Liver X receptor (LXR) α and β are members of the nuclear receptor superfamily of ligand-activated transcription factors. Best known for triggering “reverse cholesterol transport” gene programs upon their activation by endogenous oxysterols, LXRs have recently also been implicated in regulation of innate immunity. In this study, we define a role for LXRs in regulation of pulmonary inflammation and host defense and identify the lung and neutrophil as novel in vivo targets for pharmacologic LXR activation. LXR is expressed in murine alveolar macrophages, alveolar epithelial type II cells, and neutrophils. Treatment of mice with TO-901317, a synthetic LXR agonist, reduces influx of neutrophils to the lung triggered by inhaled LPS, intratracheal KC chemokine, and intratracheal Klebsiella pneumoniae and impairs pulmonary host defense against this bacterium. Pharmacologic LXR activation selectively modulates airspace cytokine expression induced by both LPS and K. pneumoniae. Moreover, we report for the first time that LXR activation impairs neutrophil motility and identify inhibition of chemokine-induced RhoA activation as a putative underlying mechanism. Taken together, these data define a novel role for LXR in lung pathophysiology and neutrophil biology and identify pharmacologic activation of LXR as a potential tool for modulation of innate immunity in the lung.
Although gliosis is a normal response to brain injury, reports on the extent of astrogliosis in the degenerating substantia nigra in Parkinson's disease (PD) are conflicting. It has also been recently suggested that accumulation of nigral α-synuclein in this disorder might suppress astrocyte activation which in turn could exacerbate the degenerative process. This study examined brain protein levels (intact protein, fragments, and aggregates, if any) of astroglial markers and their relationship to α-synuclein in PD and in the positive control parkinson-plus conditions multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). Autopsied brain homogenates of patients with PD (n=10), MSA (n=11), PSP (n=11) and matched controls (n=10) were examined for the astroglial markers glial fibrillary acidic protein (GFAP), vimentin, and heat shock protein-27 (Hsp27) by quantitative immunoblotting. As expected, both MSA (putamen > substantia nigra > caudate > frontal cortex) and PSP (substantia nigra > caudate > putamen, frontal cortex) showed widespread but regionally specific pattern of increased immunoreactivity of the markers, in particular for the partially proteolyzed fragments (all three) and aggregates (GFAP). In contrast, immunoreactivity of the three markers was largely normal in PD in brain regions examined with the exception of trends for variably increased levels of cleaved vimentin in substantia nigra and frontal cortex. In patients with PD, GFAP levels in the substantia nigra correlated inversely with α-synuclein accumulation whereas the opposite was true for MSA. Our biochemical findings of generally normal protein levels of astroglial markers in substantia nigra of PD, and negative correlation with α-synuclein concentration, are consistent with some recent neuropathology reports of mild astroglial response and with the speculation that astrogliosis might be suppressed in this disorder by excessive α-synuclein accumulation. Should astrogliosis protect, to some extent, the degenerating substantia nigra from damage, therapeutics aimed at normalization of astrocyte reaction in PD could be helpful.
The common functional single-nucleotide polymorphism (rs324420, C385A) of the endocannabinoid inactivating enzyme fatty acid amide hydrolase (FAAH) has been associated with anxiety disorder relevant phenotype and risk for addictions. Here, we tested whether the FAAH polymorphism affects in vivo binding of the FAAH positron emission tomography (PET) probe [11 C]CURB ([ 11 C-carbonyl]-6-hydroxy-[1,10-biphenyl]-3-yl cyclohexylcarbamate (URB694)). Participants (n = 24) completed one [ 11 C]CURB/PET scan and were genotyped for rs324420. Relative to C/C (58%), A-allele carriers (42%) had 23% lower [11 C]CURB binding (λk 3 ) in brain. We report evidence that the genetic variant rs324420 in FAAH is associated with measurable differences in brain FAAH binding as per PET [ 11 C]CURB measurement.
Background One of the major mechanisms for terminating the actions of the endocannabinoid anandamide is hydrolysis by fatty acid amide hydrolase (FAAH) and inhibitors of the enzyme were suggested as potential treatment for human cannabis dependence. However, the status of brain FAAH in cannabis use disorder is unknown. Methods Brain FAAH binding was measured with positron emission tomography and [11C]CURB in 22 healthy control subjects and ten chronic, frequent cannabis users during early abstinence. The FAAH genetic polymorphism (rs324420) and blood, urine and hair levels of cannabinoids and metabolites were determined. Results In cannabis users FAAH binding was significantly lower by 14–20% across the brain regions examined as compared to matched control subjects (overall Cohen’s d=0.96). Lower binding was negatively correlated with cannabinoid concentrations in blood and urine and was associated with higher trait impulsiveness. Conclusions Lower FAAH binding levels in the brain may be a consequence of chronic and recent cannabis exposure and could contribute to cannabis withdrawal. This effect should be considered in the development of novel treatment strategies for cannabis use disorder that target FAAH and endocannabinoids. Further studies are needed to examine possible changes in FAAH binding during prolonged cannabis abstinence and whether lower FAAH binding predates drug use.
Positron emission tomography with [11 C]CURB was recently developed to quantify fatty acid amide hydrolase (FAAH), the enzyme responsible for hydrolyzing the endocannabinoid anandamide. This study investigated the test-retest reliability of [ 11 C]CURB as well as its in vivo specificity and the validity of the kinetic model by using the highly specific FAAH inhibitor, PF-04457845. Five healthy volunteers completed test-retest [11 C]CURB scans 1 to 2 months apart and six subjects completed baseline and blocking scans on the same day after PF-04457845 (p.o.) administration (1, 4, or 20 mg; n = 2 each). The composite parameter λk 3 (an index of FAAH activity, λ = K 1 /k 2 ) was estimated using an irreversible two-tissue compartment model with plasma input function. There were no clinically observable responses to oral PF-04457845 or [11 C]CURB injection. Oral administration of PF-04457845 reduced [ 11 C] CURB binding to a homogeneous level at all three doses, with λk 3 values decreased by ⩾ 91%. Excellent reproducibility and good reliability (test-retest variability = 9%; intraclass correlation coefficient = 0.79) were observed across all regions of interest investigated. Our findings suggest that λk 3 /[11 C]CURB is a reliable, highly sensitive, and selective tool to measure FAAH activity in human brain in vivo. Moreover, PF-04457845 is a highly potent FAAH inhibitor (495% inhibition at 1 mg) in living human brain.
The endocannabinoid enzyme, fatty acid amide hydrolase (FAAH), has been proposed as a therapeutic target for alcohol use disorder (AUD) and co-morbid psychiatric illnesses. Investigating this target in the living human brain and its relationship to clinical outcome is a critical step of informed drug development. Our objective was to establish whether brain FAAH levels are low in individuals with AUD and related to drinking behavior. In this pilot study, treatment-seeking patients with AUD completed two PET scans with the FAAH radiotracer [C-11]CURB after 3-7 days (n = 14) and 2-4 weeks (n = 9) of monitored abstinence. Healthy controls (n = 25) completed one scan. FAAH genetic polymorphism (rs324420) and blood concentrations of anandamide and other N-acylethanolamines metabolized by FAAH were determined and AUD symptoms assessed. In AUD, brain FAAH levels were globally lower than controls during early abstinence (F(1,36) = 5.447; p = 0.025)) and FAAH substrates (anandamide, oleoylethanolamide, and N-docosahexaenoylethanolamide) were significantly elevated (30-67%). No significant differences in FAAH or FAAH substrates were noted after 2-4 weeks abstinence. FAAH levels negatively correlated with drinks per week (r = −0.57, p = 0.032) and plasma concentrations of the three FAAH substrates (r > 0.57; p < 0.04)). Our findings suggest that early abstinence from alcohol in AUD is associated with transiently low brain FAAH levels, which are inversely related to heavier alcohol use and elevated plasma levels of FAAH substrates. Whether low FAAH is an adaptive beneficial response to chronic alcohol is unknown. Therapeutic strategies focusing on FAAH inhibition should consider the possibility that low FAAH during early abstinence may be related to drinking.
The American College of Cardiology/American Heart Association (ACC/AHA) updated its guideline redefining the classification of hypertension and the blood pressure cut-off in 2017. The current cut-offs for stage 1 hypertension of 130 mm Hg systolic blood pressure or 80 mm Hg diastolic blood pressure replace the previous cut-offs of 140 mm Hg systolic blood pressure or 90 mm Hg diastolic blood pressure which were based on the ACC/AHA guidelines from 1988. However, the blood pressure cut-off for the obstetric population still remains as 140/90 mm Hg despite the scarcity of evidence for it. Recent American College of Obstetricians and Gynecologists (ACOG) bulletins for pregnant women have not reflected the new ACC/AHA change of guideline. We reviewed a mounting body of evidence prompting the implementation of the new ACC/AHA guidelines for the obstetric population. These studies examined maternal and fetal outcomes applying the new ACC/AHA guidelines during antepartum or postpartum care.
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