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Valerian root extracts are widely used as mild sedatives to promote sleep, with clinical studies confirming their efficacy. Their sleep-promoting effects are associated with the adenosine A1 receptor (A1AR), a key regulator of sleep through neural activity inhibition. Adenosine, a neuromodulator that accumulates during wakefulness, activates A1ARs to facilitate sleep transitions. Using advanced analytics, we detected adenosine at 0.05% in the valerian extract Ze 911, supporting direct A1AR activation in vitro. Additionally, we explored A1ARs’ allosteric sites for modulatory activity. Valerenic acid and pinoresinol, key constituents of Ze 911, were identified as positive allosteric modulators (PAMs) of A1ARs. Valerenic acid exhibited strong PAM activity, with high cooperativity (αβ = 4.79 for adenosine and αβ = 23.38 for CPA) and intrinsic efficacy (τB = 5.98 for adenosine and τB = 3.14 for CPA). Pinoresinol displayed weaker PAM activity, with moderate cooperativity (αβ = 3.42 for adenosine and αβ = 0.79 for CPA) and limited efficacy (τB = 0.93 for adenosine and τB = 1.66 for CPA). The allosteric modulation observed in valerian extract Ze 911 suggests a mechanism of action in which valerenic acid and pinoresinol enhance receptor activation through allosteric interactions, potentially amplifying the effects of endogenous adenosine. By targeting A1ARs’ allosteric sites, valerian extract Ze 911 offers increased therapeutic selectivity and reduced off-target effects, emphasizing its potential for managing sleep disorders.

Background Membrane lipids have an important function in the brain as they not only provide a physical barrier segregating the inner and outer cellular environments, but are also involved in cell signaling. It has been shown that the lipid composition effects membrane fluidity which affects lateral mobility and activity of membrane-bound receptors. Methods Since changes in cellular membrane properties are considered to play an important role in the development of depression, the effect of St. John’s wort extract Ze 117 on plasma membrane fluidity in peripheral blood mononuclear cells (PBMC) was investigated using fluorescence anisotropy measurements. Changes in fatty acid residues in phospholipids after treatment of cortisol-stressed [1 μM] PBMCs with Ze 117 [10–50 µg/ml] were analyzed by mass spectrometry. Results Cortisol increased membrane fluidity significantly by 3%, co-treatment with Ze 117 [50 µg/ml] counteracted this by 4.6%. The increased membrane rigidity by Ze 117 in cortisol-stressed [1 μM] PBMC can be explained by a reduced average number of double bonds and shortened chain length of fatty acid residues in phospholipids, as shown by lipidomics experiments. Conclusion The increase in membrane rigidity after Ze 117 treatment and therefore the ability to normalize membrane structure points to a new mechanism of antidepressant action of the extract.

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Pre-clinical studies suggest that extracts prepared from the fruits of Vitex agnus castus (VAC) interact with dopamine D2 receptors, leading to reduced prolactin secretion. In previous experiments, dopaminergic activity was mostly evaluated using radioligand binding assays or via the inhibition of prolactin release from rat pituitary cells. Diterpenes featuring a clerodadienol scaffold were identified as major active compounds, but no conclusive data regarding their potency and intrinsic activity are available. Utilising advances in chromatography, we re-examined this topic using HPLC-based tracking of bioactivity via microfractionation of the VAC extract Ze 440. Using a cAMP-based assay, we measured dopaminergic activity in CHO-K1 cells that overexpress the human D2 receptor. Six diterpenes were isolated from two active HPLC microfractions. Viteagnusin I emerged as the most potent diterpene (EC50: 6.6 µM), followed by rotundifuran (EC50: 12.8 µM), whereas vitexilactone was inactive (EC50: >50 µM). Interestingly, triterpenes were also identified as active, with 3-epi-maslinic acid being the most active compound (EC50: 5.1 µM). To better understand these interactions at the molecular level, selected diterpenes and triterpenes were analysed through molecular docking against D2 receptor structures. Our data show that the dopaminergic activity of VAC diterpenes seems to depend on the configuration and on ring substitution in the side chain. This study also highlights for the first time the dopaminergic contribution of triterpenes such as 3-epi-maslinic acid.

Chronic stress is a key factor in the development of depression. It leads to hyperactivation of the hypothalamic–pituitary–adrenal (HPA) axis, which in turn increases the formation of glucocorticoids (GCs). Chronically elevated GC levels disrupt neuroplasticity and affect brain lipid metabolism, which may, ultimately, contribute to the development of depression. This study aimed to investigate the effects of the antidepressants St. John’s Wort extract and escitalopram on lipid metabolism in vivo. Therefore, repeated corticosterone injections were used to induce depression-like behavior in rats. Male Sprague–Dawley rats were stressed with corticosterone injections (40 mg/kg, s.c.) over 22 consecutive days and were concomitantly treated with varying doses of the St. John’s wort extract Ze 117 (30, 90 or 180 mg/kg, p.o.) or escitalopram (10 mg/kg, p.o.) and behavioral changes were evaluated using a modified forced swim test. The results indicate that repeated corticosterone injections significantly decreased the latency to first immobility. Furthermore, co-treatment of corticosterone with Ze 117 increased latency to first immobility significantly compared to rats treated with corticosterone alone. To further investigate the biochemical effects of corticosterone-induced stress, as well as the possible counter-regulation by antidepressants, the lipidomes of the plasma and hippocampus samples were analyzed by shotgun mass spectrometry. Corticosterone-induced stress significantly altered key lipid metabolites in the plasma but not in the hippocampal samples. In the hippocampus, however, specific glycerophospholipids such as lysophosphatidylethanolamines (LPEs) increased with escitalopram treatment and with Ze 117, both showing significant correlations with behavioral parameters. In summary, our study shows significant behavioral- and lipidome-altering processes with Ze 117 and escitalopram in rat plasma and hippocampal samples, thereby providing new targets and biomarker ideas for clinical diagnosis and antidepressant intervention.

Single-particle tracking (SPT) is a method of high-resolution microscopy to investigate the dynamics of single molecules inside cells or on the cell surface. Here we describe for the first time the applicability of the HiBiT Protein Tagging System combined with the HaloTag® self-labeling protein technology for monitoring the lateral diffusion of a pharmacological relevant G protein-coupled receptor (GPCR) by SPT.

Signal transduction mechanisms and successive regulatory processes alter the lateral mobility of β2-adrenergic receptor (β2AR). In this work we combined modern single particle tracking methods in order to analyze the diffusion dynamics of SNAP-tagged β2AR in HEK 293 wild-type cells and HEK 293 β-arrestin knockout cells before and after agonist stimulation. For analysis of trajectories we first used mean squared displacement (MSD) analysis. Secondly, we applied an advanced variational Bayesian treatment of hidden Markov models (vbSPT) in combination with the recently introduced packing coefficient (Pc), which together provided a detailed model of three discrete diffusive states, interstate transitioning and spatial confinement. Interesting to note, state switching between S3 (fast-diffusing) and S1 (slow-diffusing) occurred sequentially over an intermediate state S2. After ligand stimulation more SNAP-tagged β2AR in HEK 293 wild-type cells switched occupancy into the slow-diffusing state, whereas less receptors were found in the fast diffusive state. Unexpectedly, all three states showed a fraction of confined receptor mobility that increased under stimulation, but confinement sizes were unaffected. Receptor diffusion characteristics were comparable in HEK 293 β-arrestin knockout cells under basal conditions and only minor but non-significant changes occurred upon stimulation, as expected from the depletion of β-arrestin, an important regulatory protein. The data presented here on the occurrence of different diffusion states, their transitioning and variable spatial confinements clearly indicate that lateral mobility of β2AR is much more complex than previously thought. Footnotes * The manuscript was reviewed and the obtained comments led to a substanstial improvement of the manuscript.

This study aims to evaluate the feasibility and explore the efficacy of the Arm Activity Tracker (AAT). The AAT is a device based on wrist-worn accelerometers that provides visual and tactile feedback to stimulate daily life upper extremity (UE) activity in stroke patients. Methods: A randomised, crossover within-subject study was conducted in sub-acute stroke patients admitted to a rehabilitation centre. Feasibility encompassed (1) adherence: the dropout rate and the number of participants with insufficient AAT data collection; (2) acceptance: the technology acceptance model (range: 7–112) and (3) usability: the system usability scale (range: 0–100). A two-way ANOVA was used to estimate the difference between the baseline, intervention and control conditions for (1) paretic UE activity and (2) UE activity ratio. Results: Seventeen stroke patients were included. A 29% dropout rate was observed, and two participants had insufficient data collection. Participants who adhered to the study reported good acceptance (median (IQR): 94 (77–111)) and usability (median (IQR): 77.5 (75–78.5)-). We found small to medium effect sizes favouring the intervention condition for paretic UE activity (η2G = 0.07, p = 0.04) and ratio (η2G = 0.11, p = 0.22). Conclusion: Participants who adhered to the study showed good acceptance and usability of the AAT and increased paretic UE activity. Dropouts should be further evaluated, and a sufficiently powered trial should be performed to analyse efficacy.

Wrist-worn accelerometers are often applied to measure arm use after stroke. They measure arm movements during all activities, including whole-body movements, such as walking. Whole-body movements may influence clinimetric properties of arm use measurements—however, this has not yet been examined. This study investigates to what extent arm use measurements with wrist-worn accelerometers are affected by whole-body movements. Assuming that arm movements during whole-body movements are non-functional, we quantify the effect of whole-body movements by comparing two methods: Arm use measured with wrist-worn accelerometers during all whole-body postures and movements (P&M method), and during sitting/standing only (sit/stand method). We have performed a longitudinal observational cohort study with measurements in 33 stroke patients during weeks 3, 12, and 26 poststroke. The P&M method shows higher daily paretic arm use outcomes than the sit/stand method (p < 0.001), the mean difference increased from 31% at week three to 41% at week 26 (p < 0.001). Differences in daily paretic arm use between methods are strongly related to daily walking time (r = 0.83–0.92). Changes in the difference between methods are strongly related to changes in daily walking time (r = 0.89). We show that not correcting arm use measurements for whole-body movements substantially increases arm use outcomes, thereby threatening the validity of arm use outcomes and measured arm use changes.