The present study was considered to evaluate the protective effect of taurine on malathion-induced toxicity in rats. Totally, 48 male rats were divided into 6 equal groups: 0.5ml physiological salt solution was given orally to control rats. 0.5ml corn oil was given orally to rats in corn oil group. Malathion at dose of 27mg/kg (1/50 of LD50) was dissolved in 0.5ml corn oil and given to orally rats in malathion group. The other groups; malathion (27mg/kg) and taurine (dissolved in 0.5ml physiological salt solution) at dose of 50, 100, and 200mg/kg were given orally to rats for 30days, respectively. Malathion treatment decreased acetylcholinesterase levels in serum (30%) and liver (25%) compared to the control group. Malathion resulted in a significant increase in malondialdehyde levels whereas decreased glutathione levels, superoxide dismutase, and catalase activities in rats. Also, IF-γ, IL1-β, TNF-α, and NFĸB mRNA expression levels were found to be increased 5, 1.7, 2.3, and 2.5 fold in malathion treated rats compared to control, respectively. However, treatment of taurine, in a dose-dependent manner, resulted in a reversal of malathion-induced lipid peroxidation, antioxidant enzyme activities, and mRNA expression levels of proinflammatory cytokines. Moreover, taurine demonstrated preventive action against malathion-induced histopathological changes in rat tissues. In conclusion, taurine exhibited a protective effect in rats against malathion-induced lipid peroxidation, besides it ameliorated antioxidant status, decreased mRNA expression levels of proinflammatory cytokine and repaired rat tissues.

OBJECTIVE

Migraine is an idiopathic headache of differential pathogenesis.

OBJECTIVE

The aim of this research was to establish whether the pathogenesis of migraine with or without aura is identical. In order to examine this, the differences in the level of interleukin-6 (IL-6), interleukin-1beta (IL-1beta), tumor necrosis factor (TNF) and soluble TNF receptor type I (sTNFRI) were established during a migraine attack with or without aura in children.

METHODS

30 children with migraine were included, 17 boys and 13 girls aged 10-17 (mean 13.5). In 14/30 children migraine without aura was diagnosed, in 16/30 with aura, visual in 12 and sensory in 4 children. The headache duration was in 23 children shorter and in 7 children longer than 6 hours. When the pain started during hospitalization, the blood was sampled in the first hour of the headache, then 3 hours and 6 hours since headache started (if headache persisted), and 6 hours after its termination. Two days after pain termination, the blood samples were collected, as the headache-free measurements. The levels of IL-6, IL-1 beta, TNF and sTNFRI were established using Biosource kits, all 146 samples were processed. The statistical assessment was conducted.

RESULTS

The significant differences in cytokine levels were detected between children with migraine with or without aura. During headache-free interval in children without aura the level of IL1-beta was higher than with aura (p = 0.03), during 1st hour of migraine attack as well (p = 0.046). Higher, but non significant was IL-1 beta level 3 hours since headache started and 6 hours after its termination (p = 0.06). Type of migraine influenced also the TNF level (in children with migraine without aura higher 6 hours after pain termination, p = 0.046) and sTNFRI (p = 0.07 during the same period). The differences in IL-6 levels between children with migraine with or without aura were not significant.

CONCLUSIONS

1. The significant increase in IL-1beta level observed during headache-free interval and early stage of attack of migraine without aura as compared to migraine with aura may reflect differences in pathogenesis of both types of migraine in developmental age. 2. This dissimilarity may be suggested also by the increase in TNF and sTNFRI levels in children with migraine without aura as compared to children with migraine with aura after pain termination.

Brain abscess is a focal suppurative process. Host inflammatory response in Gram type and specific bacteria has not been studied in brain abscess. A total of 57 brain abscess patients with monomicrobial infections were studied for Th1 (TNF-α, IFN-γ, IL1-β), Th2 (IL-4, IL-10) and Th17 (IL-17, IL-23) cytokine response by reverse-transcriptase PCR and ELISA. Th1 and Th17 cytokines were significantly elevated in Gram positive (Staphylococcus aureus and Streptococcus intermedius) and Th2 cytokine (IL-10) in Gram negative (Bacteroides fragilis and Escherichia coli) infections (p<0.05). Cytokine levels were significantly higher in abscess than blood (p<0.001). Elevated levels of several inflammatory cytokines (TNF-α, IFN-γ, IL1-β, IL-17 and IL-23) were associated with the duration of symptoms; predisposing factors also influenced the levels of several cytokines. The expression of inflammatory cytokines in abscess was influenced by the bacterial pathogen, duration of symptoms and predisposing factors. Local milieu of brain plays significant role in secretion of various cytokines.

IL-4, a product of the T-helper 0 (Th0) and 2 (Th2) subset, was originally described as a B-cell stimulatory factor and has subsequently been found to suppress IL-1 alpha, IL-1 beta, IL-6, IL-8, and TNF-alpha gene expression in monocytes stimulated with LPS, and to upregulate IL-1 receptor antagonist (IL1-RA) gene expression. In this study we investigated the effect of IL-4 on the expression of cytokine genes in monocytes evoked by other T-helper cell cytokines: IL-2, IL-3, and GM-CSF. IL-4 down-regulated mRNA accumulation of the proinflammatory cytokines IL-1 beta, IL-8, and TNF-alpha in monocytes stimulated with IL-2, IL-3, and GM-CSF. IL-4 also suppressed the IL-2-induced IL-6 mRNA expression. Temporal analysis of the IL-4 down-regulatory effect on the IL-2-, IL-3-, or GM-CSF-induced proinflammatory cytokine gene expression in monocytes provided evidence that IL-4 acts predominantly on the post-transcriptional level. This was supported by the observation that the down-regulatory capacity of IL-4 appeared to be dependent on de novo protein synthesis. IL-4 did not exert significant influence on the induction of expression of IL-1-RA or various CSFs by IL-2, IL-3, and GM-CSF.(ABSTRACT TRUNCATED AT 250 WORDS)

Sickle cell retinopathy (SCR) develops in up to 30% of sickle cell disease patients (SCD) during the second decade of life. Treatment for this affection remains palliative, so studies on its pathophysiology may contribute to the future development of novel therapies. SCR is more frequently observed in hemoglobin SC disease and derives from vaso-occlusion in the microvasculature of the retina leading to neovascularization and, eventually, to blindness. Circulating inflammatory cytokines, angiogenic factors, and their interaction may contribute to the pathophysiology of this complication. Angiopoietin (Ang)-1, Ang-2, soluble vascular cell adhesion molecule-1, intercellular adhesion molecule (ICAM)-1, E-selectin, P-selectin, IL1-β, TNF-α, pigment epithelium derived factor (PEDF) and vascular endothelial growth factor plasmatic levels were determined in 37 SCD patients with retinopathy, 34 without retinopathy, and healthy controls. We observed that sICAM-1 is significantly decreased, whereas PEDF is elevated in HbSC patients with retinopathy (P=0.012 and P=0.031, respectively). Ang-1, Ang-2 and IL1-β levels were elevated in SCD patients (P=0.001, P<0.001 and P=0.001, respectively), compared to controls, and HbSS patients presented higher levels of Ang-2 compared to HbSC (P<0.001). Our study supports the possible influence of sICAM-1 and PEDF on the pathophysiology of retinal neovascularization in SCD patients.

The underlying mechanism of immune privilege in hair follicle cell dermal papilla (DP) and sheath (DS) populations is not well understood, and the responsiveness of hair follicle dermal cells to pro-inflammatory challenge presently remains unknown. In this work, we describe acute NF-κB activation in human DS, DP and dermal fibroblast (DF) cells challenged with TNF-alpha and IL1-beta. In contrast, the DS and DP cells revealed an unexpected tolerance to bacterial LPS challenge relative to DF cells. Understanding follicle cell responses to typical pro-inflammatory stimuli is critical for diseases where collapse of hair follicle immune privilege is observed, and to further applications in autologous stem cell/wound healing therapeutics.

Lafora progressive myoclonus epilepsy (Lafora disease, LD) is a fatal rare autosomal recessive neurodegenerative disorder characterized by the accumulation of insoluble ubiquitinated polyglucosan inclusions in the cytoplasm of neurons, which is most commonly associated with mutations in two genes: EPM2A, encoding the glucan phosphatase laforin, and EPM2B, encoding the E3-ubiquitin ligase malin. The present study analyzes possible inflammatory responses in the mouse lines Epm2a -/- (laforin knock-out) and Epm2b -/- (malin knock-out) with disease progression. Increased numbers of reactive astrocytes (expressing the GFAP marker) and microglia (expressing the Iba1 marker) together with increased expression of genes encoding cytokines and mediators of the inflammatory response occur in both mouse lines although with marked genotype differences. C3ar1 and CxCl10 messenger RNAs (mRNAs) are significantly increased in Epm2a -/- mice aged 12 months when compared with age-matched controls, whereas C3ar1, C4b, Ccl4, CxCl10, Il1b, Il6, Tnfα, and Il10ra mRNAs are significantly upregulated in Epm2b -/- at the same age. This is accompanied by increased protein levels of IL1-β, IL6, TNFα, and Cox2 particularly in Epm2b -/- mice. The severity of inflammatory changes correlates with more severe clinical symptoms previously described in Epm2b -/- mice. These findings show for the first time increased innate inflammatory responses in a neurodegenerative disease with polyglucosan intraneuronal deposits which increase with disease progression, in a way similar to what is seen in neurodegenerative diseases with abnormal protein aggregates. These findings also point to the possibility of using anti-inflammatory agents to mitigate the degenerative process in LD.

Climate change is predicted to increase water temperatures and decrease oxygen levels in freshwater and marine environments, however, there is conflicting information regarding the extent to which these conditions may impact the immune defenses of fish. In this study, Atlantic salmon were exposed to: (1) normoxia (100-110% air saturation) at 12°C; (2) an incremental temperature increase (1°C per week from 12 to 20°C), and then held at 20°C for an additional 4 weeks; and (3) "2" with the addition of moderate hypoxia (~65-75% air saturation). These conditions realistically reflect what farmed salmon in some locations are currently facing, and future conditions in Atlantic Canada and Europe, during the summer months. The salmon were sampled for the measurement of head kidney constitutive anti-bacterial and anti-viral transcript expression levels, and blood parameters of humoral immune function. Thereafter, they were injected with either the multi-valent vaccine Forte V II (contains both bacterial and viral antigens) or PBS (phosphate-buffer-saline), and the head kidney and blood of these fish were sampled at 6, 12, 24, and 48 h post-injection (HPI). Our results showed that: (1) neither high temperature, nor high temperature + moderate hypoxia, adversely affected respiratory burst, complement activity or lysozyme concentration; (2) the constitutive transcript expression levels of the anti-bacterial genes il1β, il8-a, cox2, hamp-a, stlr5-a, and irf7-b were up-regulated by high temperature; (3) while high temperature hastened the peak in transcript expression levels of most anti-bacterial genes by 6-12 h following V II injection, it did not affect the magnitude of changes in transcript expression; (4) anti-viral (viperin-b, mx-b, and isg15-a) transcript expression levels were either unaffected, or downregulated, by acclimation temperature or V II injection over the 48 HPI; and (5) hypoxia, in addition to high temperature, did not impact immune transcript expression. In conclusion, temperatures up to 20°C, and moderate hypoxia, do not impair the capacity of the Atlantic salmon's innate immune system to respond to bacterial antigens. These findings are surprising, and highlight the salmon's capacity to mount robust innate immune responses (i.e., similar to control fish under optimal conditions) under conditions approaching their upper thermal limit.

Keywords: aquaculture; climate change; disease susceptibility; fish; global warming; high temperature; hypoxia; immune response.

The microvascular endothelium of the gut barrier plays a crucial role during inflammation in inflammatory bowel disease. We have modified a commonly used intestinal cell model based on the Caco-2 cells by adding microvascular endothelial cells (ISO-HAS-1). Transwell filters were used with intestinal barrier-forming Caco-2 cells on top and the ISO-HAS-1 on the bottom of the filter. The goal was to determine whether this coculture mimics the in vivo situation more closely, and whether the model is suitable to evaluate interactions of, for example, prospective nanosized drug vehicles or contrast agents with this coculture in a physiological and inflamed state as it would occur in inflammatory bowel disease. We monitored the inflammatory responsiveness of the cells (release of IL-8, soluble intercellular adhesion molecule 1, and soluble E-selectin) after exposure to inflammatory stimuli (lipopolysaccharide, TNF-α, INF-γ, IL1-β) and a nanoparticle (Ba/Gd: coprecipitated BaSO4 and Gd(OH)3), generally used as contrast agents. The barrier integrity of the coculture was evaluated via the determination of transepithelial electrical resistance and the apparent permeability coefficient (Papp) of NaFITC. The behavior of the coculture Caco-1/ISO-HAS-1 was compared to the respective monocultures Caco-2 and ISO-HAS-1. Based on transepithelial electrical resistance, the epithelial barrier integrity of the coculture remained stable during incubation with all stimuli, whereas the Papp decreased after exposure to the cytokine mixture (TNF-α, INF-γ, IL1-β, and Ba/Gd). Both the endothelial and epithelial monocultures showed a high inflammatory response in both the upper and lower transwell-compartments. However, in the coculture, inflammatory mediators were only detected on the epithelial side and not on the endothelial side. Thus in the coculture, based on the Papp, the epithelial barrier appears to prevent a potential inflammatory overreaction in the underlying endothelial cells. In summary, this coculture model exhibits in vivo-like features, which cannot be observed in conventional monocultures, making the former more suitable to study interactions with external stimuli.

We aim to study the optimum salinity concentration for Nile tilapia, through the assessment of its growth performance and the expression of its related genes (Gh and Igf-1), as well as its salinity adaptation and immune status through the assessment of the gene expression of ion-regulation genes (Na⁺/K⁺-ATPase α-1a and α-1b), stress-related genes (GST, HSP27, and HSP70), inflammatory-related genes (IL1, IL8, CC, and CXC chemokine), and immune-related genes (IgMH TLR7, MHC, and MX) at the osmoregulatory organs (gills, liver, and kidney). Based on the least mortality percentage and the physical appearance of the fish, three salt concentrations (6, 16, and 20 ppt) were chosen following a 6-month preliminary study using serial salt concentrations ranged from 6 to 36 ppt, which were obtained by rearing the fish in gradual elevated pond salinity through daily addition of 0.5 ppt saline water. The fish size was 10.2-12 cm and weight was 25.5-26.15 g. No significant differences in the fish weight gain were observed among the studied groups. The group reared at 16-ppt salt showed better performance than that of 20 ppt, as they have lower morality % and higher expression of ion-regulated gene (Na⁺/K⁺-ATPase α1-b), stress-related genes (GST, HSP27, and HSP70) of the gills and also GST, inflammatory-related genes (IL-1β and IL8), and TLR in the liver tissue. Higher expression of kidney-immune-related genes at 20-ppt salt may indicate that higher salinity predispose to fish infection and increased mortality. We concluded that 16-ppt salinity concentration is suitable for rearing O. niloticus as the fish are more adaptive to salinity condition without changes in their growth rate. Also, we indicate the use of immune stimulant feed additive to overcome the immune suppressive effect of hyper-salinity. Additionally, the survival of some fish at higher salinity concentrations (30-34 ppt) increase the chance for selection for salinity resistance in the Nile tilapia.

Chronic obstructive pulmonary disease (COPD) is characterized by airway inflammation associated with a Th1/17-biased cytokine environment. Acute exacerbations of COPD (AECOPD) are most often triggered by respiratory infections, which elicit an exaggerated inflammatory response in these patients, via poorly defined mechanisms. We investigated the responses of airway epithelial cells (AECs) to infective stimuli in COPD and the effects of the Th1/17-biased environment on these responses. Cytokine expression was assessed following exposure to virus-like stimuli (poly I:C or imiquimod) or bacterial LPS. The effects of pretreatment with Th1/17 cytokines were evaluated in both primary AECs and the Calu-3 AEC cell line. We found that poly I:C induced increased expression of the proinflammatory cytokines IL1β, IL6, CXCL8, and TNF and IFN-βIL1β in response to all 3 stimuli was significantly enhanced in COPD AECs. Primary AECs pretreated with Th1/17 cytokines exhibited enhanced expression of mRNA for proinflammatory cytokines in response to poly I:C. Similarly, Calu-3 cells responded to virus-like/bacterial stimuli with increased expression of proinflammatory cytokines, and a Th1/17 environment significantly enhanced their expression. Furthermore, increased expression of pattern recognition receptors for viruses (TLR3, TLR7, IFIH1, and DDX58) was induced by Th1/17 cytokines, in both primary AECs and Calu-3 cells. These findings suggest that the Th1/17-biased environment associated with COPD may enhance the proinflammatory cytokine response of AECs to viral and bacterial infections and that increased signaling via upregulated receptors may contribute to exaggerated inflammation in virus-induced AECOPD.

African swine fever (ASF) is a devastating disease for which there is no vaccine available. The ASF virus (ASFV) primarily infects cells of the myeloid lineage and this tropism is thought to be crucial for disease pathogenesis. A detailed in vitro characterization of the interactions of a virulent Sardinian isolate (22653/14) and a tissue culture adapted avirulent strain (BA71V) of ASFV with porcine monocytes, un-activated (moMΦ), classically (moM1) and alternatively (moM2) activated monocyte-derived macrophages was conducted in an attempt to better understand this relationship. Using a multiplicity-of-infection (MOI) of 1, both viruses were able to infect monocytes and macrophage subsets, but BA71V presented a reduced ability to infect moM1 compared to 22653/14, with higher expression of early compared to late proteins. Using an MOI of 0.01, only 22653/14 was able to replicate in all the macrophage subsets, with initially lowest in moM1 and moM2. No differences were observed in the expression of CD163 between ASFV infected and uninfected bystander cells. ASFV down-regulated CD16 expression but did not modulate MHC class II levels in monocytes and macrophage subsets. BA71V-infected but not 22653/14-infected moMΦ and moM2 presented with a reduced expression of MHC class I compared to the mock-infected controls. Higher levels of IL-18, IL1-β and IL-1α were released from moM1 after infection with BA71V compared to 22653/14 or mock-infected control. These results revealed differences between these ASFV strains, suggesting that virulent isolates have evolved mechanisms to counteract activated macrophages responses, promoting their survival, dissemination in the host and so ASF pathogenesis.

<A<em>b</em>stractText>This study tested the hypothesis that a patient-derived orthotopic xenograft (PDOX) model would recapitulate the common clinical phenomenon of <em>b</em>reast cancer-induced skeletal muscle (SkM) fatigue in the a<em>b</em>sence of muscle wasting. This study additionally sought to identify drivers of this condition to facilitate the development of therapeutic agents for patients with <em>b</em>reast cancer experiencing muscle fatigue.</A<em>b</em>stractText><p><div>(<em>b</em>)EXPERIMENTAL DESIGN</<em>b</em>)</div>Eight female BC-PDOX-<em>b</em>earing mice were produced via transplantation of tumor tissue from 8 female patients with <em>b</em>reast cancer. Individual hind lim<em>b</em> muscles from BC-PDOX mice were isolated at euthanasia for RNA-sequencing, gene and protein analyses, and an <i>ex vivo</i> muscle contraction protocol to quantify tumor-induced a<em>b</em>errations in SkM function. Differentially expressed genes (DEG) in the BC-PDOX mice relative to control mice were identified using DESeq2, and multiple <em>b</em>ioinformatics platforms were employed to contextualize the DEGs.</p><p><div>(<em>b</em>)RESULTS</<em>b</em>)</div>We found that SkM from BC-PDOX-<em>b</em>earing mice showed greater fatiga<em>b</em>ility than control mice, despite no differences in a<em>b</em>solute muscle mass. PPAR, mTOR, IL6, <em>IL1</em>, and several other signaling pathways were implicated in the transcriptional changes o<em>b</em>served in the BC-PDOX SkM. Moreover, 3 independent <i>in silico</i> analyses identified PPAR signaling as highly dysregulated in the SkM of <em>b</em>oth BC-PDOX-<em>b</em>earing mice and human patients with early-stage nonmetastatic <em>b</em>reast cancer.</p><A<em>b</em>stractText>Collectively, these data demonstrate that the BC-PDOX model recapitulates the expected <em>b</em>reast cancer-induced SkM fatigue and further identify a<em>b</em>errant PPAR signaling as an integral factor in the pathology of this condition.</A<em>b</em>stractText>

Osteoporosis (OP) and increased fracture risk are widely observed comorbidities in chronic inflammatory rheumatic diseases (CIRDs). Improved knowledge of the immune/inflammatory pathways, which characterise the pathophysiology of rheumatoid arthritis (RA) and seronegative spondyloarthropathies (SpA), such as ankylosing spondylitis (AS) and psoriatic arthritis (PsA), have provided the link between inflammation and bone loss, via a complex network of bone cells, T and B cells, pro-inflammatory cytokines such as TNF-α, IL1, IL6, IL1IL1 blockers, and B and T cell therapies, have demonstrated a beneficial effect on bone mineral density (BMD) and/or bone turnover markers (BTs). However, whether these drugs are able to positively influence also fracture risk has not yet been established, since the data available are sparse and inconclusive. Thus, systemic bone loss and increased fracture rates still remain relevant comorbidities that should be considered for screening and prevention, and proper treatment of patients with CIRDs despite the biologic therapy.

Blooms of cyanobacteria producing very toxic secondary metabolites (especially microcystins) are potent environmental stressors, hazardous not only to aquatic animals but also to public health. The purpose of this study was to investigate the effects of an extract containing microcystins on immune cells isolated from the common carp (Cyprinus carpio L.). In the present study it has been found that the extract induced apoptosis and inhibited in vitro lymphocyte proliferation. In addition, the results indicated the possible role of oxidative stress in this cytotoxicity and apoptosis. The in vivo investigations showed that the extract containing microcystins had greater suppressive effects on the essential functions of immune cells (intracellular reactive oxygen species production and lymphocyte proliferation) than the pure toxin alone. Moreover, immersion of fish in the toxic extract caused changes in the mRNA levels of various pro- and anti-inflammatory cytokines in carp leukocytes, while after exposure to the pure toxin, only IL1-β expression was markedly up-regulated. The observed modulatory effects on immune cells could have important implications for the health of planktivorous fish, which feed more frequently on toxic cyanobacteria.

Ankylosing spondylitis (AS) is an autoimmune disease characterized by fibroblasts ossification. However, effective drug therapy for AS is lacking. As an antidiabetic drug, metformin has demonstrated an antiosteogenic effect on osteoblasts in vitro. And it is also a kind of specific agonists for adenosine 5'-monophosphate activated protein kinase (AMPK), which is blocked in the process of AS. Given the role in antiosteogenesis and AMPK activating, metformin was investigated of its effect on fibroblasts harvested from capsular ligament of patients with femoral neck fracture and AS. Osteogenic specific makers (Alp, Bglap, Runx2, Bmp2, and Col1) in fibroblasts administered with metformin (20 μg/mL) were detected by ALP staining, alizarin red staining, qPCR, and Western blotting after 7 and 14 days of culture. Inflammation genes (il1-β and il6) and pathway (Pi3k, Akt, and Ampk) associated markers were also evaluated. Our results showed that osteogenic specific markers were greatly downregulated and ossification was effectively inhibited in AS fibroblasts after addition of metformin. Levels of inflammation markers were also decreased by metformin. Thus, metformin exerts potent effect on suppression of ossification and inflammation in AS fibroblasts via the activation of Pi3k/Akt and AMPK pathways, which may be developed as a potential agent for treatment of AS.

BACKGROUND

Circulating immune markers may be associated with preeclampsia but further investigations in early pregnancy and among preeclampsia subtypes are warranted. We examined immune markers in 208 preeclamptic women and 411 normotensive controls.

METHODS

Our study was nested within the Collaborative Perinatal Project. A total of 242 women had first trimester serum samples and 392 had second trimester serum samples. Preeclampsia was defined as hypertension >20weeks of gestation with proteinuria or pulmonary edema, oliguria, or convulsions. Preterm preeclampsia was defined as preeclampsia with delivery less than 37weeks of gestation. Associations between immune markers RANTES, interleukin (IL)-6, IL4, IL5, IL1IL1IL1-beta, interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha and beta, transforming growth factor (TGF)-beta and preeclampsia were explored using a modified version of cox regression developed to address data with non-detectable levels. Models were adjusted for body mass index, gestational age of blood sampling, fetal sex, smoking, socioeconomic status and maternal age.

RESULTS

In first trimester samples, IL-12 was associated with preeclampsia (p=0.0255). IFN-gamma (p=0.0063), IL1-beta (p=0.0006), IL5 (p=0.0422) and TNFr (p=0.0460) were associated with preterm preeclampsia only. In second trimester samples, IL1-beta was associated with preeclampsia (p=0.0180) and term preeclampsia (p=0.0454). After correction for multiple comparisons, only IL1-beta remained associated with preterm preeclampsia in the first trimester (p=0.0288).

CONCLUSIONS

Elevated first trimester IL1-beta appears to be associated with preterm preeclampsia. However, few associations were observed in the second trimester. Systemic immune markers alone may not be useful for preeclampsia prediction.

Aims: Ketogenic diet (KD) has been proposed to be an effective lifestyle intervention for metabolic syndrome. However, the effects of KD on hypertension have not been well investigated. The present study aimed to investigate the effects and underling mechanisms of KD on hypertension in spontaneously hypertensive rats (SHRs).

Materials and methods: SHRs were subjected to normal diet or KD for 4 weeks, starting at the age of 10 weeks. Then, the blood pressure and vascular function were assessed. Next, the eNOS expression, inflammatory factors and relative signaling pathway were examined. Human umbilical vein endothelial cells were used to investigate the underlying mechanism account for the effect of ketone on inflammation and eNOS expression.

Key findings: Compared with the normal diet, KD was indicated to aggravate hypertension and impaire endothelium-dependent relaxation in mesenteric arteries of SHRs. eNOS and CD31 expression in mesenteric arteries were also significantly suppressed by KD. In addition, KD markedly increased the activation of NF-κB pathway and the expression of IL1-β and TNF-α. In vitro, results showed that inhibition of NF-κB could rescue the adverse effects of ketone body and TGF-β on eNOS expression and inflammation response.

Significance: Our study indicated that KD impaired endothelium-dependent relaxation in mesenteric arteries and aggravated the development of hypertension in SHRs, suggesting that it should be more cautious to apply KD into clinical application in hypertensive individuals.

Keywords: Endothelial dysfunction; Hypertension; Ketogenic diet; NF-κB; eNOS.

BACKGROUND

The hypothesis was tested that the systemic immune milieu in recent-onset type 1 diabetes is associated with residual beta cell function and other metabolic patient characteristics.

RESULTS

All patients (n = 89, 40% female) of the Diabetes and Atorvastatin (DIATOR) Trial were analyzed at recruitment, i.e. prior to receiving the study medication. Inclusion criteria were insulin dependent diabetes for 2 weeks to 3 months, age range 18-39 years, and islet cell autoantibodies. Blood samples were analyzed for 14 immune mediators by standard methods. Concentrations of all mediators correlated with at least one other mediator (p<0.05, Spearman correlation) giving rise to a network. Interleukin 1 receptor antagonist (IL1-RA) held a central position and was associated with both pro- and anti-inflammatory mediators. Further central elements were the pro-inflammatory mediators CRP and IL-6, the soluble adhesion molecules sICAM-1 and E-selectin, and MCP-4 which held a central position in the chemokine network. The two Th1-associated mediators IFNγ and IP-10 remained outside the network but correlated with each other. All correlations were positive (r = 0.25-0.72), i.e., high levels of pro-inflammatory mediators were accompanied by increased levels of anti-inflammatory mediators. IL-1RA was the only mediator associated with fasting and liquid mixed meal stimulated C-peptide concentrations (r = 0.31 and 0.24, p = 0.003 and 0.025, after adjustment for age, sex, BMI). There were associations between the immune mediator network and BMI (IL-1RA, CRP, IL-6, MCP-4, MIP-1ß) but few or no associations with HbA1c, insulin dose, lipid parameters, age or sex.

CONCLUSIONS

In patients with recent onset type 1 diabetes, systemic acute phase proteins, cytokines, chemokines and soluble adhesion molecules form a network. Among the few central elements IL-1RA has a dominant role. IL-1RA is associated with all other groups of mediators and is the only mediator which correlates (positively) with residual beta cell function.

BACKGROUND

ClinicalTrials.gov registration number: NCT00974740.

The severe forms and worsened outcomes of COVID-19 (coronavirus disease 19) are closely associated with hypertension and cardiovascular disease. Endothelial cells express Angiotensin-Converting Enzyme 2 (ACE2), which is the entrance door for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The hallmarks of severe illness caused by SARS-CoV-2 infection are increased levels of IL-6, C-reactive protein, D-dimer, ferritin, neutrophilia and lymphopenia, pulmonary intravascular coagulopathy and microthrombi of alveolar capillaries. The endothelial glycocalyx, a proteoglycan- and glycoprotein-rich layer covering the luminal side of endothelial cells, contributes to vascular homeostasis. It regulates vascular tonus and permeability, prevents thrombosis, and modulates leukocyte adhesion and inflammatory response. We hypothesized that cytokine production and reactive oxygen species (ROS) generation associated with COVID-19 leads to glycocalyx degradation. A cohort of 20 hospitalized patients with a confirmed COVID-19 diagnosis and healthy subjects were enrolled in this study. Mechanisms associated with glycocalyx degradation in COVID-19 were investigated. Increased plasma concentrations of IL-6 and IL1-β, as well as increased lipid peroxidation and glycocalyx components were detected in plasma from COVID-19 patients compared to plasma from healthy subjects. Plasma from COVID-19 patients induced glycocalyx shedding in cultured human umbilical vein endothelial cells (HUVECs) and disrupted redox balance. Treatment of HUVECs with low molecular weight heparin inhibited the glycocalyx perturbation. In conclusion, plasma from COVID-19 patients promotes glycocalyx shedding and redox imbalance in endothelial cells, and heparin treatment potentially inhibits glycocalyx disruption.

Keywords: COVID-19; Endothelial cells; Glycocalyx; Heparan sulfate proteoglycans; Low molecular weight heparin; Vascular dysfunction.

The intestinal microbiota is a complex ecosystem implicated in host health and disease. Inflammatory bowel disease (IBD) is a multifactorial chronic disorder of the gastrointestinal mucosa. Even though the exact mechanisms are still unknown, the intestinal microbiota is crucial in IBD development. We previously showed that murine norovirus (MNV) induces colitis in the Il1-deficient (Il1^-/-) mouse model of IBD in a microbiota-dependent manner. Thus, in this study we analyzed whether distinct minimal bacterial consortia influence the outcome of MNV-triggered colitis in Il1^-/- mice. Gnotobiotic Il1^-/- mice associated with Oligo-Mouse-Microbiota 12 (OMM¹²) or Altered Schaedler Flora (ASF) developed little to no inflammatory lesions in the colon and cecum. MNV infection exacerbated colitis severity only in ASF-colonized mice, but not in those associated with OMM¹². Four weeks after MNV infection, inflammatory lesions in ASF-colonized Il1^-/- mice were characterized by epithelial hyperplasia, infiltration of inflammatory cells, and increased barrier permeability. Co-colonization of ASF-colonized Il1^-/- mice with segmented filamentous bacteria (SFB) abolished MNV-induced colitis, whereas histopathological scores in SFB-OMM¹²-co-colonized mice stayed unchanged. Moreover, SFB only colonized mice associated with ASF. The SFB-mediated protective effects in ASF-colonized mice involved enhanced activation of intestinal barrier defense mechanisms and mucosal immune responses in the chronic and acute phase of MNV infection. SFB colonization strengthened intestinal barrier function by increasing expression of tight junction proteins, antimicrobial peptides and mucus. Furthermore, SFB colonization enhanced the expression of pro-inflammatory cytokines such as Tnfα, Il1β, and Il1, as well as the expression of the regulatory cytokine Tgfβ. Altogether, our results showed that MNV-triggered colitis depends on the microbial context.

The NLRP3-IL-1β pathway plays an important role in adipose tissue (AT)-induced inflammation and the development of obesity-associated comorbidities. We aimed to determine the impact of NLRP3 on obesity and its associated metabolic alterations as well as its role in adipocyte inflammation and extracellular matrix (ECM) remodeling. Samples obtained from 98 subjects were used in a case-control study. The expression of different components of the inflammasome as well as their main effectors and inflammation- and ECM remodeling-related genes were analyzed. The impact of blocking NLRP3 using siRNA in lipopolysaccharide (LPS)-mediated inflammation and ECM remodeling signaling pathways was evaluated. We demonstrated that obesity (P < 0.01), obesity-associated T2D (P < 0.01) and NAFLD (P < 0.05) increased the expression of different components of the inflammasome as well as the expression and release of IL-1β and IL-18 in AT. We also found that obese patients with T2D exhibited increased (P < 0.05) hepatic gene expression levels of NLRP3, IL1B and IL1IL1B, IL6, IL8, S100A8, S100A9, TLR4 and TNF as well as inhibiting (P < 0.01) the secretion of IL1-β into the culture medium. Furthermore, blocking NLRP3 attenuated (P < 0.01) the LPS-induced expression of important molecules involved in AT fibrosis (COL1A1, COL4A3, COL6A3 and MMP2). These novel findings provide evidence that blocking the expression of NLRP3 reduces AT inflammation with significant fibrosis attenuation.

Alzheimer's disease (AD) is closely associated with neuroinflammation development in the brain. Co-delivery of metformin (MET) with phosphatidylserine liposomes neuroprotectant may be beneficial in ameliorating AD-related symptoms like memory impairment and inflammation. Therefore, we aimed to prepare metformin containing phosphatidylserine nanoliposomes formulation (MET-PSL) and to evaluate its effect on rats subjected to AD. Alzheimer's disease model was induced by bilateral intracerebroventricular injection of streptozotocin (3 mg/kg) into rat brains using the stereotactic technique. MET-PSL, MET, and PSL alone were administered intraperitoneally to AD-induced animals and factors including learning and memory storage in addition to cytokine and tissue inflammatory changes were evaluated after a 22-day experiment period. The learning and memory parameters significantly (P < 0.05) improved in AD-rats treated with MET-PSL. Moreover, MET-PSL administration significantly (P < 0.05) decreased cytokine levels of IL1-β, TNF-α, and TGF-β in hippocampal tissues of rats with AD. Histological results indicated a considerable reduction in inflammatory and necrotic neural cells along with significantly (P < 0.05) increased neurogenesis in MET-PSL treated rats. Furthermore, our results showed that MET-PSL formulation could potentially act better than the free form of MET and PSL alone in the recovery process of rats with AD. In general, our data suggest that combination therapy of metformin loaded phosphatidylserine liposomes may enhance the therapeutic performance in AD patients of a clinical study.

Keywords: Alzheimer; Liposome; Metformin; Morris water maze; Phosphatidylserine.

OBJECTIVE

Several studies implicated altered inflammatory response in the susceptibility to ovarian cancer, and polymorphisms in inflammatory cytokines were shown to play an important role in the development of malignancies, including ovarian cancer (OC). Here we investigated the relationship between polymorphisms in IL-1β (-511C>T), IL-1RN VNTR, TNF-α (-308G>A), and TNF RII (-322 VNTR) and OC risk in Tunisian women.

RESULTS

Study subjects comprised 62 OC patients and 126 healthy women. Genotyping was done from genomic DNA obtained from blood simple by PCR. Positive association between IL-1RN (-VNTR) A1 allele (p = 0.0069; OR = 2.04; 95% CI:1.17-3.58) and OC risk, while negative association was seen with the A3 allele (P = 0.0034; OR = 0.09; 95% CI: 0.00-0.64), suggesting a protective role by the A3 allele. For IL-1β (-511C>T), homozygous C/C genotype was associated with significantly increased risk of OC (p = 0.0002; OR = 4.14; 95% CI: 1.77-9.76), while heterozygote C/T genotype was linked with reduced risk of OC (p = 0.0033; OR = 0.40; 95% CI: 0.20-0.78). Furthermore, TNF-α -308A allele was significantly associated with heightened risk of OC (p = 0.016; OR = 1.70; 95% CI: 1.08-2.69), and homozygote G/G genotype was associated with decreased risk of OC (p = 0.0018; OR = 0.25; 95% CI: 0.09-0.66). In contrast, TNFRII (-322 VNTR) polymorphism was not associated with altered OC risk in the studied group.

CONCLUSIONS

The significant association between IL-1RN VNTR, IL1-β (-511), TNF-α (-308) and OC susceptibility in Tunisian women confirms a role for altered inflammatory response in ovarian cancer pathogenesis.