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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.

Objective/Background This study evaluated the feasibility of investigating the effect of a valerian and hops‐based herbal medication (Ze 91019) on daytime cognitive performance, psychological parameters, and sleep measures in individuals with occasional sleep problems. Methods A randomized, double‐blind, placebo‐controlled study was conducted in 40 participants over a 21‐day run‐in period and a 21‐day treatment period. Participants used Fitbit sleep trackers and completed daily online cognitive tests (i.e., reaction time and working memory), and surveys to assess subjective psychological outcomes (i.e., cognitive performance, stress levels, tiredness, mood, quality of life, and motivation). Results The study design proved feasible, with high adherence to the study protocol. Exploratory analyses revealed a statistically significant increase in sleep duration during the treatment period for participants using Ze 91019 compared to placebo (mean daily increase: 21.7 min, p = 0.019) without statistically significant effects on cognitive or psychological outcomes. Moreover, Ze 91019 statistically significantly increased the sleep duration of the shortest night in the treatment period by 48.7 minutes. The medication was well‐tolerated. Conclusions The study design proved feasible, and Ze 91019 increased sleep duration without affecting daytime cognitive or psychological outcomes. Trial Registration The trial has been preregistered at www.clinicaltrials.gov (NCT05684523). Valerian‐hops extract combination (Ze 91019) significantly increased sleep duration in individuals with occasional sleep problems by 21.7 minutes per night and 48.7 minutes on the shortest night, compared to placebo, without impairing daytime cognitive or psychological functioning. This randomized controlled trial demonstrated high adherence and proved feasibility.

Low‐dose interferon‐α 2a treatment may be considered as an alternative to cytoreductive therapy with hydroxyurea or regularly dosed interferon in high‐risk polycythemia vera patients. Low‐dose interferon‐ α 2a treatment may be considered as an alternative to cytoreductive therapy with hydroxyurea or regularly dosed interferon in high‐risk polycythemia vera patients.

The changes in blood glucose concentrations that result from an oral glucose challenge are dependent on the rate of gastric emptying, the rate of glucose absorption and the rate of insulin-driven metabolism that include the incretins, glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1). The rate of insulin-driven metabolism is clearly altered in obese subjects, but it is controversial which of these factors is predominant. We aimed to quantify gastric emptying, plasma insulin, C-peptide, glucagon and glucose responses, as well as incretin hormone secretions in obese subjects and healthy controls during increasing glucose loads. The study was conducted as a randomized, double-blind, parallel-group trial in a hospital research unit. A total of 12 normal weight (6 men and 6 women) and 12 non-diabetic obese (BMI > 30, 6 men and 6 women) participants took part in the study. Subjects received intragastric loads of 10 g, 25 g and 75 g glucose dissolved in 300 ml tap water. Main outcome measures were plasma GLP-1 and GIP, plasma glucagon, glucose, insulin, C-peptide and gastric emptying. The primary findings are: i) insulin resistance (P < 0.001) and hyperinsulinemia (P < 0.001); ii) decreased insulin disposal (P < 0.001); iii) trend for reduced GLP-1 responses at 75 g glucose; and iv) increased fasting glucagon levels (P < 0.001) in obese subjects. It seems that, rather than changes in incretin secretion, fasting hyperglucagonemia and consequent hyperglycemia play a role in reduced disposal of insulin, contributing to hyperinsulinemia and insulin resistance. ClinicalTrials.gov NCT01875575.

Background: Most patients with severe obesity show glucose intolerance. Early after sleeve gastrectomy (LSG) or gastric bypass (LRYGB), a marked amelioration in glycemic control occurs. The underlying mechanism is not yet clear. Objective: To determine whether the improvement in glycemic control on the level of endocrine pancreatic function is due to an increased first-phase insulin secretion comparing LRYGB to LSG. Setting: University of Basel Hospital and St. Clara Research Ltd., Basel, Switzerland. Methods: Sixteen morbidly obese patients with severe obesity and different degrees of insulin resistance were randomized to LSG or LRYGB, and islet cell functions were tested by intravenous glucose and intravenous arginine administration before and 4 weeks after surgery. Results: Fasting insulin and glucose levels and homeostasis model assessment insulin resistance were significantly lower in both groups after surgery compared to baseline, while no change was seen in fasting C-peptide, amylin, and glucagon. After intravenous glucose stimulation, no statistically significant pre- to postoperative change in area under the curve (AUC 0–60 min) was seen for insulin, glucagon, amylin, and C-peptide. No statistically significant pre- to postoperative change in incremental AUC for first-phase insulin release (AUC 0–10 min), second-phase insulin secretion (AUC 10–60 min), and insulin/glucose ratio could be shown in either group. Arginine-stimulated insulin and glucagon release showed no pre- to postoperative change. Conclusion: Intravenous glucose and arginine administrations show no pre- to postoperative changes of insulin release, amylin, glucagon, or C-peptide concentrations, and no differences between LRYGB and LSG were found. The postoperative improvement in glycemic control is not caused by changes in endocrine pancreatic hormone secretion.

In previous studies with glucagon-like peptide-1 (GLP-1) we have observed that this peptide modulates fluid intake and increases renal sodium excretion in healthy volunteers and in patients with diabetes mellitus type 2. The effect of GLP-1 on thirst, water intake and on osmoregulation has, however, not been examined in detail in humans. Methods: Seventeen healthy male subjects were enrolled in two double-blind, placebo-controlled studies. In study part A, 8 volunteers participated in a protocol with an intravenous salt load of 26.7 ± 0.9 g comparing the effect of an infusion of GLP-1 (1.5 pmol/kg × min) to isotonic saline (placebo). Sodium excretion and water intake were measured. In part B, 9 volunteers were challenged with an oral salt load of 27.7 ± 0.5 g; sodium excretion and water intake were determined comparing an infusion of GLP-1 (1.5 pmol/kg × min) to isotonic saline (placebo). In part C, intestinal biopsies along the gastrointestinal tract were obtained from 14 healthy subjects. Expression of human GLP-1 receptor mRNA was measured by real-time polymerase chain reaction. Results: In study part A, an increase in renal sodium excretion was demonstrated: FeNa rose from 1.6 ± 0.3 (placebo) to 2.7 ± 0.2% (GLP-1; p = 0.0005). There was no difference in water consumption between the two treatments: 1,291 ± 69 (saline) vs. 1,228 ± 74 ml (GLP-1; p = 0.49). In part B, an oral salt challenge of 27.7 ± 0.5 g led to an increased renal excretion of sodium during GLP-1: FeNa increased from 1.6 ± 0.2% (placebo) to 2.0 ± 0.2% (GLP-1; p = 0.012). In contrast to part A, oral water intake was reduced by 36% under GLP-1 treatment: 1,848 ± 331 ml (placebo) vs. 1,181 ± 177 ml (GLP-1; p = 0.0414). Three subjects in part B did not finish treatment with GLP-1 because of diarrhea. Human GLP-1 receptor mRNA expression was highest in the proximal human small intestine compared to terminal ileum and colon (p < 0.02). Conclusions: GLP-1 acts on renal tissue reducing sodium absorption, probably via similar sodium transporters, which also may be localized in the gastrointestinal tract. This hypothesis needs to be confirmed by further studies.

In vitro, both carbohydrate sugars and artificial sweeteners (AS) stimulate the secretion of glucagon-like peptide-1 (GLP-1). It has been suggested that the gut tastes sugars and AS through the same mechanisms as the tongue, with potential effects on gut hormone release. We investigated whether the human gut responds in the same way to AS and carbohydrate sugars, which are perceived by lingual taste as equisweet. We focused on the secretion of gastrointestinal (GI) satiety peptides in relation to appetite perception. We performed a placebo-controlled, double-blind, six-way, cross-over trial including twelve healthy subjects. On separate days, each subject received an intragastric infusion of glucose, fructose or an AS (aspartame, acesulfame K and sucralose) dissolved in 250 ml of water or water only (control). In a second part, four subjects received an intragastric infusion of the non-sweet, non-metabolisable sugar analogue 2-deoxy-d-glucose. Glucose stimulated GLP-1 (P = 0·002) and peptide tyrosine tyrosine (PYY; P = 0·046) secretion and reduced fasting plasma ghrelin (P = 0·046), whereas fructose was less effective. Both carbohydrate sugars increased satiety and fullness (albeit not significantly) compared with water. In contrast, equisweet loads of AS did not affect gastrointestinal peptide secretion with minimal effects on appetite. 2-Deoxy-d-glucose increased hunger ratings, however, with no effects on GLP-1, PYY or ghrelin. Our data demonstrate that the secretion of GLP-1, PYY and ghrelin depends on more than the detection of (1) sweetness or (2) the structural analogy to glucose.

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.

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.

Random forest, support vector machine, logistic regression, neural networks and k-nearest neighbor (lazar) algorithms, were applied to a new Salmonella mutagenicity dataset with 8,290 unique chemical structures utilizing MolPrint2D and Chemistry Development Kit (CDK) descriptors. Crossvalidation accuracies of all investigated models ranged from 80 to 85% which is comparable with the interlaboratory variability of the Salmonella mutagenicity assay. Pyrrolizidine alkaloid predictions showed a clear distinction between chemical groups, where otonecines had the highest proportion of positive mutagenicity predictions and monoesters the lowest.