The effect of interleukin 6 deficiency on myocardial signal transduction pathways activation induced by bacterial lipopolysaccharide in young and old mice

PurposeExaggerated release of proinflammatory mediators during sepsis contributes to inadequate vasodilatation and depressed myocardial contractility, which lead to development of shock and circulatory collapse. The aim of the study was to evaluate the effect of IL-6 and aging on activation of intracellular signaling pathways in the myocardium induced by bacterial lipopolysaccharide (LPS) administration.Material/methodsLPS was injected intraperitoneally to male 3- and 24-month old mice with systemic IL-6 gene knock-out (IL-6KO) and the reference strain (WT). LPS was given intraperitoneally in single low (0.1 mg/kg) or high (10 mg/kg) dose, or in two doses (0.1 + 10 mg/kg) with 24-h delay. The expression and phosphorylation of STAT3, ERK1/2, Akt1/2/3 proteins in the left ventricular myocardium was evaluated after 24 h using Western blotting.ResultsLow LPS dose induced higher STAT3 phosphorylation only in old IL-6KO mice, not affecting ERK1/2 and Akt1/2/3 phosphorylation in any group. High LPS dose upregulated STAT3 phosphorylation similarly in all groups, reduced ERK1/2 expression in young WT mice and upregulated Akt1/2/3 expression and phosphorylation in young IL-6KO mice. Pretreatment with low LPS dose attenuated phosphorylation of STAT3 in both old groups and phosphorylation of Akt1/2/3 in young IL-6KO group. Two-dose approach also significantly potentiated ERK1/2 phosphorylation in both old groups.ConclusionsObtained results show that IL-6 deficiency alters the activity of intracellular signaling pathways: JAK/STAT in old and Akt in young LPS-treated mice. This may indicate that lack of IL-6 attenuates Akt-related cytoprotective effect of pretreatment with low LPS dose in young but not in aged animals.     

Natural products that target macrophages in treating non-alcoholic steatohepatitis

Nonalcoholic steatohepatitis(NASH) is the progressive subtype of non-alcoholic fatty liver disease and potentiates risks for both hepatic and metabolic diseases.Although the pathophysiology of NASH is not completely understood, recent studies have revealed that macrophage activation is a major contributing factor for the disease progression. Macrophages integrate the immune response and metabolic process and have become promising targets for NASH therapy.Natural products are potential candidates for NASH treatment and have multifactorial underlying mechanisms. Macrophage involvement in the development of steatosis and inflammation in NASH has been widely investigated. In this review, we assess the evidence for natural products or their active ingredients in the modulation of macrophage activation, recruitment, and polarization, as well as the metabolic status of macrophages. Our work may highlight the possible natural products that target macrophages as potential treatment options for NASH.     

Do upsetting life events explain the relationship between low socioeconomic status and systemic inflammation in childhood? Results from a longitudinal study

BackgroundChildren from families of low socioeconomic status (SES) are more likely to be exposed to upsetting situations and stressors. Such exposures have, in turn, been linked to inflammation in some studies. In this study we explore if low SES is related to inflammation in children via such stressful life events.MethodsData on 4525 children of the Avon Longitudinal Study of Parents and Children, a general population birth cohort, were used to explore associations between SES at ages 0–3 years, upsetting life events at ages 3–9 years and inflammatory markers [interleukin 6 (IL-6) and C-reactive protein (CRP)] at age 9 years. Confounders included body mass index, gender, financial problems, and upsetting life events at ages 0–3 years.ResultsUsing Structural Equation Modelling, we found that early socioeconomic disadvantage predicted higher levels of IL-6 (β = 0.034, 95% CI = 0.005, 0.063) even after adjusting for confounders. This association was partially mediated by upsetting life events (β = 0.003, 95% CI = 0.001, 0.006).ConclusionsIn the general child population, low SES is associated with increased exposure to stressful life events, in turn associated with later inflammation. These findings highlight the role of stressors associated with poverty and disadvantage in the development of inflammation among children in the general population.     

Unemployment,employment precarity,and inflammation

Unemployment has been associated with poorer health, but few studies have examined the biological mechanisms that confer these health decrements. Further, no studies to date have examined differences across employment groups to consider whether employment (in whatever means) is preferential in terms of health. The present study utilised secondary data from Understanding Society: The Household Longitudinal Survey during the aftermath of the recent global recession. Two markers of peripheral inflammation: C-reactive protein (CRP) and fibrinogen were assessed across employment groups (unemployed; permanent, temporary, and self-employed), controlling for individual, socio-demographic and health variables to give greater context to our understanding of how employment status influences health. After controlling for relevant confounds, unemployment was associated with higher levels of fibrinogen but not CRP. Subsequent analyses of employment subgroup revealed the temporary employed have similar levels of fibrinogen to the unemployed, and may therefore be at a similar health disadvantage. The findings confirm that unemployment is associated with increases in one marker of peripheral inflammation, but that this health protection is not conferred to those in precarious employment.     

Subthalamic nucleus deep brain stimulation suppresses neuroinflammation by Fractalkine pathway in Parkinson’s disease rat model

Subthalamic nucleus deep brain stimulation (STN-DBS) is widely used to treat patients with Parkinson’s disease (PD), and recent studies have shown that it is more beneficial for early stages, suggesting a potential neuroprotective effect. And the neuroinflammation plays an indispensable role in progress of PD. However, the underlying mechanisms are not well understood. The aim of this study was to investigate the effect of STN-DBS on neuroinflammation and the potential pathway. To address this question, we established a rat PD model by unilateral 6-hydroxydopamine injection into the left striatum and implanted stimulation leads into the ipsilateral STN to deliver electrical stimulation for a week. The neuroprotective effects of STN-DBS were examined by molecular biology techniques, including western blotting, immunohistochemistry and so on. We found that motor deficits were alleviated by STN-DBS, with increased survival of dopaminergic neurons in the substantia nigra (SN). Furthermore, STN-DBS decreased Fractalkine (CX3CL1) and its receptor (CX3CR1) expression. Meanwhile, the suppressed microglia activation and nuclear factor-κB expression, decrease in the levels of pro-inflammatory cytokine interleukin (IL)-1β and IL-6 and increase in anti-inflammatory cytokine IL-4, downregulated IL-1 receptor, extracellular signal-regulated kinase (ERK) and cleaved-caspase3 were also observed in SN of PD models received STN-DBS. In conclusion, we observed a significant association between the suppressed neuroinflammation and STN-DBS, which may be attributed to CX3CL1/CX3CR1 signaling. These results provide novel insight into the mechanistic basis of STN-DBS therapy for PD.     

Effects of a synbiotic on symptoms,and daily functioning in attention deficit hyperactivity disorder – A double-blind randomized controlled trial

Some prebiotics and probiotics have been proposed to improve psychiatric symptoms in children with autism. However, few studies were placebo-controlled, and there is no study on persons with an attention deficit hyperactivity disorder (ADHD) diagnosis. Our aim was to study effects of Synbiotic 2000 on psychiatric symptoms and functioning in children and adults with ADHD without an autism diagnosis. Children and adults (n = 182) with an ADHD diagnosis completed the nine weeks randomized double-blind parallel placebo-controlled trial examining effects of Synbiotic 2000 on the primary endpoints ADHD symptoms, autism symptoms and daily functioning, and the secondary endpoint emotion regulation, measured using the questionnaires SNAP-IV, ASRS, WFIRS, SCQ, AQ and DERS-16. Levels at baseline of plasma C-reactive protein and soluble vascular cell adhesion molecule-1 (sVCAM-1), central to leukocyte-endothelial cell adhesion facilitating inflammatory responses in tissues, were measured using Meso Scale Discovery. Synbiotic 2000 and placebo improved ADHD symptoms equally well, and neither active treatment nor placebo had any statistically significant effect on functioning or sub-diagnostic autism symptoms. However, Synbiotic 2000, specifically, reduced sub-diagnostic autism symptoms in the domain restricted, repetitive and stereotyped behaviors in children, and improved emotion regulation in the domain of goal-directed behavior in adults. In children with elevated sVCAM-1 levels at baseline as well as in children without ADHD medication, Synbiotic 2000 reduced both the total score of autism symptoms, and the restricted, repetitive and stereotyped behaviors. In adults with elevated sVCAM-1 at baseline, Synbiotic 2000 significantly improved emotion regulation, both the total score and four of the five subdomains. To conclude, while no definite Synbiotic 2000-specific effect was detected, the analysis of those with elevated plasma sVCAM-1 levels proposed a reduction of autism symptoms in children and an improvement of emotion regulation in adults with ADHD.Trial registration number: ISRCTN57795429.     

Kynurenine pathway is altered in BDNF Val66Met knock-in mice: Effect of physical exercise

The Brain-Derived Neurotrophic Factor (BDNF) Val66Met polymorphism has been correlated with increased predisposition to develop cognitive and psychiatric disorders, and with a reduced response to some therapeutic treatments. However, the mechanisms underlying these impairments are currently not completely understood. Remarkably, kynurenine pathway alterations have also been implicated in cognitive and psychiatric disorders. Moreover, recent evidence suggests that physical exercise may promote beneficial effects by controlling kynurenine metabolism in the muscle.The aim of the present study was to assess whether the kynurenine pathway was differentially regulated in sedentary and exercising wild-type (BDNF^Val/Val) and homozygous knock-in BDNF Val66Met (BDNF^Met/Met) mice. We found that plasma and hippocampal levels of kynurenic acid and the hippocampal mRNA levels of IDO1 and KAT2 protein levels were increased in BDNF^Met/Met mice and were not modulated by physical exercise. On the contrary, KAT1 protein levels in the gastrocnemius muscle were reduced, whereas MCP1 mRNA in the gastrocnemius muscle and GFAP protein in the hippocampus were increased in BDNF^Met/Met mice compared to BDNF^Val/Val mice, and reduced by physical exercise. Physical exercise increased plasmatic kynurenine levels only in BDNF^Met/Met mice, and protein levels of KAT1 and KAT4 in the gastrocnemius muscle and hippocampus respectively, regardless of the genotype. Finally, we found that physical exercise was able to enhance the hippocampal-dependent memory only in the BDNF^Val/Val mice. Overall our results showing an overactivation of the kynurenine pathway in the BDNF^Met/Met mice may suggest a possible mechanism underlying the cognitive deficits reported in the BDNF Val66Met carriers.