Enoxaparin Attenuates Acute Lung Injury and Inflammasome Activation after Traumatic Brain Injury.

Traumatic brain injury (TBI) patients frequently develop cardiopulmonary system complications such as acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). However, the mechanism by which TBI causes ALI/ARDS is not fully understood. Here, we used a severe TBI model to examine the effects of a low-molecular-weight heparin, enoxaparin, on inflammasome activation and lung injury damage. We investigated whether enoxaparin inhibits ALI and inflammasome signaling protein expression in the brain and lungs after TBI in mice. C57/BL6 mice were subjected to severe TBI and were treated with vehicle or 1 mg/kg of enoxaparin 30 min after injury. Lung and brain tissue were collected 24 h post-TBI and were analyzed by immunoblotting for expression of the inflammasome proteins, caspase-1 and interleukin (IL)-1ß. In addition, lung tissue was collected for histological analysis to determine ALI scoring and neutrophil and macrophage infiltration post-injury. Our data show that severe TBI induces increased expression of inflammasome proteins caspase-1 and IL-1ß in the brain and lungs of mice after injury. Treatment with enoxaparin attenuated inflammasome expression in the brain and lungs 24 h after injury. Enoxaparin significantly decreased ALI score as well as neutrophil and macrophage infiltration in lungs at 24 h after injury. This study demonstrates that enoxaparin attenuates ALI and inhibits inflammasome expression in the brain and lungs after TBI. These findings support the hypothesis that inhibition of the neural-respiratory inflammasome axis that is activated after TBI may have therapeutic potential.

Inflammasome Proteins as Inflammatory Biomarkers of Age-Related Macular Degeneration.

Purpose: Age-related macular degeneration (AMD) can result in severe vision loss and blurriness in the older population. The early and intermediate stages of AMD typically start without noticeable symptoms and can only be detected with a comprehensive eye exam. Because of the quiet onset of the disease, it is necessary to identify potential biomarkers to aid in the diagnosis, staging, and association with disease onset. Inflammasome signaling proteins are prominent biomarkers in the central nervous system, and the inflammasome has been shown to play a role in the innate inflammatory response in aging and AMD. Methods: Serum from healthy controls and AMD patients were analyzed for the protein levels of Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), interleukin (IL)-18 and C-reactive protein (CRP) to determine cutoff points, positive and negative predictive values, and receiver operator characteristic curves, as well as univariate and multivariate linear and logistic regression models. Results: ASC, IL-18, and CRP were elevated in the serum of AMD patients when compared to healthy controls. The area under the curve (AUC) for ASC was 0.98 with a cutoff point of 365.6 pg/mL, whereas IL-18 had an AUC of 0.73 and a cutoff point of 242.4 pg/mL, and the AUC for CRP was 0.67 with a cutoff point of 8,684,152 pg/mL. Levels of IL-18 had a statistically significant linear correlation with that of ASC with an adjusted R2 of 0.1906, indicating that 19% of IL-18 could be explained by ASC protein levels in serum. Moreover, a logistic regression model for the diagnosis of AMD consists of ASC and having a diagnosis of hypertension, indicating that these two factors (elevated levels of ASC and a diagnosis of hypertension [HTN]) are associated with the diagnosis of AMD. Conclusions: ASC, IL-18, and CRP are elevated in patients with AMD, and the protein levels of IL-18 are partially the result of ASC protein expression. Moreover, elevated protein levels of ASC in serum and a diagnosis of HTN increase the odds of patients having a diagnosis of AMD. Translational Relevance: Biomarkers of AMD may be used to monitor disease risk, response to treatment and disease progression.

Assessment of the FTO gene polymorphisms (rs1421085, rs17817449 and rs9939609) in exercise-trained men and women: the effects of a 4-week hypocaloric diet.

BACKGROUND: Variations in the fat mass and obesity-associated gene (FTO) are associated with obesity; however, it is unclear if changes in energy intake affect the adaptive response to caloric restriction in those with risk variants. The three FTO single nucleotide polymorphisms (SNPs), rs1421085, rs17817449 and rs9939609, are in strong linkage disequilibrium. Thus, the purpose of this investigation was to determine the role of these FTO SNPs vis-à-vis the effects of a 4-week hypocaloric diet on body composition in exercise-trained men and women. Two salivary biomarkers that associate with energy expenditure were also assessed (cortisol and salivary alpha-amylase, sAA). METHODS: Forty-seven exercise-trained men (n = 11) and women (n = 36) (mean ± SD: age 32 ± 9 years; height 169 ± 8 cm, body mass index 24.5 ± 2.9 kg/m2, hours of aerobic training per week 4.9 ± 3.8, hours of weight training per week 3.9 ± 2.4, years of training experience 13.4 ± 7.0) completed a 4-week hypocaloric diet (i.e., decrease total calories by ~ 20-25% while maintaining a protein intake of ~ 2.0 g/kg/d). Subjects were instructed to maintain the same training regimen and to decrease energy intake via carbohydrate and/or fat restriction during the treatment period. Body composition was assessed via dual-energy X-ray absorptiometry (DXA) (Model: Hologic Horizon W; Hologic Inc., Danbury CT USA). Total body water was determined via a multifrequency bioelectrical impedance (BIA) device (InBody 770). Saliva samples were collected pre and post intervention in order to genotype the participants as well as to determine the concentrations of cortisol and sAA. RESULTS: Of the 47 subjects, 15 were of normal risk for obesity whereas 32 were carriers of the FTO gene risk alleles. Subjects were grouped based on their genotype for the three FTO SNPs (i.e., rs1421085, rs17817449 and rs9939609) due to their strong linkage disequilibrium. We have classified those with the normal obesity risk as "non-risk allele" versus those that carry the "risk allele" (i.e., both heterozygous and homozygous). Both groups experienced a significant decrease in total energy intake (p < 0.01); non-risk allele: pre kcal 2081 ± 618, post kcal 1703 ± 495; risk allele: pre kcal 1886 ± 515, post kcal 1502 ± 366). Both groups lost a significant amount of body weight (p < 0.01); however, there was no difference between groups for the change (post minus pre) in each group (risk allele change: - 1.0 ± 1.2 kg, non-risk allele change: - 1.2 ± 1.4 kg). Additionally, both groups lost a significant amount of fat mass (p < 0.01) with no differences between groups for the change in fat mass (risk allele change for fat mass: 1.1 ± 0.7 kg, non-risk allele change - 0.9 ± 0.4 kg). There were no significant changes in either group for fat free mass or total body water. The change in salivary alpha-amylase or cortisol was not different between groups. CONCLUSIONS: In the short-term (i.e., 4 weeks), exercise-trained men and women consuming a hypocaloric diet that is relatively high in protein experience similar changes in body composition due exclusively to a decrement in fat mass and independent of FTO allele status. Therefore, weight and fat loss on a hypocaloric diet is, at least in the short-term, unaffected by the FTO gene.