Concentrations Of IL-17A Research Articles

Dapagliflozin associated to sacubitril/valsartan and relationship with cardioprotection in human cardiac cells exposed to doxorubicin and HER2-blocking agents through MyD88, NLRP3 mediated pathways.

587 Background: The cumulative incidence of cardiac events in breast cancer patients treated with anthracycline and trastuzumab at 1 year after the diagnosis of cancer was 16.4%, at 2 years 23.8 %, and at 3 years 28.2%. Sodium glucose co-transporter 2 inhibitors, a new class of antidiabetic drugs, has shown measurable benefits in reduction of HF hospitalization and cardiovascular mortality. LCZ696 (neprilysin inhibitor + valsartan) as able to lower the risk of cardiovascular events in chronic heart failure. We hypothesize that dapagliflozin associated to LCZ696 could exerts cardioprotective effects in cellular models of doxorubicin and trastuzumab-induced cardiotoxicity. Methods: Human cardiomyocytes (HL-1 cells) were exposed to subclinical concentration of doxorubicin and trastuzumab (100 nM) alone or in combination with dapagliflozin (50 nM) or LCZ696 (at 100 mM) or both in combination for 48h. Cell viability, apoptosis and necrosis were performed. Quantification of malondialdehyde, 4-hydroxynonenal and intracellular Ca2+ were performed through spectrophotometric methods. Anti-inflammatory studies were also performed (expression of NLRP3 inflammasome, TLR4/MyD88 pathways, nuclear expression of NF-kB). Intracellular concentration of IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL17-α, IL-18, IFN-γ, TNF-α, G-CSF, and GM-CSF were also performed. Results: Dapagliflozin and LCZ696 increased synergistically the cell viability during exposure to doxorubicin and trastuzumab. Combination of dapagliflozin and LCZ696 reduces intracellular Ca2+ overload (-68,4% vs cells treated only to anticancer drugs; p<0,001), lipid peroxidation (mean reduction of 57-63,4 % compared to cells exposed only to anticancer drugs; p<0,05). The expression of MyD88, NLRP3 and NF-kB were strongly reduced after treatment with dapagliflozin and LCZ-696 (-52,5, -43,7 and -57,3 % vs cells exposed only to anticancer drugs, respectively; p<0.05). Notably, combination of dapagliflozin and LCZ-696 enhanced the expression Of IL-10; contrary, pro-inflammatory cytokines were reduced, such as IL-1α, IL-1β, IL-6, IL-8, IL17-α and IL-18 (p<0.05). Conclusions: During exposure to doxorubicin and trastuzumab, dapagliflozin associated to LCZ-696 exerts additive cardioprotective and anti-inflammatory effects compared to each drug alone. Their properties are mediated by the reduction of iCa2+ content that consequently reduces peroxidation and NLRP3- MyD88 expression. These results indicating the potential use of SGLT-2 inhibitors associated to LCZ696 in preclinical models of cardiotoxicity.

A nutraceutical combination of spirulina, reishi and moringa exerts significant cytoprotective effects againts doxorubicin and trastuzumab cardiotoxicity.

e24056 Background: Anthracycline and trastuzumab are essential adjuvant therapies for a variety of cancers, particularly breast, and gastric and esophageal cancers. Whilst prolonging cancer-related survival, these agents can induce drug-related cardiotoxicity. Cardioprotective agents used to mitigate cardiotoxicity, such as angiotensin antagonists, angiotensin receptor blockers and beta‐blockers, are often poorly tolerated in these patients due to intravascular volume fluctuations, which are further escalated by the hemodynamic side effects of these agents. Spiruline, Reishi and Moringa are nutaceuticals with anti-inflammatory effects that are currently used in cancer patients to improve quality of life and fatigue. We hypothesize that the combination of Spirulina, Reishi and Moringa could reduce inflammation and cardiotoxicity of anthracyclines and trastuzumab. Methods: Human cardiomyocytes were exposed to subclinical concentration of doxorubicin and trastuzumab (200 nM) alone or in combination with a formulation composed by Spiruline, Reishi and Moringa (at 10, 25 and 50 µg/ml) for 48h. Cell viability, apoptosis and necrosis were performed. Quantification of malondialdehyde and intracellular Ca2+ were performed through spectrophotometric methods. Anti-inflammatory studies were also performed (expression of NLRP3, TLR4/MyD88 pathways, nuclear expression of NF-kB). Intracellular concentration of IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL17-α were also performed. Results: Spiruline, Reishi and Moringa in combination increased synergistically the cell viability during exposure to doxorubicin and trastuzumab. The nutraceutical formulation reduces intracellular Ca2+ overload (-48,8% vs cells treated only to anticancer drugs; p < 0,001), lipid peroxidation (- 47,2 % compared to cells exposed only to anticancer drugs; p < 0,001). The expression of MyD88 and NLRP3 inflammasome were also reduced (-36,3 and -28,58 % vs cells exposed only to anticancer drugs, respectively; p < 0.001). Notably, Spiruline, Reishi and Moringa increased of 26,3% the production of IL-10 and IL-2. Cytokines involved in cardiotoxicity and chemoresistance were reduced, such as IL-1α and IL-1β (-18,3 and -27,4 % vs DOXO-TRA group), IL-6 (-31,2 % vs DOXO-TRA group) and IL17-α (-27,3 % vs DOXO-TRA group) (p < 0.01 for all). Conclusions: During exposure to doxorubicin and trastuzumab, the combination of Spiruline, Reishi and Moringa exerts cardioprotective and anti-inflammatory effects. Their properties are mediated by the reduction of iCa2+ content that consequently reduces lipid peroxidation and the expression of NLRP3- MyD88. These results indicating the potential use of this nutraceutical formulation in preclinical models of anthracycline and anti HER2 antibodies-mediated cardiotoxicity.

Показники цитокінового статусу дітей раннього віку з алергічним ураженням шлунково-кишкового тракту залежно від забезпеченості вітаміном D

The rapid growth in the prevalence of allergic diseases among children in the modern world dictates the need for detailed study of pathogenetic mechanisms, the search for new methods of diagnosis, treatment and prevention of this pathology. Recent studies of the important immunological effects of vitamin D in allergic pathology make it important to study its effect on the course of gastrointestinal food allergy (GIFA) in young children. Purpose - to determine the serum concentrations of IL-10 and IL-17 in young children with GIFA, depending on the supply of vitamin D. Materials and methods. We examined 34 children aged from 2 months to 3 years with isolated gastrointestinal symptoms or a combination of gastrointestinal and skin symptoms associated with food. The comparison group consisted of 22 children of the same age with an unencumbered individual and family history of allergies. All examined children had quantified serum cytokine (IL-10, IL-17A) levels by enzyme-linked immunosorbent assays and serum hydroxycalciferol (25(OH)D) levels. Vitamin D deficiency in subjects was considered at a concentration of 25(OH)D in serum <20 ng/ml (or <50 nmol/l), a concentration of 21 ng/ml to 29 ng/ml (or from 50.1 nmol/l up to 74.9 nmol/l) was assessed as vitamin D deficiency. A sufficient concentration of vitamin D was considered to be 25(OH)D serum level >30 ng/ml. Data of clinical and laboratory researches were processed by methods of mathematical statistics accepted in biology and medicine. Results. There was a significantly increase in the average concentrations of IL-17A (180.4±23.0 pg/ml) and IL-10 (113.8±15.0 pg/ml) in children with gastrointestinal food allergy and in the comparison group - 45.7±18.1 pg/ml and 32.1±11.4 pg/ml, respectively, (p<0.05), which reflects the intensity of the allergic inflammatory process in the gastrointestinal tract. In children with allergic gastrointestinal inflammation who were deficient in vitamin D, the mean concentrations of proinflammatory cytokine IL-17A and regulatory cytokine IL-10 were significantly higher than in children with GIFA and optimal supply of vitamin D 244.9±19.7 ng/ml and 49.45±2.14 ng/ml respectively against 135.2±33.3 ng/ml and 26.41±1.81 ng/ml respectively, (p<0,05), which indicates a more intense activity of the inflammatory process in the intestine of children with insufficient supply of vitamin D. Conclusions. Allergic gastrointestinal inflammation in young children is characterized by increased concentrations of serum proinflammatory and regulatory cytokines - IL-10 and IL-17A, that is a protective reaction of the immune system and can be used as a marker of allergic inflammation in GIFA. The study of the regulatory effect of vitamin D on the expression of cytokines (IL-10 and IL-17A) in allergic gastrointestinal inflammation in young children will optimize the pathogenetic treatment of gastrointestinal food allergies. The research was carried out in accordance with the principles of the Helsinki Declaration. The study protocol was approved by the Local ethics committee of the participating institution. The informed consent of the patient was obtained for conducting the studies. No conflict of interests was declared by the authors. Key words: cytokine status, young children, allergic pathology of the gastrointestinal tract, vitamin D.

Serum IL-17A concentration and a IL17RA single nucleotide polymorphism contribute to the risk of autoimmune type 1 diabetes.

Interleukin (IL)-17 is associated with autoimmunity. This study aimed to affirm the role of IL-17A, IL-17F and single nucleotide polymorphisms (SNPs) in genes related to them and their receptors in autoimmune type 1 diabetes (T1D) for Chinese population. In this study, 130 patients with autoimmune T1D and 140 non-T1D controls were included for analysis. Clinical and biochemical data were collected, and serum levels of IL-17A, IL-17F, IL-6, and high-sensitivity C reactive protein were measured using ELISA. The SNPs rs2275913, rs8193036, rs3819025, rs763780, rs879577, rs4819554, and rs708567 were genotyped using the SNaPshot assay. IL-17A levels were higher in patients with autoimmune T1D than in controls (median [IQR] 28.83[37.38] vs. 16.68[8.10], p<0.001) and high IL-17A was a risk factor for autoimmune T1D (odds ratio (OR), 1.013; 95% CI, 1.003-1.023; p=0.013) after adjusting for confounding factors. Linear regression analysis revealed that log10 IL-17A levels were independently associated with fasting C-peptide, IL-6, body mass index, and IL-17F. However, no independent association was found between IL-17F and autoimmune T1D. The GG genotype of SNP rs4819554 in the interleukin 17 receptor A (IL17RA) gene was associated with a decreased risk of autoimmune T1D (OR, 0.458; 95% CI, 0.246-0.852; p=0.014) after adjusting for other confounders. The IL17RA rs4819554GG genotype was negatively correlated with serum glutamic acid decarboxylase antibody appearance (p<0.05). Increased serum IL-17A, but not IL-17F, is a risk factor for autoimmune T1D. The GG genotype of IL17RA rs4819554 might decrease the risk for autoimmune T1D.

Identifying correlates of protection from &lt;i&gt;Yersinia pestis&lt;/i&gt; on a mouse model and assessing an opportunity for their use as markers of human vaccination efficiency

In case no assessment of changes in incidence rate can be used as an indicator for effectiveness of applied live plague vaccine, it is really necessary to search for other, particularly immunological correlates for vaccine-based protection. The aim of this study was to reveal immunological correlates for plague protection in mice immunized with Yersinia pestis EV NIIEG, and assess dynamics changes in select markers of plague vaccinated subjects. BALB/c mice were immunized with Y. pestis EV at dose of 2 102, 1 103, 5 103, 2.5 104 CFU, and on day 21 they were challenged with Y. pestis 231 at a dose of 400 LD50. Immunogenicity was calculated by the Kerber method and ImD50 was determined. Volunteers 20 subjects who were first vaccinated with live plague vaccine and 20 subjects who were not vaccinated against the plague. Blood cytokine production was measured on the LAZURIT analyzer (Dynex Technologies, USA) in mouse groups before Y. pestis 231 infection on day 14 as well as 21 days after vaccination, in humans before vaccination, 1, 6 and 12 months after vaccination. The immunized mice showed a significant increase (by 2.2 times) in the induced production of IFN and a moderate increase in the concentration of TNF, IL-10 and IL-17A on day 14 of disease. A high correlation was found between the survival rate of animals and the level of antigen-/mitogen-induced IFN production (r = 0.94, p = 0.039), both on day 14 and 21, as well as a noticeable relationship with the level of produced IL-10 and IL-17A on day 14. One month after vaccination volunteers had significantly increase by month 6 (p 0.05) levels of IFN, TNF, IL-10, IL-17A, although only for IFN and IL-17A, the persistence of induced production was noted at a fairly high level for up to a year. Thus, IFN and IL-17A can be considered as possible informative correlates of mouse protection against Y. pestis on days 14 and 21, considering the increase in the induced production of these cytokines as adequate markers of the protective efficacy of immunization, and assessing dynamics in these parameters of volunteers vaccinated with the plague live vaccine, the increase in the levels of IFN and IL-17A can be considered as a favorable prognostic marker of the immunological efficacy of the vaccine in the period from the month 6 to 12 of observation.

The PD-1 with PD-L1 Axis Is Pertinent with the Immune Modulation of Atrial Fibrillation by Regulating T Cell Excitation and Promoting the Secretion of Inflammatory Factors.

Objective To analyze the role of PD-1/PD-L1 signaling pathway in regulating T cell activation and secretion of proinflammatory factors in atrial fibrillation. Methods Forty-five patients with atrial fibrillation admitted to the cardiology department of our hospital from July 2019 to March 2021 were selected to be included in the atrial fibrillation group, and another 45 healthy volunteers were selected as the control group to compare the changes of T cell CD69 and human leukocyte antigen-DR (HLA-DR) expression in the peripheral blood of the two study groups; compare the changes of programmed death factor-1 on CD4+ and CD8+ lymphocytes in the peripheral blood of the two groups (PD-1) expression changes and PD-L1 and PD-L2 expression changes on peripheral blood myeloid dendritic cells (mDCs) cells; compare the changes of interleukin-2, interleukin-6, interleukin-10, and interleukin-17A (IL-2, IL-6, IL-10, and IL-17), tumor necrosis factor (TNF), and interferon gamma (IFN-γ) concentrations on peripheral blood inflammatory factors in the two groups; and isolate the two groups of peripheral blood mDCs cells; α interferon upregulated PD-L1 expression in the cells and analyzed the effect of PD-L1 expression on the ability of mDCs to stimulate T cells to secrete cytokines.Results The positive expression rates of CD69 and HLA-DR on peripheral blood CD3+ T lymphocytes were significantly higher in patients in the atrial fibrillation group than in the control group, and the differences were statistically significant (P < 0.01). The positive expression rate of PD-1 on CD4+ lymphocytes was significantly lower in patients in the atrial fibrillation group than in the control group (P < 0.01). There was no statistically significant difference between the two groups in terms of PD-1 positive expression rate on CD8+ lymphocytes (P > 0.05). The positive expression rate of PD-L1 on mDCs cells was significantly lower in patients in the atrial fibrillation group than in the control group (P < 0.01), and there was no statistically significant difference between the two groups in the positive expression rate of PD-L2 on mDCs cells, PD-L1, and PD-L2 on CD4+ and CD8+ T cells (P > 0.05). The concentrations of IL-2, IL-6, IL-10, and IFN-γ in peripheral blood were significantly higher in patients in the atrial fibrillation group than in the control group (P < 0.05), and there was no statistically significant difference in the comparison of IL-17A and TNF concentrations in peripheral blood between the two groups (P > 0.05). In the atrial fibrillation group, the ability of mDCs to stimulate T cells to secrete IL-2 and IFN-γ was significantly higher, and the ability to secrete IL-10 was significantly lower compared with the control group (P < 0.05). After α interferon upregulated PD-L1 expression in cells, the ability of mDCs to stimulate T cells to secrete IL-2, IL-10, and IFN-γ cytokines was reversed in patients in the atrial fibrillation group, and the differences compared with the control group were not statistically significant (P > 0.05). Conclusion PD-1/PD-L1 signaling pathway may play an immunomodulatory role in the pathogenesis of atrial fibrillation by promoting increased secretion of inflammatory factors through regulating T cell activation.

Batf3-dependent regulation of the antifungal inflammatory response after pulmonary Aspergillus fumigatus challenge

Abstract Aspergillus fumigatus is a ubiquitous fungus that causes invasive aspergillosis in immunocompromised individuals. The innate immune system is critical in the maintenance of host resistance against A. fumigatus. While it is well established that monocyte-derived dendritic cells (moDC) are critical in maintaining host resistance against A. fumigatus, the role of other dendritic cells populations has not been thoroughly explored. Here we demonstrate that Batf3-dependent cells, likely classical type 1 dendritic cells (cDC1s), are critical in preventing invasive aspergillosis. Surprisingly, Batf3(−/−) mice display an elevated inflammatory response against A. fumigatus, particularly IL-17A/F. We show that elevated concentrations of IL-17A/F in the lungs of Batf3(−/−) mice following A. fumigatus infection perpetuates the secretion of various inflammatory lung cytokines in vivo. Neutralization of both IL-17A and IL-17F in Batf3(−/−) mice prevent excessive cytokine secretion and mortality due to A. fumigatus challenge of Batf3(−/−) mice. Following A. fumigatus challenge regulatory T cells are known to limit inflammation. Our preliminary antibody-mediated depletion studies demonstrate that CD4+ CD25+ T cells may be involved in preventing excessive IL-17A/F release in immunocompetent mice. In this study we have identified a critical role for Batf3-dependent cells in limiting A. fumigatus induced inflammatory and mortality due to IL-17 driven lung pathology. Supported by NIH: [R01 AI139133-01A1]

Ossified Particles in the Peripheral Circulation of Young and Old male Fischer‐344 Rats following Bone Marrow Ablation and Interleukin‐1 Receptor Antagonism

BACKGROUNDA pro‐inflammatory marrow microenvironment presumably augments ossification in bone marrow blood vessels. We speculate that ossifying blood vessels results in bone‐like particles (i.e., ossified particles, OSP) in the peripheral blood. By performing bone marrow ablation (BMA) and administering an interleukin‐1 receptor antagonist (IL‐1RA) during recovery, we sought to reduce the number of OSP in the circulation.METHODSYoung (6‐mon) and old (24‐mon) male Fischer‐344 rats were assigned accordingly: Control (young CON, n=10; old CON, n=8), IL‐1RA (young, n=11; old, n=8), BMA (young, n=12; old, n=7) and combined treatment (young IL‐1RA+BMA, n=8; old IL‐1RA+BMA, n= 8). In the BMA and IL‐1RA+BMA rats, bone marrow in the right femoral shaft was ablated. During 3 weeks of recovery, CON and BMA rats received PBS (100 μL, 3 d/wk, i.p.), while IL‐1RA and IL‐1RA+BMA rats received the antagonist (3 μg/kg, 3 d/wk, i.p.). At sacrifice, left ventricular whole blood samples were collected. Plasma IL‐1α and IL‐1β were measured by ELISA. Five‐hundred microliters of blood were prepared for flow cytometry and OSP were sorted to obtain a count. The diameters of OSP were determined with a Cellometer. Some samples were pooled to meet the minimum detection threshold. These data are expressed as a percent of the total OSP count according to diameter, i.e., % OSP per 0‐14µm, 15‐30µm, 31‐45µm, and 46‐60µm. ELISA data were analyzed by two‐way ANOVA using SPSS (v. 25). The OSP count distributions were highly positively skewed with a mean and variance indicating overdispersed data. Therefore, negative binomial models were used to compare OSP count and % OSP using SAS GENMODE (v. 9.4). Data are presented as Means ± Standard Error.RESULTSMain effects for Age and Condition were detected in the ELISAs. Plasma IL‐1α did not differ; however, IL‐1β was higher (p&lt;0.05) in Old (30.8±4.6 pg/mL) vs. Young (15.0±4.3 pg/mL). For Condition, IL‐1RA+BMA (49.6±14.1 pg/mL) had higher (p&lt;0.05) plasma IL‐1α vs. CON (7.5E‐15±12.7 pg/mL) and IL‐1RA (9.4±13.2 pg/mL), and both CON (31.7±6.1 pg/mL) and IL‐1RA (41.2±6.3 pg/mL) had higher plasma IL‐1β vs. BMA (6.5±5.8 pg/mL) and IL‐1RA+BMA (12.3±6.8 pg/mL). For the OSP, Age x Condition interactions were detected. OSP count was higher (p&lt;0.05) in Old IL‐1RA+BMA (3977±1631) vs. all other groups except Old IL‐1RA (1422±476). In addition, OSP count was higher (p&lt;0.05) in Old IL‐1RA vs. Young IL‐1RA (212±67), Young BMA (276±80), and Young IL‐1RA+BMA (298±106). OSP count did not differ between Young CON (399±134) and Old CON (561±199). Analysis of % OSP revealed a main effect for diameter. Of the total in circulation, 38.4±7.8% were 15‐30µm, higher (p&lt;0.05) than those 31‐45µm (5.7±1.2%) and 46‐60µm (2.2±0.5%). In addition, the % OSP 0‐14 µm (25.7±3.8%) were higher (p&lt;0.05) vs. 31‐45µm and 45‐60µm. Further, the % OSP 31‐45µm was higher (p&lt;0.05) vs. 46‐60µm.CONCLUSIONPlasma concentrations of IL‐1α and IL‐1β varied with age and condition. Treatment with the IL‐1RA in old rats exacerbated the number of OSP in circulation, with the combined treatment (i.e., IL‐1RA+BMA) having the most dramatic effects. The majority of circulating OSP were 15‐30 µm in diameter, i.e., diameters amenable to embolism.

Infertile women with endometriosis possess differences in cytokine levels in various tissues

Objective (1) To characterize the cytokine expression profiles of endometriosis related infertile women in comparison to fertile women with endometriosis; (2) to investigate the correlation of the cytokine levels from different tissues. Methods 100 stage IV endometriosis patients were recruited and grouped by infertility status (n = 50, separately). Concentrations of TNF-α, TGF-β1, IL-10, and IL-17A from the serum, peritoneal fluid (PF), eutopic, and ectopic endometrium samples were measured. Results (1) In the infertile group, the concentrations of IL-10 within serum, PF and eutopic endometrium were all significantly higher (p = .022 and <.01, .013, respectively), the levels of TGF-β1 in serum and eutopic endometrium samples were both higher (p = .025 and p < .01), the levels of IL-17A in the PF, eutopic, and ectopic endometrium were all lower (p < .01, all). (2) Significant positive correlation was observed between IL-17A from PF and the ectopic endometrium (p = .014), IL-17A from PF and eutopic endometrium (p < .01). The PF IL-10 levels positively correlated with those in the serum (p = .007). Conclusions This is the first study comparing the levels of cytokines within four different tissues of endometriosis women with or without infertility. The study revealed that endometriosis-related infertile women possess significant differences in cytokine levels in comparison to fertile women with endometriosis. The levels of inflammatory factors from different tissues had certain positive correlations. Infertility may indicate the progress of the disease.

Interferon γ, IL-17, and IL-1β impair sperm motility and viability and induce sperm apoptosis.

Urogenital inflammation is a known cause of male infertility. Increased levels of inflammatory cytokines, leukocyte counts and oxidative stress are highly detrimental for sperm quality thus compromising male fertility. Although cytokines affect sperm by recruiting and activating leukocytes consequently inducing tissue inflammation and oxidative stress, scarce to absent data have been reported about the putative direct effects of inflammatory cytokines on spermatozoa. Herein, we analyzed whether IFNγ, IL-17A, IL-1β, and IL-8 can alter human sperm motility and viability per se. Fractions of viable and motile spermatozoa from normospermic healthy donors were in vitro incubated with recombinant human IFNγ, IL-17A, IL-1β or IL-8 and sperm ROS production, motility, viability and apoptosis were analyzed. Sperm exposed to different concentrations of IFNγ, IL-17A and IL-1β, or a combination of them, for either 1 or 3h showed significantly increased levels of mitochondrial ROS production and reduced motility and viability with respect to sperm incubated with vehicle. Moreover, the exposure to IFNγ, IL-17A and IL-1β resulted in significantly higher levels of early and/or late apoptotic and/or necrotic spermatozoa. Interestingly, no significant differences in sperm motility, viability and apoptosis were observed in sperm incubated with the concentrations of IL-8 analyzed, for either 1 or 3h, with respect to sperm incubated with vehicle. In conclusion, our results indicate that IFNγ, IL-17A and IL-1β per se impair sperm motility and decreases viability by triggering increased mitochondrial ROS production and inducing sperm apoptosis. Our results suggest that screening inflammatory cytokines in semen would be an additional helpful tool for the diagnostic workup of male infertility.

ADAPTED MEDITERRANEAN DIET IMPACT ON THE SYMPTOMS OF CHRONIC FATIGUE, SERUM LEVELS OF OMEGA-3 POLYUNSATURATED FATTY ACIDS (PUFAS) AND INTERLEUKIN 17 (IL-17) IN PATIENTS WITH RELAPSING-REMITTING MULTIPLE SCLEROSIS UNDERGOING DISEASE-MODIFYING THERAPY: A PILOT STUDY

Purpose: This pilot study was designed to investigate the impact of a moderate-calorie Mediterranean diet compared to a regular diet with omega-3 PUFAs (eicosapentaenoic and docosahexaenoic acids) supplementation on fatigue symptoms in patients with relapsing-remitting multiple sclerosis (RRMS) and to assess the optional benefit of the diet on their quality of life. Material/Methods: This 12-month pilot study was conducted in 2021 at the Department of Neurology, Medical University – Pleven, Bulgaria. A total of 60 patients with RRMS aged 18-64 were selected from the database of the Neurology Clinic at the University Hospital "Dr Georgi Stranski" – Pleven. From the selected patients, only 30 were included in the pilot phase and respectively assigned to the nutritional arms. Blood samples were collected twice – at the first and second visit in 3 months, for metabolic and dietary parameters analysis. Symptoms of fatigue were assessed with Fatigue Scale for Motor and Cognitive Functions (FSMC) and Modified Fatigue Impact Scale (MFIS). Results: From the 30 participants included in the study, 17 patients attended the clinic centre for complete follow-up; the remaining 13 were only partially observed. The dynamics of the followed-up parameters showed a statistically significant change in the body mass index (BMI), the fatigue symptoms in the FSMC and MFIS scales, total cholesterol and triglycerides levels, and the serum concentrations of IL17A, EPA and DHA. The metabolic caloric values were also found to be significantly changed. Conclusions: Despite the small study size limitation, this pilot study might be of benefit for further extensive research on the potential favorable impact of diet and lifestyle modifications on the symptoms of fatigue in multiple sclerosis patients.

Infection with HIV-1 subtype D among acutely infected Ugandans is associated with higher median concentration of cytokines compared to subtype A

ObjectiveThe observation that HIV-1 subtype D progresses faster to disease than subtype A prompted us to examine cytokine levels early after infection within the predominant viral subtypes that circulate in Uganda and address the following research questions: (1) Do cytokine levels vary between subtypes A1 and D? (2) Do cytokine profiles correlate with disease outcomes? MethodsTo address these questions, HIV-1 subtypes were determined by population sequencing of the HIV-1 pol gene and 37 plasma cytokine concentrations were evaluated using V-Plex kits on Meso Scale Discovery platform in 65 recent sero-converters. ResultsHIV-1 subtype D (pol) infections exhibited significantly higher median plasma concentrations of IL-5, IL-16, IL-1α, IL-7, IL-17A, CCL11 (Eotaxin-1), CXCL10 (IP-10), CCL13 (MCP-4) and VEGF-D compared to subtype A1 (pol) infections. We also found that IL-12/23p40 and IL-1α were associated with faster CD4+T cell count decline, while bFGF was associated with maintenance of CD4+ counts above 350 cells/microliter. ConclusionOur results suggest that increased production of cytokines in early HIV infection may trigger a disruption of the immune environment and contribute to pathogenic mechanisms underlying the accelerated disease progression seen in individuals infected with HIV-1 subtype D in Uganda.

Evaluation of Serum Proinflammatory Cytokine IL-17A and Tight Junction Protein Claudin-1 in Psoriasis

Objective This study aimed to estimate serum IL-17A and Claudin-1 levels, investigate their correlation, and evaluate their diagnostic significance as potential blood-based biomarkers in psoriasis. Methods Serum IL-17A and Claudin-1 concentrations were determined using enzyme-linked immunosorbent assay (ELISA). Statistical analyses were performed to determine differences in serum levels of IL-17A and Claudin-1, their bivariable correlation with psoriasis severity, as Psoriasis Area Severity Index (PASI), and their predictive abilities using receiver operating characteristic (ROC) curves. Results Significantly higher IL-17A and lower Claudin-1 levels were found in psoriasis (p < 0.05). PASI did not correlate significantly with either IL-17A or Claudin-1 in psoriasis and their subtypes. The only significant correlation between serum IL-17A and Claudin-1 was shown in late-onset psoriasis (r = 0.630, p = 0.028). ROC curve analysis indicated the serum IL-17A, serum Claudin-1, and combination of IL-17A and serum Claudin-1 for predicting psoriasis with the areas under the curve (AUC) of 0.951 (p < 0.0001), 0.709 (p = 0.0119), and 0.949 (p < 0.0001), respectively. Moreover, the potential role in distinguishing between early-onset and late-onset psoriasis: we obtained serum IL-17A, serum Claudin-1, and their combination AUC of 0.590 (p = 0.3126), 0.741 (p = 0.0045), and 0.741 (p = 0.0067), respectively. However, none of the serum IL-17A, serum Claudin-1, and their combination was well-performed discriminating mild psoriasis from moderate-to-severe psoriasis with AUC of 0.553 (p = 0.5596), 0.518 (p = 0.8539), and 0.559 (p = 0.5225), respectively. Conclusion These preliminary results suggest that the serum Claudin-1 as a potential biomarker and the relationship and possible regulatory interactions between IL-17A and Claudin-1 in psoriasis are distinguishable by age of onset.

Investigating the inflammatory status in the patients candidate for second angiography after coronary stent implantation

Background Inflammation has been shown to be an important feature of atherosclerosis. We aimed to assess a profile of inflammatory cytokines and growth factors in patients with established coronary artery disease (CAD), 12 months after stent implantation. Methods A total of 193 patients with CAD, who were candidates for angiography, 12 months after stent implantation (cases), were compared with 107 patients with CAD, who were candidates for their first angiography (controls). Fasting blood glucose (FBG), triglycerides (TGs), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and high-sensitive C-reactive protein (hs-CRP) were measured using routine methods. The serum concentrations of IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, TNF-α, IFN-γ, MCP-1, EGF and VEGF were determined using competitive chemiluminescence immunoassays. Results Serum levels of FBG (p = .002), TG (p = .029) and hs-CRP (p = .005) were significantly lower in cases than controls. The cytokines and growth factor profiles in cases were significantly different from controls. After multivariate analysis, serum levels of IL-2 (p < .001), IL-4 (p = .028) were significantly lower in cases compared with the controls while serum levels of IL-8, TNF-α, MCP-1, EGF and VEGF were significantly higher in the cases (p < .001). Conclusions In patients with CAD and higher consumption of drug used (statins, aspirin and glucose lowering agents) to mitigate the risk of a secondary event, the level of hs-CRP one year after stent implantation decreased despite of significant higher serum levels of pro- and anti-inflammatory cytokines and growth factors.

Saireito (114) Increases IC50 and Changes T-Cell Phenotype When Used in Combination with Prednisolone Therapy in Human Peripheral Blood Mononuclear Cells.

Prednisolone (PSL), a type of corticosteroid used to treat autoimmune diseases, can increase the risk of infection and osteoporosis. Saireito (114), a Kampo medicine, has an immunosuppressive effect; with its use, the dose of steroids can be reduced. However, its mechanism when used with PSL is still unclear. We used peripheral blood mononuclear cells (PBMCs) from healthy adults to examine the effect of 114 and PSL treatment on PBMC proliferation, T-cell subsets, and cytokine production. PBMCs were cotreated with concanavalin A and 300 μM 114 (either Tsumura & Co. (TJ) or Kracie Holdings (KR)) and 0.0001–1.0 μM PSL for 96 h to create the T-cell mitogen. We then measured the PBMC proliferation; ratio of CD4+ T cells, CD8+ T cells, and T-follicular helper (Tfh) cells; and concentration of cytokines (TNF, IFN-γ, IL-6, IL-10, IL-17A, and IL-21). The proliferation of PBMCs was dose dependently suppressed in both the PSL and PSL + 114 groups (p < 0.05). Combination therapy increased the IC50 in the PSL group (0.0947 μM) by 2.02 and 1.64-fold in the PSL + TJ114 and PSL + KR114 groups, respectively. Both the PSL + 114 groups had an increased ratio of CD4+ T cells compared to the PSL group, with no effect on the ratio of CD8+ T and Tfh cells. Furthermore, the PSL + 114 groups showed increased IL-6 and IL-10 compared to the PSL monotherapy group, although the difference was not significant. There was no significant difference in the TNF, IFN-γ, IL-17A, and IL-21 concentrations between the PSL and PSL + 114 groups. The elevated IC50 with 114 cotreatment suggests diminished immunosuppressive action. Moreover, increased cytokine production by Th2 with 114 cotreatment suggests a restoration of T-cell balance in Th1-mediated autoimmune diseases. However, increased IL-6 suggests potential exacerbation of IL-6-mediated diseases, such as rheumatoid arthritis. Therefore, it is necessary to monitor these clinical parameters when using 114 in combination with PSL.

Experimental Arthritis Inhibits Adult Hippocampal Neurogenesis in Mice.

Background: Adult-born neurons of the hippocampal dentate gyrus play a role in specific forms of learning, and disturbed neurogenesis seems to contribute to the development of neuropsychiatric disorders, such as major depression. Neuroinflammation inhibits adult neurogenesis, but the effect of peripheral inflammation on this form of neuroplasticity is ambiguous. Objective: Our aim was to investigate the influence of acute and chronic experimental arthritis on adult hippocampal neurogenesis and to elucidate putative regulatory mechanisms. Methods: Arthritis was triggered by subcutaneous injection of complete Freund’s adjuvant (CFA) into the hind paws of adult male mice. The animals were killed either seven days (acute inflammation) or 21 days (chronic inflammation) after the CFA injection. Behavioral tests were used to demonstrate arthritis-related hypersensitivity to painful stimuli. We used in vivo bioluminescence imaging to verify local inflammation. The systemic inflammatory response was assessed by complete blood cell counts and by measurement of the cytokine/chemokine concentrations of TNF-α, IL-1α, IL-4, IL-6, IL-10, KC and MIP-2 in the inflamed hind limbs, peripheral blood and hippocampus to characterize the inflammatory responses in the periphery and in the brain. In the hippocampal dentate gyrus, the total number of newborn neurons was determined with quantitative immunohistochemistry visualizing BrdU- and doublecortin-positive cells. Microglial activation in the dentate gyrus was determined by quantifying the density of Iba1- and CD68-positive cells. Results: Both acute and chronic arthritis resulted in paw edema, mechanical and thermal hyperalgesia. We found phagocytic infiltration and increased levels of TNF-α, IL-4, IL-6, KC and MIP-2 in the inflamed hind paws. Circulating neutrophil granulocytes and IL-6 levels increased in the blood solely during the acute phase. In the dentate gyrus, chronic arthritis reduced the number of doublecortin-positive cells, and we found increased density of CD68-positive macrophages/microglia in both the acute and chronic phases. Cytokine levels, however, were not altered in the hippocampus. Conclusions: Our data suggest that acute peripheral inflammation initiates a cascade of molecular and cellular changes that eventually leads to reduced adult hippocampal neurogenesis, which was detectable only in the chronic inflammatory phase.

Studying of Some Immunological Parameters in Patients with Inflammatory Bowel Disease ( IBD ) in Al-Anbar Province

The serum levels of interlukine-17A and interlukine-17F were determined using ELISA technique for quantitative determination of IL-17A and IL-17F concentrations in serum. A comparison in Immunological parameters between the two groups (patients and control) showed that there was a significant difference in levels of IL-17 A and IL-17F with p-value (<0.05). The means were: IL-17 A (79.29 pgml),( 18.72 pgml ) and IL-17F(226.4 pgml ),( 29.09 pgml ) respectively. Also the serum levels of p ANCA and c ANCA were determined using Enzyme-linked immunosorbent assay ELISA technique for quantitative determination of pANCA and c ANCA concentrations in human serum. There was a significant difference in levels of perinuclear antineutrophil cytoplasmic antibodies (pANCA) and cytoplasmic antineutrophil cytoplasmic antibodies(c ANCA ) with p-value(<0.05), the means were: pANCA ( 60.93 ngml), (10.31ngml), and c ANCA (35.78 ngml), (8.341ngml) respectively.

IL-17A, IL-17E and IL-17F as Potential Biomarkers for the Intensity of Low-Grade Inflammation and the Risk of Cardiovascular Diseases in Obese People.

Low-grade inflammation is a factor that predisposes to many obesity-related comorbidities. The immune mechanisms controlling the inflammatory response related to the secretory activity of adipocytes and its consequences for the organism are still under investigation. Methods: 84 obese adult volunteers (BMI ≥ 30 kg/m2) were tested by BIA. Serum samples were collected to analyze the concentrations of interleukins IL-17A, IL-17E and IL-17F. The subjects completed the original questionnaire, the FFQ-6 food consumption frequency questionnaire and the food diary. Results: The level of IL-17E and IL-17F was positively correlated with the BMI value and the level of IL-17E increased with the content of subcutaneous fat. Its increased blood concentration was also observed in individuals who declared that they were diagnosed with atherosclerosis and/or were taking beta-blockers. Products that were related with a low level of the above-mentioned interleukins were vegetables, groats, eggs, red meat, fast-food and alcohol. The level of these interleukins was positively correlated with the frequent consumption of confectionery and breakfast cereals. Nutrients that decreased the concentrations of IL-17 isoforms were potassium, iron, vitamins B6 and C, and folic acid. Conclusions: Both IL-17E and IL-17F may be closely related to the intensity of low-grade inflammation and be biomarkers of cardiovascular disease risk. Food products or the nutrients they contain may affect the levels of the above-mentioned interleukins as well as IL-17A.

The association of IL-3, IL-17A, and IL 27 serum levels with susceptibility to toxoplasmosis in recurrent abortion of Iraqi women

Cytokines are a group of immunomodulatory proteins leading to a variety of immune reactions in the human; these cytokines play a significant role in the development of appropriate immune responses against T. gondii. This study aims to reveal the association of toxoplasmosis with serum levels of IL-3, IL-17A, and IL-27 in aborted women. The blood samples of patients and controls were collected from Al-Alawiya Maternity Teaching Hospital/Baghdad/Iraq from 2019 to 2020 for detecting anti-T. gondii antibodies (IgG and IgM) and the level of interleukins by ELISA. The results of TORCH by rapid test for recurrent abortion recorded 25.3% seropositive for anti-Toxoplasma antibodies, and 31.5% seropositive for one or more cases of TORCH test (Cytomegalovirus, Rubella, and Herpes). Whereas the results for anti-T. gondii IgG and IgM antibodies were shown elevated positivity percentages by ELISA test; these percentages were 56.2% in recurrent abortion women with significant differences (P < 0.05). The results suggested that the IL-3 serum concentration of pregnant women, recurrent abortion, and recurrent abortion with toxoplasmosis was declined versus healthy women with significant differences (p < 0.05). However, the results revealed that the concentration of IL-17A in recurrent abortion, and recurrent abortion with toxoplasmosis elevated versus healthy women and pregnant women with significant difference (p < 0.05). Whereas the results indicated that the IL-27 serum concentration elevated with significant differences in recurrent abortion with toxoplasmosis group compared to healthy women, pregnant women, and recurrent abortion. Interestingly, the serum levels for IL-27 increased comparing to the levels of IL-3 and IL-17A in all groups with significant differences (P < 0.05). In conclusion, it appeared in this study that the role of IL-3, IL-17A, and IL-27 in the maternal immune response during infections can lead to abortion.

Assessment of RANTES, MIP4A, MMP7, MMP9, MMP14, TIMP 1, TIMP 2 and TIMP 3 concentration in the follicular fluid of patients undergoing in vitro fertilization/embryo transfer procedure.

Matrix metalloproteinases (MMP) degrade extracellular matrix. Some studies show that MMP9 concentration in follicular fluid (FF) may play a role in oocyte maturation and in vitro fertilization (IVF) success. The immunology of follicular fluid is still not fully understood. Assessment of RANTES, MIP4A, MMP7, MMP9, MMP14, TIMP 1, TIMP 2 and TIMP 3 concentration in the follicular fluid of patients undergoing in vitro fertilization/embryo transfer procedure. This case-control study included 20 randomly selected patients with a positive pregnancy (PPG) test and 20 patients with a negative pregnancy (NPG) test after IVF/ET. In FF obtained during oocyte retrieval, the concentrations of MIP4A, MMP7, MMP14, TIMP 1, TIMP 2, TIMP 3, RANTES, IL-12p40, and IL-17A were measured. Their effect on the characteristics of follicles, embryos, and the efficiency of IVF and ET were analysed. There was no statistically significant relationship between a positive pregnancy test and the results of the immunoassay performed. The number of COC-1 correlates significantly and positively with RANTES (r = 0.34; p = 0.038) and IP-10 (r = 0.329; p = 0.038). MII correlates significantly and positively with RANTES (r = 0.341, p = 0.031). The number of top-quality embryos correlates significantly and positively with IL-17A (r = 0.451, p = 0.004) and TIMP 1 (r = 0.44, p = 0.005). The concentration of IL-17A and TIMP 1 may predict IVF/ET success. Further studies are required on the influence of the follicular fluid immunological environment on oocyte maturation and quality and, subsequently, embryo development.