18A suppresses the Rab7 expression that is induced by starvation. Overexpressed CLEC18A does not affect autophagosome formation but does reduce the recruitment of Rab7 to autophagosomes, thereby retarding the maturation of autophagosomes and affecting autophagosome-lysosome fusion. We offer a novel molecular machinery with which to understand the association of HCV infection with autoimmunity and propose that CLEC18A may act as a candidate biomarker for HCV-associated MC. IMPORTANCE During infection, the host immune system produces cellular factors to protect against pathogen invasion. However, when the immune response overreacts and there is dysregulated cytokine homeostasis, autoimmunity occurs following an infection. We identified a cellular factor that is involved in HCV-related extrahepatic manifestation, namely, CLEC18A, which is expressed abundantly in hepatocytes and phagocytes. It inhibits HCV replication in hepatocytes by interacting with Rab5/7 and enhancing type I/III IFN expression. However, overexpressed CLEC18A inhibited FcγRIIA expression in phagocytes to impair phagocytosis. Furthermore, the interaction between CLEC18A and Rab5/7 may reduce the recruitment of Rab7 to autophagosomes and thereby retard autophagosome maturation and cause immune complex accumulation. A decreasing trend in CLEC18A levels that was accompanied by reduced HCV RNA titers and diminished cryoglobulin was observed in the sera of HCV-MC patients after direct-acting antiviral therapy. CLEC18A may be used for the evaluation of anti-HCV therapeutic drug effects and could be a potential predisposing factor for the development of MC syndrome.

The Curcumin and Gingerol Combination as an Immune Regulator and Anti-Inflammatory Agent of SARS-CoV Infection According to a Nutrigenomic Approach: A Mini-Review

Introduction: The COVID-19 pathophysiology caused by SARS-Cov-2 is closely related to immunoregulation and the process of inflammation. There are therapeutic targets in both, which are ideal for the healing process of infected patients. Phytonutrients are closely related to nutrigenomics. Curcumin and gingerol are two types of phytonutrients that have been studied, researched, and developed as therapeutic agents for diseases. Objective: This study aimed to examine the potential of curcumin and gingerol as immune regulators and anti-inflammatory agents in SARS-CoV-2 infections using a nutrigenomic approach. Methods: The literature review method was used in this study. Relevant information was gathered from scientific engines and databases (Google Scholar, Elsevier, Science Direct, Scopus, Wiley Online Library, PubMed) published during 2010-2021, and the data were analyzed by deductive qualitative descriptive technique. Result and Discussion: Curcumin in turmeric and gingerol in ginger have the potential to be used as a therapy for COVID-19 as they could be immune regulators and anti-inflammatory agents for SARS-CoV-2 infection. Curcumin and gingerol can act as primary and secondary antioxidants that can activate endogenous antioxidant enzymes, regulate cell signaling related to immunity such as interferons, nuclear factor-kappa beta, nitric oxide, and tumor necrosis factor-alpha, as well as stimulate anti-inflammatory and pro-inflammatory cytokine homeostasis, especially interleukins (IL-1β, IL-6, IL-17, IL-8). In silico, these two compounds were also proven to have potential as SARS-CoV-2 antivirals by acting as viral protease inhibitors. Conlclusion: The combination of curcumin and gingerol showed synergistic activity with increasing antioxidant and anti-inflammatory capacities. Thus, it has great potential for use in COVID-19 therapy.

Rheumatoid Arthritis and Pain Management: Literature Review

Background: Rheumatoid arthritis (RA) is a chronic, immune-mediated, systemic inflammatory disease of the synovial joints that influences approximately 0.5-1% of the population global. Degrees of RA vary in different patients and are assessed according to intensity, pain, and disability in daily life. Purpose: The purpose of this literature review is to review RA pain, and mediators primarily cytokines, inflammation mediators, and various RA mechanisms. Method: This is a descriptive review. Relevant literature was identified by searching PubMed using key search terms, including arthritis, cytokines, cytokine signaling, inflammation, Janus kinases, pain, mechanisms, rheumatoid arthritis. Results: Several cytokines that target the treatment of RA, such as TNF-α, IL-1, and IL-6, have been well characterized in the pathogenesis of RA and associated pain through autoimmunity promotion, chronic inflammatory synovitis, and destruction of adjacent joint tissue. The range of epigenetic and other mechanisms by which such variants could disrupt cytokine homeostasis to increase disease risk is only beginning to be understood, along with the recognition that in relevant disease contexts they are best dissected at the cellular level. Another descriptive review talks about the role of the central nervous system. Many studies have explored the mechanisms of CNS pain in fibromyalgia and research on CNS pain mechanisms in osteoarthritis is growing. Conclusions: We conclude that there are different pathways to explain pain in rheumatoid arthritis.&#x0D; &#x0D; Received: 9 September 2022 / Accepted: 22 November 2022 / Published: 20 December 2022

The content of cytokines in the blood of patients with various stages of breast cancer

Background. Cytokine homeostasis is an important factor characterizing the general condition and adaptive capabilities of the body of patients with malignant neoplasms. However, the role of various growth factors and their significance in the development and enhancement of malignant growth in breast cancer remain poorly understood.&#x0D; Aim. To evaluate the levels of cytokines - tumor necrosis factor , interleukins-4, -6, -8 and -10 in the blood serum of patients with different stages of breast cancer in comparison with healthy volunteers.&#x0D; Material and methods. The study was conducted in 65 patients aged 25 to 67 years (mean age 44.5 [40.056.5] years). Two groups were distinguished: the first with stage 12, the second with stage 34 of breast cancer. The comparison group consisted of 15 apparently healthy women without cancer, aged 29 to 66 years (mean age 51.0 [39.061.0] years). Blood levels of tumor necrosis factor , interleukins-4, -6, -8 and -10 were studied by enzyme immunoassay. The obtained data were processed using the methods of variation statistics, the Statistica 10.0 software package. The significance of differences was assessed by calculating the median and interquartile interval, analysis of variance was performed using the KruskalWallis H-test, and Dan's Q-test was used for multiple comparisons. The critical significance level p for statistical tests was taken equal to 0.05.&#x0D; Results. In the group of patients with stage 12 breast cancer, an increase in the blood levels of all studied cytokines was revealed in comparison with the group of healthy women: interleukin-6 (p=0.00719), interleukin-8 (p=0.00259), tumor necrosis factor (p=0.00014), interleukin-4 (p1=0.0133), interleukin-10 (p1 0.00001). In the group of patients with stage 34 breast cancer, an increase in blood levels was characteristic of all studied cytokines: interleukin-8 (p=0.00009), tumor necrosis factor (p=0.000004), interleukin-4 (p 0.00001), interleukin-10 (p 0.00001), except for interleukin-6 (p=0.15608). The established patterns in changes in the content of cytokines in the blood of patients with breast cancer at different stages of development can serve as the basis for developing approaches to the diagnosis and treatment of the disease.&#x0D; Conclusion. In patients with breast cancer, the levels of tumor necrosis factor , interleukins-4, -6, -8, -10 (p 0.05) are higher than in healthy women.

Modulatory effect of exogenous Coenzyme Q10 on redox and inflammatory biomarkers during aging in rats.

An impaired redox homeostasis is an important hallmark of biological aging. Coenzyme Q10 is an endogenous lipophilic antioxidant that decreases with age and has been linked to oxidative stress. The purpose of this study was to evaluate the effect of CoQ10 supplementation on redox homeostasis and levels of inflammatory cytokines in young and old rats. Male Wistar rats (young and old) were randomly divided into four groups (n = 6). Group I: young control, Group II: young rats treated with CoQ10, Group III: old control, Group IV: old rats treated with CoQ10. CoQ10 (20mg/kg) was administered daily to Group II and IV via oral gavage. After 28days of treatment, rats were sacrificed and biomarkers of oxidative stress and inflammatory cytokines were evaluated. Results demonstrated a significant (p ≤ 0.05) increase in malondialdehyde, protein carbonyl oxidation, advanced oxidation protein products, inflammatory cytokines: CRP, IL-6, TNF-α, and a decline in levels of superoxide dismutase, catalase, reduced glutathione, ferric reducing antioxidant potential in plasma and plasma membrane redox system in old rats when compared to young rats. After treatment with CoQ10 significant decrease in the level of MDA, PCO, AOPP, CRP, IL-6, and TNF-α was observed. Also, significant up-regulation of SOD, CAT, GSH, FRAP, and PMRS was observed. The results show that supplementing rats with CoQ10 aids in the maintenance of redox equilibrium with replenishment of antioxidant reserves and down-regulation of inflammatory biomarkers. Thus CoQ10 supplementation could be a potential anti-aging therapy.

Synergistic action of organophosphates and COVID-19 on inflammation, oxidative stress, and renin-angiotensin system can amplify the risk of cardiovascular maladies

Organophosphates (OPs) are ubiquitous environmental contaminants, widely used as pesticides in agricultural fields. In addition, they serve as flame-retardants, plasticizers, antifoaming or antiwear agents in lacquers, hydraulic fluids, and floor polishing agents. Therefore, world-wide and massive application of these compounds have increased the risk of unintentional exposure to non-targets including the human beings. OPs are neurotoxic agents as they inhibit the activity of acetylcholinesterase at synaptic cleft. Moreover, they can fuel cardiovascular issues in the form of myocardities, cardiac oedema, arrhythmia, systolic malfunction, infarction, and altered electrophysiology. Such pathological outcomes might increase the severity of cardiovascular diseases which are the leading cause of mortality in the developing world. Coronavirus disease-19 (COVID-19) is the ongoing global health emergency caused by SARS-CoV-2 infection. Similar to OPs, SARS-CoV-2 disrupts cytokine homeostasis, redox-balance, and angiotensin-II/AT1R axis to promote cardiovascular injuries. Therefore, during the current pandemic milieu, unintentional exposure to OPs through several environmental sources could escalate cardiac maladies in patients with COVID-19.

Emerging and legacy PFAS and cytokine homeostasis in women of childbearing age

Per- and polyfluoroalkyl substances (PFAS) are widespread chemicals. Legacy PFAS have been phased out of production in most developed countries and emerging PFAS (short-chain PFAS and polyfluorinated compounds) are used as legacy PFAS alternatives. The effect of legacy and emerging PFAS on cytokine homeostasis in human remains poorly understood. This study aimed to evaluate the associations between legacy and emerging PFAS and cytokine profiles, and identify the main contributors to the disturbance of cytokine homeostasis. We quantified 21 PFAS in 198 Chinese women of childbearing age from 2015 to 2016. 13 cytokines were measured using the Meso Scale Discovery U-PLEX and V-PLEX platforms. The associations between PFAS exposure and cytokine levels were assessed using multiple linear regression (single-exposure), and Bayesian kernel machine regression (BKMR) models (PFAS mixture exposure). In single PFAS models, legacy and alternative PFAS were positively associated with Th1 and Treg cytokines, and negatively associated with Th2 and Th17 cytokines. For instance, each ln-unit increase in 6:2 chlorinated perfluoroalkyl ether sulfonic acid (6:2 Cl-PFESA), perfluorooctanoic acid (PFOA), and perfluorooctane sulfonate (PFOS) was associated with a decrease in IL-10 by − 0.228 (95% CI: − 0.336, − 0.120), − 0.153 (95% CI: − 0.277, − 0.030), and − 0.174 (95% CI: − 0.339, − 0.010), respectively. The BKMR model showed a significantly positive association of PFAS mixture with TGF-β and a negative association with IL-10. Overall, these results indicate that both legacy and emerging PFAS may affect the homeostasis of cytokines.

Дослідження цитокінового спектру ротової рідини хворих із генералізованим пародонтитом на тлі метаболічного синдрому

The purpose of the study was to study the state of cytokine regulation of oral fluid in patients with generalized periodontitis and metabolic syndrome. Materials and methods. For this study, 3 groups of surveys were formed. The main group included 30 people with generalized periodontitis on the background of metabolic syndrome; 30 people with generalized periodontitis, without somatic pathology, formed a comparison group. The obtained results were compared with the data of 20 practically healthy individuals with intact periodontium who were included in the control group. The content of pro-inflammatory cytokines IL-1β, IL-6, TNF-α and anti-inflammatory cytokines IL-4, TGF-β1 in the oral fluid of the study groups was determined by solid-phase enzyme-linked immunosorbent assay. Results and discussion. According to the research, on average, the highest levels of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) were observed in patients with periodontal disease on the background of metabolic syndrome. We investigated increase in the concentration of proinflammatory IL-1β. The average value of IL-6 in the oral fluid of patients with metabolic syndrome exceeded this figure in persons not burdened with somatic pathology by 1.3 times, the difference with healthy individuals was more significant: the indicators differed by 2 times. That can be considered an immune response to the inflammatory process in periodontal tissues. The next stage is the beginning of the cytokine cascade, which is characterized by increased production of IL-6 and TNF-α – inducers of acute phase protein synthesis. TNF-α causes an increase in the number of free radicals and can lead to intensification of apoptosis. Due to the fact that anti-inflammatory IL-4 blocks the induced expression of pro-inflammatory IL-6 and TNF-α, a decrease in its level in oral fluid can be considered an unfavorable factor in the course of inflammatory-dystrophic periodontal lesions in patients with syndrome X. Given that TGF-β1 is an immunosuppressive factor, a decrease in its concentration indicates a deficiency of local factors of immune protection in patients with periodontal disease on the background of metabolic syndrome. Conclusion. Patients with metabolic syndrome and periodontal disease have significant disorders of cytokine regulation, which are complicated by age: expression of proinflammatory IL-1β, IL-6, TNF-α on the background of reduced anti-inflammatory cytokines IL-4 and TGF-β1. Such changes in cytokine homeostasis indicate chronic inflammation, insufficient efficiency of regenerative processes in tooth-retaining tissues, and, as a consequence, lead to a more severe course of periodontal disease in people with metabolic syndrome

P463 Serum and mucosal Serpin E1 concentration correlates with endoscopic activity in inflammatory bowel disease - potential new activity marker

Abstract Background Inflammatory bowel disease (IBD) is characterized by an unregulated immune response generating unbalance cytokine homeostasis. Analysis of patient-specific cytokine profiles may open new therapeutic targets or identify biomarkers that distinguish responders from non-responders before initiating therapy. Therefore, the aim of the present study was to determine cytokine profile of IBD patients and identify cytokines with predictive potential. Methods Blood and biopsy samples were obtained from 79 clinically active IBD patients and 28 controls without IBD. Inclusion criteria included change of therapy or initiation of new treatment for IBD patients. Organoid culture (OC) was generated from 5 clinically active IBD patients and 5 controls. Cytokine Array was used to analyse cytokine expression patterns. Total protein and mRNA were isolated from biopsies and from OCs. Protein levels were measured by ELISA and gene expression by qRT-PCR in serum, mucosa and in OCs. Results Pro-inflammatory cytokines were not detected in control samples, whereas in IBD biopsies the cytokine profiles enabled the discrimination between inflamed or non-inflamed areas. The mucosal expression of Serpin E1 was detected in all inflamed biopsy samples, whereas it was below the detection limit in healthy subjects. In responders Serpin E1 gene expressions were significantly (p&amp;lt;0.001) lower than in non-responders. On the other hand, we were not able to detect significant changes between responders and non-responders in gene expression of TNF-α, IL-1β, IL-6 and TGF-β. In responders, mucosal Serpin E1 concentration significantly decreased (p&amp;lt;0,05) after the initiation of therapy compared to non-responders. Serum and mucosal Serpin E1 concentrations were significantly higher in patients with endoscopically and clinically active disease compared to inactive (endoscopic: p&amp;lt;0.0001, clinical: p&amp;lt;0.05). Correlation analysis revealed that serum Serpin E1 level correlates with disease activity (p&amp;lt;0.01). In OCs the level and expression of Serpin E1 was lower in healthy organoids compared to OCs generated from inflamed samples. Conclusion Our results suggest that serum and mucosal Serpin E1 expression reflects endoscopic activity in IBD, which could be used to follow-up disease activity and possibly therapeutic response. Organoids mimicked the expression of Serpin E1 in the original biopsies suggesting that OCs can be used to study the effect of Serpin E1 inhibition.

Magnetic labeling of primary murine monocytes using very small superparamagnetic iron oxide nanoparticles.

Due to their very small size, nanoparticles can interact with all cells in the central nervous system. One of the most promising nanoparticle subgroups are very small superparamagnetic iron oxide nanoparticles (VSOP) that are citrate coated for electrostatic stabilization. To determine their influence on murine blood-derived monocytes, which easily enter the injured central nervous system, we applied VSOP and carboxydextran-coated superparamagnetic iron oxide nanoparticles (Resovist). We assessed their impact on the viability, cytokine, and chemokine secretion, as well as iron uptake of murine blood-derived monocytes. We found that (1) the monocytes accumulated VSOP and Resovist, (2) this uptake seemed to be nanoparticle- and time-dependent, (3) the decrease of monocytes viability was treatment-related, (4) VSOP and Resovist incubation did not alter cytokine homeostasis, and (5) overall a 6-hour treatment with 0.75 mM VSOP-R1 was probably sufficient to effectively label monocytes for future experiments. Since homeostasis is not altered, it is safe to label blood-derived monocles with VSOP. VSOP labeled monocytes can be used to study injured central nervous system sites further, for example with drug-carrying VSOP.

PI3-Kinase p110α Deficiency Modulates T Cell Homeostasis and Function and Attenuates Experimental Allergic Encephalitis in Mature Mice.

Class I phosphoinositide 3-kinases (PI3K) are involved in the development of normal and autoimmune responses, including Experimental Autoimmune Encephalomyelitis (EAE), a mouse model for human multiple sclerosis (MS). Here, the role of the ubiquitously expressed class IA PI3K p110α catalytic subunits in EAE has been analyzed using a model of Cre/flox mediated T cell specific deletion of p110α catalytic chain (p110αΔT). Comparison of two month-old (young) and six month-old (mature) p110αΔT mice and their wild type (WT) counterparts indicated loss of spleen CD4+ T cells that increased with age, indicating a role of p110α in their homeostasis. In contrast, CD4+ T regulatory (Treg) cells were enhanced in mature p110αΔT mice when compared to WT mice. Since Myelin Oligodendrocyte Glycoprotein (MOG) peptide-induced EAE is dependent on, or mediated by CD4+ T cells and CD4+ T cell-derived cytokines and controlled by Treg cells, development of EAE in young and mature WT or p110αΔT mice was analyzed. EAE clinical symptoms and disease scores in six month p110αΔT mice were significantly lower than those of mature WT, or young WT and p110αΔT mice. Furthermore, ex vivo antigen activation of lymph node cells from MOG immunized mature p110αΔT mice induced significantly lower levels of IFN-γ and IL-17A than young p110αΔT or young and mature WT mice. Other cytokines including IL-2, IL-10 or TNF-α showed no significant differences between p110αΔT and WT mature mice. Our data show a lower incidence of MOG-induced EAE in mature p110αΔT mice linked to altered T cell homeostasis and lower secretion of inflammatory cytokines.