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Current Opinion in Structural Biology Jun 2023Over the past three years (2020-2022) more structures of GPCRs have been determined than in the previous twenty years (2000-2019), primarily of GPCR complexes that are... (Review)
Review
Over the past three years (2020-2022) more structures of GPCRs have been determined than in the previous twenty years (2000-2019), primarily of GPCR complexes that are large enough for structure determination by single-particle cryo-EM. This review will present some structural highlights that have advanced our molecular understanding of promiscuous G protein coupling, how a G protein receptor kinase and β-arrestins couple to GPCRs, and GPCR dimerisation. We will also discuss advances in the use of gene fusions, nanobodies, and F fragments to facilitate the structure determination of GPCRs in the inactive state that, on their own, are too small for structure determination by single-particle cryo-EM.
Topics: Receptors, G-Protein-Coupled; Cryoelectron Microscopy; GTP-Binding Proteins
PubMed: 36963163
DOI: 10.1016/j.sbi.2023.102574 -
Metabolites Jan 2024Recent research has identified a unique population of 'Lean Mass Hyper-Responders' (LMHR) who exhibit increases in LDL cholesterol (LDL-C) in response to...
Recent research has identified a unique population of 'Lean Mass Hyper-Responders' (LMHR) who exhibit increases in LDL cholesterol (LDL-C) in response to carbohydrate-restricted diets to levels ≥ 200 mg/dL, in association with HDL cholesterol ≥ 80 mg/dL and triglycerides ≤ 70 mg/dL. This triad of markers occurs primarily in lean metabolically healthy subjects, with the magnitude of increase in LDL-C inversely associated with body mass index. The lipid energy model has been proposed as one explanation for LMHR phenotype and posits that there is increased export and subsequent turnover of VLDL to LDL particles to meet systemic energy needs in the setting of hepatic glycogen depletion and low body fat. This single subject crossover experiment aimed to test the hypothesis that adding carbohydrates, in the form of Oreo cookies, to an LMHR subject on a ketogenic diet would reduce LDL-C levels by a similar, or greater, magnitude than high-intensity statin therapy. The study was designed as follows: after a 2-week run-in period on a standardized ketogenic diet, study arm 1 consisted of supplementation with 12 regular Oreo cookies, providing 100 g/d of additional carbohydrates for 16 days. Throughout this arm, ketosis was monitored and maintained at levels similar to the subject's standard ketogenic diet using supplemental exogenous d-β-hydroxybutyrate supplementation four times daily. Following the discontinuation of Oreo supplementation, the subject maintained a stable ketogenic diet for 3 months and documented a return to baseline weight and hypercholesterolemic status. During study arm 2, the subject received rosuvastatin 20 mg daily for 6 weeks. Lipid panels were drawn water-only fasted and weekly throughout the study. Baseline LDL-C was 384 mg/dL and reduced to 111 mg/dL (71% reduction) after Oreo supplementation. Following the washout period, LDL-C returned to 421 mg/dL, and was reduced to a nadir of 284 mg/dL with 20 mg rosuvastatin therapy (32.5% reduction). In conclusion, in this case study experiment, short-term Oreo supplementation lowered LDL-C more than 6 weeks of high-intensity statin therapy in an LMHR subject on a ketogenic diet. This dramatic metabolic demonstration, consistent with the lipid energy model, should provoke further research and not be seen as health advice.
PubMed: 38276308
DOI: 10.3390/metabo14010073 -
Science Advances Sep 2023Neuron-derived extracellular vesicles (NDEVs) are potential biomarkers of neurological diseases although their reliable molecular target is not well established. Here,...
Neuron-derived extracellular vesicles (NDEVs) are potential biomarkers of neurological diseases although their reliable molecular target is not well established. Here, we demonstrate that ATPase Na/K transporting subunit alpha 3 (ATP1A3) is abundantly expressed in extracellular vesicles (EVs) isolated from induced human neuron, brain, cerebrospinal fluid, and plasma in comparison with the presumed NDEV markers NCAM1 and L1CAM by using super-resolution microscopy and biochemical assessments. Proteomic analysis of immunoprecipitated ATP1A3 brain-derived EVs shows higher enrichment of synaptic markers and cargo proteins relevant to Alzheimer's disease (AD) compared to NCAM1 or LICAM EVs. Single particle analysis shows the elevated amyloid-β positivity in ATP1A3 EVs from AD plasma, providing better diagnostic prediction of AD over other plasma biomarkers. Thus, ATP1A3 is a reliable target to isolate NDEV from biofluids for diagnostic research.
Topics: Humans; Proteomics; Brain; Alzheimer Disease; Extracellular Vesicles; Neural Cell Adhesion Molecules; Neurons; Sodium-Potassium-Exchanging ATPase
PubMed: 37713494
DOI: 10.1126/sciadv.adi3647 -
Respiratory Research Sep 2023Small airways disease plays a key role in the pathogenesis of chronic obstructive pulmonary disease (COPD) and is a major cause of obstruction; therefore, it is a...
BACKGROUND
Small airways disease plays a key role in the pathogenesis of chronic obstructive pulmonary disease (COPD) and is a major cause of obstruction; therefore, it is a critical pharmacotherapy target. This study evaluated lung deposition of two inhaled corticosteroid (ICS)/long-acting β-agonist/long-acting muscarinic antagonist single-inhaler triple therapies using in silico functional respiratory imaging (FRI). Deposition was assessed using real-world inhalation profiles simulating everyday use where optimal inhalation may be compromised.
METHODS
Three-dimensional airway models were produced from 20 patients with moderate-to-very severe COPD. Total, central, and regional small airways deposition as a percentage of delivered dose of budesonide/glycopyrronium/formoterol fumarate dihydrate (BGF) 160/7.2/5 µg per actuation and fluticasone furoate/umeclidinium/vilanterol (FF/UM/VI) 100/62.5/25 µg were evaluated using in silico FRI based on in vitro aerodynamic particle size distributions of each device. Simulations were performed using multiple inhalation profiles of varying durations and flow rates representing patterns suited for a pressurized metered-dose inhaler or dry-powder inhaler (four for BGF, two for FF/UM/VI, with one common profile). For the common profile, deposition for BGF versus FF/UM/VI was compared post-hoc using paired t-tests.
RESULTS
Across inhalation profiles, mean total lung deposition was consistently higher with BGF (47.0-54.1%) versus FF/UM/VI (20.8-22.7%) and for each treatment component, with greater deposition for BGF also seen in the central large airways. Mean regional small airways deposition was also greater across inhalation profiles with BGF (16.9-23.6%) versus FF/UM/VI (6.8-8.7%) and for each treatment component. For the common profile, total, central, and regional small airways deposition were significantly greater for BGF versus FF/UM/VI (nominal p < 0.001), overall and for treatment components; notably, regional small airways deposition of the ICS components was approximately five-fold greater with budesonide versus fluticasone furoate (16.1% vs. 3.3%).
CONCLUSIONS
BGF was associated with greater total, central, and small airways deposition for all components versus FF/UM/VI. Importantly, using an identical inhalation profile, there was an approximately five-fold difference in small airways deposition for the ICS components, with only a small percentage of the ICS from FF/UM/VI reaching the small airways. Further research is needed to understand if the enhanced delivery of BGF translates to clinical benefits.
Topics: Humans; Pulmonary Disease, Chronic Obstructive; Fluticasone; Budesonide; Dry Powder Inhalers; Lung
PubMed: 37742015
DOI: 10.1186/s12931-023-02534-y -
Foods (Basel, Switzerland) Jun 2023A Pickering emulsion was prepared using β-cyclodextrin (β-CD) and a cinnamaldehyde (CA)/β-CD composite as emulsifiers and corn oil, camellia oil, lard oil, and fish...
A Pickering emulsion was prepared using β-cyclodextrin (β-CD) and a cinnamaldehyde (CA)/β-CD composite as emulsifiers and corn oil, camellia oil, lard oil, and fish oil as oil phases. It was confirmed that Pickering emulsions prepared with β-CD and CA/β-CD had good storage stability. The rheological experiments showed that all emulsions had G' values higher than G″, thus confirming their gel properties. The results of temperature scanning rheology experiments revealed that the Pickering emulsion prepared with β-CD and CA/β-CD composites had high stability, in the range of 20-65 °C. The chewing properties of Pickering emulsions prepared by β-CD and corn oil, camellia oil, lard, and herring oil were 8.02 ± 0.24 N, 7.94 ± 0.16 N, 36.41 ± 1.25 N, and 5.17 ± 0.13 N, respectively. The chewing properties of Pickering emulsions made with the CA/β-CD composite and corn oil, camellia oil, lard, and herring oil were 2.51 ± 0.05 N, 2.56 ± 0.05 N, 22.67 ± 1.70 N, 3.83 ± 0.29 N, respectively. The texture properties confirmed that the CA/β-CD-composite-stabilized-emulsion had superior palatability. After 28 days at 50 °C, malondialdehyde (MDA) was detected in the emulsion. Compared with the β-CD and CA + β-CD emulsion, the CA/β-CD composite emulsion had the lowest content of MDA (182.23 ± 8.93 nmol/kg). The in vitro digestion results showed that the free fatty acid (FFA) release rates of the CA/β-CD composite emulsion (87.49 ± 3.40%) were higher than those of the β-CD emulsion (74.32 ± 2.11%). This strategy provides ideas for expanding the application range of emulsifier particles and developing food-grade Pickering emulsions with antioxidant capacity.
PubMed: 37372577
DOI: 10.3390/foods12122366 -
International Journal of Molecular... Jul 2023Radiopharmaceuticals are rapidly developing as a field, with the successful use of targeted beta emitters in neuroendocrine tumors and prostate cancer serving as... (Review)
Review
Radiopharmaceuticals are rapidly developing as a field, with the successful use of targeted beta emitters in neuroendocrine tumors and prostate cancer serving as catalysts. Targeted alpha emitters are in current development for several potential oncologic indications. Herein, we review the three most prevalently studied conjugated/chelated alpha emitters (actinium, lead, and astatine) and focus on contemporary clinical trials in an effort to more fully appreciate the breadth of the current evaluation. Phase I trials targeting multiple diseases are now underway, and at least one phase III trial (in selected neuroendocrine cancers) is currently in the initial stages of recruitment. Combination trials are now also emerging as alpha emitters are integrated with other therapies in an effort to create solutions for those with advanced cancers. Despite the promise of targeted alpha therapies, many challenges remain. These challenges include the development of reliable supply chains, the need for a better understanding of the relationships between administered dose and absorbed dose in both tissue and tumor and how that predicts outcomes, and the incomplete understanding of potential long-term deleterious effects of the alpha emitters. Progress on multiple fronts is necessary to bring the potential of targeted alpha therapies into the clinic.
Topics: Humans; Male; Alpha Particles; Prostatic Neoplasms; Radiopharmaceuticals; Clinical Trials as Topic
PubMed: 37511386
DOI: 10.3390/ijms241411626