Production Of Inflammatory Molecules Research Articles

Influence of a polymorphic genes combination on the risk of developing intestinal infections, induction of regulatory and effector peptides

Background. The high incidence rate, the severity and the occurrence of complications determine the relevance of intestinal infections today. The individual’s immune response, which is controlled by the polymorphism of inflammatory protein genes is significant in the development and course of the disease. This issue in relation to intestinal infections has been understudied and is of interest in researching the influence of gene polymorphism on the development of intestinal infections.The aim. To establish the presence of an associative relationship between the set of IL-2 T330G and TLR-4 ASP299GLY polymorphic genes and the likelihood of developing an acute intestinal infection, as well as the role of a combination of genes in induction of inflammatory proteins.Materials and methods. The study included 108 people with acute intestinal infection and 94 apparently healthy volunteers. To determine the concentration of cytokines, immunoglobulins, we used blood serum and Vector-Best (Koltsovo, Russian Federation) test systems. The polymorphism of the IL-2 T330G and TLR-4 ASP299GLY genes was determined by PCR using Litekh LLC (Moscow, Russian Federation) primers. Statistical analysis was carried out using the ICMJE (International Committee of Medical Journal Editors) principle and SAMPL (Statistical Analyses and Methods in Published Literature) recommendations by MS Excel 2010 (Microsoft Corp., USA) and Statistica 6.0 (StatSoft Inc., USA) software.Results. When constructing the ROC curve, the area under the curve was within 0.77, sensitivity – 0.9, specificity – 0.5 (95% confidence interval: 0.7–0.84; p < 0.001). These results are at a good prognostic level with a high risk of the disease development. Comparing the level of pro-inflammatory and anti-inflammatory cytokines, immunoglobulins between the patients with -299А/А+-330GG haplotype of TLR4 ASP299GLY and IL-2 T330G genes and the carriers of only the dominant allele A of the TLR4 A/A299 genotype or only the minor allele G of IL-2 G/G330 we found no significant differences (p ≥ 0.05).Conclusion. Among carriers of the -299А/А+-330GG haplotype of the TLR4 ASP299GLY and IL-2 T330G genes, the risk of the intestinal infection development increases, but this haplotype does not affect the production of inflammatory molecules.

Plasmodium vivaxtryptophan-rich antigen reduces type I collagen secretion via the NF-κBp65 pathway in splenic fibroblasts.

The spleen plays a critical role in the immune response against malaria parasite infection, where splenic fibroblasts (SFs) are abundantly present and contribute to immune function by secreting type I collagen (collagen I). The protein family is characterized by Plasmodium vivax tryptophan-rich antigens (PvTRAgs), comprising 40 members.PvTRAg23 has been reported to bind to human SFs (HSFs) and affect collagen I levels. Given the role of type I collagen in splenic immune function, it is important to investigate the functions of the other members within the PvTRAg protein family. Protein structural prediction was conducted utilizing bioinformatics analysis tools and software. A total of 23 PvTRAgs were successfully expressed and purified using an Escherichia coli prokaryotic expression system, and the purified proteins were used for co-culture with HSFs. The collagen I levels and collagen-related signaling pathway protein levels were detected by immunoblotting, and the relative expression levels of inflammatory factors were determined by quantitative real-time PCR. In silico analysis showed that P. vivax has 40 genes encoding the TRAg family. The C-terminal region of all PvTRAgs is characterized by the presence of a domain rich in tryptophan residues. A total of 23 recombinant PvTRAgs were successfully expressed and purified. Only five PvTRAgs (PvTRAg5, PvTRAg16, PvTRAg23, PvTRAg30, and PvTRAg32) mediated the activation of the NF-κBp65 signaling pathway, which resulted in the production of inflammatory molecules and ultimately a significant reduction in collagen I levels in HSFs. Our research contributes to the expansion of knowledge regarding the functional role of PvTRAgs, while it also enhances our understanding of the immune evasion mechanisms utilized by parasites.

Covalent Conjugation of Small Molecule Inhibitors and Growth Factors to a Silk Fibroin-Derived Bioink to Develop Phenotypically Stable 3D Bioprinted Cartilage.

Implantation of a phenotypically stable cartilage graft could represent a viable approach for repairing osteoarthritic (OA) cartilage lesions. In the present study, we investigated the effects of modulating the bone morphogenetic protein (BMP), transforming growth factor beta (TGFβ), and interleukin-1 (IL-1) signaling cascades in human bone marrow stromal cell (hBMSC)-encapsulated silk fibroin gelatin (SF-G) bioink. The selected small molecules LDN193189, TGFβ3, and IL1 receptor antagonist (IL1Ra) are covalently conjugated to SF-G biomaterial to ensure sustained release, increased bioavailability, and printability, confirmed by ATR-FTIR, release kinetics, and rheological analyses. The 3D bioprinted constructs with chondrogenically differentiated hBMSCs were incubated in an OA-inducing medium for 14 days and assessed through a detailed qPCR, immunofluorescence, and biochemical analyses. Despite substantial heterogeneity in the observations among the donors, the IL1Ra molecule illustrated the maximum efficiency in enhancing the expression of articular cartilage components, reducing the expression of hypertrophic markers (re-validated by the GeneMANIA tool), as well as reducing the production of inflammatory molecules by the hBMSCs. Therefore, this study demonstrated a novel strategy to develop a chemically decorated, printable and biomimetic SF-G bioink to produce hyaline cartilage grafts resistant to acquiring OA traits that can be used for the treatment of degenerated cartilage lesions.

Mononuclear cells from patients with rhupus are influenced by TNF in their production of gp130/sIL-6Rb and APRIL

ObjectiveRhupus is a rare disease that shares characteristics of systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). While several studies have explored the clinical and immunological profiles of patients with...

Oral microbial dysbiosis in cardiovascular diseases

The most common diseases in humans are oral infections. Although modern research is mainly concerned with the role of the gut microbiota in systemic diseases, there are also reports indicating that oral infections, and especially periodontal infection, are one of the risk factors for atherosclerotic cardiovascular disease (CVD).The composition of the oral biofilm is a community of several hundred species of bacteria, fungi, spirochetes, viruses and protozoa. It varies depending on the state of health and disease. Pathogenic bacteria in the oral cavity can cause systemic disease by entering the bloodstream or by triggering immune responses at the cellular level. The discovery of the role of the oral microbiome in CVD is leading to new methods of prevention and their treatment. In this review, we discuss the various mechanisms by which oral dysbiosis may contribute to the pathogenesis of CVD as well as available options for their prevention and treatment. Oral dysbiosis, or the imbalance of bacteria in the oral cavity, has been linked to an increased risk of CVD. Several mechanisms have been proposed to explain how oral dysbiosis may contribute to CVD, including: The production of inflammatory molecules by oral bacteria. The activation of the immune system, which can lead to inflammation throughout the body. The entry of oral bacteria into the bloodstream, where they can travel to other organs and tissues. There are a number of things that can be done to prevent oral dysbiosis and reduce the risk of CVD, including: Good oral hygiene, such as brushing and flossing twice a day. Regular dental checkups and cleanings. Avoiding tobacco use. Eating a healthy diet. Conclusions. The evidence is growing that oral dysbiosis is a risk factor for CVD. Further research is needed to better understand the mechanisms involved and to develop effective interventions for prevention and treatment. The following are some other important points: The role of oral dysbiosis in CVD is likely to be complex and involve multiple factors. The effects of oral dysbiosis on CVD may vary depending on the individual's overall health status and other risk factors. More research is needed to determine the optimal methods for preventing and treating oral dysbiosis in order to reduce the risk of CVD.

Hydrogen sulfide ameliorates senescence in vascular endothelial cells through ameliorating inflammation and activating PPARδ/SGLT2/STAT3 signaling pathway.

Mounting evidence demonstrates that hydrogen sulfide (H 2S) promotes anti-inflammatory molecules and inhibits pro-inflammatory cytokines in endothelial cells (ECs). This study aims to investigate the favorable action of H 2S on endothelial function in senescence by inhibiting the production of inflammatory molecules. Senescent ECs exhibit a reduction in H 2S, endothelial nitric oxide synthase (eNOS) and peroxisome proliferator-activated receptor δ (PPARδ), coupled with increased inflammatory molecules, sodium glucose transporter type 2 (SGLT2) and phosphorylation of STAT3, which could be reversed by the administration of a slow but sustained release agent of H 2S, GYY4137. Decreased production of eNOS and upregulated p-STAT3 and SGLT2 levels in senescent ECs are reversed by replenishment of the SGLT2 inhibitor EMPA and the PPARδ agonist GW501516. The PPARδ antagonist GSK0660 attenuates eNOS expression and increases the production of p-STAT3 and SGLT2. However, supplementation with GYY4137 has no beneficial effect on GSK0660-treated ECs. GYY4137, GW501516 and EMPA preserve endothelial-dependent relaxation (EDR) in D-gal-treated aortae, while GSK0660 destroys aortic relaxation even with GYY4137 supplementation. In summary, senescent ECs manifest aggravated the expressions of the inflammatory molecules SGLT2 and p-STAT3 and decreased the productions of PPARδ, eNOS and CSE. H 2S ameliorates endothelial dysfunction through the anti-inflammatory effect of the PPARδ/SGLT2/p-STAT3 signaling pathway in senescent ECs and may be a potential therapeutic target for anti-ageing treatment.

Effect of antidepressant therapy on the severity of COVID 19 symptomatology in the hospitalized patients

IntroductionSome studies reported that vaccines are extremely good at preventing serious illness but that many countries have had difficulty vaccinating their citizens, and even some vaccinated people may still be at risk for serious COVID-19 symptoms due to underlying medical illness or reduced immunity over time.ObjectivesSome researches reported that drugs known as selective serotonin-reuptake inhibitors (SSRIs) interacts strongly with the sigma-1 receptor, a protein inside cells that helps regulate the body’s inflammatory response. So its believe that this drug most likely is interacting with the sigma-1 receptor to reduce the production of inflammatory molecules in the body, So treatment with this therapy may be highly effective to reducing severe of COVID symptomatology.MethodsThe cross-section study included two groups of patients (N = 30) of different sex ±49,2 age, all were treated in Covid Centre , Skopje. The study was conducted for 6 months all the patients was writing informed consent. The first group consisted of COVID patients who had previously suffered from psychiatric illness and had been treated with antidepressant therapy (SSRi). The second group are the COVID patients who had not been treated with antidepressant before. The severity of COVID 19 symptomatology (based on medical documentation- classification of disease severity) was determined using the Modified Early Warning Score (MEWS scale) . MEWS score 0-2 mild or asymptomatic (stable patients), 3-4 moderately severe (unstable patients), ≥ 5 highly critical(critical patients). The obtained data were processed by descriptive method and Student t-test.Results. The results in our study show that the patients who were treated with antidepressants before covid disease showed a lower score on the NEWS scale but there is a not statistically significant results p=0,06 when compare with another examination groupConclusions: The results in our study supports considerations about the possible impact of antidepressant therapy on alleviating COVID 19 symptomatology.Disclosure of InterestNone Declared

Toll-like receptor-2 (TLR-2) rs111200466 variant offers protection against SARS-CoV-2 infections and mortality: a worldwide epidemiological correlation analysis

Recently Toll-like receptor-2 has been shown to sense the envelope protein of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and initiate the production of inflammatory molecules. The expression and function of the TLR2 has been associated with several functional polymorphisms such as a 23 bp ins/del (rs111200466), Arg677Trp (rs121917864), and Arg753Gln (rs5743708). In the present study, we hypothesized that the TLR2 common functional variants would be associated with the worldwide incidence and mortality rate of SARS-CoV-2. The frequency of TLR2 polymorphisms and coronavirus disease-19 (COVID-19) were acquired from multiple databases, including genomAD, 1000 genome, dbSNP, and worldometer, respectively. The Spearman rank correlation coefficient analysis revealed a significant inverse correlation between the del allele of rs111200466 polymorphism with susceptibility to SARS-CoV-2 infection and related mortality at different times. In conclusion, the TLR2 rs111200466 minor allele (del) may be linked with susceptibility to SARS-CoV-2 infections and bad outcomes. However, further case-control studies in different populations are required to validate our observations.

ACTIVATION OF THE MITOCHONDRIAL ANTIVIRAL SIGNALING PROTEIN (MAVS) FOLLOWING LIVER ISCHEMIA/REPERFUSION AND ITS EFFECT ON INFLAMMATION AND INJURY.

ABSTRACTResuscitation of trauma patients after hemorrhagic shock causes global I/R, which may contribute to organ dysfunction. Oxidative stress resulting from I/R is known to induce signaling pathways leading to the production of inflammatory molecules culminating in organ dysfunction/injury. Our recent work demonstrated that oxidative stress was able to induce activation of the mitochondrial antiviral signaling protein (MAVS), a protein known to be involved in antiviral immunity, in an in vitro model. We therefore hypothesized that the MAVS pathway might be involved in I/R-induced inflammation and injury. The present studies show that MAVS is activated in vivo by liver I/R and in vitro in RAW 264.7 cells by hypoxia/reoxygenation (H/R). We utilized both in vivo (liver I/R in MAVS knockout mice) and in vitro (MAVS siRNA in RAW 264.7 cells followed by H/R) models to study the role of MAVS activation on downstream events. In vivo, we demonstrated augmented injury and inflammation in MAVS knockout mice compared with wild-type animals; as shown by increased hepatocellular injury, induction of hepatocyte apoptosis augmented plasma TNF-α levels. Further, in vitro silencing of MAVS by specific siRNA in RAW 264.7 and exposure of the cells to H/R caused activation of mitophagy. This may represent a compensatory response to increased liver inflammation. We conclude that activation of MAVS by hypoxia/reoxygenation dampens inflammation, potentially suggesting a novel target for intervention.

Age-Related Lysosomal Dysfunctions.

Organismal aging is normally accompanied by an increase in the number of senescent cells, growth-arrested metabolic active cells that affect normal tissue function. These cells present a series of characteristics that have been studied over the last few decades. The damage in cellular organelles disbalances the cellular homeostatic processes, altering the behavior of these cells. Lysosomal dysfunction is emerging as an important factor that could regulate the production of inflammatory molecules, metabolic cellular state, or mitochondrial function.

Increased Endogenous Production of Pro‐inflammatory Adipokines by 3T3‐L1 Adipocytes Differentiated with Arachidonic Acid

Inflammatory factors derived from adipose tissue (AT) can set the stage for chronic, low‐grade inflammation. This meta‐inflammation can predispose the individual to further inflammatory‐based disorders and diseases. Polyunsaturated fatty acids (PUFAs) are known to have immune modulating effects, with omega‐6 (n‐6) PUFAs typically being associated with increased production of inflammatory molecules, and n‐3 PUFAs having been shown to be anti‐inflammatory, in both in vivo and in vitro studies. The 3T3‐L1 cell line is an embryonic mouse fibroblast line that can be differentiated into an adipocyte phenotype making it a suitable line for studies on the effects of PUFAs on inflammatory molecule production by AT. The aim of this research was to determine the effects of n‐6 and n‐3 PUFAs on the release of inflammatory adipokines in lipopolysaccharide (LPS)‐challenged and LPS‐unchallenged adipocytes. Fibroblasts were differentiated into adipocytes with the addition of 100 μM of linoleic acid (LA; n‐6), arachidonic acid (ARA; n‐6) or eicosapentaenoic acid (EPA; n‐3) throughout the differentiation period, followed by a 6 h, 1 μg/ml LPS challenge. Cell‐conditioned media was collected before and after the LPS challenge for interleukin (IL)‐6 and prostaglandin E2 (PGE2) quantification via enzyme‐linked immunosorbent assays. Differentiation of adipocytes with n‐6 ARA caused a significant increase in PGE2 levels compared to control cells, or cells differentiated with LA or EPA, both after LPS challenge (two‐way ANOVA; p<0.0001) and before LPS challenge (two‐way ANOVA; p<0.0001). We did not observe differences in PGE2 levels between LPS‐challenged and non‐challenged cells differentiated with ARA (matched pairs t‐test; p=0.42) and EPA (p=0.57), while control (p=0.0005) and LA‐treated cells (p=0.0003) produced higher amounts of PGE2 after LPS stimulation. Interestingly, quantified levels of IL‐6 across treatments did not differ before and after LPS stimulation (matched pairs t‐test; p=0.75), although, as observed with PGE2, there was a significant increase in IL‐6 production by ARA‐differentiated cells compared to control, LPS, LA, and EPA‐treated cells (two‐way ANOVA; p=0.004). In conclusion, use of ARA in the differentiation process of 3T3‐L1 fibroblasts into a final adipocyte phenotype increases their endogenous (non‐LPS stimulated) production of IL‐6 and PGE2.

Methyl p‑hydroxycinnamate exerts anti‑inflammatory effects in mouse models of lipopolysaccharide‑induced ARDS.

Methyl p-hydroxycinnamate (MH), an esterified derivative of p-Coumaric acid exerts anti-inflammatory effects on lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Based on these effects, the present study investigated the protective role of MH in a mouse model of LPS-induced acute respiratory distress syndrome (ARDS). The results demonstrated that administration of LPS (5 mg/kg intranasally) markedly increased the neutrophil/macrophage numbers and levels of inflammatory molecules (TNF-α, IL-6, IL-1β and reactive oxygen species) in the bronchoalveolar lavage fluid (BALF) of mice. On histological examination, the presence of inflammatory cells was observed in the lungs of mice administered LPS. LPS also notably upregulated the secretion of monocyte chemoattractant protein-1 and protein content in BALF as well as expression of inducible nitric oxide synthase in the lungs of mice; it also caused activation of p38 mitogen-activated protein kinase (MAPK) and NF-κB signaling. However, MH treatment significantly suppressed LPS-induced upregulation of inflammatory cell recruitment, inflammatory molecule levels and p38MAPK/NF-κB activation, and also led to upregulation of heme oxygenase-1 (HO-1) expression in the lungs of mice. In addition, the ability of MH to induce HO-1 expression was confirmed in RAW264.7 macrophages. Taken together, the findings of the present study indicated that MH may exert protective effects against airway inflammation in ARDS mice by inhibiting inflammatory cell recruitment and the production of inflammatory molecules.

Immunostimulatory activity and anti-obesity activity of Hibiscus manihot leaves in mouse macrophages, RAW264.7 cells and mouse adipocytes, 3T3-L1 cells

• HML activates the production of immunostimulatory factors and phagocytosis in RAW264.7 cells. • HML induces MAPK/TLR2/4-dependent production of immunostimulatory factors in RAW264.7 cells. • HML inhibits the accumulation of lipid and triglyceride in 3T3-L1 cells. • HML decreases the levels of differentiation and adipogenesis-related protein in 3T3-L1 cells. In this study, we investigated whether Hibiscus manihot leaves (HML) exhibits immune-enhancing activity and anti-obesity in RAW264.7 and 3T3-L1 cells. HML increased the production of inflammatory molecules, cell viability and phagocytosis in RAW264.7 cells. TLR2 and TLR4 blocked HML-mediated production of inflammatory molecules in RAW264.7 cells. In addition, the inhibition of MAPK signaling pathway reduced HML-mediated production of inflammatory molecules and the activation of MAPK signaling pathway by HML suppressed the inhibition of TLR2/4. HML reduced the lipid accumulation and TG contents in 3T3-L1 cells. HML inhibited the protein expressions such as CEBPα, PPARγ, perilipin-1, adiponectin and FABP4 related to the lipid accumulation of the mature adipocytes. In addition, HML reduced CEBPα and PPARγ during the differentiation process from preadipocytes to mature adipocytes.

LncRNA MIR31HG is induced by tocilizumab and ameliorates rheumatoid arthritis fibroblast-like synoviocyte-mediated inflammation via miR-214-PTEN-AKT signaling pathway.

Fibroblast-like synoviocytes (FLS) obtained from the joint synovium of rheumatoid arthritis (RA) patients exhibit hyperplasia and aggressive inflammatory phenotypes. This study was designed to explore the anti-inflammatory mechanism of IL-6R inhibitor, tocilizumab, in FLS-mediated inflammation in RA from the perspective of non-coding RNAs (ncRNAs). To this end, we sorted primary FLS obtained from the synovium of patients with RA and cultured them in vitro. The cells were then treated with tocilizumab and subjected to lncRNA- and miRNA-seq to identify the ncRNAs regulated by tocilizumab treatment using bioinformatic analysis and experimental verification. Tocilizumab treatment enhanced the expression of lncRNA MIR31HG and reduced that of micoRNA-214 (miR-214). In addition, miR-214 activated the AKT signaling pathway by directly targeting MIR31HG and PTEN. In addition, the tocilizumab-MIR31HG-miR-214-PTEN-AKT axis regulated the proliferation, migration, and production of inflammatory molecules and matrix metalloproteinases (MMPs) in RA-FLS. Furthermore, co-culture experiments showed that this axis could inhibit the inflammatory phenotype of macrophages and protect chondrocytes. In summary, our study shows that tocilizumab suppresses RA-FLS inflammation by regulating the MIR31HG-miR-214-PTEN-AKT pathway, and presents new insights on RA pathogenesis and potential targets for RA therapy.

Neutralization of Inflammasome-Processed Cytokines Reduces Inflammatory Mechanisms and Leukocyte Recruitment in the Vasculature of TNF-α-Stimulated Sickle Cell Disease Mice

The chronic inflammatory state associated with sickle cell disease (SCD) incurs pan-cellular activation and the recruitment of leukocytes to the activated endothelium of blood vessels. The resultant rheological alterations and red cell sickling culminate in acute vaso-occlusive processes. Cytokines IL-1β and IL-18, the bio-active products of the activated inflammasome, are elevated in the plasma of SCD patients (ASH Abstract (2016) 128 (22): 854), and a previous study reported that anti-IL1β therapy alleviated reperfusion injury and flow stasis in NY1DD transgenic sickle mice exposed to hypoxia/reoxygenation (ASH Abstract (2011) 118(21): 848). The aim of this study was to determine whether antibodies that neutralize IL-1β and IL-18 could individually, or synergistically, diminish inflammatory processes and leukocyte recruitment in mice with SCD. Townes mice (5-months old; N=4-7 per group) received an i.p. administration of either saline, 200 µg/mouse anti-murine IL-1β (01BSUR), and/or 250 or 500 µg/mouse anti-murine IL-18 (SK113AE-4), or an IgG1 control antibody (iProt105125; 200 or 500 µg/mouse). At 21h after treatments, vaso-occlusive-like processes were induced in mice by the injection of tumor necrosis factor-α (TNF; 0.5μg, i.p.). At 3h after TNF, the cremaster muscles of anesthetized mice were surgically exposed, and leukocyte TNF recruitment and extravasation in venules of the microcirculation were observed using intravital microscopy. Another set of Townes mice (N=4-12 per group) was submitted to the same procedures, with blood sampling for ELISA at 3h post TNF. Optimal concentrations of antibodies were determined by observing leukocyte recruitment by intravital microscopy (doses; 100, 200 µg/mouse anti-IL-1β [N=2; 3, respectively] and 250, 500 µg/mouse anti-IL-18, [N=2 each]) in TNF-stimulated C57BL/6J mice (data not shown). Figure 1 (A-C) demonstrates the extensive recruitment and extravasation of leukocytes that occurs in the microvasculature of Townes mice at 3h post-TNF (saline group). Pre-treatment of mice with either anti-IL-1β or anti-IL-18 significantly abrogated (P<0.01) the TNF-induced adhesion (Fig. 1B) and extravasation (Fig. 1C) of leukocytes in venules, while only anti-IL-18 significantly reduced leukocyte rolling along the venule endothelium (Fig. 1A; P<0.05). In contrast, the administration of 500 µg/mouse (Fig. 1) or 200 µg/mouse (data not shown) of a non-specific IgG1 did not significantly affect TNF-induced leukocyte recruitment/extravasation (P>0.05). The combined use of the anti-IL-1β (200 µg/mouse) together with an intermediate dose of anti-IL-18 (250 µg/mouse) did not further reduce leukocyte recruitment and extravasation in this model, when compared with the effects of anti-IL-1β alone (Fig. 1A-C; P>0.05). Investigating the effects of these biological agents on inflammatory molecules production in TNF-stimulated Townes mice, we found that the administration of anti-IL-1β (200 µg) reduced IL-6 production, a pleiotropic inflammatory molecule that is upregulated by IL-1β (Fig. 1D), as did the combination of anti-IL-1β plus anti-IL-18 (200 µg and 250 µg/mouse, respectively). Pre-treatment of TNF-stimulated SCD mice with anti-IL-1β plus anti-IL-18 decreased Interferon (IFN)-γ production, a molecule that is upregulated synergistically by IL-18 and IL-12 and that mediates early host immune defenses (Fig. 1E). In contrast, anti-inflammatory IL-10 production was not significantly modulated by the pre-treatment of TNF-stimulated mice with these biological agents (Fig. 1F). As such, IL-1β and IL-18 neutralization significantly reduced inflammatory processes and leukocyte recruitment in the microvasculature of mice with SCD, indicating that biological agents that inhibit the effects of inflammasome-processed cytokines may hold potential for reducing vaso-occlusive processes in patients with this disease. [Display omitted] DisclosuresKovarik: Novartis Institutes for Biomedical Research: Current Employment. Costa: Novartis: Consultancy. Conran: Novartis Pharma AG: Research Funding.

The Role of Polyphenols in Regulation of Heat Shock Proteins and Gut Microbiota in Weaning Stress.

Gut microbiota is the natural residents of the intestinal ecosystem which display multiple functions that provide beneficial effects on host physiology. Disturbances in gut microbiota in weaning stress are regulated by the immune system and oxidative stress-related protein pathways. Weaning stress also alters gut microbiota response, limits digestibility, and influences animal productive performance through the production of inflammatory molecules. Heat shock proteins are the molecular chaperones that perform array functions from physiological to pathological point of view and remodeling cellular stress response. As it is involved in the defense mechanism, polyphenols ensure cellular tolerance against enormous stimuli. Polyphenols are nature-blessed compounds that show their existence in plenty of amounts. Due to their wider availability and popularity, they can exert strong immunomodulatory, antioxidative, and anti-inflammatory activities. Their promising health-promoting effects have been demonstrated in different cellular and animal studies. Dietary interventions with polyphenols may alter the gut microbiome response and attenuate the weaning stress related to inflammation. Further, polyphenols elicit health-favored effects through ameliorating inflammatory processes to improve digestibility and thereby exert a protective effect on animal production. Here, in this article, we will expand the role of dietary polyphenol intervention strategies in weaning stress which perturbs gut microbiota function and also paid emphasis to heat shock proteins in gut health. This review article gives new direction to the feed industry to formulate diet containing polyphenols which would have a significant impact on animal health.

Anti-Inflammatory Effects of the Fraction from the Leaves of Pyrus pyrifolia on LPS-Stimulated THP-1 Cells.

Pyrus pyrifolia Nakai (P. pyrifolia) has been traditionally used in East Asia to treat diseases such as phlegm, cough, hangover, and fever. However, there is no investigation that evaluates the biological activities of the leaves of P. pyrifolia. This study aims at describing the anti-inflammatory effects of PP, a bioactive fraction from the leaves of P. pyrifolia, in lipopolysaccharide (LPS)-stimulated THP-1 cells. Initially, PP decreased the protein and RNA expression of TNF-α, MCP-1, IL-8, and IL-6 induced by LPS. Moreover, PP attenuated the phosphorylation of p38, JNK, and ERK. In addition, after stimulation with LPS, the degradation of IκB-α was suppressed by PP, and the phosphorylation of IκB-α and p65 was suppressed by PP. Additionally, PP increased HO-1, which controls the production of inflammatory molecules, by activating Nrf2. These results indicated that PP could be used as an anti-inflammatory drug to promote wellness.

Non-acidic bifunctional benzothiazole-based thiazolidinones with antimicrobial and aldose reductase inhibitory activity as a promising therapeutic strategy for sepsis.

Sepsis is a life-threatening disease that affects millions of people worldwide. Microbial infections that lead to sepsis syndrome are associated with an increased production of inflammatory molecules. Aldose reductase has recently emerged as a molecular target that is involved in various inflammatory diseases, including sepsis. Herein, a series of previously synthesized benzothiazole-based thiazolidinones that exhibited strong antibacterial and antifungal activities has been evaluated for inhibition efficacy against aldose reductase and selectivity toward aldehyde reductase under in vitro conditions. The most promising inhibitor 5 was characterized with IC50 value of 3.99 μM and a moderate selectivity. Molecular docking simulations revealed the binding mode of compounds at the active site of human aldose reductase. Moreover, owning to the absence of an acidic pharmacophore, good membrane permeation of the novel aldose reductase inhibitors was predicted. Excellent “drug-likeness” was assessed for most of the compounds by applying the criteria of Lipinski’s “rule of five”.

4-Ethylguaiacol modulates neuroinflammation and Th1/Th17 differentiation to ameliorate disease severity in experimental autoimmune encephalomyelitis

Abstract Multiple sclerosis (MS) is a progressive autoimmune disease characterized by the accumulation of pathogenic inflammatory immune cells in the central nervous system (CNS) that subsequently causes focal inflammation, demyelination, and neuronal damage. Experimental Autoimmune Encephalomyelitis (EAE) is a well-established murine model of MS. Presently, growing evidences show that phenolic compounds exert anti-inflammatory effects by inhibiting the production of inflammatory molecules. 4-ethylguaiacol (4-EG), a phenolic compound, which was detected in foods, such as green bell peppers, corns, sesames, and coffee has been shown to possess anti-inflammatory effects through attenuating peripheral immune responses. However, whether 4-EG exerts anti-inflammatory effects on modulating the CNS inflammatory immune responses remains unexplored. In this study we assessed the therapeutic effect of 4-EG in EAE using both chronical and relapsing-remitting animal models. Our results showed that 4-EG not only ameliorated disease severity in chronic EAE but also mitigated disease progression in relapsing-remitting EAE. Further investigations revealed that 4-EG suppressed MG activation, inhibited Th1 and Th17 infiltration, and mitigated BBB disruption in the CNS of EAE. Furthermore, 4-EG suppressed Th1 and Th17 differentiation in the periphery of EAE. Finally, 4-EG induced HO-1 expression in the CNS of EAE as well as in MG and macrophages. In summary, our work demonstrates for the first time that 4-EG confers a protection against autoimmune disease EAE through modulating neuroinflammation and inhibiting Th1/Th17 differentiation, suggesting that 4-EG could be developed as a therapeutic agent for the treatment of MS/EAE.

Fucoidan isolated from the popular edible brown seaweed Sargassum fusiforme suppresses lipopolysaccharide-induced inflammation by blocking NF-κB signal pathway

The anti-inflammatory effect of a fucoidan with a molecular weight of 102.67 kDa isolated from an enzymatic digest of Sargassum fusiforme was investigated in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages and zebrafish. The results indicated that the fucoidan significantly and dose-dependently inhibited the production of inflammatory molecules, including tumor necrosis factor-alpha (TNF-α), nitric oxide (NO), prostaglandin E2 (PGE2), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6), as well as improved the viability of LPS-stimulated RAW 264.7 cells. Moreover, the fucoidan suppressed the expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) by regulating the nuclear factor kappa B (NF-κB) pathway in LPS-stimulated RAW 264.7 cells. Furthermore, in vivo test results suggested that the fucoidan remarkably reduced reactive oxygen species (ROS), cell death, and NO levels in LPS-stimulated zebrafish in a dose-dependent manner. Taken together, these results demonstrated that the fucoidan isolated from S. fusiforme possesses strong anti-inflammatory activities in vitro and in vivo, and could prove as an important candidate to be used to develop anti-inflammatory agents in pharmaceutical and cosmeceutical industries.