Exploring the Relationship between Diamine Oxidase and Psychotropic Medications in Fibromyalgia Treatment, Finding No Reduction in Diamine Oxidase Levels and Activity except with Citalopram.

Background: Histamine intolerance manifests when there is an imbalance between the production of histamine and the body's capacity to metabolise it. Within the gastrointestinal tract, diamine oxidase (DAO) plays a pivotal role in breaking down ingested histamine. Insufficient levels of DAO have been linked to various diseases affecting the respiratory, cardiovascular, nervous, muscular, and digestive systems; some of these symptoms are evidenced in fibromyalgia syndrome. This underscores the crucial role of DAO in maintaining the histamine balance and highlights its association with diverse physiological systems and health conditions. The management of fibromyalgia commonly involves the use of psychotropic medications; however, their potential interactions with DAO remain not fully elucidated. Methods: This study delved into the influence of various psychotropic medications on DAO activity through in vitro experiments. Additionally, we explored their impact on the human intestinal cell line Caco-2, examining alterations in DAO expression at both the mRNA and protein levels along with DAO activity. Results: Notably, the examined drugs-sertraline, pregabalin, paroxetine, alprazolam, and lorazepam-did not exhibit inhibitory effects on DAO activity or lead to reductions in DAO levels. In contrast, citalopram demonstrated a decrease in DAO activity in in vitro assays without influencing DAO levels and activity in human enterocytes. Conclusions: These findings imply that a collaborative approach involving psychotropic medications and DAO enzyme supplementation for individuals with fibromyalgia and a DAO deficiency could offer potential benefits for healthcare professionals in their routine clinical practice.

Metabolic adaptations in severe obesity: Insights from circulating oxylipins before and after weight loss.

BACKGROUND: The relationship between lipid mediators and severe obesity remains unclear. Our study investigates the impact of severe obesity on plasma concentrations of oxylipins and fatty acids and explores the consequences of weight loss. METHODS: In the clinical trial identifier NCT05554224 study, 116 patients with severe obesity and 63 overweight/obese healthy controls matched for age and sex (≈2:1) provided plasma. To assess the effect of surgically induced weight loss, we requested paired plasma samples from 44 patients undergoing laparoscopic sleeve gastrectomy one year after the procedure. Oxylipins were measured using ultra-high-pressure liquid chromatography coupled to a triple quadrupole mass spectrometer via semi-targeted lipidomics. Cytokines and markers of interorgan crosstalk were measured using enzyme-linked immunosorbent assays. RESULTS: We observed significantly elevated levels of circulating fatty acids and oxylipins in patients with severe obesity compared to their metabolically healthier overweight/obese counterparts. Our findings indicated that sex and liver disease were not confounding factors, but we observed weak correlations in plasma with circulating adipokines, suggesting the influence of adipose tissue. Importantly, while weight loss restored the balance in circulating fatty acids, it did not fully normalize the oxylipin profile. Before surgery, oxylipins derived from lipoxygenase activity, such as 12-HETE, 11-HDoHE, 14-HDoHE, and 12-HEPE, were predominant. However, one year following laparoscopic sleeve gastrectomy, we observed a complex shift in the oxylipin profile, favoring species from the cyclooxygenase pathway, particularly proinflammatory prostanoids like TXB2, PGE2, PGD2, and 12-HHTrE. This transformation appears to be linked to a reduction in adiposity, underscoring the role of lipid turnover in the development of metabolic disorders associated with severe obesity. CONCLUSIONS: Despite the reduction in fatty acid levels associated with weight loss, the oxylipin profile shifts towards a predominance of more proinflammatory species. These observations underscore the significance of seeking mechanistic approaches to address severe obesity and emphasize the importance of closely monitoring the metabolic adaptations after weight loss.

Diamine Oxidase Interactions with Anti-Inflammatory and Anti-Migraine Medicines in the Treatment of Migraine.

Histamine intolerance arises when there is a disparity between the production of histamine and the body's ability to break it down. In the gastrointestinal tract, the primary enzyme responsible for metabolizing ingested histamine is diamine oxidase (DAO), and a shortage of this enzyme has been associated with some diseases related to the respiratory, cardiovascular, nervous, muscular, and digestive systems, in addition to migraines. The treatment of migraines typically revolves around the utilization of both anti-migraine and anti-inflammatory drugs, but their interaction with DAO is not thoroughly understood. In this study, we examined the impact of nonsteroidal anti-inflammatory drugs (NSAIDs) and anti-migraine medications on DAO activity through in vitro experiments. We also investigated their effects on the human intestinal cell line Caco-2, assessing changes in DAO expression (both at the mRNA and protein levels) as well as DAO activity. The tested drugs, including ibuprofen, acetylsalicylic acid, paracetamol, a combination of acetylsalicylic acid with paracetamol and caffeine, zolmitriptan, and sumatriptan, did not inhibit DAO activity or reduce their levels. However, naproxen reduced DAO protein levels in human enterocyte cultures while not affecting DAO activity. These results suggest that combining anti-inflammatory and anti-migraine drugs with DAO enzyme supplementation for migraine patients with DAO deficiency could be beneficial for healthcare professionals in their daily practice.

Interaction of Diamine Oxidase with Psychostimulant Drugs for ADHD Management.

Histamine intolerance occurs when there is an imbalance between histamine production and the capacity for histamine degradation. Diamine oxidase (DAO) is the main enzyme for the catabolism of ingested histamine degradation in the gastrointestinal tract and its deficiency has been linked to allergy-like symptoms. Psychostimulant drugs are commonly used to treat Attention Deficit Hyperactivity Disorder (ADHD), but their interaction with DAO is not well characterized. In this work, we evaluated the effects of psychostimulant drugs (methylphenidate and lisdexamfetamine) on in vitro DAO activity and in the human cell line of enterocytes (Caco-2), evaluating DAO expression (mRNA and protein) and DAO activity. Methylphenidate and lisdexamfetamine did not repress the in vitro DAO activity. In addition, in Caco-2 cells, lisdexamfetamine promoted a strong upregulation of DAO mRNA levels, whereas methylphenidate tended to induce DAO activity. To sum up, methylphenidate and lisdexamfetamine treatments do not reduce DAO activity. These findings could be useful for physicians prescribing these two drugs to ADHD patients affected by DAO deficiency.

Optimization of a GC-MS Injection-Port Derivatization Methodology to Enhance Metabolomics Analysis Throughput in Biological Samples.

Advances in metabolomics analysis and data treatment increase the knowledge of complex biological systems. One of the most used methodologies is gas chromatography-mass spectrometry (GC-MS) due to its robustness, high separation efficiency, and reliable peak identification through curated databases. However, methodologies are not standardized, and the derivatization steps in GC-MS can introduce experimental errors and take considerable time, exposing the samples to degradation. Here, we propose the injection-port derivatization (IPD) methodology to increase the throughput in plasma metabolomics analysis by GC-MS. The IPD method was evaluated and optimized for different families of metabolites (organic acids, amino acids, fatty acids, sugars, sugar phosphates, etc.) in terms of residence time, injection-port temperature, and sample/derivatization reagent ratio. Finally, the method's usefulness was validated in a study consisting of a cohort of obese patients with or without nonalcoholic steatohepatitis. Our results show a fast, reproducible, precise, and reliable method for the analysis of biological samples by GC-MS. Raw data are publicly available at MetaboLights with Study Identifier MTBLS5151.

Hesperidin Bioavailability Is Increased by the Presence of 2S-Diastereoisomer and Micronization-A Randomized, Crossover and Double-Blind Clinical Trial.

Hesperidin is a flavanone abundantly found in citrus fruits for which health beneficial effects have been reported. However, hesperidin shows a low bioavailability among individuals. The aim of this study was to evaluate the effects of the micronization process and 2R- and 2S-hesperidin diastereoisomers ratio on hesperidin bioavailability. In a first phase, thirty healthy individuals consumed 500 mL of orange juice with 345 mg of hesperidin, and the levels of hesperidin metabolites excreted in urine were determined. In the second phase, fifteen individuals with intermediate hesperidin metabolite levels excreted in urine were randomized in a crossover, postprandial and double-blind intervention study. Participants consumed 500 mg of the hesperidin-supplemented Hesperidin epimeric mixture (HEM), the micronized Hesperidin epimeric mixture (MHEM) and micronized 2S-Hesperidin (M2SH) in each study visit with 1 week of washout. Hesperidin metabolites and catabolites were determined in blood and urine obtained at different timepoints over a 24 h period. The bioavailability-relative urinary hesperidin excretion (% of hesperidin ingested)-of M2SH (70 ± 14%) formed mainly by 2S-diastereoisomer was significantly higher than the bioavailability of the MHEM (55 ± 15%) and HEM (43 ± 8.0%), which consisted of a mixture of both hesperidin diastereoisomers. Relative urinary excretion of hesperidin metabolites for MHEM (9.2 ± 1.6%) was significantly higher compared to the HEM (5.2 ± 0.81%) and M2SH (3.6 ± 1.0%). In conclusion, the bioavailability of 2S-hesperidin extract was higher compared to the standard mixture of 2S-/2R-hesperidin extract due to a greater formation of hesperidin catabolites. Furthermore, the micronization process increased hesperidin bioavailability.

Analysis of oxylipins to differentiate between organic and conventional UHT milks.

Nowadays, there is a strong interest in analytical approaches for assessing organic farming practices. Here, we propose that oxylipins, a group of oxidised metabolites derived from various polyunsaturated fatty acids, could be promising biomarkers for organic milk assessment because their biosynthesis is modulated by both precursor fatty acid availability and physiological or pathological status. Thus, we determined 31 fatty acids, 53 triacylglycerols and 37 oxylipins in one hundred commercial UHT milks by chromatographic methods coupled to mass spectrometry. Of these, 52 milks were conventional (34 whole milk, 11 semi-skimmed milk and 7 skimmed milk) and 48 were organic (31 whole milk, 11 semi-skimmed milk and 6 skimmed milk). Several oxylipins (8-HEPE, 5-HEPE, 11-HEPE, 9-HEPE, 18-HEPE, 9-HOTrE, 13-HOTrE, 12,13-DiHODE and 15,16-DiHODE) could distinguish between organic and conventional milks. Within these oxylipins, arachidonic and linoleic acid derived do not correlate with their fatty acid precursors; therefore these oxylipins could be promising as not only diet-dependent biomarkers for organic milk assessment.

Gender-Related Differences on Polyamine Metabolome in Liquid Biopsies by a Simple and Sensitive Two-Step Liquid-Liquid Extraction and LC-MS/MS.

Polyamines are involved in the regulation of many cellular functions and are promising biomarkers of numerous physiological conditions. Since the concentrations of these compounds in biological fluids are low, sample extraction is one of the most critical steps of their analysis. Here, we developed a comprehensive, sensitive, robust, and high-throughput LC-MS/MS stable-isotope dilution method for the simultaneous determination of 19 metabolites related to polyamine metabolism, including polyamines, acetylated and diacetylated polyamines, precursors, and catabolites from liquid biopsies. The sample extraction was optimized to remove interfering compounds and to reduce matrix effects, thus being useful for large clinical studies. The method consists of two-step liquid-liquid extraction with a Folch extraction and ethyl acetate partitioning combined with dansyl chloride derivatization. The developed method was applied to a small gender-related trial concerning human serum and urine samples from 40 obese subjects. Sex differences were found for cadaverine, putrescine, 1,3-diaminopropane, γ-aminobutyric acid, N8-acetylspermidine, and N-acetylcadaverine in urine; N1-acetylspermine in serum; and spermine in both serum and urine. The results demonstrate that the developed method can be used to analyze biological samples for the study of polyamine metabolism and its association with human diseases.

Type 2 Diabetes Is Associated with a Different Pattern of Serum Polyamines: A Case⁻Control Study from the PREDIMED-Plus Trial.

Objective: Polyamines are naturally occurring cationic molecules present in all living cells. Dysregulation of circulating polyamines has been reported in several conditions, but little is known about the levels of serum polyamines in chronic metabolic disorders such as type 2 diabetes (T2D). Therefore, the aim of this study was to evaluate the polyamine-related metabolome in a cohort of metabolic syndrome individuals with and without T2D. Design and methods: This was a nested case⁻control study within the PREDIMED-Plus trial that included 44 patients with T2D and 70 patients without T2D. We measured serum levels of arginine, ornithine, polyamines, and acetyl polyamines with an ultra-high performance liquid chromatography tandem mass spectrometry platform. Results: Our results showed that serum putrescine, directly generated from ornithine by the catalytic action of the biosynthetic enzyme ornithine decarboxylase, was significantly elevated in patients with T2D compared to those without T2D, and that it significantly correlated with the levels of glycosylated hemoglobin (HbA1c). Correlation analysis revealed a significantly positive association between fasting insulin levels and spermine. Multiple logistic regression analysis (adjusted for age, gender and body weight index) revealed that serum putrescine and spermine levels were associated with a higher risk of T2D. Conclusions: Our study suggests that polyamine metabolism is dysregulated in T2D, and that serum levels of putrescine and spermine are associated with glycemic control and circulating insulin levels, respectively.