ABSTRACT An ultrahigh-performance liquid chromatography coupled with quadrupole-Orbitrap high-resolution mass spectrometry (UHPLC-Q-Orbitrap HRMS) method was applied to characterize Pingchuanning (PCN) decoction and its absorbed serum constituents in asthmatic rats. A total of 107 compounds were identified in PCN, of which 36 prototypes were detected in rat serum. Network pharmacology and molecular docking of these absorbed compounds predicted ADORA2A as the core therapeutic target, with 5-O-methylvisammioside, nobiletin, sec-O-glucosylhamaudol, and 9-oxo-ODE showing binding affinity. In an ovalbumin-induced asthmatic rat model, PCN alleviated airway hyperresponsiveness and lung inflammation. Mechanistically, PCN upregulated ADORA2A, elevated cAMP and PKA phosphorylation, and suppressed NLRP3 expression. This UHPLC-Q-Orbitrap HRMS-based serum pharmacochemistry method effectively identified the bioactive components of PCN, and the integrated strategy demonstrates that PCN exerts anti-asthmatic effects through the ADORA2A/cAMP/PKA/NLRP3 axis.

Scientific Reports - Genetic Polymorphisms in ADORA2A and CYP1A2 Influence Caffeine’s Effect on Postprandial Glycaemia

Animals Male and female adult mice, aged between 2 and 7 months old, from the following mouse lines were used: C57BL/6 J wild-type (Charles River), Drd1-Cre (Gensat: EY262), Adora2a-cre (Gensat: KG139), Slc6a3-cre (JAX: 006660), Ai14 (tdTomato, JAX: 007914), Ai35 (Arch-GFP, JAX: 012735) and Ai32 (channelrhodopsin-2/EYFP, JAX: 024109). Mice were housed in HVC cages with free access to chow and water on a 12 h:12 h inverted light:dark cycle and tested during the dark phase.

Un estudio realizado por expertos de la Universidad St Mary's de Twickenham ha analizado la relación entre el consumo habitual de cafeína, la genética y el rendimiento cognitivo, destacando cómo las variaciones en genes como CYP1A2, AHR y ADORA2A influyen…

Male and female adult mice, aged between 2 and 7 months old, from the following mouse lines were used: C57BL/6 J wild-type (Charles River), Drd1-Cre (Gensat: EY262), Adora2a-cre (Gensat: KG139), Slc6a3-cre (JAX: 006660), Ai14 (tdTomato, JAX: 007914), Ai35 (Arch-GFP, JAX:...

Background: Research on caffeine and cognitive performance remains controversial. Variations in genes associated with caffeine metabolism and response such as C...

ADORA2A activation suppresses NFκB-dependent CCL5 production in cNK cells during chronic HBV infection, disrupting intrahepatic DC recruitment and HBV-specific CD8 + T-cell differentiation and function. Targeting the ADORA2A/NFκB/CCL5 axis restores antiviral immunity and facilitates HBV clearance. ABSTRACT Understanding the immunological mechanisms underlying chronic hepatitis B virus (HBV) infection-induced immune tolerance is critical for developing effective therapeutic strategies, yet the mechanisms by which natural killer (NK)-cell subsets regulate dendritic cell (DC)-mediated antiviral immunity during chronic HBV infection remain unclear. Here, we demonstrated that chronic HBV infection disrupted intrahepatic DCs accumulation and activation by suppressing CC chemokine ligand 5 (CCL5) production from hepatic NK cells. Importantly, chronic HBV infection reduced the number of hepatic conventional NK (cNK) cells, the main source of hepatic CCL5, whereas liver-resident NK (LrNK) cells increased and exhibited lower CCL5 expression and immunosuppressive features. Adoptive transfer of CCL5-competent hepatic cNK cells promoted DCs accumulation and activation, enhanced HBV-specific CD8 + T-cell responses, and facilitated viral clearance. Mechanistically, chronic HBV infection promoted the activation of adenosine A2a receptor (ADORA2A)/nuclear factor kappa-B (NF-κB) pathway in hepatic NK cells, thereby antagonizing NF-κB activation, reducing the proportion of cNK cells, suppressing CCL5 production, and ultimately impairing hepatic aggregation and activation of DCs, leading to defective anti-HBV immune responses. This study revealed a novel mechanism involved in chronic HBV infection-induced immune tolerance and indicated that targeting the ADORA2A/NFκB/CCL5 axis in cNK cells may represent a potential therapeutic strategy for chronic HBV infection.

The overexpression of brain-specific RagA leads to depressive-like behaviors, memory impairment, and hippocampal neuron loss in mice. This is accompanied by an upregulation of the adenosine A2a receptor (ADORA2A) and coordinated changes in the levels of depression-related metabolites, proteins, and lncRNA. The RagA-ADORA2A pathway is a new target for the development of new antidepressant drugs. Abstract Neuroinflammation hallmarks the pathology of depression although the etiological complexity has not yet been resolved. Previous studies demonstrate that bacterial lipopolysaccharide induces depressive-like behaviors by activating RagA-mTOR-p70S6K signaling pathway. The current project aims to investigate whether and how brain-specific RagA overexpression triggers depressive-like behaviors in mice. Full-length RagA cDNA is cloned into the mammalian expression vector under the control of brain specific promoter, and subsequently overexpressed in the brain of mouse embryos. Indeed, RagA transgenic mice exhibit depressive-like behaviors and memory impairments. RNA-seq profiling of the prefrontal cortex (PFC) transcriptome highlights adenosine A2a receptor (ADORA2A) as a key differentially expressed gene (DEG). Western blotting confirms that ADORA2A and phospho-p70S6K are markedly elevated in RagA transgenic mice. Behavioral assessments demonstrate that ADORA2A inhibitor istradefylline markedly attenuates depressive-like behaviors. Further metabolomics reveals that N-acetylserotonin and several depression-related metabolites are downregulated while proteomic profiling showed that OLIG1 and other proteins are significantly regulated in RagA transgenic mice. Collectively, RagA overexpression alters the expression patterns of signaling proteins and the metabolism of depression-associated metabolites. RagA may cause depressive-like behaviors in mice via activating p70S6K/ADORA2A signaling pathway. Thus, RagA-p70S6K-ADORA2A signaling pathway may be a target for the development of new antidepressant therapies.