Neutrophil diversity and function in health and disease

Signal Transduction and Targeted Therapy, Год журнала: 2024, Номер 9(1)

Опубликована: Дек. 5, 2024

Abstract Neutrophils, the most abundant type of granulocyte, are widely recognized as one pivotal contributors to acute inflammatory response. Initially, neutrophils were considered mobile infantry innate immune system, tasked with immediate response invading pathogens. However, recent studies have demonstrated that versatile cells, capable regulating various biological processes and impacting both human health disease. Cytokines other active mediators regulate functional activity by activating multiple receptors on these thereby initiating downstream signal transduction pathways. Dysfunctions in disruptions neutrophil homeostasis been implicated pathogenesis numerous diseases, including cancer disorders, often due aberrant intracellular signaling. This review provides a comprehensive synthesis functions, integrating advancements this field. Moreover, it examines roles signaling pathways involved regulation activity. The pathophysiology diseases emerging therapeutic approaches targeting them also elaborated. addresses current limitations within field research, highlighting critical gaps knowledge warrant further investigation. In summary, seeks establish multidimensional model regulation, providing new perspectives for potential clinical applications research.

Язык: Английский

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Integrating molecular and cellular components of endothelial shear stress mechanotransduction

AJP Heart and Circulatory Physiology, Год журнала: 2024, Номер 327(4), С. H989 - H1003

Опубликована: Авг. 23, 2024

The lining of blood vessels is constantly exposed to mechanical forces exerted by flow against the endothelium. Endothelial cells detect these tangential (i.e., shear stress), initiating a host intracellular signaling cascades that regulate vascular physiology. Thus, health tethered endothelial cells' capacity transduce stress. Indeed, mechanotransduction stress underlies variety cardiovascular benefits, including some those associated with increased physical activity. However, impaired in aging and disease states such as obesity type 2 diabetes, precipitating development disease. Understanding stress, molecular cellular mechanisms which this process becomes defective, critical for identification novel therapeutic targets In review, we detail primary mechanosensitive structures have been implicated detecting junctional proteins platelet cell adhesion molecule-1 (PECAM-1), extracellular glycocalyx its components, ion channels piezo1. We delineate molecules are truly may simply be indispensable downstream transmission force. Furthermore, discuss how mechanosensors interact other structures, cytoskeleton membrane lipid rafts, translating biochemical signals. Based on findings date, also seek integrate view deciphering tenet

Язык: Английский

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Exploring the constitutive activation mechanism of the class A orphan GPR20

Acta Pharmacologica Sinica, Год журнала: 2024, Номер unknown

Опубликована: Сен. 10, 2024

Язык: Английский

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GHRH and the prostate

Reviews in Endocrine and Metabolic Disorders, Год журнала: 2024, Номер unknown

Опубликована: Ноя. 7, 2024

Язык: Английский

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Molecular insights into the activation mechanism of GPR156 in maintaining auditory function

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Дек. 5, 2024

The class C orphan G-protein-coupled receptor (GPCR) GPR156, which lacks the large extracellular region, plays a pivotal role in auditory function through Gi2/3. Here, we firstly demonstrate that GPR156 with high constitutive activity is essential for maintaining function, and further reveal structural basis of sustained GPR156. We present cryo-EM structures human apo GPR156–Gi3 complex, unveiling small region formed by loop 2 (ECL2) N-terminus. dimer both state Gi3 protein-coupled adopt transmembrane (TM)5/6-TM5/6 interface, indicating state. Furthermore, C-terminus G-bound subunit dual promoting G protein binding within while preventing G-free from to additional protein. Together, these results explain how maintained dimerization provide mechanistic insight into function. has been identified as regulator hair cells. authors complex activation mechanism

Язык: Английский

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SMARTpy: A Python Package for the Generation of Cavity Steric Molecular Descriptors and Applications to Diverse Systems

Digital Discovery, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

Steric molecular descriptors designed for machine learning (ML) applications are critical connecting structure–function relationships to mechanistic insight.

Язык: Английский

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Comprehensive review of extraction, purification, structural characteristics, pharmacological activities, structure-activity relationship and application of seabuckthorn protein and peptides

International Journal of Biological Macromolecules, Год журнала: 2025, Номер 294, С. 139447 - 139447

Опубликована: Янв. 5, 2025

Язык: Английский

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Efficacy and Safety of SHR8554 on Postoperative Pain in Subjects with Moderate to Severe Acute Pain Following Orthopedic Surgery: A Multicenter, Randomized, Double-blind, Dose-explored, Active-controlled, Phase II/III Clinical Trial

Pharmacological Research, Год журнала: 2025, Номер 212, С. 107576 - 107576

Опубликована: Янв. 5, 2025

Biased µ-opioid receptor (MOR) agonists enhance pain relief by selectively activating G protein-coupled signaling and minimizing β-arrestin-2 activation, resulting in fewer side effects. This multicenter Phase II/III trial evaluated the optimal dosage, efficacy, safety of SHR8554, a biased MOR agonist, for postoperative management following orthopedic surgery. In II, 121 patients were divided into four groups to receive varying patient-controlled analgesia (PCA) doses SHR8554 or morphine. III involved 320 with similar groupings, including placebo group. The primary outcome was resting summed intensity difference over 24 hours (rSPID24). Secondary outcomes included rSPID active-SPID (aSPID) at other time points, rescue received, cumulative dose analgesics, satisfaction scores. Safety endpoints treatment-emergent adverse events (TEAEs) AE special interest (AESIs). both phases, demonstrated significant analgesic efficacy. least squares (LS) mean differences rSPID24 compared morphine 0.05 mg,0.1 mg, 0.2 mg 16.8 (p = 0.01), 7.4 0.27), 0.98), respectively. confirmed efficacy 0.1 placebo, LS 15.4 0.0001) -19.8 < 0.0001), Trends secondary mirrored these findings. analysis revealed that group had higher incidences TEAEs (83.3 %) AESIs (33.3 II. Similarly, III, 81.0 %, 73.4 74.1 % groups, respectively, 61.3 group, while 29.1 20.3 24.7 12.5 conclusion, exhibited comparable experiencing moderate-to-severe acute unilateral total knee replacement ligament reconstruction TRIAL REGISTRATION: Trial Name: Study on Efficacy Injection Postoperative Analgesia Orthopedics: Multicenter, Randomized, Double Blind, Dose Exploration, Placebo/Positive Control, Clinical Registered on: chinadrugtrials.org.cn Identifier: CTR20220639.

Язык: Английский

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Ligand and Residue Free Energy Perturbations Solve the Dual Binding Mode Proposal for an A_2BAR Partial Agonist

The Journal of Physical Chemistry B, Год журнала: 2025, Номер unknown

Опубликована: Янв. 8, 2025

Adenosine receptors, particularly A2BAR, are gaining attention for their role in pathological conditions such as cancer immunotherapy, prompting the exploration promising therapeutic applications. Despite numerous selective A2BAR antagonists, lack of full agonists makes partial agonist BAY60-6583 one most interesting activators this receptor. Recent cryo-EM structures have univocally revealed binding mode nonselective ribosidic adenosine and its derivative NECA to A2BAR; however, two independent with show alternative orientations, raising question which is physiologically relevant mode. In situations this, computational simulations that accurately predict shifts free energy can complement experimental structures. Our study combines QligFEP QresFEP protocols directly compare affinity between modes well providing a direct comparison silico mutagenesis studies on each pose mutational effects. Both methods converge experimentally determined better explains both existing SAR data ligand. results allow elucidation orientation should be considered basis designing derivatives improved selectivity underscore value perturbation aiding structure-based drug design.

Язык: Английский

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The influence of phosphoinositide lipids in the molecular biology of membrane proteins: recent insights from simulations

Journal of Molecular Biology, Год журнала: 2025, Номер unknown, С. 168937 - 168937

Опубликована: Янв. 1, 2025

The phosphoinositide family of membrane lipids play diverse and critical roles in eukaryotic molecular biology. Much this biological activity derives from interactions with integral peripheral proteins, leading to modulation protein structure, function, cellular distribution. Since the discovery phosphoinositides 1940s, combined biology, biophysical, structural approaches have made enormous progress untangling vast network interactions. More recently, silico such as dynamics simulations proven be an asset prospectively identifying, characterising, explaining basis these interactions, best cases providing atomic level testable hypotheses on how control function a given protein. This review details number recent seminal discoveries enabled by advanced biomolecular simulation, its integration biology approaches. results simulation studies agree well experimental work, notable arrived at key conclusion several years advance structures. Condensed title:Simulations proteins SUMMARY: Hedger Yen developments proteins.

Язык: Английский

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