Death due to sepsis by S. aureus is rapidly increasing because of their potent weaponries against macrophage mediated killing. Macrophages serve as intracellular reservoirs of S. aureus. Although significant resources have been invested during the last decade in new treatments for sepsis, only antibiotic therapy has failed to improve outcomes. Moreover the host pathogen interaction resulted in host cell death triggering inflammation. So, successful therapy requires amalgamation of therapies to delineate pathogen along with providing protection to host cell. With this idea, LNMMA, the iNOS inhibitor is used along with antibiotics Ofloxacin or Chloramphenicol on S. aureus infected mouse peritoneal macrophage. ROS like H2O2, O2- production has been measured. NO inhibition by iNOS inhibitor and antioxidant levels has been analysed. COX2, TLR2 and iNOS expression along with proinflammatory cytokine level was studied. It was found that the use of iNOS inhibitor LNMMA along with antibiotics not only enhances bacterial clearance but also decreases proinflammatory responses in Staphylococcus aureus infected macrophages. Inhibition of TLR2 as well as COX2 has also been found in combined treatment groups. The use of iNOS inhibitor LNMMA plus Ofloxacin or Chloramphenicol pretreatment enhanced bacterial clearance by increasing ROS. Decreases in NO protect the cell from harmful peroxynitril as well as inflammatory damage by changes in iNOS, COX2 activity along with reduced proinflammatory cytokines like TNFα, IFNγ, IL1-β etc. Changes in antioxidant level has been found. This in-vitro realm of augmented bacterial clearance and regulated inflammation may be considered as a novel and important therapeutic intervention.

The goal of this study was to assess the diagnostic accuracy of acute phase proteins and proinflammatory cytokines in sheep with pneumonic pasteurellosis. Blood samples were collected from 56 sheep (36 naturally infected with Pasteurella multocida and 20 healthy controls) belonging to one farm in Eastern region, Saudi Arabia. Serum samples were evaluated for acute phase proteins (Haptoglobin (Hp), serum amyloid A (SAA) and fibrinogen (Fb)), and the proinflammatory cytokines (interleukins (IL-1α, IL-1β, and IL-6), tumor necrosis factor-alpha (TNF-α), and interferon-gamma (IFN-ϒ)). Additionally, nasopharyngeal swabs and bronchoalveolar lavages were collected from all animals for bacteriological examinations. Receiver operating characteristic curve was used to assess the diagnostic performance of each parameter. All parameters showed moderate to high degree of positive correlation with case-control status. There was no significant difference in the area under the curve (AUC) among acute phase proteins; however, both Hp and SAA showed better sensitivity and specificity than Fb. The proinflammatory cytokines (IL1-α, IL1-β, and IL6) showed similar and highly accurate diagnostic performance (AUC>> 0.9), whereas IFN-ϒ was moderately accurate (AUC = 0.79). In conclusion, this study confirms the value of acute phase proteins and cytokines as diagnostic biomarkers of naturally occuring pneumonic pasteurellosis in sheep.

Periodontitis is an immuno-inflammatory disease, which can lead to tooth loss. This study aimed to investigate the efficacy of Platymiscium floribundum Vog., a Brazilian tree which has been used in folk medicine as an anti-inflammatory agent, in a pre-clinical trial of periodontitis in rats. Periodontitis was induced by placing a sterilized nylon (3.0) thread ligature around the cervix of the second left upper molar of the rats, which received (per os) P. floribundum extract (0.1, 1 or 10 mg/kg) or vehicle 1h before periodontitis-challenge and once daily during 11 days. Treatment with P. floribundum (10mg/kg) decreased alveolar bone loss, MPO activity nitrite/nitrate levels, oxidative stress, TNF-α, IL1-β, IL-8/CINC-1, and PGE2 gingival levels, and transcription of TNF-α, IL1-β, COX-2, iNOS, RANK, and RANKL genes, while elevated both BALP serum levels and IL-10 gingival levels. The animals did not show signs of toxicity throughout the experimental course. These findings show that P. floribundum has anti-inflammatory and anti-resorptive properties in a pre-clinical trial of periodontitis, representing an interesting biotechnological tool.

<A<em>b</em>stractText>It has <em>b</em>een well known that the degeneration of hip articular cartilage with osteonecrosis of the femoral head (ONFH) increases the insta<em>b</em>ility of hip and accelerates the development process of ONFH. A <em>b</em>etter understanding of the expression of chondrogenesis-related and arthritis-related genes of cartilage along with the progression of ONFH seems to <em>b</em>e essential for further insight into the molecular mechanisms of ONFH pathogenesis.</A<em>b</em>stractText><A<em>b</em>stractText>We analyzed the differentially expressed gene profile (GSE74089) of human hip articular cartilage with ONFH. The functions and pathway enrichments of differentially expressed genes (DEGs) were analyzed via GO and KEGG analysis. The expression of six selected critical chondrogenesis-related and four arthritis-related genes in eight human hip articular cartilage with femoral neck fracture (FNF) and 26 human hip articular cartilage with different stages ONFH (6 cases of Ficat stage II, 10 cases of Ficat stage III and 10 cases of Ficat stage IV) were detected.</A<em>b</em>stractText><p><div>(<em>b</em>)Results</<em>b</em>)</div>A total of 2,174 DEGs, including 1,482 up-regulated and 692 down-regulated ones, were o<em>b</em>tained in the ONFH cartilage specimens compared to the control group. The GO and KEGG enrichment analysis indicated that the function of these DEGs mainly enriched in extracellular matrix, angiogenesis, antigen processing and presentation. The results showed a significant stepwise up-expression of chondrogenesis-related genes, including MMP13, ASPN, COL1A1, OGN, COL2A1 and BMP2, along with the progression of ONFH. The arthritis-related genes <em>IL1</em><i><em>β</em></i>, IL6 and TNF<i>α</i> were only found up-expressed in Ficat IV stage which indicated that the arthritis-related molecular changes were not significant in the progression of ONFH <em>b</em>efore Ficat III stage. However, the arthritis-related gene PTGS2 was significant stepwise up-expression along with the progression of ONFH which makes it to <em>b</em>e a sensitive arthritis-related <em>b</em>iomarker of ONFH.</p><A<em>b</em>stractText>Expression changes of six chondrogenesis-related and four arthritis-related genes were found in hip articular cartilage specimens with different ONFH Ficat stages. These findings are expected to a get a further insight into the molecular mechanisms of ONFH progression.</A<em>b</em>stractText>

Objective: Air pollution has been recently identified as a risk factor for multiple sclerosis. Aim of this study was to investigate the immunological mechanism underlying the clinical association between air pollution, namely exposure to particulate matter 10 (PM10), and inflammatory activity of multiple sclerosis (MS) METHODS: Daily recording of PM10 was obtained by monitors depending on the residence of subjects. Expression of molecules involved in activation, adhesion, and migration of T lymphocytes were tested by flow cytometry in 57 MS patients and 19 healthy controls. We next assessed in vitro the effect of PM10 on expression of C-C chemokine receptors 6 (CCR6) by peripheral blood mononuclear cells (PBMCs), on cytokine production by monocyte-derived dendritic cells (mdDC), and on T cell polarization in PBMC/mdDC mixed cultures.

<strong class="sub-title"> Results: </strong> We identified a significant correlation between mean PM10 levels and expression of CCR6 CD4+ T circulating cells in MS patients. This was paralleled by the observation in vitro of a higher level of CCR6 expression on PBMC following treatment with increased doses of particulate matter. Moreover, in mdDC cultures, particulate matter induced the secretion by mdDC of Th17 polarizing <em>IL1</em> <em>beta</em>, IL6, and IL23 and, in mdDC/PBMC mixed cultures, enhanced generation of <em>IL1</em>7-producing T cells.

Conclusions: Ex vivo and in vitro studies support the pro-inflammatory role of PM in MS, by upregulating expression of CCR6 on circulating CD4+ T cells and inducing in innate immune cells the production of Th17 polarizing cytokines. Therefore, we speculate that in MS respiratory exposure to PM10 may induce the production in the lung of autoreactive Th17 lymphocytes and boost their migratory properties through the blood-brain barrier.

Keywords: Adhesion molecules; Air pollution; Multiple sclerosis; Particulate matter; Th 17 lymphocytes.

(<em>b</em>)Background:</<em>b</em>) Interleukin 37 (IL-37), a mem<em>b</em>er of IL-1 family, <em>b</em>roadly suppresses inflammation in many pathological conditions <em>b</em>y acting as a dual-function cytokine in that IL-37 signals via the extracellular receptor complex <em>IL1</em>-R5/IL-1R8, <em>b</em>ut it can also translocate to the nucleus. However, whether IL-37 exerts <em>b</em>eneficial actions in neuroinflammatory diseases, such as multiple sclerosis, remains to <em>b</em>e elucidated. Thus, the goals of the present study were to evaluate the therapeutic effects of IL-37 in a mouse model of multiple sclerosis, and if so, whether this is mediated via the extracellular receptor complex IL-1R5/IL-1R8. (<em>b</em>)Methods:</<em>b</em>) We used a murine model of MS, the experimental autoimmune encephalomyelitis (EAE). We induced EAE in three different single and dou<em>b</em>le transgenic mice (hIL-37tg, IL-1R8 KO, hIL-37tg-IL-1R8 KO) and wild type littermates. We also induced EAE in C57Bl/6 mice and treated them with various forms of recom<em>b</em>inant human IL-37 protein. Functional and histological techniques were used to assess locomotor deficits and demyelination. Luminex and flow cytometry analysis were done to assess the protein levels of pro-inflammatory cytokines and different immune cell populations, respectively. qPCRs were done to assess the expression of IL-37, IL-1R5 and IL-1R8 in the spinal cord of EAE, and in <em>b</em>lood peripheral mononuclear cells and <em>b</em>rain tissue samples of MS patients. (<em>b</em>)Results:</<em>b</em>) We demonstrate that IL-37 reduces inflammation and protects against neurological deficits and myelin loss in EAE mice <em>b</em>y acting via <em>IL1</em>-R5/<em>IL1</em>-R8. We also reveal that administration of recom<em>b</em>inant human IL-37 exerts therapeutic actions in EAE mice. We finally show that IL-37 transcripts are not up-regulated in peripheral <em>b</em>lood mononuclear cells and in <em>b</em>rain lesions of MS patients, despite the IL-1R5/IL-1R8 receptor complex is expressed. (<em>b</em>)Conclusions:</<em>b</em>) This study presents novel data indicating that IL-37 exerts therapeutic effects in EAE <em>b</em>y acting through the extracellular receptor complex IL-1R5/IL-1R8, and that this protective physiological mechanism is defective in MS individuals. IL-37 may therefore represent a novel therapeutic avenue for the treatment of MS with great promising potential.

Keywords: IL-1R8; IL-37; cytokines; experimental autoimmune encephalomyelitis; multiple sclerosis.

The interleukin-1 (IL1) system likely mediates mammalian embryo-maternal communication. In cattle, we have reported that the uterine fluid of heifers carrying early embryos shows downregulated IL1 beta (IL1B), which could lead to reduced NFkB expression and dampening of maternal innate immune responses. In this work, we assessed the expression of IL 1 beta (IL1B) and its receptor, interleukin 1 receptor type I (IL1R1) in the bovine endometrium and embryos by RT-PCR, immunohistochemistry and Western blot at the time of blastocyst development. Day 8 endometrium, both collected from animals after transfer of day 5 embryos (ET) and sham transferred (ST), showed IL1B and IL1R1 mRNA transcription and protein co-localization. Similarly, day 8 blastocyst, from ET animals and entirely produced in vitro, showed IL1R1 mRNA transcription and IL1B and IL1R1 protein co-localization. IL1B mRNA was detected in the analyzed blastocysts, but at very low levels that precluded its quantification. IL1B and IL1R1 immunostaining was observed in luminal epithelial cells, glandular epithelium and stromal cells. The presence of embryos increased endometrial IL1B protein locally, while no differences regarding IL1R1 protein and IL1B and IL1R1 mRNA were detected. These results suggest that the early preimplantation bovine embryo in the maternal tract might interact with the maternal immune system through the IL1 system. Such a mechanism may allow the embryo to elicit local endometrial responses at early stages, which are required for the development of a receptive endometrium.

Sepsis is associated with a strong inflammatory reaction triggering a complex and prolonged immune response. Septic patients have been shown to develop sustained immunosuppression due to a reduced responsiveness of leukocytes to pathogens. Changes in cellular metabolism of leukocytes have been linked to this phenomenon and contribute to the ongoing immunological derangement. However, the underlying mechanisms of these phenomena are incompletely understood. In cell culture models, we mimicked LPS tolerance conditions to provide evidence that epigenetic modifications account for monocyte metabolic changes which cause immune paralysis in restimulated septic monocytes. In detail, we observed differential methylation of CpG sites related to metabolic activity in human PBMCs 18 h after septic challenge. The examination of changes in immune function and metabolic pathways was performed in LPS-tolerized monocytic THP-1 cells. Passaged THP-1 cells, inheriting initial LPS challenge, presented with dysregulation of cytokine expression and oxygen consumption for up to 7 days after the initial LPS treatment. Proinflammatory cytokine concentrations of TNFα and IL1β were significantly suppressed following a second LPS challenge (p < 0.001) on day 7 after first LPS stimulation. However, the analysis of cellular metabolism did not reveal any noteworthy alterations between tolerant and nontolerant THP-1 monocytes. No quantitative differences in ATP and NADH synthesis or participating enzymes of energy metabolism occurred. Our data demonstrate that the function and epigenetic modifications of septic and tolerized monocytes can be examined in vitro with the help of our LPS model. Changes in CpG site methylation and monocyte function point to a correlation between epigenetic modification in metabolic pathways and reduced monocyte function under postseptic conditions.

The antisynthetase syndrome (ASSD) is an autoimmune disorder characterized by myositis, arthritis, mechanic's hands, fever, Raynaud phenomenon, and interstitial lung disease (ILD). We aimed to evaluate single-nucleotide polymorphisms in the interleukin 1B (IL1B) gene and their association between ILD with antisynthetase autoantibodies, as well as IL-1β serum levels. The most frequent antisynthetase autoantibody was anti-Jo1. The most frequent tomographic pattern was non-specific interstitial pneumonia, whereas in the anti-Jo1 subjects, it was organized pneumonia. Anti-Jo1 patients tend to have more significant arthritis, and Raynaud phenomenon have higher levels of creatinine phosphokinase. In the IL1B gene, the GG genotype and G allele of rs1143634 [odds ratio (OR) = 2.21 and OR = 2.60, respectively, p < 0.05] are associated with an increased risk, as well as with the dominant and recessive models (p < 0.05). This finding is maintained after logistic regression analysis adjusting for potential confounding variables (p < 0.05). Subjects with the rs16944/AG heterozygous genotype had higher serum levels of IL-1β compared to homozygous (p < 0.05). In conclusion, rs1143634 is associated with a higher risk of ASSD. Also, the GA genotype is associated with higher levels of IL-1β in ASSD patients.

Keywords: IL1-beta; IL1B gene; SNP; anti-Jo1; antisynthetase syndrome; genetic association.

During surgery or infection, peripheral inflammation can lead to neuroinflammation, which is associated with cognitive impairment, neurodegeneration, and several neurodegenerative diseases. Dexmedetomidine, an α-2-adrenoceptor agonist, is known to exert anti-inflammatory and neuroprotective properties and reduces the incidence of postoperative cognitive impairments. However, on the whole the molecular mechanisms are poorly understood. This study aims to explore whether dexmedetomidine influences microRNAs (miRNAs) in a rat model of lipopolysaccharide (LPS)-induced neuroinflammation. Adult Wistar rats were injected with 1 mg/kg LPS intraperitoneal (i.p.) in the presence or absence of 5 µg/kg dexmedetomidine. After 6 h, 24 h, and 7 days, gene expressions of interleukin 1-β (IL1-β), tumor necrosis factor-α (TNF-α), and microRNA expressions of miR 124, 132, 134, and 155 were measured in the hippocampus, cortex, and plasma. Dexmedetomidine decreased the LPS-induced neuroinflammation in the hippocampus and cortex via significant reduction of the IL1-β and TNF-α gene expressions after 24 h. Moreover, the LPS-mediated increased expressions of miR 124, 132, 134, and 155 were significantly decreased after dexmedetomidine treatment in both brain regions. In plasma, dexmedetomidine significantly reduced LPS-induced miR 155 after 6 h. Furthermore, there is evidence that miR 132 and 134 may be suitable as potential biomarkers for the detection of neuroinflammation.

Intervertebral disc (IVD) degeneration is a major contributor to chronic low back pain and is characterized by decreases in cellularity and proteoglycan synthesis, upregulation of matrix degradation, and increases in pro-inflammatory factors with neurovascular invasion. Current treatments fail to target the underlying pathology or promote tissue repair and approaches such as viral transfection raise safety concerns due to mutagenesis and unwarranted immune responses. To avoid such concerns, nonviral transfection is a viable method of gene delivery into the host cell while bypassing the caveats of viral delivery. Brachyury is expressed in the developing notochord and is associated with an immature healthy nucleus pulposus (NP). We hypothesize that Brachyury can reprogram degenerate NP cells to a healthy pro-anabolic phenotype with increased proteoglycan content and decreased expression of catabolic, inflammatory, and neurovascular markers. NP cells obtained from human autopsy and surgical tissues were transfected with plasmids encoding for Brachyury or an empty vector control via bulk electroporation. Post transfection, cells were seeded in three-dimensional agarose constructs cultured over 4 weeks and analyzed for viability, gene expression, and proteoglycan. Results demonstrated successful transfection of both autopsy and surgical NP cells. We observed long-term Brachyury expression, significant increased expression of NP phenotypic markers FOXF1, KRT19, and chondrogenic marker SOX9 with decreases in inflammatory cytokines IL1-β/IL6, NGF, and MMPs and significant increases in glycosaminoglycan accumulation. These results highlight nonviral transfection with developmental transcription factors, such as Brachyury, as a promising method to reprogram degenerate human disc cells toward a healthy NP phenotype. Clinical significance: This project proposes a novel translational approach for the treatment of intervertebral disc degeneration via direct reprogramming of diseased human patient-derived IVD cells to a healthy phenotype.

Recently, diabetes has been linked to rotator cuff disease and adhesive capsulitis, conditions with increased stiffness and inflammation. Unfortunately, limited research exists examining how hyperglycemia affects the native shoulder (tendon and capsule) properties. Therefore, the objectives of this study were to compare shoulder joint mechanics, tendon properties (mechanics and immunohistochemistry), and capsule of healthy control and hyperglycemic rats 8 weeks following induction of hyperglycemia with a submaximal dose of streptozotocin (STZ). Eighteen rats were injected with STZ to induce hyperglycemia or citrate buffer (control) and underwent normal cage activity for 8 weeks. Passive joint mechanics demonstrated significantly less external rotation in the hyperglycemic group compared to controls, with no other group differences. Tendon mechanical properties (stiffness and modulus) were not significantly different between groups at both the insertion site and mid-substance. Immunohistochemistry staining of the tendon and capsule demonstrated significantly increased interleukin 1-beta (IL1-β) and advanced glycated end-products (AGE) staining localized to the insertion and mid-substance of the tendon but not the capsule. In addition, tumor necrosis factor alpha (TNF-α) staining was significantly increased in the superior capsule but not the supraspinatus tendon. This study demonstrates that isolated hypergylcemia does not diminish shoulder mechanical properties but does induce a chronic inflammatory response.

Background: Cigarette smoke exposure (SE) during pregnancy is the largest modifiable risk factor for the development of lung disorders in offspring. We have previously shown that maternal L-Carnitine treatment can reduce the adverse impacts of maternal SE on renal and brain disorders in offspring. Here, we investigated the effect of maternal L-Carnitine supplementation on lung inflammatory pathways, autophagy, and mitophagy markers in the offspring in response to maternal SE.

Methods: Female BALB/c mice (8 weeks) were exposed to cigarette smoke for 6 weeks prior to mating, during gestation and lactation. Some of the SE dams were given L-Carnitine supplementation (1.5 mM in drinking water, SE + LC) during gestation and lactation. Lungs from the offspring were studied at birth and adulthood (13 weeks).

Results: At birth, in male offspring, there were increased levels of inflammatory markers (phosphorylated(p)-ERK1,2, p-P38 MAPK, p- NF-κB), and inflammasome marker (NLRP3), as well as mitophagy fission marker Drp-1 and autophagosome marker (LC3A/B-II) in the lung. Maternal L-Carnitine supplementation significantly reduced NLRP3 level. In contrast, maternal SE only increased IL1-β in female offspring, which was reversed by maternal L-Carnitine supplementation. At 13 weeks, there was an increase in LC3A/B-II and p- NF-κB in the male SE offspring with reduced p-JNK1,2, which were partially normalised by maternal L-Carnitine treatment. Female offspring were not affected by maternal SE at this age.

Conclusion: Maternal SE had adverse impacts on the male offspring's lung, which were partially alleviated by maternal L-Carnitine supplementation. Females seem to be less affected by the adverse effects of maternal SE.

Keywords: Antioxidant; Inflammasome; Mitophagy; Sex differences.

Depression is highly prevalent in patients suffering from chronic inflammatory diseases. Dysregulated neuroinflammation and concomitant activated microglia play a pivotal role in the pathogenesis of depression. Paricalcitol (Pari), a vitamin D2 analogue, has been demonstrated to exert anti-inflammative effects on renal and cardiovascular diseases. In this study, mice were pretreated with Pari before being induced to acute depression-like behaviors by systemic lipopolysaccharide (LPS) injection. To determine the therapeutic effects of Pari, alterations in acute body weight, sucrose preference, forced swimming and tail suspension tests were assessed. Then, alterations of pro-inflammation cytokine IL1-β level and microglia activity in the hypothalamus, which are involved in the pathophysiology of depression, were examined. The results showed that Pari significantly alleviated systemic LPS injection induced depressive-like behaviors as shown by increased sucrose preference and decreased TST and FST immobility. Pari could specifically regulate microglia-mediated neuroinflammation process and local activity of renin-angiotensin system to exert its anti-depressant effects. This study demonstrated a potential for paricalcitol in treating depressive symptoms induced by systemic inflammation, particularly in patients with chronic hypertension.

Animal models of maternal immune activation study the effects of infection, an environmental risk factor for schizophrenia, on brain development. Microglia activation and cytokine upregulation may have key roles in schizophrenia neuropathology. We hypothesised that maternal immune activation induces changes in microglia and cytokines in the brains of the adult offspring. Maternal immune activation was induced by injecting polyriboinosinic:polyribocytidylic acid into pregnant rats on gestational day (GD) 10 or GD19, with brain tissue collected from the offspring at adulthood. We observed no change in Iba1, Gfap, IL1-β and TNF-α mRNA levels in the cingulate cortex (CC) in adult offspring exposed to maternal immune activation. Prenatal exposure to immune activation had a significant main effect on microglial IBA1-positive immunoreactive material (IBA1+IRM) in the corpus callosum; post-hoc analyses identified a significant increase in GD19 offspring, but not GD10. No change in was observed in the CC. In contrast, maternal immune activation had a significant main effect on GFAP+IRM in the CC at GD19 (not GD10); post-hoc analyses only identified a strong trend towards increased GFAP+IRM in the GD19 offspring, with no white matter changes. This suggests late gestation maternal immune activation causes subtle alterations to microglia and astrocytes in the adult offspring.

Gold nanoparticles hold a great promise for both clinical and preclinical applications. The major factors impeding such applications are toxicity of new nanomaterials including e.g., pro-apoptotic activities or inflammatory effects, but also their potential to accumulate in the body or inadequate absorption, distribution, metabolism and excretion (ADME) profiles. Since such adverse effects depend on the size, form and coating of nanomaterials, the search for new, less toxic nanomaterials with low tendency to accumulate is highly active domain of research. Here, we describe optical and biological properties of Au18 gold nanoclusters (NCs), small gold nanoparticles composed of 18 atoms of gold and stabilized with glutathione ligands. These nanoclusters may be suitable for in vivo applications owing to their low toxicity and biodistribution profile. Specifically, using lactate dehydrogenase (LDH) test in P19 cell line we found that Au18 NCs display low toxicity in vitro. Importantly, using primary microglial cells we showed that at low concentrations Au18 NCs display anti-inflammatory signaling on evidence of reduced interleukin 1-β (IL1-β) levels and unchanged levels of tumor necrosis factor (TNF-α) or Ym1/2. Such effect was dose dependent as higher concentrations of Au18 NCs induced expression of pro-inflammatory cytokines and suppression of anti-inflammatory cytokine Ym1/2, pointing, thus, to global inflammatory activity. Finally, we also showed that within 3 days Au18 NCs can be completely eliminated from the liver reported as the major target organ for accumulation of gold nanoparticles. These data point to a potential of gold nanoparticles for further biomedical studies.

Keywords: biodistribution; cytotoxicity; immunological response; nanoparticles.

Sepsis caused <em>b</em>y Gram-negative <em>b</em>acteria is the consequence of an unrestrained infection that continuously releases lipopolysaccharide (LPS) into the <em>b</em>loodstream, which triggers an uncontrolled systemic inflammatory response leading to multiorgan failure and death. After scrutinizing the immune modulation exerted <em>b</em>y a recom<em>b</em>inant <i>Fasciola hepatica</i> fatty acid <em>b</em>inding protein termed Fh15, our group demonstrated that addition of Fh15 to murine macrophages 1 h prior to LPS stimulation significantly suppresses the expression of proinflammatory cytokines tumor necrosis factor alpha (TNF-α) and interleukin-1<em>β</em> (<em>IL1</em>-<em>β</em>). The present study aimed to demonstrate that Fh15 could exert a similar anti-inflammatory effect <i>in vivo</i> using a mouse model of septic shock. Among the novel findings reported in this article, (i) Fh15 suppressed numerous serum proinflammatory cytokines/chemokines when injected intraperitoneally 1 h after exposure of animals to lethal doses of LPS, (ii) concurrently, Fh15 increased the population of large peritoneal macrophages (LPMs) in the peritoneal cavity (PerC) of LPS-injected animals, and (iii) Fh15 downregulated the expression on spleen macrophages of CD38, a cell surface ectoenzyme with a critical role during inflammation. These findings present the first evidence that the recom<em>b</em>inant parasitic antigen Fh15 is an excellent modulator of the PerC cell content and <i>in vivo</i> macrophage activation, endorsing Fh15's potential as a drug candidate against sepsis-related inflammatory response.(<em>b</em>)IMPORTANCE</<em>b</em>) Sepsis is a potentially life-threatening complication of an infection. Sepsis is mostly the consequence of systemic <em>b</em>acterial infections leading to exacer<em>b</em>ated activation of immune cells <em>b</em>y <em>b</em>acterial products, resulting in enhanced release of inflammatory mediators. Lipopolysaccharide (LPS), the major component of the outer mem<em>b</em>rane of Gram-negative <em>b</em>acteria, is a critical factor in the pathogenesis of sepsis, which is sensed <em>b</em>y Toll-like receptor 4 (TLR4). The scientific community highly pursues the development of antagonists capa<em>b</em>le of <em>b</em>locking the cytokine storm <em>b</em>y <em>b</em>locking TLR4. We report here that a recom<em>b</em>inant molecule of 14.5 kDa <em>b</em>elonging to the <i>Fasciola hepatica</i> fatty acid <em>b</em>inding protein (Fh15) is capa<em>b</em>le of significantly suppressing the LPS-induced cytokine storm in a mouse model of septic shock when administered <em>b</em>y the intraperitoneal route 1 h after a lethal LPS injection. These results suggest that Fh15 is an excellent candidate for drug development against endotoxemia.

Sleep deprivation (SD) induces learning and memory deficits via inflammatory responses and oxidative stress. On the other hand, sericin (Ser) possesses potent antioxidant and neuroprotective effects. We investigated the effect of different doses of Ser on the SD-induced cognitive impairment. Ser (100, 200, and 300 mg/kg) was administered to animals via oral gavage for 8 days, 5 days before to SD, and during SD. SD was induced in mice using a modified multiple platform model, starting on the 6^th day for 72 h. Spatial learning and memory were assessed using the Lashley III maze. Serum corticosterone level, and hippocampal malondialdehyde (MDA), total antioxidant capacity (TAC), and the activity of superoxide dismutase (SOD) and glutathione peroxidase (GPx) enzymes were evaluated. The expression of growth-associated protein 43 (GAP-43), post-synaptic density-95 (PSD-95), synapsin 1 (SYN-1), and synaptophysin (SYP), and inflammation markers were detected by western blotting. SD caused cognitive impairment, while Ser pretreatment prevented such an effect. Serum corticosterone also increased with SD, but its levels were suppressed in SD mice receiving Ser. Furthermore, Ser normalized SD-induced reduction in the hippocampus activity of SOD and GPx, increased TAC, and decreased MDA levels. Besides, Ser pretreatment increased GAP-34, SYP, SYN-I, and PSD-95 and reduced IL1-β and TNF-α in the hippocampus. SD induced memory impairment and pretreatment with Ser improved memory via its antioxidant, anti-inflammation, and up-regulation of synaptic proteins in the hippocampus.

Keywords: Memory impairment; Neuroinflammation; Oxidative stress; Sericin; Sleep deprivation; Synaptic dysfunction.

Fetal growth restriction (FGR) and stillbirth are associated with placental dysfunction and inflammation and hypoxia, oxidative and nitrative stress are implicated in placental damage. Damage-associated molecular patterns (DAMPs) are elevated in pregnancies at increased risk of FGR and stillbirth and are associated with increase in pro-inflammatory placental cytokines. We hypothesised that placental insults lead to release of DAMPs, promoting placental inflammation. Placental tissue from uncomplicated pregnancies was exposed in vitro to hypoxia, oxidative or nitrative stress. Tissue production and release of DAMPs and cytokines was determined. Oxidative stress and hypoxia caused differential release of DAMPs including uric acid, HMGB1, S100A8, cell-free fetal DNA, S100A12 and HSP70. After oxidative stress pro-inflammatory cytokines (IL-1α, IL-1β, IL-6, IL-8, TNFα, CCL2) were increased both within explants and in conditioned culture medium. Hypoxia increased tissue IL-1α/β, IL-6, IL-8 and TNFα levels, and release of IL-1α, IL-6 and IL-8, whereas CCL2 and IL-10 were reduced. IL1 receptor antagonist (IL1Ra) treatment prevented hypoxia- and oxidative stress-induced IL-6 and IL-8 release. These findings provide evidence that relevant stressors induce a sterile inflammatory profile in placental tissue which can be partially blocked by IL1Ra suggesting this agent has translational potential to prevent placental inflammation evident in FGR and stillbirth.

<A<em>b</em>stractText>As we all know, curative resection remains the only effective treatment for hepatocellular cancer (HCC). However, systemic inflammatory response syndrome always correlates with surgery, which may impose an impact on the clinical outcome of HCC patients who had undergone curative treatment. The present study is aimed at exploring the correlation <em>b</em>etween perioperative inflammatory mediators and recurrence risk of HCC.</A<em>b</em>stractText><A<em>b</em>stractText>This study retrospectively included 157 histologically confirmed single HCC patients (88 patients developed HCC again) who had received radical hepatectomy <em>b</em>etween January 2016 and May 2018 at the Department of Hepato<em>b</em>iliary Surgery, the People's Li<em>b</em>eration Army General Hospital (PLAGH), China. The cut-off values for predicting recurrence were determined <em>b</em>y receiver operating characteristic (ROC) curve analysis with estimation of the Youden index. Recurrence-free survival (RFS) was assessed using the Kaplan-Meier method, and the difference was compared <em>b</em>etween groups <em>b</em>y the log-rank test. Univariate/multivariate analysis was performed to identify independent risk factors of postoperative tumor recurrence.</A<em>b</em>stractText><p><div>(<em>b</em>)Results</<em>b</em>)</div>The perioperative serum <em>IL1</em>, IL2, and <em>IL1</em>0 levels showed no difference <em>b</em>etween groups, whereas the serum IL6, IL8, and TNF-<i>α</i> levels showed significant differences <em>b</em>etween groups. High preoperative serum IL6, IL8, and TNF-<i>α</i> levels were significantly associated with shorter RFS. Multivariate analysis revealed that preoperative serum IL6 > 8.45 pg/ml, preoperative serum IL8 > 68 pg/ml, preoperative serum TNF - <i>α</i> > 14.9 pg/ml, microvascular invasion (MVI), and maximum tumor size > 6 cm were independent predictors of RFS.</p><p><div>(<em>b</em>)Conclusions</<em>b</em>)</div>The present study confirmed that high preoperative serum IL6, IL8, and TNF-<i>α</i> levels were distinctly correlated with the postoperative tumor recurrence risk of HCC patients.</p>

A localized acute phase response occurs in the brain in Alzheimer's disease. Acute phase proteins have previously been measured in brain homogenates to quantify this response. The extent to which measurements of these proteins reflect brain parenchymal contents, as opposed to vascular contents, is unknown. In this study, the acute phase proteins ceruloplasmin (CP), complement factor 3 (C3), haptoglobin (HP), and albumin were measured in regional brain homogenates from phosphate buffered saline-perfused and sham-perfused rats (n = 7-9/group). Interleukin 1-beta (IL1-beta) and copper were also measured. Mean CP, C3, HP, and albumin concentrations in perfused specimens decreased by 94%, 88%, 90%, and 81% vs. sham-perfused specimens (all p < 0.001), while IL1-beta and copper were unchanged. These results suggest that acute phase protein measurements in brain homogenates reflect primarily vascular contents. However, IL1-beta and copper concentrations in brain homogenates are minimally influenced by vascular contents.

Frailty syndrome is a functional state that includes a loss of ability to react to stressors, and is associated with poor outcomes, morbidity and premature mortality. The first line treatment in many men with prostate cancer (PCa) consists of an androgen-deprivation therapy (ADT) which can promote or favor frailty syndrome and ADT may therefore favor the progression of frailty over time. Among the pathophysiological bases of frailty, the presence of chronic low-grade inflammation has been associated with its adverse outcomes, but longitudinal studies are needed to validate these biomarkers. In this study, we prospectively evaluate frailty syndrome and blood inflammatory markers (IL1-beta, IL-6, IL-8, TNF alpha, C reactive protein) and leukocytes were measured at baseline and an average of 1 year later in PCa under ADT. Frailty was defined as having three or more of the following components: low lean mass, weakness, self-reported exhaustion, low activity level, and slow walking speed; prefrailty was defined as having one or two of those components. Multinomial regression analysis showed that among the inflammatory biomarkers, those significantly and repeatedly (baseline and follow-up time points) (p < 0.05) associated with frailty syndrome were high IL-6 levels and low lymphocyte counts in blood. Other biomarkers such as IL-8, monocyte counts and C reactive protein were significantly associated with frailty syndrome (p < 0.05) in cross-sectional analyses, but they do not predict frailty progression at 1 year-follow-up. Receiver operating characteristic curve analysis showed that both lymphocyte counts and IL-6 concentration significantly (p < 0.05) (although moderately) discriminate PCa patients that progressed in the severity of frailty syndrome. IL-6 and lymphocytes count are possible biomarkers, useful for identifying frail patients and predicting the progression of frailty in PCa under ADT. Our study suggests the use of these biomarkers to guide clinical decisions on prostate cancer treatment based on a multidisciplinary approach.

Keywords: biomarker; geriatric assessment; inflammation; interleukin-1 beta; interleukin-6; leukocytes.

Patients with diabetes mellitus show increased risk of infectious disease as well as disturbances in innate immunity. In critical care settings, hyperglycemia is associated with increased risk of sepsis. It is unclear whether elevated glucose concentrations and innate immunity are associated in a non-clinical setting. We aimed to assess the association between glucose concentrations and innate immune response in the oldest old, who are at increased risk of both disturbed glucose metabolism as well as infectious disease. This study was part of the Leiden 85-plus Study. In 562 subjects aged 85 years old of the general population, venous blood samples were taken for measurement of morning glucose, C-reactive protein (CRP) and glycated hemoglobin (HbA1c). The innate immune response was assessed by performing ex vivo whole blood lipopolysaccharide (LPS) stimulation for production capacity of tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), interleukin 1-beta (IL1-β), interleukin 10 (IL-10) and interleukin 1 receptor antagonist (IL-1Ra). Using linear regression analysis, cross-sectional analysis between glucose and cytokine production capacity was performed. We found a significant negative association between glucose concentrations, but not HbA1c, and cytokine response capacity in four out of five measured cytokines (all p < 0.05). Both glucose and HbA1c were positively associated with circulating levels of CRP. Higher glucose concentrations in non-diabetic elderly are associated with lower innate immune response. As elderly show increased vulnerability for disturbances in glucose metabolism as well as infectious disease, this relation could be of clinical significance.

Mildly elevated serum unconjugated bilirubin (UCB) concentrations are associated with protection against disease conditions underpinned by cellular and metabolic stress. To determine the potential therapeutic efficacy of UCB we tested it in an in vitro model of gut inflammation. Tunicamycin TUN (10 µg/mL) was used to induce endoplasmic reticular stress (ERS) affecting N-glycosylation in LS174T cells. Cultured cells were investigated with addition of UCB at doses 0.1, 1 and 10µM (resulting in bilirubin:albumin ratios of 0.325-0.003)against ER stress-mediated effects including inflammation, cell survival (determined by apoptosis) and proliferation. Gene expression of ER stress markers (Grp78, Perk, XBP1 and ATF6) were evaluated in addition to cytokine concentrations in media after six hours of treatment. We then verified the potential role of UCB in executing programmed cell death via PARP, Caspase3 and Annexin V assays and further explored cell proliferation using the Click-iT EdU assay. A dose of 10µM UCB most potently reduced tunicamycin-mediated effects on enhanced UPR markers, inflammatory cytokines and proliferation; however all the doses (i.e.0.1-10µM) reduced the expression of ER stress and inflammatory markers Grp78, NLRP3, IL1-b, XBP1, PERK and ATF6. Furthermore, media concentrations of pro-inflammatory cytokines IL-8, IL-4 and TNFα decreased and the anti-inflammatory cytokine IL-10 increased (P<0.05). A dose of 10µM UCB initiated intrinsic apoptosis via Caspase 3 and in addition reduced cellular proliferation. Collectively, these data indicate that co treatment with UCB resulted in reducing ER stress response to TUN in gastrointestinal epithelial cells, reduced the subsequent inflammatory response, induced cancer cell death and decreased cellular proliferation. These data suggest that mildly elevated circulating or enteric UCB might protect against gastrointestinal inflammatory disorders.