Search Results (26)

Post-traumatic stress disorder (PTSD) has traditionally been viewed as a psychiatric disorder of fear, memory, and emotional regulation. However, growing evidence implicates systemic and neuroinflammation as key contributors. Individuals with PTSD often exhibit elevated blood levels of pro-inflammatory cytokines such as IL-1β, IL-6, TNF-α, and C-reactive protein, indicating immune dysregulation. Dysfunctions in the hypothalamic–pituitary–adrenal (HPA) axis marked by reduced cortisol levels impair the body’s ability to regulate inflammation, allowing persistent immune activation. Circulating cytokines cross a weakened blood–brain barrier and activate microglia, which release additional inflammatory mediators. This neuroinflammatory loop can damage brain circuits critical to emotion processing including the hippocampus, amygdala, and prefrontal cortex, and disrupt neurotransmitter systems like serotonin and glutamate, potentially explaining PTSD symptoms such as hyperarousal and persistent fear memories. Rodent models of PTSD show similar inflammatory profiles, reinforcing the role of neuroinflammation in disease pathology. Bromo-epi-androsterone (BEA), a synthetic analog of dehydroepiandrosterone (DHEA), has shown potent anti-inflammatory effects in clinical trials, significantly reducing IL-1β, IL-6, and TNF-α. By modulating immune activity, BEA represents a promising candidate for mitigating neuroinflammation and its downstream effects in PTSD. These findings support the rationale for initiating clinical trials of BEA as a novel therapeutic intervention for PTSD. Full article

Burnout syndrome, which significantly impacts both individual and societal quality of life, is primarily characterized by three key criteria: depersonalization, emotional exhaustion, and low personal accomplishment, all linked to work-related stress. Purpose: Comparative evaluation of urine metabolite patterns that may discriminate the burnout levels and the effects of night shifts on healthcare professionals. The Maslach Burnout Inventory survey was administered to 64 physicians and nurses working day and night shifts, with scores for each criterion recorded. Methods: Urine samples were collected, and metabolomic patterns were analyzed using UHPLC-QTOF-ESI+-MS technology. This analysis employed both untargeted and semi-targeted metabolomics, coupled with multivariate and ANOVA statistics, utilizing the online Metaboanalyst 6.0 platform. Partial Least Squares Discriminant Analysis (PLSDA) was performed, along with VIP values, Random Forest graphs, and heatmaps based on 79 identified metabolites. These were further complemented by biomarker analysis (AUC ranking) and pathway analysis of metabolic networks. Results: The findings highlighted the biochemical effects of night shifts and their correlation with burnout scores from each dimension. Conclusions: This study demonstrated the involvement of three major metabolic pathways in diagnosing burnout: lipid metabolism, particularly related to steroid hormones (cortisol, cortisone, and androsterone metabolites); energetic metabolism, involving long-chain acylated carnitines as transporters of free fatty acids, which play a role in burnout control; and a third pathway affecting catecholamine metabolism (neurotransmitters derived from tyrosine, such as dopamine, adrenaline, and noradrenaline), as well as tryptophan metabolism (serotonin and melatonin metabolites) and amino acid metabolism (including aspartate, arginine, and valine). Full article

SPS is characterized by progressive spasmodic muscular rigidity. SPS is thought to be an autoimmune disease with a prominent feature of antibodies against glutamic acid decarboxylase (GAD). GAD is responsible for the enzymatic conversion of glutamic acid (glutamate) into the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). Reduced GABA activity leads to increased excitability in the central nervous system, resulting in muscle rigidity and spasms characteristic of SPS. While SPS is rare, anti-GAD antibodies seen in SPS are also seen in the much more common autoimmune disease, type 1 diabetes (T1D). There is evolving research showing that the anti-GAD antibodies of T1D are produced in response to the presence of mycobacterial heat shock protein 65 (mHSP65), and the mHSP65 is produced in response to an occult infection by a bacterium, Mycobacterium avium subspecies Paratuberculosis (MAP). Humans are broadly exposed to MAP in food, water, and air. There are linear and conformational similarities between the epitopes of GAD and mHSP65. This article proposes that MAP is also an infectious trigger for SPS. Dehydroepiandrosterone (DHEA) is a principal component of the steroid metabolome; it plateaus in young adults and then steadily declines. Bromo-epi-androsterone (BEA) is a potent synthetic analog of DHEA; unlike DHEA, it is non-androgenic, non-anabolic, and an effective modulator of immune dysregulation. BEA is also an anti-infective agent and has been shown to benefit mycobacterial infections, including tuberculosis and leprosy. With the immune stabilizing capacity of BEA as well as its anti-mycobacterial properties, there is reason to believe that a randomized clinical trial with BEA may be beneficial for SPS. Full article

Background/Objectives: Despite substantial research, the causal relationships between gut microbiota (GM) and age-related macular degeneration (AMD) remain unclear. We aimed to explore these causal associations using Mendelian randomization (MR) and elucidate the potential mechanisms mediated by blood metabolites. Methods: We utilized the 211 GM dataset (n = 18,340) provided by the MiBioGen consortium. AMD outcome data were sourced from the MRC Integrated Epidemiology Unit (IEU) OpenGWAS Project. We performed bidirectional MR, two mediation analyses, and two-step MR to assess the causal links between GM and different stages of AMD (early, dry, and wet). Results: Our findings indicate that the Bacteroidales S24.7 group and genus Dorea are associated with an increased risk of early AMD, while Ruminococcaceae UCG011 and Parasutterella are linked to a higher risk of dry AMD. Conversely, Lachnospiraceae UCG004 and Anaerotruncus are protective against dry AMD. In the case of wet AMD, Intestinimonas and Sellimonas increase risk, whereas Anaerotruncus and Rikenellaceae RC9 reduce it. Additionally, various blood metabolites were implicated: valine, arabinose, creatine, lysine, alanine, and apolipoprotein A1 were associated with early AMD; glutamine and hyodeoxycholate—with a reduced risk of dry AMD; and androsterone sulfate, epiandrosterone sulfate, and lipopolysaccharide—with a reduced risk of wet AMD. Notably, the association between family Oxalobacteraceae and early AMD was mediated by valine, accounting for 19.1% of the association. Conclusions: This study establishes causal links between specific gut microbiota and AMD, mediated by blood metabolites, thereby enhancing our understanding of the gut–retina axis in AMD pathophysiology. Full article

Background/Objectives: Irritable bowel syndrome (IBS) is a complex disorder affecting 10% of the global population, but the underlying mechanisms remain poorly understood. By integrating multifluid metabolomics, we aimed to identify metabolite markers of IBS in a large population-based cohort. Methods: We included individuals from TwinsUK with and without IBS, ascertained using the Rome III criteria, and analysed serum (232 cases, 1707 controls), urine (185 cases, 1341 controls), and stool (186 cases, 1284 controls) metabolites (Metabolon Inc.). Results: After adjusting for covariates, and multiple testing, 44 unique metabolites (25 novel) were associated with IBS, including lipids, amino acids, and xenobiotics. Androsterone sulphate, a sulfated steroid hormone precursor, was associated with lower odds of IBS in both urine (0.69 [95% confidence interval = 0.56–0.85], p = 2.34 × 10⁻⁴) and serum (0.75 [0.63–0.90], p = 1.54 × 10⁻³. Moreover, suberate (C8-DC) was associated with higher odds of IBS in serum (1.36 [1.15–1.61]; p = 1.84 × 10⁻⁴) and lower odds of IBS in stool (0.76 [0.63–0.91]; p = 2.30 × 10⁻³). On the contrary, 32 metabolites appeared to be fluid-specific, including indole, 13-HODE + 9-HODE, pterin, bilirubin (E,Z or Z,Z), and urolithin. The remaining 10 metabolites were associated with IBS in one fluid with suggestive evidence (p < 0.05) in another fluid. Finally, we identified androgenic signalling, dicarboxylates, haemoglobin, and porphyrin metabolism to be significantly over-represented in individuals with IBS compared to controls. Conclusions: Our results highlight the utility of a multi-fluid approach in IBS research, revealing distinct metabolic signatures across biofluids. Full article

Background/Objectives: Metabolomics provides insights into the biological underpinnings of disease development and treatment. This systematic review investigated the impact of acupuncture on metabolite levels and associated metabolic pathways using a metabolomic approach. Methods: Five databases (i.e., PubMed, Embase, Scopus, CINAHL, and Cochrane Central) were searched using terms such as “acupuncture” and “metabolites” to retrieve relevant journal articles published through January 2024. Studies utilizing mass spectrometry or nuclear magnetic resonance were included. Risk of bias was evaluated using the Cochrane Risk of Bias tool and the Newcastle–Ottawa scale. Metabolic pathway analysis was conducted using MetaboAnalyst 6.0 to identify common significant pathways affected by acupuncture. Additionally, subgroup pathway enrichment analysis identified metabolites significantly altered in more than two studies. Results: Among 4019 articles, 22 studies met inclusion criteria, examining changes in metabolomic biomarkers before and after acupuncture for various diseases and symptoms. A total of 226 metabolites showed significant changes, with 14 common metabolites altered in more than two studies (glutamine, androsterone glucuronide, choline, citric acid, decanoylcarnitine, estrone, glutathione, glycine, hypoxanthine, lactic acid, pyruvic acid, serine, proline, and sn-glycero-3-phosphocholine). Common pathways affected by acupuncture were glycine, serine, and threonine metabolism, glutathione metabolism, arginine biosynthesis, and glyoxylate and dicarboxylate metabolism. Conclusions: This review provides insights of the metabolomic mechanisms underlying acupuncture, highlighting its impact on specific metabolic pathways. Recognizing these changes can enhance acupuncture’s effectiveness and support the development of personalized treatments. The findings underscore metabolomics as a valuable tool for understanding and optimizing acupuncture for various diseases and symptoms. Full article

Adrenosterone (Androst-4-ene-3,11,17-trione, 11OXO) is forbidden in sports according to the Prohibited List of the World Anti-Doping Agency. The administration of 11OXO may be detected by monitoring the urinary concentrations of its main human metabolites 11β-hydroxy-androsterone and 11β-hydroxy-etiocholanolone. Preliminary urinary concentration and concentration ratio thresholds have been established for sports drug testing purposes, but adaptations are desirable as the suggested limits would result in numerous suspicious findings due to naturally elevated concentrations and ratios. Recently, the metabolism of 11-oxo-testosterone (KT) was investigated in the context of anti-doping research, resulting in a preliminary urinary concentration threshold and a confirmation procedure based on the determination of carbon isotope ratios (CIRs). Gas chromatography coupled to isotope ratio mass spectrometry was employed to investigate the CIRs of selected steroids. As KT is also a metabolite of 11OXO, the developed protocols for KT have been tested to elucidate their potential to detect the administration of 11OXO after a single oral dose of 100 mg. In order to further improve the analytical approach, the threshold for urinary concentrations of KT was re-investigated by employing a reference population of n = 5232 routine doping control samples. Quantification of urinary steroids was conducted by employing gas chromatography coupled to triple quadrupole mass spectrometry. Derived from these, a subset of n = 106 samples showing elevated concentrations of KT was investigated regarding their CIRs. By means of this, potentially positive samples due to the illicit administration of 11OXO or KT could be excluded, and the calculation of reference population-derived thresholds for the concentrations and CIR of KT was possible. Based on the results, the urinary concentration threshold for KT is suggested to be established at 130 ng/mL. Full article

This study involved a comprehensive examination of sensory attributes in dry-cured Bísaro loins, including odor, androsterone, scatol, lean color, fat color, hardness, juiciness, chewiness, flavor intensity and flavor persistence. An analysis of 40 samples revealed a wide variation in these attributes, ensuring a robust margin for multivariate calibration purposes. The respective near-infrared (NIR) spectra unveiled distinct peaks associated with significant components, such as proteins, lipids and water. Support vector regression (SVR) models were methodically calibrated for all sensory attributes, with optimal results using multiplicative scattering correction pre-treatment, MinMax normalization and the radial base kernel (non-linear SVR model). This process involved partitioning the data into calibration (67%) and prediction (33%) subsets using the SPXY algorithm. The model parameters were optimized via a hybrid algorithm based on particle swarm optimization (PSO) to effectively minimize the root-mean-square error (RMSECV) derived from five-fold cross-validation and ensure the attainment of optimal model performance and predictive accuracy. The predictive models exhibited acceptable results, characterized by R-squared values close to 1 (0.9616–0.9955) and low RMSE values (0.0400–0.1031). The prediction set’s relative standard deviation (RSD) remained under 5%. Comparisons with prior research revealed significant improvements in prediction accuracy, particularly when considering attributes like pig meat aroma, hardness, fat color and flavor intensity. This research underscores the potential of advanced analytical techniques to improve the precision of sensory evaluations in food quality assessment. Such advancements have the potential to benefit both the research community and the meat industry by closely aligning their practices with consumer preferences and expectations. Full article

The effects of vitamin E supplementation on cancer and other chronic diseases are not clear. We compared the serum metabolomic profile of differing vitamin E dosages in order to re-examine the previously observed changes in a novel C₂₂ lactone sulfate compound, androgenic steroids, and other metabolites. A total of 3409 women and men previously selected for metabolomics studies in the PLCO Cancer Screening Trial were included in this investigation. Serum metabolites were profiled using ultrahigh-performance liquid and gas chromatography/tandem mass spectrometry. Seventy known metabolites including C₂₂ lactone sulfate and androgens were significantly associated with vitamin E supplementation. In the sex-stratified analysis, 10 cofactors and vitamins (e.g., alpha-CEHC sulfate and alpha-CEHC glucuronide), two carbohydrates (glyceric and oxalic acids), and one lipid (glycocholenate sulfate) were significantly associated with vitamin E dose in both males and females (FDR-adjusted p-value < 0.01). However, the inverse association between C₂₂ lactone sulfate and daily vitamin E supplementation was evident in females only, as were two androgenic steroids, 5-androstenediol and androsterone glucuronide. Our study provides evidence of distinct steroid hormone pathway responses based on vitamin E dosages. Further studies are needed to gain biological insights into vitamin E biochemical effects relevant to cancer and other chronic diseases. Full article

Two series of novel steroidal[17,16-d]pyrimidines derived from natural epiandrosterone and androsterone were designed and synthesized, and these compounds were screened for their potential anticancer activities. The preliminary bioassay indicated that some of these prepared compounds exhibited significantly good cytotoxic activities against human gastric cancer (SGC-7901), lung cancer (A549), and hepatocellular liver carcinoma (HepG2) cell lines compared with 5-fluorouracil (5-FU), epiandrosterone, and androsterone. Especially the respective pairs from epiandrosterone and androsterone showed significantly different inhibitory activities, and the possible configuration-activity relationships have also been summarized and discussed based on kinase assay and molecular docking, which indicated that the inhibition activities of these steroidal[17,16-d]pyrimidines might obviously be affected by the configuration of the hydroxyl group in the part of the steroidal scaffold. Full article

Prenatal alcohol exposure can produce offspring growth deficits and is a leading cause of neurodevelopmental disability. We used untargeted metabolomics to generate mechanistic insight into how alcohol impairs fetal development. In the Western Cape Province of South Africa, 52 women between gestational weeks 5–36 (mean 18.5 ± 6.5) were recruited, and they provided a finger-prick fasting bloodspot that underwent mass spectrometry. Metabolomic data were analyzed using partial least squares-discriminant analyses (PLS-DA) to identify metabolites that correlated with alcohol exposure and infant birth outcomes. Women who consumed alcohol in the past seven days were distinguished by a metabolite profile that included reduced sphingomyelins, cholesterol, and pregnenolones, and elevated fatty acids, acyl and amino acyl carnitines, and androsterones. Using PLS-DA, 25 of the top 30 metabolites differentiating maternal groups were reduced by alcohol with medium-chain free fatty acids and oxidized sugar derivatives having the greatest influence. A separate ortho-PLS-DA analysis identified a common set of 13 metabolites that were associated with infant length, weight, and head circumference. These included monoacylglycerols, glycerol-3-phosphate, and unidentified metabolites, and most of their associations were negative, implying they represent processes having adverse consequences for fetal development. Full article

Alcohol-associated liver disease is a major public health concern globally. Alterations of steroid hormones and gut microbiota were both found in patients with alcohol-associated liver disease. However, their correlation has not been well characterized in these patients. In this study, we measured the level of 30 steroid hormones in serum and fecal samples collected from non-alcoholic controls, patients with alcohol use disorder, and patients with alcohol-associated hepatitis. The profile of serum and fecal steroid hormones was quite different in patients with alcohol-associated hepatitis from that in patients with alcohol use disorder and control subjects. Stronger alterations were observed in male patients than in females. Correlations were found not only between serum steroids and gut bacteria but also between serum steroids and gut fungi. These correlations need to be taken into consideration during the development of treatment strategies for alcohol-associated liver disease. Full article

Enzymes are powerful biological catalysts for natural substrates but they have low catalytic efficiency for non-natural substrates. Protein engineering can be used to optimize enzymes for catalysis and stability. 3α-Hydroxysteroid dehydrogenase/carbonyl reductase (3α-HSD/CR) catalyzes the oxidoreduction reaction of NAD⁺ with androsterone. Based on the structure and catalytic mechanism, we mutated the residues of T11, I13, D41, A70, and I112 and they interacted with different portions of NAD⁺ to switch cofactor specificity to biomimetic cofactor nicotinamide mononucleotide (NMN⁺). Compared to wild-type 3α-HSD/CR, the catalytic efficiency of these mutants for NAD⁺ decreased significantly except for the T11 mutants but changed slightly for NMN⁺ except for the A70K mutant. The A70K mutant increased the catalytic efficiency for NMN⁺ by 8.7-fold, concomitant with a significant decrease in NAD⁺ by 1.4 × 10⁴-fold, resulting in 9.6 × 10⁴-fold cofactor specificity switch toward NMN⁺ over NAD⁺. Meanwhile, the I112K variant increased the thermal stability and changed to a three-state transition from a two-state transition of thermal unfolding of wild-type 3α-HSD/CR by differential scanning fluorimetry. Molecular docking analysis indicated that mutations on these residues affect the position and conformation of the docked NAD⁺ and NMN⁺, thereby affecting their activity. A70K variant sterically blocks the binding with NAD⁺, restores the H-bonding interactions of catalytic residues of Y155 and K159 with NMN⁺, and enhances the catalytic efficiency for NMN⁺. Full article

Background: Social behavior is mediated by steroid hormones, whereby various lines of evidence indicate that metformin might improve the symptoms of social withdrawal. This directly yields to the aim of the study to correlate the impact of metformin treatment on the potential alterations in steroid hormone homeostasis, which is ultimately impacting social behavior. Therefore, urinary samples of patients before and after treatment with metformin will be correlated to social behavior to elucidate potential changes in steroid hormone profiles and social behavior. Material and Methods: An observational study in healthy adults with a new indication for metformin. Steroid hormone analysis, including the most prominent androgen, estrogen, progesterone, aldosterone, corticosterone, cortisone and cortisol metabolites analyzed with gas chromatography–mass spectrometry and a questionnaire on social behavior (Autism Spectrum Questionnaire (AQ)) will be administered prior to and after around a 12-week phase of metformin treatment. Discussion: It is likely that due to different pathophysiological mechanisms such as an effect on the respiratory chain in mitochondria or via AMP-activated protein kinase, a general alteration of steroid hormone levels can be detected prior to post treatment. The encompassing measurement of steroid hormones shall give hints concerning the involvement of specific cascades yielding potential pharmacological targets for future research. Full article

Background: Increasing evidence exists that higher levels of androgens can be found in individuals with autism. Evidence yields to a susceptible role of Cytochrome P450 17A1 (CYP17A1) with its catalyzation of the two distinct types of substrate oxidation by a hydroxylase activity (17-alpha hydroxylase) and C17/20 lyase activity. However, to what extent steps are altered in affected children with autism versus healthy controls remains to be elucidated. Methods: Urine samples from 48 boys with autism (BMI 19.1 ± 0.6 kg/m², age 14.2 ± 0.5 years) and a matched cohort of 48 healthy boys (BMI 18.6 ± 0.3 kg/m², 14.3 ± 0.5 years) as well as 16 girls with autism (BMI 17.5 ± 0.7 kg/m², age 13.8 ± 1.0 years) and a matched cohort of 16 healthy girls (BMI 17.2 ± 0.8 kg/m², age 13.2 ± 0.8 years) were analyzed for steroid hormone metabolites by gas chromatography-mass spectrometry. Results: The activity of 17-alpha Hydroxylase increased by almost 50%, whereas activity of 17/20 Lyase activity increased by around 150% in affected children with autism. Furthermore, the concentration of Cortisol was higher as compared to the average increase of the three metabolites TH-Corticosterone, 5α-TH-Corticosterone and TH-11β-DH-Corticosterone, indicating, in addition, a stimulation by the CRH-ACTH system despite a higher enzymatic activity. Discussion: As it was shown that oxidative stress increases the 17/20-lyase activity via p38α, a link between higher steroid hormone levels and oxidative stress can be established. However, as glucocorticoid as well as androgen metabolites showed higher values in subjects affected with autism as compared to healthy controls, the data indicate, despite higher CYP17A1 activity, the presence of increased substrate availability in line with the Cholesterol theory of autism. Full article