5-hydroxyindoleacetic Acid Concentrations Research Articles

Circulating Gut Microbe-Derived Metabolites Are Associated with Hepatocellular Carcinoma.

Forty-one patients with HCC and 96 healthy controls were enrolled from surgical clinics at the Cleveland Clinic from 2016 to 2020. Gut microbiota-derived circulating metabolites detectable in plasma were compared between patients with HCC and healthy controls. Hierarchical clustering was performed for generating heatmaps based on circulating metabolite concentrations using ClustVis, with Euclidean and Ward settings and significant differences between metabolite concentrations were tested using a binary logistic regression model. In patients with HCC, 25 (61%) had histologically confirmed cirrhosis. Trimethylamine (TMA)-related metabolites were found at higher concentrations in those with HCC, including choline (p < 0.001), betaine (p < 0.001), carnitine (p = 0.007), TMA (p < 0.001) and trimethylamine N-oxide (TMAO, p < 0.001). Notably, concentrations of P-cresol glucuronide (p < 0.001), indole-lactic acid (p = 0.038), 5-hydroxyindoleacetic acid (p < 0.0001) and 4-hydroxyphenyllactic acid (p < 0.001) were also increased in those with HCC compared to healthy controls. Hierarchical clustering of the metabolite panel separated patients based on the presence of HCC (p < 0.001), but was not able to distinguish between patients with HCC based on the presence of cirrhosis (p = 0.42). Gut microbiota-derived metabolites were differentially abundant in patients with HCC versus healthy controls. The observed perturbations of the TMAO pathway in HCC seem particularly promising as a target of future research and may have both diagnostic and therapeutic implications.

Isomalt attenuates hepatic steatosis in rats via modulating gut microbiota and its metabolic function

Growing studies have shown the preventive effects of isomalt against metabolic diseases, nevertheless, its efficacy and action mechanisms on nonalcoholic fatty liver disease (NAFLD) remain unknown. Herein, isomalt supplementation significantly attenuated the high-sucrose diet-induced hepatic steatosis. Mechanically, dietary isomalt restored hepatic de novo lipogenesis dysfunction and intestinal epithelial integrity. Moreover, isomalt consumption regulated gut microbiota composition, including improving abundance of probiotic Akkermansia, but suppressing pathogens Acinetobacter and Corynebacterium_1. Quantification analyses of short-chain fatty acids showed that isomalt reduced faecal acetate concentrations, whereas elevated propionate and butyrate in hepatic steatosis. Additionally, targeted metabolomics profiling of tryptophan metabolism showed that isomalt increased faecal levels of 5-hydroxytryptophan, indole-3-carboxaldehyde and kynurenic acid, but reduced concentrations of 5-hydroxyindoleacetic acid and xanthurenic acid in rats. Thereby, our data demonstrate that dietary isomalt attenuates hepatic steatosis possibly via modulation of gut microbiota and its metabolic function, which provides new insights into preventing and treating NAFLD in future.

Serotonin and 5-hydroxyindoleacetic acid are involved in the pathogenesis of COVID-19 in children

Background. The new coronavirus infection COVID-19 is a pressing health problem around the world. This disease affects the respiratory, cardiovascular and other systems. The role of serotonin as one of the key factors in COVID-19 is discussed in the literature.&#x0D; Aim. Determination of the concentration of serotonin and its metabolite 5-hydroxyindoleacetic acid in the blood serum of children in the acute period of COVID-19 for use as a diagnostic criterion for the severity of the disease.&#x0D; &#x0D; Material and methods. A study that included 141 children aged 0 to 17 years was conducted: 92 patients hospitalized in a hospital with a diagnosis of COVID-19 without concomitant pathology made up the study group, 49 healthy children were included in the control group. The subjects were divided into two age groups: younger (0–2 years) and older (3–17 years). The groups of patients and children from the control group were comparable in age and gender. A study of the concentration of serotonin and its metabolite — 5-hydroxyindoleacetic acid — in the blood was carried out using high-performance liquid chromatography, and the results of laboratory and instrumental research methods (obtained from medical records) were evaluated. Based on the results of computed tomography, the proportion of involvement of the lung parenchyma in the pathological process was calculated: CT0 — absence of lung damage; CT1 — less than 25%; CT2 — 25–49%; CT3 — 50–74%; CT4 — more than 75%. Quantitative data were described using median (Me) and lower and upper quartiles (Q1–Q3). To analyze the data, the Pearson χ2 test, nonparametric Kruskal–Wallis and Mann–Whitney tests, as well as the ROC curve method were used. A correlation analysis was carried out using the Spearman coefficient and an assessment of the dependence of a quantitative variable on factors using the linear regression method.&#x0D; Results. In children with COVID-19 aged 0–2 years, the concentration of serotonin (969.41 pmol/ml) in the blood serum was statistically significantly higher by 49.1 times, in the group of 3–17 years (637.87 pmol/ml) — by 24.5 times compared to age-matched controls (19.74 pmol/ml; p 0.001 and 26.0 pmol/ml; p 0.001, respectively). The concentration of 5-hydroxyindoleacetic acid in patients 0–2 years old (204.90 pmol/ml) was 4.7 times higher relative to healthy children (43.56 pmol/ml; p=0.003), and in the older age group (78.25 pmol/ml) — 2.4 times higher (32.65 pmol/ml; p=0.012), which suggests increased breakdown of serotonin under the influence of monoamine oxidase A. Maximum concentrations of serotonin in blood serum were detected in children aged 0–2 years (1808.79 pmol/ml) with damage to the lung parenchyma from 50 to 74% (grade 3 according to computed tomography). However, in children aged 3–17 years, the maximum concentrations of serotonin (2036.95 pmol/ml) were detected with lung damage ranging from 25 to 49% (grade 2 according to computed tomography). In patients with COVID-19, when the concentration of serotonin in the blood was above 1046.5 pmol/ml, grade 2–4 lung lesions were predicted according to computed tomography, sensitivity 62.5%, specificity 75%.&#x0D; Conclusion. With COVID-19, a significant increase in the concentration of serotonin and 5-hydroxyindoleacetic acid in the blood was detected in children.

Serotonin Metabolism and Serotonin Receptors Expression Are Altered in Colon Diverticulosis.

Background and Objectives: Diverticulosis is frequently accompanied by altered bowel habits. The biogenic amines within colonic mucosa control bowel motility, and in particular, alterations in serotonin signaling may play a role in colon diverticulosis. The aim of the study was to assess the concentration of biogenic amines and serotonin receptor expression in the colonic mucosa in patients with diverticulosis and healthy controls. Materials and Methods: This prospective, comparative study included 59 individuals: 35 with sigmoid diverticulosis and 24 healthy controls. The study was held at the Department of Gastroenterology and Internal Medicine, Medical University of Warsaw, Poland. Mucosal samples were taken from the right and left colon during a colonoscopy in all patients. Concentrations of norepinephrine, 3-methoxy-4-hydroxyphenylglycol, dopamine, homovanillic acid, serotonin, and 5-hydroxyindoleacetic acid were measured with high-performance liquid chromatography. Expressions of human 5-hydroxytryptamine receptor 3A, 5-hydroxytryptamine receptor 4, 5-hydroxytryptamine receptor 7, solute carrier family 6 member 4 (SERT) for serotonin, as well as the neuroglia activation markers glial fibrillary acidic protein, S100 calcium-binding protein B, and proteolipid protein 1, were assessed with polymerase chain reaction. Results: The median age and sex distribution were comparable in both study groups (median 69 y vs. 52 y; p < 0.455 and males/females in cases 11/17 vs. 18/19 in controls; p < 0.309). In diverticulosis patients, there was a higher concentration of serotonin in the left affected colon compared to the right healthy part of the colon (median 8239 pg/mg vs. 6326 pg/mL; p < 0.01). The SERT expression was lower in the affected left segment compared to the right colon (median 0.88 vs. 1.36; p < 0.01). There was a higher colonic mucosa concentration of serotonin (median 8239 pg/mg vs. 6000 pg/mL; p < 0.02) and 5-hydroxyindoleacetic acid/serotonin ratio (median 0.27 vs. 0.47; p < 0.01) in diverticulosis patients compared to controls in the left side of the colon. Conclusions: The concentration of serotonin in the mucosa of the colon segment affected by diverticula is higher than in the healthy segment in the same individuals and higher than in healthy controls. These results underline serotonin signaling in colon diverticulosis pathophysiology.

Metabolomics analysis reveals four biomarkers associated with the gouty arthritis progression in patients with sequential stages

ObjectivesThe gouty arthritis (GA) progression was multistage, yet the GA clinical diagnosis guidelines were more inclined to suitable for acute gouty arthritis (AGA), thus neglecting of the progress of GA. This study aimed to identify specific biomarkers that were competent for reflecting the progression of GA and attempted to provide evidence for seasonable intervention of appropriate clinical treatment. MethodsA total of 547 patients with GA at sequential stages and healthy volunteers were divided into a training set (n = 347) and a validation set (n = 200). Serum metabolic profiles were determined by UHPLC-QTOF-MS-MS untargeted metabolomics, and biomarkers were identified by logistic regression and receiver operating characteristic analysis. Further, UHPLC-QE-MS was applied for accurate quantitative validation of identified potential biomarkers in the validation set samples. ResultsAfter serum metabolic profiles analysis by untargeted metabolomics, 12 metabolites with monotonous change trend were screened, and were verified by targeted metabolomics subsequently. The quantitative results showed the serum concentration of kynurenic acid(KYNA), N1-Methyl-2-pyridone-5-carboxamide(2PY), DL-2-Aminoadipic acid(2AMIA) and 5-hydroxyindole acetic acid(5-HIAA) of patients with sequential stages showed a strictly monotonic trend, and AUC was 0.97, 0.97, 0.96 and 0.95, respectively. ConclusionsKYNA and 5-HIAA are related to acute inflammation of GA, while 2PY and 2AMIA are related to renal function damage caused by long-term HUA. Therefore, we believe it is inappropriate to use a single biomarker to define the phase of GA. Actually, four biomarkers obtained in this paper should be integratedly adopted to evaluate the progression of GA with sequential stages.

Effects of food quantity on aggression and monoamine levels of juvenile pufferfish (Takifugu rubripes).

Aggressive behavior is important for animals to obtain limited resources. Understanding fish behavior and physiological response is of great significance to evaluate aquaculture production and fish welfare. Food is an important trigger of aggressive behavior in juvenile fish under high-density aquaculture conditions. The aim of this study was to investigate the aggressive behavior and monoamine levels of juvenile pufferfish (mean body mass of 6.29 ± 0.33 g) under normal feeding and restricted feeding. Our main results included the following: (1) The mortality and fin damage were higher and aggression was more intense of juvenile pufferfish at the 1% ration than those of the 3% ration; (2) during feeding, the velocity, body contact, and activity at the 1% ration were significantly higher than that of the 3% ration; (3) the concentrations of brain 5-hydroxyindoleacetic acid (5-HIAA) and monoamine oxidase A (MAOA) at the 1% ration were significantly lower, and dopamine (DA) concentrations were significantly higher. These results suggest that juvenile pufferfish shows serious aggressive behavior at the low ration, which may be related to the decrease of 5-HIAA and MAOA concentrations, and the increase of DA concentrations.

Early Rearing Conditions Affect Monoamine Metabolite Levels During Baseline and Periods of Social Separation Stress: A Non-human Primate Model (Macaca mulatta).

A variety of studies show that parental absence early in life leads to deleterious effects on the developing CNS. This is thought to be largely because evolutionary-dependent stimuli are necessary for the appropriate postnatal development of the young brain, an effect sometimes termed the “experience-expectant brain,” with parents providing the necessary input for normative synaptic connections to develop and appropriate neuronal survival to occur. Principal among CNS systems affected by parental input are the monoamine systems. In the present study, N = 434 rhesus monkeys (233 males, 201 females) were reared in one of two conditions: as mother-reared controls (MR; n = 269) or without adults with 24-h access to same-aged peers (PR; n = 165). When subjects were six-months-old, they underwent a separation paradigm involving 4, sequential, four-day social separations from their mothers or peers, with each separation followed by three-day reunions with their mothers or their peers. Prior to the separation paradigm, baseline cisternal CSF samples were obtained, as well as at the end of each the four social separations, and after final separation, during a recovery period. CSF was assayed for concentrations of monoamine metabolites and a blood sample was genotyped for the serotonin transporter (5-HTT) genotype. Replicating earlier landmark findings, PR subjects with the s allele exhibited lower baseline concentrations of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA), when compared to PR subjects homozygous for the L allele. MR subjects were undifferentiated by genotype. PR subjects exhibited lower CSF 5-HIAA concentrations during baseline, but higher CSF 5-HIAA during social separations, when compared to MR subjects. There were rearing effects for the dopamine metabolite homovanillic acid (HVA) and for the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG), with PR subjects showing higher HVA and lower MHPG when compared to MR subjects. These findings indicate that there are long-term deficits in the response of monoamines following early maternal absence. The results of this study confirm and extend earlier findings that early parental absence has deleterious consequences for the development of the monoamine systems, and that these consequences are modulated by the 5-HTT genotype.

Sex and race differences of cerebrospinal fluid metabolites in healthy individuals.

Analyses of cerebrospinal fluid (CSF) metabolites in large, healthysamples have been limited and potential demographic moderators of brain metabolism are largely unknown. Our objective in this study was to examine sex and race differences in 33 CSF metabolites within a sample of 129 healthy individuals (37 African American women, 29 white women, 38 African American men, and 25 white men). CSF metabolites were measured with a targeted electrochemistry-based metabolomics platform. Sex and race differences were quantified with both univariate and multivariate analyses. Type I error was controlled for by using a Bonferroni adjustment (0.05/33 = .0015). Multivariate Canonical Variate Analysis (CVA) of the 33 metabolites showed correct classification of sex at an average rate of 80.6% and correct classification of race at an average rate of 88.4%. Univariate analyses revealed that men had significantly higher concentrations of cysteine (p < 0.0001), uric acid (p < 0.0001), and N-acetylserotonin (p = 0.049), while women had significantly higher concentrations of 5-hydroxyindoleacetic acid (5-HIAA) (p = 0.001). African American participants had significantly higher concentrations of 3-hydroxykynurenine (p = 0.018), while white participants had significantly higher concentrations of kynurenine (p < 0.0001), indoleacetic acid (p < 0.0001), xanthine (p = 0.001), alpha-tocopherol (p = 0.007), cysteine (p = 0.029), melatonin (p = 0.036), and7-methylxanthine (p = 0.037). After the Bonferroni adjustment, the effects for cysteine, uric acid, and 5-HIAA were still significant from the analysis of sex differences and kynurenine and indoleacetic acid were still significant from the analysis of race differences. Several of the metabolites assayed in this study have been associated with mental health disorders and neurological diseases. Our data provide some novel information regarding normal variations by sex and race in CSF metabolite levels within the tryptophan, tyrosine and purine pathways, which may help to enhance our understanding of mechanisms underlying sex and race differences and potentially prove useful in the future treatment of disease.

Антагонист грелина [D-Lys3]-GHRP-6 снижает проявления поведения риска в модели игровой зависимости у крыс, изменяя обмен дофамина и серотонина

The effect of the ghrelin receptor antagonist [D-Lys3] -GHRP-6 on the elements of gambling and monoamine metabolism in the rat brain was investigated. For three weeks, the rats were trained in a three-arm maze using the food reinforcement (sunflower seeds). During the first five days, at the end of the 1st arm, the animals received 1 seed, at the end of the 2nd arm, 2 seeds, and at the end of the 3rd arm, 3 seeds. In the following days, the reinforcement was differentiated: each entry in arm 1was reinforced with 1 seed, each second entry in arm 2 was reinforced with 2 seeds and every third entry in arm 3 was reinforced with 3 seeds. Thus, when visiting the 1st arm, the amount of reinforcement was minimal, and the probability of its delivery was maximal. The entry to the 3rd arm was reinforced as much as possible, but with the lowest probability. Rats that had developed a stable conditional locomotion in the maze were injected intranasally with 0.9% NaCl or D-Lys3-GHRP-6 and studied the behavior. 3 days after testing the rats were re-administered with 0.9% NaCl or D-Lys3-GHRP-6. After 80 minutes, the rats were decapitated and the brain structures were isolated. HPLC was used to determine the content of dopamine, serotonin and their metabolites in the hypothalamus, hippocampus, striatum, and olfactory tubercle (the part of ventral striatum). Intranasal administration of the ghrelin receptor antagonist [D-Lys3] -GHRP-6 (20 μl, 1 mg/ml) increased the number of entries into the 1st arm (with a high (100%) probability, but less reinforcement). No significant changes were found in the content of dopamine and serotonin after [D-Lys3]-GHRP-6 administration in the hypothalamus. The serotonin content significantly increased in the left hippocampus. The turnover of monoamines in the olfactory tubercle and striatum changed only in the right hemisphere, while the ratio of the content of 5-hydroxyindoleacetic acid to the content of serotonin increased in both structures. In the right striatum, these changes were also accompanied by an increase in the content of serotonin and dopamine metabolites. Thus, the ability of [D-Lys3] -GHRP-6 to change the strategy of choice in favor of the greatest probability, but the least amount of reinforcement, is based on an increase in the activity of the dopaminergic and serotoninergic systems in the dorsal and ventral striatum of the right hemisphere of the brain and the serotonin content in the hippocampus of the left hemisphere.

Pattern of postruminal administration of l-tryptophan affects blood serotonin in cattle

Serotonin (5-HT) has many important functions in both central and peripheral nervous systems. Although it has been demonstrated that manipulation of serotonin metabolism is possible in many species, there is limited information about l-tryptophan (TRP), a serotonin precursor, in cattle, and these provide conflicting results. Furthermore, there is no study evaluating how different patterns of intra-abomasal infusion of TRP impact circulating 5-HT. The objective of this study was to evaluate if intra-abomasal infusion patterns of TRP can affect circulating 5-HT and other metabolites from TRP metabolism in the plasma and serum and circulating glucose and insulin in cattle. Eight ruminally cannulated Holstein steers were used in a replicated 4 × 4 Latin square design. Each received intra-abomasal water infusion (control) or intra-abomasal TRP infusion (50 mg/kg BW) in 3 different patterns: a pulse infusion once a day (pulse once), pulse infusion twice a day (pulse twice), or continuous infusion (continuous). For continuous treatment, the TRP dose was diluted in tap water and infused by a peristaltic pump (300 mL/h). To equalize conditions, the other treatments had a water infusion (300 mL/h). The steers were fed every 2 h, and blood was collected from a jugular vein catheter every 4 h for 24 h after the initial infusion. Urine produced during the 24 h period was collected. Serum and plasma TRP, 5-HT and kynurenine, plasma glucose, and serum insulin concentrations were analyzed. Urine was analyzed for concentrations of 5-hydroxyindoleacetic acid. Both serum TRP and kynurenine were increased (P < 0.05) by all TRP infusion treatments, but concentrations in pulse dose treatments were greater than those in continuous infusion. Serum 5-HT increased (P < 0.05) with both pulse TRP infusion treatments; however, the continuous TRP infusion did not increase the serum 5-HT. Plasma 5-HT, glucose, and insulin had a tendency to increase with TRP pulse infusions. The urinary 5-hydroxyindoleacetic acid excretion was highest for pulse dose treatments. An acute supply of TRP in 1 or 2 daily doses increases serum 5-HT and increases circulating glucose and insulin in cattle. The TRP and kynurenine concentrations are similar in plasma and serum. However, the serum 5-HT concentration is more responsive to TRP administration than plasma.

Simultaneous Determination of Eight Urinary Metabolites by HPLC-MS/MS for Noninvasive Assessment of Traumatic Brain Injury.

Traumatic brain injury (TBI) is a serious public health concern for which sensitive and objective diagnostic methods remain lacking. While advances in neuroimaging have improved diagnostic capabilities, the complementary use of molecular biomarkers can provide clinicians with additional insight into the nature and severity of TBI. In this study, a panel of eight metabolites involved in distinct pathophysiological processes related to concussion was quantified using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Specifically, the newly developed method can simultaneously determine urinary concentrations of glutamic acid, homovanillic acid, 5-hydroxyindoleacetic acid, methionine sulfoxide, lactic acid, pyruvic acid, N-acetylaspartic acid, and F2α-isoprostane without intensive sample preparation or preconcentration. The method was systematically validated to assess sensitivity (method detection limits: 1-20 μg/L), accuracy (81-124% spike recoveries in urine), and reproducibility (relative standard deviation: 4-12%). The method was ultimately applied to a small cohort of urine specimens obtained from healthy college student volunteers. The method presented here provides a new technique to facilitate future work aiming to assess the clinical efficacy of these putative biomarkers for noninvasive assessment of TBI.

Antidepressant-Like Effects of Hesperidin in Animal Model of Post-Traumatic Stress Disorder

Post-traumatic stress disorder (PTSD) is a psychiatric disorder characterized by depression and anxiety, that arises due to an imbalance of neurotransmitters in response to excessive stress. Hesperidin (HSD) is a naturally occurring flavonoid shown to exert a variety of biological activities, including antioxidant, anti-inflammatory, and neuroprotective effects. This study was used the open field test (OFT) and forced swimming test (FST) to examine the effects of HSD on the depression-like response of rats after exposure to a single prolonged stress (SPS) leading to the dysregulation of the serotonergic activation system. Male rats were given HSD (20, 50, and 100 mg/kg, intraperitoneal injection, n=6-7 per group) once daily for 14 days after exposure to SPS. The influence of administration of HSD on SPS-induced behavioral responses and concentrations of serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), and monoamine oxidase-A (MAO-A) in the rat brain were also investigated using enzyme-linked immunoassays (ELISAs). Daily HSD administration signifificantly improved depression-like behaviors in the FST (P0.05), increased the number of lines crossed in the central zone of the OFT (P0.01), and reduced freezing behavior both in contextual and cued fear conditioning. HSD treatment also attenuated the reduction in SPS-induced 5-HT concentrations in the hippocampus and amygdala. This increase in 5-HT concentrations during HSD treatment was partially attributed to a decrease in the 5-HIAA/5-HT ratio in the hippocampus of rats with PTSD. Furthermore, HSD treatment inhibited activity of MAO-A and decreases of tryptophan hydroxylase-1 expression in the hippocampus. HSD was shown to exert antidepressant effects in rats exposed to SPS, suggesting that this natural flflavonoid may be an effective medicine for PTSD.

Alpha-naphthylisothiocyanate-induced cholestatic mice display anxiety-like behavior closely related with enhanced serotoninergic signaling transduction in central nervous system.

Cholestasis is a pathophysiological process caused by the damage of hepatocytes or obstruction of bile flow, which often leads to emotional disorder in central nervous system. Alpha-naphthylisothiocyanate (ANIT) is the most widely used chemical to induce cholestatic models; however, the neurobehavior of ANIT-induced cholestatic model has not been investigated. The present study was designed to evaluate the anxiety-like behavior of cholestatic mice induced by a single (i.p.) injection of ANIT and its potential mechanism. For validating the model, the alanine aminotransferase, glutamic oxaloacetic transaminase, alkaline phosphatase, and total bile acid in the serum of mice were detected, and the pathological sections of hepatic lobes were also observed. After that, a series of behavioral tests were used to detect the anxiety-like behavioral changes of the ANIT-induced cholestatic mice, and then the level of 5-hydroxytryptamine and 5-hydroxyindole acetic acid in serum and prefrontal cortex were detected. Our data showed that ANIT-induced cholestatic mice exhibited increased anxiety-like behaviors in the open-field test and elevated plus maze test. Moreover, the concentration of 5-hydroxyindole acetic acid significantly decreased in the serum and the prefrontal cortex of ANIT-induced cholestatic mice compared with the control group. In addition, the expression of 5-hydroxytryptamine 1A, 5-hydroxytryptamine 2C, 5-hydroxytryptamine 3A, and 5-hydroxytryptamine 7 receptors increased in the prefrontal cortex of the model mice compared to their controls. Our results suggest that ANIT-induced cholestatic mice can display anxiety-like behavior closely related with enhanced serotoninergic signaling transduction in central nervous system.

Bisphenol A and bisphenol S disruptions of the mouse placenta and potential effects on the placenta–brain axis

Placental trophoblast cells are potentially at risk from circulating endocrine-disrupting chemicals, such as bisphenol A (BPA). To understand how BPA and the reputedly more inert bisphenol S (BPS) affect the placenta, C57BL6J mouse dams were fed 200 μg/kg body weight BPA or BPS daily for 2 wk and then bred. They continued to receive these chemicals until embryonic day 12.5, whereupon placental samples were collected and compared with unexposed controls. BPA and BPS altered the expression of an identical set of 13 genes. Both exposures led to a decrease in the area occupied by spongiotrophoblast relative to trophoblast giant cells (GCs) within the junctional zone, markedly reduced placental serotonin (5-HT) concentrations, and lowered 5-HT GC immunoreactivity. Concentrations of dopamine and 5-hydroxyindoleacetic acid, the main metabolite of serotonin, were increased. GC dopamine immunoreactivity was increased in BPA- and BPS-exposed placentas. A strong positive correlation between 5-HT+ GCs and reductions in spongiotrophoblast to GC area suggests that this neurotransmitter is essential for maintaining cells within the junctional zone. In contrast, a negative correlation existed between dopamine+ GCs and reductions in spongiotrophoblast to GC area ratio. These outcomes lead to the following conclusions. First, BPS exposure causes almost identical placental effects as BPA. Second, a major target of BPA/BPS is either spongiotrophoblast or GCs within the junctional zone. Third, imbalances in neurotransmitter-positive GCs and an observed decrease in docosahexaenoic acid and estradiol, also occurring in response to BPA/BPS exposure, likely affect the placental-brain axis of the developing mouse fetus.

Neuroprotective effect and mechanism of baicalin on Parkinson's disease model induced by 6-OHDA.

ObjectiveThis research was aimed to investigate the effects of baicalin on 6-hydroxydopamine (6-OHDA)-induced rat model of Parkinson’s disease (PD) and the main mechanism of baicalin based on metabolomics.MethodsThe rat model of PD was induced by 6-OHDA. The protective effects of baicalin on rat model of PD were evaluated by open field test and rotarod test. The anti-PD efficacy of baicalin was evaluated by examining the morphologic changes of neurons and the level of monoamine neurotransmitters in the striatum, the number and morphology of tyrosine hydroxylase (TH)-positive neurons, and oxidative stress. Combined with metabolomics methods, the pharmacodynamic mechanism of baicalin on PD pathogenesis was also explored.ResultsBaicalin treatment improved the rod time and voluntary movement in rat model of PD (P<0.05) by the open field test and rotarod test. In addition, baicalin also protected from oxidative stress injury (P<0.05), and regulated the content of monoamine neurotransmitters dopamine, 3,4-dihydroxyphenylacetic acid, 5-hydroxytryptamine, and 5-hydroxyindoleacetic acid (P<0.05) and the number and morphology of TH-positive cells in 6-OHDA-induced PD model rats. By metabolomics, multivariate statistical analysis, and receiver operating characteristic curve analysis, we found that two metabolites N-acetyl aspartic acid and glutamic acid had a good diagnostic value. Quantitative analysis of metabolites showed a regulatory function of baicalin.ConclusionBaicalin has significant protective effect on 6-OHDA-induced PD rats, which may play a protective role through an antioxidant, promoting the release of neurotransmitters and regulating the metabolism of N-acetyl aspartate and glutamate.

Prevalence of Aromatic l-Amino Acid Decarboxylase Deficiency in At-Risk Populations

BackgroundAromatic l-amino acid decarboxylase (AADC) deficiency is an autosomal recessive metabolic disorder that results from disease-causing pathogenic variants of the dopa decarboxylase (DDC) gene. Loss of dopamine and serotonin production in the brain from infancy prevents achievement of motor developmental milestones. MethodsWe retrospectively evaluated data obtained from requests to Medical Neurogenetics Laboratories for analyses of neurotransmitter metabolites in the cerebrospinal fluid, AADC enzyme activity in plasma, and/or Sanger sequencing of the DDC gene. Our primary objective was to estimate the prevalence of AADC deficiency in an at-risk population. ResultsApproximately 20,000 cerebrospinal fluid samples were received with a request for neurotransmitter metabolite analysis in the eight-year study period; 22 samples tested positive for AADC deficiency based on decreased concentrations of 5-hydroxyindoleacetic acid and homovanillic acid, and increased 3-O-methyldopa, establishing an estimated prevalence of approximately 0.112%, or 1:900. Of the 81 requests received for plasma AADC enzyme analysis, 25 samples had very low plasma AADC activity consistent with AADC deficiency, resulting in identification of nine additional cases. A total of five additional patients were identified by Sanger sequencing as the primary request leading to the diagnosis of AADC deficiency. ConclusionsOverall, these analyses identified 36 new cases of AADC deficiency. Sequencing findings showed substantial diversity with identification of 26 different DDC gene variants; five had not previously been associated with AADC deficiency. The results of the present study align with the emerging literature and understanding of the epidemiology and genetics of AADC deficiency.

Quantitative Profiling of Platelet-Rich Plasma Indole Markers by Direct-Matrix Derivatization Combined with LC-MS/MS in Patients with Neuroendocrine Tumors.

Currently, several indole markers are measured separately to support diagnosis and follow-up of patients with neuroendocrine tumors (NETs). We have developed a sensitive mass spectrometry method that simultaneously quantifies all relevant tryptophan-related indoles (tryptophan, 5-hydroxytryptophan, serotonin, 5-hydroxyindoleacetic acid) in platelet-rich plasma. Direct-matrix derivatization was used to make the chemical properties of the indoles uniform and to improve the analytical sensitivity and specificity of the assay. In situ derivatization was performed directly in platelet-rich plasma with propionic anhydride at an ambient temperature. The derivatized indoles were extracted by online solid-phase extraction and eluted to the analytical column for separation followed by mass spectrometric detection. The method was validated according to international guidelines. Platelet-rich plasma samples from 68 healthy individuals and 40 NET patients were analyzed for tryptophan, 5-hydroxytryptophan, serotonin, and 5-hydroxyindoleacetic acid. The method reproducibly quantified relevant indoles in 8.5 min, including online sample cleanup. Intra- and interassay imprecision, evaluated at 3 different concentrations, ranged from 2.0% to 12% and 1.9% to 13%, respectively. The limit of quantification was sufficient to measure endogenous concentrations of all 4 indoles. Healthy individuals and NET patients had different concentrations of 5-hydroxytryptophan, serotonin, and 5-hydroxyindoleacetic acid, but tryptophan concentrations were the same. Direct-matrix derivatization in combination with LC-MS/MS is a powerful tool for the simultaneous quantification of all tryptophan-related indoles in platelet-rich plasma. Simultaneous profiling of relevant indoles improves the biochemical characterization and follow-up of NETs.

Urine 5-hydroxyindoleacetic acid in Cavalier King Charles spaniels with preclinical myxomatous mitral valve disease

Higher concentrations of circulating serotonin have been reported in Cavalier King Charles spaniels (CKCS) compared to other dog breeds. The CKCS is also a breed highly predisposed to myxomatous mitral valve disease (MMVD). The aim of this study was to determine urine concentrations of 5-hydroxyindoleacetic acid (5-HIAA), the major metabolite and excretion product of serotonin, in a population of CKCS with preclinical MMVD, and to evaluate whether urine 5-HIAA concentrations were associated with MMVD severity, dog characteristics, setting for urine sampling, platelet count, and serotonin concentration in serum and platelet-poor plasma (PPP). The study population consisted of 40 privately-owned CKCS (23 females; 17 males) with and without preclinical MMVD as follows: American College of Veterinary Internal Medicine (ACVIM) group A (n = 11), ACVIM group B1 (n = 21) and ACVIM group B2 (n = 8).Urine 5-HIAA concentrations were not significantly associated with preclinical MMVD disease, platelet count or circulating concentrations of serotonin (in serum and PPP; P > 0.05). Females had higher 5-HIAA concentrations than males in morning urine collected at home (females, 3.1 [2.9–3.7] μmol/mmol creatinine [median and quartiles]; males, 1.7 [1.2–2.2] μmol/mmol creatinine; P = 0.0002) and urine collected at the clinic (females, 3.5 [3.1–3.9] μmol/mmol creatinine; males, 1.6 [1.3–2.1] μmol/mmol creatinine; P < 0.0001). Five-HIAA concentrations in urine collected at home and at the clinic were significantly associated (P = 0.0004; r = 0.73), and higher concentrations were found in urine collected at the clinic (P = 0.013). Urine 5-HIAA concentration was influenced by sex and setting of urine sampling. Urine 5-HIAA concentration was not associated with MMVD severity or circulating concentrations of serotonin in CKCS with preclinical disease.

Maternal neglect and the serotonin system are associated with daytime sleep in infant rhesus monkeys.

Environmental and biological factors contribute to sleep development during infancy. Parenting plays a particularly important role in modulating infant sleep, potentially via the serotonin system, which is itself involved in regulating infant sleep. We hypothesized that maternal neglect and serotonin system dysregulation would be associated with daytime sleep in infant rhesus monkeys. Subjects were nursery-reared infant rhesus macaques (n = 287). During the first month of life, daytime sleep-wake states were rated bihourly (0800-2100). Infants were considered neglected (n = 16) if before nursery-rearing, their mother repeatedly failed to retrieve them. Serotonin transporter genotype and concentrations of cerebrospinal fluid 5-hydroxyindoleacetic acid (5-HIAA) were used as markers of central serotonin system functioning. t tests showed that neglected infants were observed sleeping less frequently, weighed less, and had higher 5-HIAA than non-neglected nursery-reared infants. Regression revealed that serotonin transporter genotype moderated the relationship between 5-HIAA and daytime sleep: in subjects possessing the Ls genotype, there was a positive correlation between 5-HIAA and daytime sleep, whereas in subjects possessing the LL genotype there was no association. These results highlight the pivotal roles that parents and the serotonin system play in sleep development. Daytime sleep alterations observed in neglected infants may partially derive from serotonin system dysregulation.

P211 Relationship between the concentrations of free sulphates and 5-hydroxyindoleacetic acid (5-HIAA) in urine for IBD patients

P211 Relationship between the concentrations of free sulphates and 5-hydroxyindoleacetic acid (5-HIAA) in urine for IBD patients