Significant Reduction In IL-6 Research Articles

Immunomodulation and anticancer evaluation of quinazoline-based thalidomide analogs: Design, synthesis, docking, and dynamic simulation

A new series of thalidomide analogs were synthesized and evaluated against HepG-2, HCT-116, PC3, and MCF-7. With IC50 values ranging from 2.41 to 14.78 μM, compounds 4c, 5g, and 7 demonstrated substantial potencies against all examined cell lines in comparison to thalidomide (IC50 = 32.12 - 76.91 μM)). The most active compounds were further evaluated for their in vitro immunomodulatory activities via IL6, TNF-α and human caspase-3 in MCF-7 cells using thalidomide as a positive control. Compounds 5g and 4c showed significant reductions in IL6 (80.65 %) and TNF-α (76.14 %), compared to thalidomide (45.11 % and 41.39, respectively). Furthermore, compound 4c exhibited a significant elevation in caspase-3 level (409.33 pg/mL) compared to thalidomide (349.55 pg/mL). In addition, the most active compounds were examined for their COX-I, COX-II, VEGFR inhibitory activities. Compound 5g was the most active member against COX-I (0.80 μM), compound 4c was the most active member against COX-II (0.80 μM), and compound 4c was the most active member against VEGFR (253 nM). Furthermore, the flowcytometry analyses revealed that compound 4c can arrest the cell line at Pre-G1 phase and induce a significant apoptotic effect (75.75 %) compared to control cells (2.62 %) and thalidomide (65.34 %). Our derivatives were subjected to molecular modeling to assess their binding to Cereblon and also dynamic simulations.

The Impact of Exercise on Interleukin-6 to Counteract Immunosenescence: Methodological Quality and Overview of Systematic Reviews.

This study evaluated the methodological quality of published systematic reviews on randomized and non-randomized clinical trials to synthesize evidence on the association between IL-6, immunosenescence, and aerobic and/or resistance exercise. The Preferred Reporting Items for Overviews of Systematic Reviews (PRIO-harms) guideline was used, with registration number CRD42022346142-PROSPERO. Relevant databases such as Cochrane Library, PubMed, Web of Science, Scopus, and Google Scholar were searched using English Medical Subject Headings terms. Inclusion criteria were systematic reviews analyzing aerobic exercise, resistance exercise, or a combination of both and assessing IL-6 as a biomarker of cellular immunosenescence in humans. The Measurement Tool to Assess Systematic Reviews 2 (AMSTAR-2) was employed. Out of 742 identified articles, 18 were eligible, and 13 were selected for analysis. Sample sizes ranged from 249 to 1421 participants, mostly female, with ages ranging from 17 to 95 years. Aerobic exercise was the most studied type (46.15%), followed by combined exercise (38.46%) and resistance exercise (15.38%). Aerobic exercise showed a statistically significant reduction in IL-6, C-reactive protein (CRP), and tumor necrosis factor-alpha (TNF-α) levels. Among the 13 reviews analyzed using AMSTAR-2, 8 were rated as critically low quality, and 5 were classified as low quality. Aerobic exercise has anti-inflammatory properties and the potential to modulate IL-6, CRP, and TNF-α levels in immunosenescence. However, the limited methodological quality of the analyzed systematic reviews highlights the urgent need for robust, high-quality studies to improve access to information and facilitate evidence-based decision-making in healthcare.

HIITING CANCER BACK: THE EFFECTS OF ONE MONTH OF HIGH INTENSITY INTERVAL TRAINING ON INFLAMMATION, BODY COMPOSITION, AND CARDIORESPIRATORY FITNESS IN CANCER SURVIVORS

INTRODUCTION/AIMS Chronic inflammation, low fitness, and unfavourable body composition are often side effects of anti-cancer therapies and are associated with an increased risk of cancer recurrence. However, the response of these variables to high intensity interval training (HIIT), and the relationship among these predictors of cancer recurrence, is yet to be explored in cancer survivors. The aim of this study was to investigate the effect of one month of HIIT on inflammation, body composition, and cardiorespiratory fitness and explore the relationships among these variables in breast, prostate, and colorectal cancer survivors. METHODS Survivors (n=131) of breast, prostate, and colorectal cancer (60.1±10.3 years, 26.9±4.9 kg/m2, 67% female) completed one month of HIIT (12 sessions: 4x4min at 85-95% peak heart rate (HRpeak), interspersed with 3-minutes at 50-75% HRpeak). Body composition via dual-energy X-ray absorptiometry, cardiorespiratory fitness via V̇O2peak, and fasted blood were measured at baseline and at one month. Blood was analysed for inflammatory factors (interleukin (IL)-6, IL-10), and tumour necrosis factor alpha (TNF-α)). RESULTS HIIT resulted in significant reductions in IL-6, IL-10, TNF-α (-37-39%, p<0.001) and significant increases in leg lean mass (+400g, p=0.008) and absolute V̇O2peak (+0.2 L/min, p<0.001). Despite this, the only significant association among the changes in these variables was a weak correlation between IL-10 and absolute V̇O2peak (rs=0.256, p=0.013). CONCLUSION One month of HIIT elicited significant improvement in markers of systemic inflammation, body composition, and cardiorespiratory fitness. However, improvements in these variables were not strongly related and occur independent of each other. The findings of this study demonstrate 4x4 HIIT is an effective prescriptive tool to elicit rapid improvements in physiological markers, through apparent independent pathways. Therefore, exercise physiologists working with cancer survivors should consider utilising 4x4 HIIT to their exercise prescriptions as a time efficient means to reduce the risk of cancer recurrence and improve survivorship.

Polyphenolic Characterization and Anti-Inflammatory Effect of In Vitro Digested Extracts of Echinacea purpurea L. Plant Parts in an Inflammatory Model of Human Colon Cells.

Echinacea purpurea L. (EP) preparations are globally popular herbal supplements known for their medicinal benefits, including anti-inflammatory activities, partly related to their phenolic composition. However, regarding their use for the management of inflammation-related intestinal diseases, the knowledge about the fate of orally ingested constituents throughout the human gastrointestinal tract and the exposition of in vitro digested extracts in relevant inflammatory models are unknown. This study investigated for the first time the impact of in vitro gastrointestinal digestion (INFOGEST) on the phenolic composition and anti-inflammatory properties of EP extracts from flowers (EF), leaves (EL), and roots (ER) on IL-1β-treated human colon-derived CCD-18Co cells. Among the seven hydroxycinnamic acids identified using HPLC-UV-MS/MS, chicoric and caftaric acids showed the highest concentrations in EL, followed by EF and ER, and all extracts exerted significant reductions in IL-6, IL-8, and PGE2 levels. After digestion, despite reducing the bioaccessibility of their phenolics, the anti-inflammatory effects were preserved for digested EL and, to a lesser extent, for EF, but not for digested ER. The lower phenolic content in digested EF and ER could explain these findings. Overall, this study emphasizes the potential of EP in alleviating intestinal inflammatory conditions and related disorders.

Lactobacillus delbrueckii subsp. bulgaricus OLL1073R-1 eps gene knockout mutants reduced exopolysaccharide synthesis and immunomodulatory activities

In this study, eps genes in Cluster I of Lactobacillus delbrueckii subsp. bulgaricus OLL1073R-1 were deleted via conjugal transformation to understand the role of key eps genes in exopolysaccharide (EPS) synthesis and their immunomodulatory effects. Eps gene knockout mutants of OLL1073R-1, ΔepsIB, ΔepsIC, ΔepsID, ΔepsIE, and ΔepsIF were isolated by homologous recombination with the conjugative plasmid pGMβ1. Significant reductions in high molecular weight EPS (H-EPS) production were observed in ΔepsIB, ΔepsIC, and ΔepsIE and partly in ΔepsIF, but not in ΔepsID fermented milk. H-EPS purified from OLL1073R-1 fermented milk showed significant induction of IL-6, IL-10 and IL-12, whereas low molecular weight EPS (L-EPS) showed significant induction of IL-10 and IL-12 in THP-1 dendritic cells. ΔepsIE with less production of H-EPS exhibited significant reductions in IL-6, IL-10 and IL-12 productions. The present study firstly reported that H-EPS in OLL1073R-1 contributes to IL-6, IL-10 and IL-12 production in THP-1 dendritic cells.

EFFECT OF ANTI-TSLPR MONOCLONAL ANTIBODY ON VIABILITY, PROAPOPTOTIC GENES EXPRESSION, AND PRODUCTION OF PRO-INFLAMMATORY CYTOKINES IN MCF-7 AND A549 CELLS.

Thymic stromal lymphopoietin (TSLP) and its receptor (TSLPR) are expressed in various cancer cells. However, their role in cancer development is not well defined. To investigate the effects of anti-TSLPR antibody on the viability, proapoptotic genes expression, and production of pro-inflammatory cytokines in MCF-7 and A549 cancer cells. MCF-7 and A549 cells were exposed to anti-TSLPR monoclonal antibody for 24, 48, and 72 h. The effect on cell viability was examined by MTT assay. The expression levels of TP53, BAX, and CASP3 genes were evaluated by the quantitative reverse transcription polymerase chain reaction (qRT-PCR). Levels of interleukin (IL)-6, tumor necrosis factor-alpha (TNF-α), and transforming growth factor (TGF-β1) were measured by the enzyme-linked immunosorbent assay (ELISA). The treatment of MCF-7 cells with anti- TSLPR antibody slightly stimulates cell proliferation after 48 h and 72 h following initial cytotoxicity in 24 h with a significant reduction in IL-6 and TNF-α production. A significant increase in the BAX expression in anti-TSLPR treated cells at a concentration of 2.5 μg/ml at 24-h point was evident. In anti-TSLPR-treated A549 cells, no decrease in cell count was observed, and slight dose-dependent stimulation of cell proliferation was evident in 48 h and 72 h of culture. A significant increase in TP53, BAX, and CASP3 expression upon treatment with 2.5 μg/ml of anti-TSLPR was evident in A549 cells. The effects of anti-TSLPR on cell viability, proapoptotic gene expression, and production of pro-inflammatory cytokines (IL-6 and TNF-α) vary in MCF-7 and A549 cells.

Tehranolid and Artemisinin Effects on Ameliorating Experimental Autoimmune Encephalomyelitis by Modulating Inflammation and Remyelination.

Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system. Artemisinin (ART) is a natural sesquiterpene lactone with an endoperoxide bond that is well-known for its anti-inflammatory effects in experimental autoimmune encephalomyelitis (EAE), the most commonly used animal model of MS. Tehranolide (TEH) is a novel compound with structural similarity to ART. In this study, we aimed to investigate the ameliorating effect of TEH on EAE development by targeting proteins and genes involved in this process and compare its effects with ART. Female C57BL/6 mice were immunized with MOG35-55. Twelve days post-immunization, mice were treated with 0.28mg/kg/day TEH and 2.8mg/kg/day ART for 18 consecutive days, and the clinical score was measured daily. The levels of pro-inflammatory and anti-inflammatory cytokines were assessed in mice serum and splenocytes by ELISA. We also evaluated the mRNA expression level of cytokines, as well as genes involved in T cell differentiation and myelination in the spinal cord tissue by qRT-PCR. Administration of TEH and ART significantly alleviated EAE signs. A significant reduction in IL-6 and IL-17 secretion and IL-17 and IL-1 gene expression in spinal cord were observed in the TEH-treated group. ART had similar or less significant effects. Moreover, TGF-β, IL-4, and IL-10 genes were stimulated by ART and TEH in the spinal cord, while the treatments did not affect IFN-γ expression. Both treatments dramatically increased the expression of FOXP3, GATA3, MBP, and AXL. Additionally, the T-bet gene was reduced after TEH administration. The compounds made no changes in RORγt, nestin, Gas6, Tyro3, and Mertk mRNA expression levels in the spinal cord. The study revealed that both TEH and ART can effectively modulate the genes responsible for inflammation and myelination that play a crucial role in EAE. Interestingly, TEH demonstrated a greater potency compared to ART and hence may have the potential to be evaluated in interventions for the management of MS.

Effects of Chemotherapy on Aortic 18-Fluorodeoxyglucose Uptake in Patients With Hodgkin and Non-Hodgkin Lymphoma

BackgroundDespite advances in the treatment of oncology patients, therapy-related side effects may lead to premature morbidity. Inflammatory activation that has been linked to cardiovascular disease is crucial for the pathogenesis of both Hodgkin (HL) and non-Hodgkin lymphoma (NHL). ObjectivesThe purpose of this study was to assess the vascular effects of chemotherapy in patients with HL and NHL by positron emission tomography/computed tomography with 18-fluorodeoxyglucose (18-FDG PET/CT) and to investigate interactions with systemic inflammation as assessed by circulating inflammatory markers. MethodsBetween July 2015 and July 2019, 65 consecutive patients (mean age 56 ± 17.78 years) with confirmed diagnosis of either HL (n = 33) or NHL (n = 32) were prospectively studied. PET/CT imaging was performed at baseline, at an interim phase, and after first-line treatment. Aortic FDG uptake was assessed by measuring global aortic target-to-background ratio (GLA-TBR). Serum biomarkers interleukin (IL)-6 and IL-1b were measured at each phase. ResultsPatients with HL demonstrated significant reduction in aortic TBR after first-line treatment (median GLA-TBR baseline: 1.98, median GLA-TBR third scan: 1.75, median difference = −0.20, 95% CI: −0.07 to −0.33, P = 0.006), which remained significant after adjustment for confounders (adj. R2 of model = 0.53). In contrast, patients with NHL did not demonstrate a significant aortic inflammation response (P = 0.306). Furthermore, patients with HL demonstrated a significant reduction in IL-6 (P = 0.048) and IL-1b (P = 0.045), whereas patients with NHL did not demonstrate significant reduction in IL-6 (P = 0.085) and IL-1b levels (P = 0.476). ConclusionsAortic inflammation, as assessed by 18-FDG PET/CT, is reduced in HL patients after first-line treatment but not in NHL patients. These findings imply that different pathophysiological pathways and different therapies might affect the arterial bed in different ways for patients with lymphoma.

The Probable Protective Effect of Photobiomodulation on the Immunologic Factor's mRNA Expression Level in the Lung: An Extended COVID-19 Preclinical and Clinical Meta-analysis.

Different expression of cytokine genes in the body determines the type of immune response (Th1 or Th2), which can play an important role in the pathogenesis of the COVID-19 disease. This meta-analysis was conducted to evaluate the probable effect of photobiomodulation (PBMT) therapy on the cytokine's mRNA expression in the lung. We systematically searched indexing databases, including PubMed/Medline, ISI web of science, Scopus, EMBASE, and Cochrane central, using standard terms without language, study region or type restrictions. Studies on using PBM in lung injury modeling with samples collected from lung tissue to observe IL-1β, TNF-α, IL-10, and IL-6 mRNA expression were included. RevMan 5.3 software was used for data analysis and standardized mean difference as effect size. Of the 438 studies found through initial searches, 17 met the inclusion criteria. The main properties of 13 articles on 384 animals included in this meta-analysis with a wide range of species include rats (n = 10) and rabbits (n = 3). The analysis revealed that PBMT reduced the mRNA expression of TNFα (SMD: -3.70, 95% CI: -6.29, -1.11, P = .005,I 2 = 71%) and IL-1β (SMD: -5.85, 95% CI: -8.01, -3.69, P < .00001,I 2 = 37%) significantly, but no statistically significant reduction in IL-6 (SMD: -2.89, 95% CI: -5.79, 0.01, P = .05,I 2 = 88%) was observed compared with the model controls. Also, PBMT increased IL-10 mRNA expression significantly compared with the model controls (SMD: 1.04, 95% CI: 0.43, 1.64, P = .0008,I 2 = 17%). This meta-analysis revealed that the PBMT utilizes beneficial anti-inflammatory effects and modulation of the immune system on lung damage in animal models and clinical studies. However, animal models and clinical studies appear limited considering the evidence's quality; therefore, large clinical trials are still required.

Rutin and selenium nanoparticles protected against STZ-induced diabetic nephropathy in rats through downregulating Jak-2/Stat3 pathway and upregulating Nrf-2/HO-1 pathway

Diabetic nephropathy (DN) is a renal complication of diabetic hyperglycemia. The Signal transducer and activator of transcription 3 (Stat3) is a center molecule of the chronic inflammation causing DN progression. Therefore, the study investigated the possible inhibitory effects of Rutin (Ru) and Selenium (Se), formulated as nanoparticles (SeNPs), on Stat3 pathway in streptozotocin (STZ)-induced DN in Sprague-Dawley rats. Ru (100 mg/kg/orally) and SeNPs (equivalent to 5 mg of Se/kg/orally) were given as treatment for eight weeks. An assessment of fasting blood glucose, renal function biomarkers, GSH, and MDA was carried out spectrophotometrically. ELISA assessment of renal IL-6, NF-κB, TNF-α, Jak-2, and p-Stat3 was performed. Sirt-1, Nrf-2, and HO-1 were assessed immunohistochemically.DN group receiving Ru + SeNPs showed a decrease in fasting blood glucose, serum creatinine, and urea (163.8 ± 22.8, 0.54 ± 0.1, and 53.6 ± 25.7 mg/dl, respectively), compared to the DN group (443.8 ± 42.72, 1.58 ± 0.4, and 281.8 ± 47.35 mg/dl, respectively). In addition, it exhibited elevation in the levels of Sirt-1, Nrf-2 and HO-1 compared to the DN group. Finally, Ru + SeNPs exhibited a significant reduction in IL-6, NF-κB, TNF-α, Jak-2, and p-Stat3 (42.8 ± 10.3, 1.2 ± 0.1, 53.4 ± 3.87, 0.8 ± 0.06 and 1.1 ± 0.2 U/g tissue, respectively) when compared to the DN group (155.3 ± 13.97, 2.8 ± 0.3, 105.5 ± 32.84, 2.03 ± 0.2 and 2.56 ± 0.15 U/g tissue, respectively).Therefore, combining Ru with SeNPs has a potential renoprotective effect against DN by upregulating Nrf-2/HO-1 and downregulating Jak-2/Stat3 Pathways.

Hesperetin from Root Extract of Clerodendrum petasites S. Moore Inhibits SARS-CoV-2 Spike Protein S1 Subunit-Induced NLRP3 Inflammasome in A549 Lung Cells via Modulation of the Akt/MAPK/AP-1 Pathway.

Inhibition of inflammatory responses from the spike glycoprotein of SARS-CoV-2 (Spike) by targeting NLRP3 inflammasome has recently been developed as an alternative form of supportive therapy besides the traditional anti-viral approaches. Clerodendrum petasites S. Moore (C. petasites) is a Thai traditional medicinal plant possessing antipyretic and anti-inflammatory activities. In this study, C. petasites ethanolic root extract (CpEE) underwent solvent-partitioned extraction to obtain the ethyl acetate fraction of C. petasites (CpEA). Subsequently, C. petasites extracts were determined for the flavonoid contents and anti-inflammatory properties against spike induction in the A549 lung cells. According to the HPLC results, CpEA significantly contained higher amounts of hesperidin and hesperetin flavonoids than CpEE (p < 0.05). A549 cells were then pre-treated with either C. petasites extracts or its active flavonoids and were primed with 100 ng/mL of spike S1 subunit (Spike S1) and determined for the anti-inflammatory properties. The results indicate that CpEA (compared with CpEE) and hesperetin (compared with hesperidin) exhibited greater anti-inflammatory properties upon Spike S1 induction through a significant reduction in IL-6, IL-1β, and IL-18 cytokine releases in A549 cells culture supernatant (p < 0.05). Additionally, CpEA and hesperetin significantly inhibited the Spike S1-induced inflammatory gene expressions (NLRP3, IL-1β, and IL-18, p < 0.05). Mechanistically, CpEA and hesperetin attenuated inflammasome machinery protein expressions (NLRP3, ASC, and Caspase-1), as well as inactivated the Akt/MAPK/AP-1 pathway. Overall, our findings could provide scientific-based evidence to support the use of C. petasites and hesperetin in the development of supportive therapies for the prevention of COVID-19-related chronic inflammation.

Effect of aerobic exercise on inflammatory markers in polycystic ovary syndrome: a randomized controlled trial.

Chronic low-grade inflammation has emerged as a key contributor to the pathogenesis of Polycystic Ovary Syndrome (PCOS). In this regard, the present study examined the potential effects of aerobic exercise on interleukin-6 (IL6), tumor necrosis factor (TNF), and C-reactive protein (CRP) in PCOS women. This was a randomized clinical trial that included 40 females aged 25-35 years diagnosed with PCOS. The participants were divided into two groups equal in number: the aerobic exercise group (AEM), and the metformin group (M). The AEM group performed aerobic exercise three times a week for 12 weeks in addition to metformin treatment. The M group received metformin only. Participants were assessed for IL-6, TNF-α, and CRP at baseline and after 12 weeks of intervention. The findings showed a significant reduction in IL-6, TNF-α, and CRP values in both AEM and M groups (p=0.001, p=0.01, respectively) after the end of the 12 weeks of the intervention. However, the participants who received aerobic exercise plus metformin, group AEM, showed a greater reduction in IL-6, TNF-α, and CRP (p=0.01, p = 0.01 and p=0.001, respectively). Aerobic exercise is effective in lowering IL-6, TNF-α, and CRP in polycystic ovarian women. Further clinical trials are recommended to assess the potential effects of aerobic exercise on PCOS-associated risk factors.

Co-Administration of Iron and Bioavailable Curcumin Reduces Levels of Systemic Markers of Inflammation and Oxidative Stress in a Placebo-Controlled Randomised Study.

Ferrous sulphate (FS) is widely used as an iron supplement to treat iron deficiency (ID), but is known to induce inflammation causing gastric side-effects resulting in poor adherence to supplement regimens. Curcumin, a potent antioxidant, has been reported to suppress inflammation via down regulation of NF-κB. The aim of the present double blind, placebo-controlled randomised trial was to assess whether co-administration of FS with a formulated, bioavailable form of curcumin (HydroCurc™) could reduce systemic inflammation and/or gastrointestinal side-effects. This study recruited 155 healthy participants (79 males; 26.42 years ± 0.55 and 76 females; 25.82 years ± 0.54), randomly allocated to one of five different treatment groups: iron and curcumin placebo (FS0_Plac), low dose (18 mg) iron and curcumin placebo (FS18_Plac), low dose iron and curcumin (FS18_Curc), high dose (65 mg) iron and curcumin placebo (FS65_Plac), and high dose iron and curcumin (FS65_Curc). Completed questionnaires and blood samples were collected from all participants at baseline (day 1), mid-point (day 21), and at end-point (day 42). Results showed a significant reduction in IL-6 in the FS65_Curc group (0.06 pg/mL ± 0.02, p = 0.0073) between the mid-point and end-point. There was also a significant reduction in mean plasma TNF levels in the FS65_Curc (0.65 pg/mL ± 0.17, p = 0.0018), FS65_Plac (0.39 pg/mL ± 0.15, p = 0.0363), and FS18_Curc (0.35 pg/mL ± 0.13, p = 0.0288) groups from mid-point to end-point. A significant increase was observed in mean plasma TBARS levels (0.10 µM ± 0.04, p = 0.0283) in the F18_Plac group from baseline to end-point. There was a significant association with darker stools between FS0_Plac vs. FS65_Plac (p = 0.002, Fisher’s exact test) suggesting that high iron dose in the absence of curcumin leads to darker stools. A reduction in inflammation-related markers in response to co-administering supplemental iron alongside formulated curcumin suggests a reduction in systemic inflammation. This supplementation approach may therefore be a more cost effective and convenient alternative to current oral iron-related treatments, with further research to be conducted.

Abstract WMP9: Pharmacological Characterization Of The Water Soluble Neurosteroid NTS-104 In The Rat Embolic Stroke Model

Background: Our objective was to characterize the pharmacodynamic changes induced by NTS-104/105 within the brain and plasma in rats following embolic middle cerebral artery occlusion (eMCAO). Previous pharmacokinetic analysis indicated that NTS-104 is rapidly metabolized in the blood to form the active compound NTS-105, which is readily detected in the brain. In contrast, NTS-104 does not cross the blood-brain barrier. Methods: Adult, male Wistar rats were subjected to eMCAO. Stroke severity was defined by Neurological Severity Score (NSS) assessment. Only rats that scored &gt;8 on a 13-point scale were included. Rats were dosed IM with vehicle, or NTS-104 (5mg/kg or 20mg/kg) at 6 hours after stroke. Brain and plasma samples rats were collected at 6, 12, or 24hrs after injection. Samples were screened for expression of AKT, pAKT and against a panel of 67 cytokines by quantitative ELISA. Results: We found that NTS-104 treatment induced a significant reduction in IL-6, GM-CSF, MCP-1, IL-1α, RAGE, VEGF, and ICAM-1 levels within the brains of rats following intramuscular injection of 20 mg/kg NTS-104 at 6-hours after eMCAO compared to vehicle treated control rats. In contrast, treatment with 5mg/kg NTS-104 did not induce similar time and dose dependent changes in these specific cytokines relative to vehicle treated controls. NTS-104 treatment also significantly reduced IL-6 and GM-CSF levels, while increasing galectin-1 levels, within the plasma of these same rats in a time and dose dependent manner similar to what was observed within the brain. We further detected a significant increase in the levels of phosphorylated AKT (pAKT) within the brains of stroked rats treated with 20 mg/kg NTS-104 but not with 5 mg/kg. Conclusion: These data demonstrate that treatment with NTS-104 results in the significant activation of the AKT cell survival signaling pathway and significantly reduces critical neuroinflammatory signaling after stroke in a time and dose dependent manner.

Effects of 15-lipoxygenase overexpressing adipose tissue mesenchymal stem cells on the Th17 / Treg plasticity

15-lipoxygenase (15-LOX) is a critical enzyme that allows the direction of arachidonic acid metabolism to change from inflammation into the resolution. This study aims to reveal how the immunomodulation properties of mesenchymal stem cells (MSC) alter by the 15-LOX overexpression. For this purpose, peripheral blood mononuclear cells (PBMCs) isolated from seven healthy volunteers, and both MSCs and 15-LOX overexpressing MSCs (15-LOXMSCs) were co-cultured at different cell ratios (1/1, 1/5 and 1/10). Alterations of CD4+Tbet+, CD4+Gata3+, CD4+RoRC2+, and CD4+FoxP3+ lymphocyte frequencies were detected by flow cytometry, and IFN-γ, IL-4, IL-6, IL-10, IL-17a, TGF-β and LXA4 levels of medium supernatants were measured by ELISA method. According to our findings, MSC and 15-LOXMSCs have a suppressive effect on PHA activated PBMCs. However, as the ratio of PBMCs increased, the effects of 15-LOXMSCs increased significantly, while the effects of MSCs decreased. The most notable effect of the 15-LOX modification was the significant reduction in IL-6, IL-10 and IL-17a expression and the accompanying increase in TGF-β and LXA4 levels. We also observed a similar situation between CD4+RoRC2+ and CD4+FoxP3+ cell frequencies. These data suggested that the effects of MSCs on the balance of Th17 / Treg could change by the 15-LOX overexpression, and this might be in favor of the Treg cells.

Targeting Tumor-Stromal IL6/STAT3 Signaling through IL1 Receptor Inhibition in Pancreatic Cancer.

A hallmark of pancreatic ductal adenocarcinoma (PDAC) is the presence of a dense, desmoplastic stroma and the consequent altered interactions between cancer cells and their surrounding tumor microenvironment (TME) that promote disease progression, metastasis, and chemoresistance. We have previously shown that IL6 secreted from pancreatic stellate cells (PSC) stimulates the activation of STAT3 signaling in tumor cells, an established mechanism of therapeutic resistance in PDAC. We have now identified the tumor cell-derived cytokine IL1α as an upstream mediator of IL6 release from PSCs that is involved in STAT3 activation within the TME. Herein, we show that IL1α is overexpressed in both murine and human PDAC tumors and engages with its cognate receptor IL1R1, which is strongly expressed on stromal cells. Further, we show that IL1R1 inhibition using anakinra (recombinant IL1 receptor antagonist) significantly reduces stromal-derived IL6, thereby suppressing IL6-dependent STAT3 activation in human PDAC cell lines. Anakinra treatment results in significant reduction in IL6 and activated STAT3 levels in pancreatic tumors from Ptf1aCre/+;LSL-KrasG12D/+; Tgfbr2flox/flox (PKT) mice. Additionally, the combination of anakinra with cytotoxic chemotherapy significantly extends overall survival compared with vehicle treatment or anakinra monotherapy in this aggressive genetic mouse model of PDAC. These data highlight the importance of IL1 in mediating tumor-stromal IL6/STAT3 cross-talk in the TME and provide a preclinical rationale for targeting IL1 signaling as a therapeutic strategy in PDAC.

The Comparison of the Effects of Voluntary Running Wheel and Endurance Training on Il-6 and Testosterone Levels in the Rats With PCOS

Background and Aim: Polycystic Ovary Syndrome (PCOS) is an endocrine disorder in women of reproductive age. In cross-sectional and longitudinal studies, exercise training is an effective solution for treating and declining the symptoms. This study aims to compare the effects of the voluntary and the endurance exercise on some of the inflammatory and hormonal markers in rats with PCOS. Methods &amp; Materials: In this study, Which was experimental and applied in terms of purpose, 40 female Wistar rats with Mean±SD weight of 220±20 g were divided randomly into four groups of ten: 1) control, 2) PCOS, 3) PCOS + Running wheel and 4) PCOS + endurance training. The rats in the voluntary group experienced voluntary activity of wheel running for 8 weeks (5 times a week). Alternatively, the endurance training group underwent aerobic exercises for 8 weeks (5 sessions in a week) on a treadmill. The blood samples were taken from the heart to measure the concentration of interleukin-6 and testosterone level and were analyzed by one-way analysis of variance and LSD post hoc test. Ethical Considerations: This study was approved by the Tehran University, Iran (Code: IR.UT.REC.1395016). Results: The results showed no significant difference in IL-6 and testosterone indices between endurance and voluntary training groups (P=0.565), (P=0.496). Both training groups (endurance and voluntary) separately resulted in a significant reduction in il6 and testosterone compared to rats with PCOS (P=0.002), (P=0.000), (P=0.038), (P=0.007). Conclusion: Altogether, the present study’s findings suggest that voluntary and endurance training in rats have similar effects on IL-6, Testosterone, and weight.

The Effect of the Hydroalcoholic Extract of Watercress on the Levels of Protein Carbonyl, Inflammatory Markers, and Vitamin E in Chronic Hemodialysis Patients.

Introduction Chronic kidney disorder is a main public health concern. Inflammatory processes and oxidative stress are common in end-stage renal disease patients. We aimed to evaluate the effect of the hydroalcoholic extract of watercress (WC) on the inflammatory cytokines and protein carbonyl (PCO) contents in chronic hemodialysis patients. Methods This was a double-blind randomized clinical trial performed on 46 hemodialysis patients. The participants were randomly divided into two groups: intervention group (500 mg hydroalcoholic extract of WC every day for 4 weeks) and control group (500 mg of white flour every night for 4 weeks). The blood samples were taken to determine the levels of vitamin E, PCO, and inflammatory cytokines at baseline and the end of treatment. Results Forty-five patients completed the study (22 patients in the intervention group and 23 patients in the control group). There was a significant reduction in the PCO level (20.33 ± 4.40 vs. 15.06 ± 6.41, P=0.001) in the intervention group; also, this change was statistically significant relative to the control group. Furthermore, there were significant reductions in hs-CRP (8953.30 ± 5588.06 vs. 7249.86 ± 5091.62, P=0.007) and IL-6 (60.10 (55.99, 73.10) vs. 55.21 (53.39, 60.48), P=0.050) in the intervention group, but these changes were not significant in comparison with the control group. Conclusion We conclude that the hydroalcoholic extract of WC reduced the PCO content in hemodialysis patients via inhibition of protein oxidation. Although WC administration had caused a significant reduction in IL-6 and CRP levels, these differences were not statistically significant relative to the control group. Further research is needed to identify the antioxidant and anti-inflammatory effects of WC in hemodialysis patients.

Evaluation of Nutritional Gel Supplementation in C57BL/6J Mice Infected with Mouse-Adapted Influenza A/PR/8/34 Virus.

Mice are a common animal model for the study of influenza virus A (IAV). IAV infection causes weight loss due to anorexia and dehydration, which can result in early removal of mice from a study when they reach a humane endpoint. To reduce the number of mice prematurely removed from an experiment, we assessed nutritional gel (NG) supplementation as a support strategy for mice infected with mouse-adapted Influenza A/Puerto Rico/8/34 (A/PR/8/34; H1N1) virus. We hypothesized that, compared with the standard of care (SOC), supplementation with NG would reduce weight loss and increase survival in mice infected with IAV without impacting the initial immune response to infection. To assess the effects of NG, male and female C57BL/6J mice were infected with IAV at low, intermediate, or high doses. When compared with SOC, mice given NG showed a significant decrease in the maximal percent weight loss at all viral doses in males and at the intermediate dose for females. Mice supplemented with NG had no deaths for either sex at the intermediate dose and a significant increase in survival in males at the high viral dose. Supplementation with NG did not alter the viral titer or the pulmonary recruitment of immune cells as measured by cell counts and flow cytometry of cells recovered in bronchoalveolar lavage (BAL) fluid in either sex. However, mice given NG had a significant reduction in IL6 and TNFα in BAL fluid and no significant differences in CCL2, IL4, IL10, CXCL1, CXCL2, and VEGF. The results of this study show that as compared with infected SOC mice, infected mice supplemented with NG have reduced weight loss and increased survival, with males showing a greater benefit. These results suggest that NG should be considered as a support strategy and indicate that sex is an important biologic variable in mice infected with IAV.

Consumption of whole purple and regular wheat modestly improves metabolic markers in adults with elevated high-sensitivity C-reactive protein: a randomised, single-blind parallel-arm study.

Whole-grain wheat, in particular coloured varieties, may have health benefits in adults with chronic metabolic disease risk factors. Twenty-nine overweight and obese adults with chronic inflammation (high-sensitivity C-reactive protein) > 1·0 mg/l) replaced four daily servings of refined grain food products with bran-enriched purple or regular whole-wheat convenience bars (approximately 41-45 g fibre, daily) for 8 weeks in a randomised, single-blind parallel-arm study where body weight was maintained. Anthropometrics, blood markers of inflammation, oxidative stress, and lipaemia and metabolites of anthocyanins and phenolic acids were compared at days 1, 29 and 57 using repeated-measures ANOVA within groups and ANCOVA between groups at day 57, with day 1 as a covariate. A significant reduction in IL-6 and increase in adiponectin were observed within the purple wheat (PW) group. TNF-α was lowered in both groups and ferulic acid concentration increased in the regular wheat (RW) group. Comparing between wheats, only plasma TNF-α and glucose differed significantly (P < 0·05), that is, TNF-α and glucose decreased with RW and PW, respectively. Consumption of PW or RW products showed potential to improve plasma markers of inflammation and oxidative stress in participants with evidence of chronic inflammation, with modest differences observed based on type of wheat.