The systemic expression of the bile acid (BA) sensor farnesoid X receptor (FXR) has led to promising new therapies targeting cholesterol metabolism, triglyceride production, hepatic steatosis and ...biliary cholestasis. In contrast to systemic therapy, bile acid release during a meal selectively activates intestinal FXR. By mimicking this tissue-selective effect, the gut-restricted FXR agonist fexaramine (Fex) robustly induces enteric fibroblast growth factor 15 (FGF15), leading to alterations in BA composition, but does so without activating FXR target genes in the liver. However, unlike systemic agonism, we find that Fex reduces diet-induced weight gain, body-wide inflammation and hepatic glucose production, while enhancing thermogenesis and browning of white adipose tissue (WAT). These pronounced metabolic improvements suggest tissue-restricted FXR activation as a new approach in the treatment of obesity and metabolic syndrome.
Activation of the nuclear hormone receptor peroxisome proliferator-activated receptor δ (PPARδ) has been shown to improve insulin resistance, adiposity, and plasma HDL levels. However, its ...antiatherogenic role remains controversial. Here we report atheroprotective effects of PPARδ activation in a model of angiotensin II (AngII)-accelerated atherosclerosis, characterized by increased vascular inflammation related to repression of an antiinflammatory corepressor, B cell lymphoma-6 (Bcl-6), and the regulators of G protein-coupled signaling (RGS) proteins RGS4 and RGS5. In this model, administration of the PPARδ agonist GW0742 (1 or 10 mg/kg) substantially attenuated AngII-accelerated atherosclerosis without altering blood pressure and increased vascular expression of Bcl-6, RGS4, and RGS5, which was associated with suppression of inflammatory and atherogenic gene expression in the artery. In vitro studies demonstrated similar changes in AngII-treated macrophages: PPARδ activation increased both total and free Bcl-6 levels and inhibited AngII activation of MAP kinases, p38, and ERK1/2. These studies uncover crucial proinflammatory mechanisms of AngII and highlight actions of PPARδ activation to inhibit AngII signaling, which is atheroprotective.
Brown adipose tissue (BAT) adaptively transfers energy from glucose and fat into heat by inducing a gene network that uncouples mitochondrial electron transport. However, the innate transcription ...factors that enable the rapid adaptive response of BAT are unclear. Here, we identify estrogen-related receptor gamma (ERRγ) as a critical factor for maintaining BAT identity. ERRγ is selectively expressed in BAT versus WAT, in which, in the absence of PGC1α, it drives a signature transcriptional network of thermogenic and oxidative genes in the basal (i.e., thermoneutral) state. Mice lacking ERRγ in adipose tissue (ERRγKO mice) display marked downregulation of BAT-selective genes that leads to a pronounced whitening of BAT. Consistent with the transcriptional changes, the thermogenic capacity of ERRγKO mice is severely blunted, such that they fail to survive an acute cold challenge. These findings reveal a role for ERRγ as a critical thermoneutral maintenance factor required to prime BAT for thermogenesis.
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•ERRγ is a critical factor for maintaining BAT identity•ERRγ drives a transcriptional network of thermogenic genes in the basal state•Adipose ERRγKO mice exhibit decreased thermogenic gene expression at thermoneutrality•Adipose ERRγKO mice fail to survive an acute cold challenge
Ahmadian et al. find that estrogen-related receptor gamma (ERRγ) is a critical factor for maintaining brown fat identity. They find that ERRγ controls a transcriptional network of thermogenic genes in the basal state. Mice lacking ERRγ exhibit a whitening of brown fat and are unable to survive an acute cold challenge.
With the recent addition of airflow and respiratory effort channels, our group has observed central and mixed apnea events during drug-induced sleep endoscopy (DISE). We measured the frequency and ...timing of sentinel central and/or mixed events (SCents), as well as assessed for differences in velum, oropharynx, tongue, and epiglottis (VOTE) classification compared to obstructive events.
Prospective single-cohort study.
Tertiary Care Academic Medical Center.
Patients underwent DISE between June 2020 and November 2022. Nasal airflow, thoracoabdominal effort belt signals, and videoendoscopy were simultaneously captured. Demographics, sleep study, and DISE data were compared among patients with and without SCents using Student's T tests or χ
tests.
On average, the cohort (n = 103) was middle-aged (53.5 ± 12.1 years), overweight (body mass index of 29.7 ± 5.3 kg/m
), and had severe obstructive sleep apnea (apnea-hypopnea index of 30.7 ± 18.7 events/h). Forty-seven patients (46%) were found to have at least 1 SCent. Among those with SCent, 45 (95.7%) transitioned to obstructive pathology after an average of 7.91 ± 2.74 minutes, with at least 95% of patients expected to do so within 12.57 minutes. Twenty-nine out of 47 patients (61.2% 95% confidence interval: 46.4.9%, 75.5%) with SCent had meaningful differences between central/mixed and obstructive VOTE scores.
Central events were present in almost half of our cohort. At least 95% of patients were expected to transition to obstructive events within 12 to 13 minutes of propofol initiation. In addition, over half of patients demonstrate significantly different VOTE scores between central and obstructive events. These factors should raise awareness of central events and scoring passive apneas during DISE and consider delaying VOTE scoring.
A pulmonary vein atlas for radiotherapy planning Walls, Gerard M; McCann, Conor; Ball, Peter ...
Radiotherapy and oncology,
July 2023, 2023-Jul, 2023-07-00, 20230701, Letnik:
184
Journal Article
Recenzirano
Odprti dostop
•intrathoracic radiation is associated with short- and medium-term cardiac events.•conduction abnormalities such as AF are common after lung/oesophageal treatment.•in general cardiology ...arrhythmogenesis is commonly localised to the pulmonary veins.•radiation-induced pulmonary vein inflammation/fibrosis may cause conduction issues.•a multidisciplinary team developed a pulmonary vein atlas for RT planning CT scans.
Cardiac arrhythmia is a recognised potential complication of thoracic radiotherapy, but the responsible cardiac substructures for arrhythmogenesis have not been identified. Arrhythmogenic tissue is commonly located in the pulmonary veins (PVs) of cardiology patients with arrhythmia, however these structures are not currently considered organs-at-risk during radiotherapy planning. A standardised approach to their delineation was developed and evaluated.
The gross and radiological anatomy relevant to atrial fibrillation was derived from cardiology and radiology literature by a multidisciplinary team. A region of interest and contouring instructions for radiotherapy computed tomography scans were iteratively developed and subsequently evaluated. Radiation oncologists (n = 5) and radiation technologists (n = 2) contoured the PVs on the four-dimensional planning datasets of five patients with locally advanced lung cancer treated with 1.8–2.75 Gy fractions. Contours were compared to reference contours agreed by the researchers using geometric and dosimetric parameters.
The mean dose to the PVs was 35% prescription dose. Geometric and dosimetric similarity of the observer contours with reference contours was fair, with an overall mean Dice of 0.80 ± 0.02. The right superior PV (mean DSC 0.83 ± 0.02) had better overlap than the left (mean DSC 0.80 ± 0.03), but the inferior PVs were equivalent (mean DSC of 0.78). The mean difference in mean dose was 0.79 Gy ± 0.71 (1.46% ± 1.25).
A PV atlas with multidisciplinary approval led to reproducible delineation for radiotherapy planning, supporting the utility of the atlas in future clinical radiotherapy cardiotoxicity research encompassing arrhythmia endpoints.
SB-399885 (N-3,5-dichloro-2-(methoxy)phenyl-4-(methoxy)-3-(1-piperazinyl)benzenesulfonamide) has high affinity for human recombinant and native 5-HT(6) receptors, with pK(i) values 9.11+/-0.03 and ...9.02+/-0.05, respectively and is a potent competitive antagonist (pA(2) 7.85+/-0.04). It displays over 200-fold selectivity for the 5-HT(6) receptor over all other receptors, ion channels and enzymes tested to date. SB-399885 inhibited ex vivo (125)ISB-258585 (4-Iodo-N-4-methoxy-3-(4-methyl-piperazin-1-yl)-phenyl-benzenesulfonamide) binding with an ED(50) of 2.0+/-0.24 mg/kg p.o. in rats. It had a minimum effective dose of 1 mg/kg p.o. in a rat maximal electroshock seizure threshold test and a long duration of action, overall demonstrating an excellent pharmacokinetic-pharmacodynamic correlation. Repeated administration of this agent (10 mg/kg p.o., b.i.d. for 7 days) significantly reversed a scopolamine-induced deficit (0.5 mg/kg i.p.) in a rat novel object recognition paradigm. Moreover, in aged rats (22 months old) SB-399885 (10 mg/kg p.o., b.i.d. for 7 days) fully reversed the age-dependent deficit in water maze spatial learning compared to vehicle-treated age-matched controls and significantly improved recall of the task measured by increases in the searching of the target quadrant on post-training days 1, 3 and 7. In vivo microdialysis in the rat medial prefrontal cortex demonstrated that acute SB-399885 (10 mg/kg p.o.) significantly increased extracellular acetylcholine levels. These data demonstrate that SB-399885 is a potent, selective, brain penetrant, orally active 5-HT(6) receptor antagonist with cognitive enhancing properties that are likely to be mediated by enhancements of cholinergic function. These studies provide further support for the potential therapeutic utility of 5-HT(6) receptor antagonists in disorders characterised by cognitive deficits such as Alzheimer's disease and schizophrenia.
6-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy-N-methyl-3-pyridinecarboxamide hydrochloride (GSK189254) is a novel histamine H(3) receptor antagonist with high affinity for human (pK(i) ...= 9.59 -9.90) and rat (pK(i) = 8.51-9.17) H(3) receptors. GSK189254 is >10,000-fold selective for human H(3) receptors versus other targets tested, and it exhibited potent functional antagonism (pA(2) = 9.06 versus agonist-induced changes in cAMP) and inverse agonism pIC(50) = 8.20 versus basal guanosine 5'-O-(3-(35)Sthio)triphosphate binding at the human recombinant H(3) receptor. In vitro autoradiography demonstrated specific (3)HGSK189254 binding in rat and human brain areas, including cortex and hippocampus. In addition, dense H(3) binding was detected in medial temporal cortex samples from severe cases of Alzheimer's disease, suggesting for the first time that H(3) receptors are preserved in late-stage disease. After oral administration, GSK189254 inhibited cortical ex vivo R-(-)-alpha-methylimidazole-2,5(n)-(3)Hhistamine dihydrochloride ((3)HR-alpha-methylhistamine) binding (ED(50) = 0.17 mg/kg) and increased c-Fos immunoreactivity in prefrontal and somatosensory cortex (3 mg/kg). Microdialysis studies demonstrated that GSK189254 (0.3-3 mg/kg p.o.) increased the release of acetylcholine, noradrenaline, and dopamine in the anterior cingulate cortex and acetylcholine in the dorsal hippocampus. Functional antagonism of central H(3) receptors was demonstrated by blockade of R-alpha-methylhistamine-induced dipsogenia in rats (ID(50) = 0.03 mg/kg p.o.). GSK189254 significantly improved performance of rats in diverse cognition paradigms, including passive avoidance (1 and 3 mg/kg p.o.), water maze (1 and 3 mg/kg p.o.), object recognition (0.3 and 1 mg/kg p.o.), and attentional set shift (1 mg/kg p.o.). These data suggest that GSK189254 may have therapeutic potential for the symptomatic treatment of dementia in Alzheimer's disease and other cognitive disorders.
Abstract Social isolation from weaning in rats produces behavioural and hippocampal structural changes at adulthood. Here, rats were group or isolation reared for eight-weeks. Following the initial ...four-week period of rearing, fluoxetine (10 mg/kg i.p.) was administered for 28 days. Changes in recognition memory, hippocampal monoamines, and cytoskeletal microtubules were investigated. Isolation-rearing for four- or eight-weeks produced recognition memory deficits that were not reversed by fluoxetine. Eight-weeks of isolation decreased α-tubulin acetylation (Acet-Tub) and the tyrosinated/detyrosinated α-tubulin ratio (Tyr/Glu-Tub), suggesting major alterations in microtubule dynamics and neuronal plasticity. In grouped rats, fluoxetine decreased Acet-Tub without changes in Tyr/Glu-Tub. In isolates, fluoxetine did not affect Acet-Tub but increased Tyr/Glu-Tub. Finally, fluoxetine altered serotonin metabolism in grouped, but not in isolated animals. Therefore, isolation-rearing changes the hippocampal responses of the serotonergic and microtubular system to fluoxetine. These findings show that early-life experience induces behavioural changes paralleled by alterations in cytoskeletal and neurochemical functions.
This supportive statement examines how my upbringings influenced my cultural and societal perspectives and how I strive to challenge perceptions of race, history, and culture through my artwork. I ...include representations of people from various diasporas in drawings, prints, and animations to speak to the global reach of colorism and Eurocentrism. Influenced by the DIY nature of punk art and the urgency of protest art, I utilize materials such as Sharpies, fabric markers, collage, and cardboard. Use of cardboard suggests commercial exchange and the physical movement of goods from one place to another, as well as modern throw-away culture. Parallels are drawn between the medium of cardboard to the disposability of black and brown people and their cultures and the subsequent disinvestment in communities of color.
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