5-HIAA Levels Research Articles

Exposure to hexafluoropropylene oxide trimer acid (HFPO-TA) impairs 5-HT metabolism by impacting the brain-gut axis in mice

Hexafluoropropylene oxide trimer acid (HFPO-TA) has been found to cause hepatotoxicity, lipotoxicity, and cytotoxicity. However, the effects of HFPO-TA exposure on nervous system toxicity are still unclear. Here, six-week-old male C57BL/6J mice were treated with 2, 20, and 200 μg/L HFPO-TA for six weeks. The untargeted transcriptome analysis was employed to identify differentially expressed mRNAs in the tissue of mouse hippocampi. Then, the levels of neurotransmitters were detected by ELISA analysis in hippocampal and colonic tissues. Real-time quantitative PCR and western blotting analysis were performed to detect the expression of genes associated with modulation of serotonin (5-HT) metabolism and blood-brain barrier. HFPO-TA exposure reduced the mRNA and protein expression of several tight junction protein-coded genes, including Occludin, Claudin-1, and ZO-1, in mice hippocampi, indicating that the blood-brain barrier was disrupted. Moreover, HFPO-TA exposure elevated the expression of neuroinflammatory factors, including TNF-α, IL-6, IL-1β, TGF-α, and TGF-β. Analysis of hippocampal transcriptomics suggested that HFPO-TA exposure would impair 5-HT generation and metabolic pathways. In keeping with this prediction, our findings confirmed that the levels of several neurotransmitters, including tryptophan (TRP), 5-HT, 5-HTP, and 5-HIAA, were all impaired by HFPO-TA exposure in the serum, colon, and hippocampus, as was the colonic and hippocampal expression of TRP and 5-HT metabolism-related genes such as SERT, MAO-A, and IDO. These results suggest that HFPO-TA nervous system toxicity in mice may be partly modulated by the brain-gut axis and that HFPO-TA exposure may negatively impact human mental health.

Serum neuroactive metabolites of the tryptophan pathway in patients with acute phase of affective disorders.

Many studies showed disrupted tryptophan metabolism in patients with affective disorders. The aims of this study were to explore the differences in the metabolites of tryptophan pathway (TP) and the relationships between TP metabolites and clinical symptoms, therapeutic effect in patients with bipolar disorder with acute manic episode (BD-M), depressive episode (BD-D) and major depressive disorder (MDD). Patients with BD-M (n=52) and BD-D (n=39), MDD (n=48) and healthy controls (HCs, n=49) were enrolled. The serum neuroactive metabolites levels of the TP were measured by liquid chromatography-tandem mass spectrometry. Hamilton Depression Scale-17 item (HAMD-17) and Young Mania Rating Scale (YMRS) were used to evaluate depressive and manic symptoms at baseline and after 8 weeks of antidepressants, mood stabilizers, some also received antipsychotic medication. The levels of tryptophan (TRP) and kynurenic acid (KYNA) were significantly lower and the ratios of tryptophan/kynurenine (TRP/KYN), 5-hydroxytryptamine/tryptophan (5-HT/TRP), quinolinic acid/kynurenic acid (QUIN/KYNA) were higher in BD-M, BD-D, MDD vs. HC. The levels of QUIN and the ratios of QUIN/KYNA were higher in BD-M than in BD-D, MDD, and HCs. The 5-hydroxyindoleacetic acid (5-HIAA) levels of patients with MDD were significantly higher than those in BD-M and BD-D. Binary logistic regression analysis showed the lower peripheral KYNA, the higher the QUIN level, and the higher the risk of BD-M; the lower peripheral KYNA and the higher KYN/TRP and 5-HT/TRP, the higher the risk of BD-D; and the lower the peripheral KYNA level and the higher the KYN/TRP and 5-HT/TRP, the higher the risk of MDD. Correlation analysis, showing a significant association between tryptophan metabolites and improvement of clinical symptoms, especially depression symptoms. Patients with affective disorders had abnormal tryptophan metabolism, which involved in 5-HT and kynurenine pathway (KP) sub-pathway. Tryptophan metabolites might be potential biomarkers for affective disorders and some metabolites have been associated with remission of depressive symptoms.

Gut microbiota-derived 5-hydroxyindoleacetic acid from pumpkin polysaccharides supplementation alleviates colitis via MAPKs-PPARγ/NF-κB inhibition

Polysaccharides from Pumpkin (Cucurbita moschata Duchesne) (PPs) have many pharmacological activities, including anti-oxidant, immune, and intestinal microbiota regulation. These activities have provided some reminders of its potential therapeutic effect on ulcerative colitis (UC), but this has not yet been confirmed. This study preliminarily confirmed its significant anti-UC activity superior to Salicylazosulfapyridine. The average molecular weight of PPs was 3.10 × 105 Da, and PPs mainly comprised Mannose, Rhamnose, Galacturonic acid, Galactosamine, Glucose, and Xylose with molar ratios of 1.58:3.51:34.54:1.00:3.25:3.02. PPs (50, 100 mg/kg) could significantly resist dextran sodium sulfate induced UC on C57BL/6 mice by improving gut microbiota dysbiosis, such as the changes of relative abundance of Bacteroides, Culturomica, Mucispirillum, Escherichia-Shigella, Alistipes and Helicobacter. PPs also reverse the abnormal inflammatory reaction, including abnormal level changes of TNF-α, IFN-γ, IL-1β, IL-4, IL-6, IL-10, and IL-18. Metabolomic profiling showed that PPs supplementation resulted in the participation of PPAR and MAPK pathways, as well as the increase of 5-hydroxyindole acetic acid (5-HIAA) level. 5-HIAA also exhibited individual and synergistic anti-UC activities in vivo. Furthermore, combination of PPs and 5-HIAA could also elevate the levels of PPARγ in nuclear and inhibit MAPK/NF-ĸB pathway in the colon. This study revealed that PPs and endogenous metabolite 5-HIAA might be developed to treat UC.

Affective dysfunction mediates the link between neuroimmune markers and the default mode network functional connectivity, and the somatic symptoms in somatic symptom disorder

ObjectiveSomatic symptom disorder (SSD) is characterized by physical symptoms and associated functional impairments that are often comorbid with depression and anxiety disorders. In this study, we explored relationships between affective symptoms and the functional connectivity of the default mode network (DMN) in SSD patients, as well as the impact of peripheral inflammation. We employed mediation analyses to investigate the potential pathways between these factors. MethodsWe recruited a total of 119 individuals (74 unmedicated SSD patients and 45 healthy controls), who were subjected to comprehensive psychiatric and clinical evaluations, blood tests, and resting-state functional magnetic resonance imaging scanning. We assessed neuroimmune markers (interleukin-6 (IL-6), high-sensitivity C-reactive protein (hs-CRP), tumor necrosis factor-α (TNF-α), tryptophan, serotonin, and 5-hydroxyindoleacetic acid (5-HIAA)), clinical indicators of somatic symptoms, depression, anxiety, anger, alexithymia, and functional connectivity (FC) within the DMN regions. Data were analyzed using correlation and mediation analysis, with a focus on exploring potential relations between clinical symptoms, blood indices, and DMN FCs. ResultsPatients with SSD had higher clinical scores as well as IL-6 and TNF-α levels compared with those in the control group (P < 0.05). The SSD group exhibited lower FC strength between the left inferior parietal lobule and left prefrontal cortex (Pfalse discovery rate (FDR) < 0.05). Exploratory correlation analysis revealed that somatic symptom scores were positively correlated with affective symptom scores, negatively correlated with the FC strength between the intra prefrontal cortex regions, and correlated with levels of IL-6, TNF- α, and tryptophan (uncorrected P < 0.01). Mediation analysis showed that levels of anxiety and trait anger significantly mediated the relations between DMN FC strength and somatic symptoms. In addition, the DMN FC mediated the level of trait anger with respect to somatic symptoms (all PFDR < 0.05). The levels of depression and trait anger exhibited significant mediating effects as suppressors of the relations between the level of 5-HIAA and somatic symptom score (all PFDR < 0.05). Further, the level of 5-HIAA had a mediating effect as a suppressor on the relation between DMN FC and state anger. Meanwhile, the levels of hs-CRP and IL-6 had full mediating effects as suppressors when explaining the relations of DMN FC strengths with the level of depression (all PFDR < 0.05). The patterns of valid mediation pathways were different in the control group. ConclusionsAffective symptoms may indirectly mediate the associations between DMN connectivity, somatic symptoms, and neuroimmune markers. Inflammatory markers may also mediate the impact of DMN connectivity on affective symptoms. These results emphasize the importance of affective dysregulation in understanding the mechanisms of SSD and have potential implications for the development of tailored therapeutic approaches for SSD patients with affective symptoms. Furthermore, in SSD research using DMN FC or neuroimmune markers, considering and incorporating such mediating effects of affective symptoms suggests the possibility of more accurate prediction and explanation.

A phase 2, open-label, safety and efficacy study of telotristat ethyl plus first-line chemotherapy in patients with advanced biliary tract cancer.

472 Background: Patients (pts) with unresectable biliary tract cancer (BTC) have a poor prognosis. In preclinical models of cholangiocarcinoma (CCA) telotristat ethyl (TE), a tryptophan hydroxylase inhibitor that reduces production of serotonin, enhanced the antiproliferative effects of gemcitabine and cisplatin (GC) chemotherapy. This trial assessed the safety and efficacy of adding TE to GC chemotherapy in pts with advanced BTC. Methods: This was a Phase 2 open-label study. Eligible pts had unresectable, locally advanced, or metastatic BTC, were treatment naïve and had plans to initiate GC chemotherapy. On Day 1, pts received Gem 1000mg/m2 and Cis 25mg/m2 with TE 250 mg orally three times daily (TID) for 7 days. Thereafter, pts received TE 500 mg TID continuously plus GC therapy on days 1 and 8 of each 21-day cycle. The study comprised of 2 stages: stage 1 would enroll 20 patients with a safety run-in cohort in the first 6 pts to monitor safety and tolerability of TE + GC treatment for 21 days. Stage 2 would enroll 33 patients if no significant/unresolved grade 3 or higher toxicities related to study drug occurred in stage 1. The primary endpoint was 6-month (mo) progression free survival (PFS) rate according to RECIST 1.1. If 60% of pts (≥34) in the safety population were alive and progression free at 6-mos, the study was considered successful. Secondary endpoints included overall response rate (ORR) and disease control rate (DCR). Restaging occurred every 9 weeks using RECIST 1.1 and toxicities were graded using CTCAE v 5.0. Results: Between 2019 and 2021, fifty-three pts were enrolled across 12 study sites and comprised the safety population. The majority of pts were female (62.3%) and median age was 66 yrs (range 33 to 79). Baseline mean plasma 5-HIAA was 11.1 µg/L (ULN defined as &gt;10.8 µg/L). Thirty-one pts (58.5%) had plasma 5-HIAA levels ≤ULN and 22/53 (41.5%) had 5-HIAA levels &gt;ULN. Majority of pts had metastatic BTC (85%) and liver was the most common primary tumor site (66%). The 6-month PFS rate was 22.6% (12/53). Based on blinded independent central review, the ORR was 13.2% and DCR was 62.3%. Mean reduction in plasma 5-HIAA at 6 mos was -1.735 µg/L (SD 8.69) in 24 patients with available data. There was no difference in 6-mo PFS rate based on pts baseline 5-HIAA status; 58% (14/24) pts had ≥30% decrease from baseline in 5-HIAA, however there was no correlation with 6-month PFS. The most common TE related TEAEs were constipation (43.4%), nausea (28.3%) and fatigue (28.3%). Conclusions: The study did not achieve its primary endpoint of 60% of patients on TE plus GC chemotherapy being alive and progression free at 6 months. TE did reduce 5-HIAA levels in a subset of pts; however, this did not correlate to improved clinical outcomes. No significant safety issues noted with TE in combination with GC chemotherapy. Clinical trial information: NCT03790111 .

Increased stress vulnerability in the offspring of socially isolated rats: Behavioural, neurochemical and redox dysfunctions

Stressful events during pregnancy impact on the progeny neurodevelopment. However, little is known about preconceptional stress effects. The rat social isolation represents an animal model of chronic stress inducing a variety of dysfunctions. Moreover, social deprivation during adolescence interferes with key neurodevelopmental processes. Here, we investigated the development of behavioural, neurochemical and redox alterations in the male offspring of socially isolated female rats before pregnancy, reared in group (GRP) or in social isolation (ISO) from weaning until young-adulthood. To this aim, females were reared in GRP or in ISO conditions, from PND21 to PND70, when they were mated. Their male offspring was housed in GRP or ISO conditions through adolescence and until PND70, when passive avoidance-PA, novel object recognition-NOR and open field-OF tests were performed. Levels of noradrenaline (NA), serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), glutamate (GLU) and GABA were assessed in the prefrontal cortex (PFC). Moreover, cortical ROS levels were quantified, as well as NF-kB and the NADPH oxidase NOX2 expression, redox status (expressed as GSH:GSSG ratio) and SOD1 amount.A significant decrease of the latency time in the PA was observed in the offspring of ISO females. In the NOR test, while a significant increase in the exploratory activity towards the novel object was observed in the offspring of GRP females, no significant differences were found in the offspring of ISO females. No significant differences were found in the OF test among experimental groups. Theoffspring of ISO females showed increased NA and 5-HIAA levels, whereas in the offspring persistently housed in isolation condition from weaninguntil adulthood, we detected reduced 5-HT levels and ehnanced 5-HIAA amount. No significant changes in GLU concentrations were detected, while decreased GABA content was observed in the offspring of ISO females exposed to social isolation. Increased ROS levels as well as reduced NF-κB, NOX2 expression were detected in the offspring of ISO females. This was accompanied by reduced redox status and enhanced SOD1 levels.In conclusion, our results suggest that female exposure to chronic social stress before pregnancy might have a profound influence on the offspring neurodevelopment in terms of cognitive, neurochemical and redox-related alterations, identifying this specific time window for possible preventive and therapeutic strategies.

Use of perioperative telotristat in a patient with carcinoid heart disease.

Carcinoid heart disease is a rare complication of carcinoid syndrome, resulting in right-sided valvular heart disease and subsequent heart failure due to long-term exposure to vasoactive substances. The management of this condition is complex, often requiring surgical intervention. Current perioperative regimens entail the use of prophylactic somatostatin analogs to prevent carcinoid crisis; however, regimens vary widely among practitioners and evidence supporting their efficacy in this clinical setting is mixed. This case report describes the perioperative management of a 65-year-old man with carcinoid heart disease requiring tricuspid and pulmonary valve replacement surgery. As an adjunct to somatostatin analog therapy, the novel tyrosine hydroxylase inhibitor, telotristat, was initiated preoperatively. This combination resulted in normalization of preoperative urinary 5-HIAA levels. The patient successfully underwent tricuspid and pulmonic valve replacement without evidence of carcinoid crisis. This clinical case is the first published documenting the use of telotristat in the perioperative period in a patient with carcinoid syndrome and carcinoid heart disease and was associated with a good long-term outcome despite the high-risk nature of the case. Carcinoid crisis is a life-threatening complication of carcinoid syndrome, resulting in hemodynamic instability, bronchospasm, and arrhythmia. Cardiac surgical patients with carcinoid syndrome present a unique challenge as they are subject to physiologic conditions and medications which can potentiate intraoperative carcinoid crisis. Perioperative management of patients with carcinoid syndrome currently entails the use of prophylactic somatostatin analogs; however, these agents do not prevent carcinoid crisis in all cases. Telotristat, a tryptophan hydroxylase inhibitor, shows promise as an adjunctive therapy to somatostatin analogs to reduce the risk of intraoperative carcinoid crisis.

Tryptophan Metabolism in Postmenopausal Women with Functional Constipation.

Constipation belongs to conditions commonly reported by postmenopausal women, but the mechanism behind this association is not fully known. The aim of the present study was to determine the relationship between some metabolites of tryptophan (TRP) and the occurrence and severity of abdominal symptoms (Rome IV) in postmenopausal women with functional constipation (FC, n = 40) as compared with age-adjusted postmenopausal women without FC. All women controlled their TRP intake in their daily diet. Urinary levels of TRP and its metabolites, 5-hydroxyindoleacetic acid (5-HIAA), kynurenine (KYN), and 3-indoxyl sulfate (indican, 3-IS), were determined by liquid chromatography/tandem mass spectrometry. Dysbiosis was assessed by a hydrogen-methane breath test. Women with FC consumed less TRP and had a lower urinary level of 5-HIAA, but higher levels of KYN and 3-IS compared with controls. The severity of symptoms showed a negative correlation with the 5-HIAA level, and a positive correlation with the 3-IS level. In conclusion, changes in TRP metabolism may contribute to FC in postmenopausal women, and dysbiosis may underlie this contribution.

Sex differences of cerebrospinal fluid biomarkers in Alzheimer’s disease

AbstractBackgroundAlzheimer’s disease (AD) is more common in women than in men. Thus, to investigate the sex‐specific mechanism is important to understand the pathogenesis of AD. We examined the sex differences in levels of CSF biomarkers (tau, ptau‐181, Aβ42, HVA and 5HIAA) in AD.MethodThe subjects of this study consisted of clinically diagnosed 386 patients with AD (age 75.9±8.4 years, 237 women and 149 men). The clinical diagnosis was made based on the AD diagnostic criteria (NIA/AA, McKhann GM, et al., Alzheimers Dement 2011; 7: 263‐269). The CSF samples were obtained by lumbar puncture after informed consent was obtained. The levels of CSF tau, ptau‐181 and Aβ42 were measured by ELISA (Fujirebio, Belgium) according to the manufacturer’s protocol. The levels of CSF HVA and 5HIAA were measured by HPLC. We compared the levels of CSF biomarkers between women and men.ResultAge, the levels of CSF tau, ptau‐181 and Aβ42 showed no sex differences. The levels of CSF HVA (ng/ml) were 32.6±19.3 in women and 25.9±14.4 in men. The levels of 5HIAA were 19.1±11.7 in women and 14.8±7.7 in men. The levels of CSF HVA and 5HIAA were significantly higher in women than those in men (t‐test, HVA: p&lt;0.001, 5HIAA: p&lt;0.001).It has been reported that women have higher values of HVA and 5HIAA among normal subjects, due to higher monoamine oxidase (MAO) activity in women. The MAO‐A and MAO‐B genes are located on the X chromosome, and are controlled by XCI (X‐chromosome inactivation). However, the MAO genes may escape XCL MAO‐B has also been reported to be γ‐secretase associated protein and regulate neuronal amyloid β‐peptide levels. Thus, increased MAO‐B activity may be one of the reasons why AD is more common in women.ConclusionBoth CSF levels of HVA and 5HIAA were significantly higher in women in AD, presumably due to increased MAO activity.

Effect of Prolonged Exposure to Short Daylight and a Tryptophan Hydroxylase Inhibitor on the Behavior and Brain Serotonin System in Danio rerio.

We studied the effect of reduced tryptophan hydroxylase (TPH) activity and short daylight exposure on the behavior and the 5-HT system of the brain in D. rerio. Male and female D. rerio were exposed for 30 days to standard (12:12 h light:dark) and short (4:20 h light:dark) photoperiods in the presence or absence of TPH inhibitor (p-chlorophenylalanine, pCPA, 5 mg/liter). On day 31, the fish behavior in the "novel tank diving" test, their sex and body weight were determined, and the levels of pCPA, 5-HT, and its metabolite 5-HIAA were measured by HPLC; the levels of the key genes encoding metabolism enzymes (Tph1a, Tph1b, Tph2, and Mao) and receptors of 5-HT (Htr1aa, Htr2aa) were assessed by real-time PCR with reverse transcription. The short daylight exposure caused masculinization of females, reduced body weight, and motor activity in the "novel tank diving" test, but did not affect the 5-HT system of the brain. Long-term pCPA treatment had no effect on sex and body weight, significantly reduced the 5-HIAA level, but increased Tph1a and Tph2 gene expression in the brain. No effects of the interaction of short daylight and pCPA exposure on the sex, body weight, behavior, and 5-HT system of the brain were found. Thus, a moderate decrease in TPH activity cannot potentiate the negative effects of short daylight exposure on the sex, body weight, behavior, and 5-HT system of D. rerio.

B-206 The Determination of Vanillylmandelic Acid (VMA), Homovanillic Acid (HVA) and 5-Hydroxyindolacetic Acid (5-HIAA) by LC-Ms/MS Assay in Urine Samples for Diagnosis of Neuroendocrynes Tumors

Abstract Background The catecholamines dopamine, norepinephrine and epinephrine, as well the neurotransmitter serotonin are biogenic amines that were formed by enzymatic descarboxylation of aminoacids in the body. They realize an important function in central nervous system. Vanillylmandelic acid (VMA) and Homovanillic Acid (HVA) are degradation products of the catecholamines, and 5-Hydroxyindolacetic Acid (5-HIAA) is a serotonine degradation product. They are important to the diagnosis of neuroendocrynes tumors, that produce catecholamines and/or serotonine in excess, resulting in elevated levels of VMA, HVA, and/or 5-HIAA in 24 h collection urine. Objective This study aimed to validate a simple LC-MS/MS method for quantification of VMA, HVA and 5-HIAA in isolated and 24 h urine samples for the diagnosis of neuroendocrines tumors. Methods Using a deep-well microtiter plate, 20 µL of isolated or 24 h urine was diluted in 540 µL of 0.05% of formic acid solution. Then, 20 µL of an internal standard solution containing stable isotopes of the analytes were added (VMA-D3, HVA-13C6,18O and 5-HIAA-13C6). The plate was sealed, homogenized for 30 s at 2500 rpm, and centrifuged for 15 min at 4000 rpm and ambient temperature. Then, 5.0 µL of the supernatant was injected into the LC-MS/MS system. Chromatographic separation was performed on the Waters ACQUITY UPLC system equipped with Kinetex XB-C18 1.7 µm X 50 mm X 2.1 mm column (Phenomenex), and methanol and formic acid 0.2% solution as mobile phase in 3.5 min of gradient mode separation. The detection was performed on a Waters XEVO TQ-S Micro mass spectrometer with electrospray ionization (ESI+). The current method was validated for carryover, linearity, precision, recovery, and limit of quantification, and it was evaluated by comparing the analysis in the developed method and a commercial kit by HCPL-ECD, of 15 real samples from volunteers in the laboratory. Results The method was successfully validated for all the parameters. The linearity was between 0.5–100.0 mg/L. The precision was less than 6.3%, the recovery was between 85.4%–103.4% and the quantification limit was 0.5 mg/L. The comparison with the reference method showed good coefficient correlations (R2 &amp;gt; 0.92) for the three analytes. Conclusion We validate a simple LC-MS/MS method to quantify three metabolites to help the diagnosis of neuroendocrynes tumors. The method represents a simplification of the extraction compared with the commercial kit employing HPLC-ECD, and an important reduction of the per sample production cost, without loss of quality.

Neurochemical Effects of Methylphenidate and Modafinil in Ameliorating Stress-Induced Cognitive Deficits.

Chronic stressful situations result in altered monoaminergic activity of neurotransmitters, resulting in various conditions characterized by deficits in learning, memory and attention. Stimulant effects can be visualized in terms of increased cognitive abilities through enhancement of dopamine (DA) release. This study examined cognitive responses and brain DA and 5-hydroxytryptamine (5HT) levels after prolonged methylphenidate (MPH) and modafinil administration, to demonstrate their effect on stress-induced cognitive deficits in rats. Effects on cognition were evaluated by passive avoidance and water maze tests. Furthermore brain levels of DA, homovanillic acid (HVA), dihydroxyphenylacetic acid (DOPAC), 5HT and 5-hydroxyindoleacetic acid (5HIAA) were analyzed by high-performance liquid chromatography coupled with electrochemical detection. We found that both MPH and modafinil improved cognition in both restrained and unrestrained rats, as examined through water maze and passive avoidance tests. Furthermore, these substance were associated with increased brain DA and 5-HT levels. Notabily, we observed decrease in DOPAC and HVA levels, while 5-HIAA levels exhibited a slight increase. The prevention of stress-induced cognitive deficits by MPH and modafinil could be elucidated through the interaction between 5HT and DA in regulating cognitive function.

Validated ultraviolet high-performance liquid chromatography method for post-mortem 5-hydroxy-indoleacetic acid measurement in human cerebrospinal fluid

Objectives: The objective of this study was to develop an ultraviolet high-performance liquid chromatography (UV-HPLC) method for the measurement of 5-hydroxyindoleacetic acid (5-HIAA) in human cerebrospinal fluid (CSF) as a potential biomarker for neurological and psychiatric illnesses, including depressive disorders with suicidal behavior. Materials and Methods: The study utilized CSF samples from individuals brought for medicolegal autopsy. The 5-HIAA concentration was measured using a UV-HPLC method with three mobile-phase solvents. The most effective mobile phase solvent was then used to measure 5-HIAA in the CSF samples. The materials used in the study included CSF samples obtained from individuals brought for medico-legal autopsy, UV-HPLC equipment, and mobile phase solvents, including 5-hydroxyindole-3-acetic acid (Merck/sigma), acetonitrile, concentrated formic acid, concentrated acetic acid, methanol, and phosphoric acid. Statistical Analysis: This was done using R Studio (version 4.2.0). Results: The study found that the UV-HPLC method utilizing formic acid (0.05–0.1%): acetonitrile in a 1:9 as mobile phase was the most effective for measuring 5-HIAA in human CSF. The method exhibited excellent linearity, accuracy, and precision. Conclusion: The study concludes that the developed UV-HPLC method is reliable and effective for measuring 5-HIAA in human CSF. Measuring 5-HIAA levels in CSF can serve as a potential biomarker for neurological and psychiatric illnesses, including depressive disorders with suicidal behavior. This method is promising for clinical and forensic practice to diagnose suicidal cases. Further research is needed to determine the clinical significance of these findings and the potential for broader application in psychiatry. This article helps to give a practical, cost-effective methodology to detect CSF 5-HIAA.

Preparation of gold nanoparticles loaded MOF-199 for SERS detection of 5-hydroxyindole-3-acetic acid in serum

5-Hydroxyindole-3-acetic acid (5-HIAA) is regarded as a biomarker for diagnosis of carcinoid tumors, and it is of great significance to developing a precision assay for monitoring 5-HIAA levels. In this work, gold nanoparticles loading on the surface of MOF-199 (Au NPs/MOF-199) is prepared to propose a surface enhanced Raman scattering (SERS) assay for 5-HIAA. When 4-mercaptopyridine (4-MPy) is used as a SERS probe, on Au NPs/MOF-199, limit of detection (LOD) at 10−9 mol/L can be achieved. In addition, Au NPs/MOF-199 substrate with good preparation reproducibility shows long-term storage stability at 4 °C. Under optimal condition, the Au NPs/MOF-199-based SERS method is applied to determine 5-HIAA in serum. The concentration linear range is from 10−9 to 10−5 mol/L and LOD is of 6.40 × 10−11 mol/L. Much importantly, Au NPs/MOF-199 substrate exhibits specific response toward 5-HIAA against other metabolites in the serum due to the capturing selectivity from porous MOF-199. The recoveries obtained on spiked human serum samples locate in the span from 94.30% to 106.00% with RSD of 4.01–7.43%. Au NPs/MOF-199-based SERS sensing strategy is a promising avenue for on-field monitoring biomedical species for clinic diagnosis purpose.

Analytical method for urinary homovanillic acid and 5-hydroxyindoleacetic acid levels using HPLC with electrochemical detection applied to evaluate children environmentally exposed to manganese.

Homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) are the urinary metabolites of dopamine (DA) and serotonin (5-HA), respectively. We aimed to develop an extraction method for the determination of HVA and 5-HIAA, using strong anionic exchange cartridges combined with HPLC with electrochemical detection, and apply it to measure the levels of HVA and 5-HIAA in children living near a ferro-manganese alloy plant in Simões Filho, Brazil. The validated method showed good selectivity, sensitivity, precision, and accuracy. The limits of detection (LOD) were 4 and 8 μmol/L for 5-HIAA and HVA, respectively, in urine. Recoveries ranged from 85.8 to 94%. The coefficients of determination (R2 ) of the calibration curves were greater than 0.99. Spot urine samples of 30 exposed children and 20 nonexposed ones were processed accordingly. The metabolite levels in exposed and reference children were within the physiological ranges. The medians (range) for 5-HIAA and HVA of the exposed ones were 36.4 μmol/L (18.4-58.0) and 32.9 μmol/L (<LOD-91.9), respectively. There was no significant difference between the values presented by children in the reference group: 25.7 μmol/L (19.9-81.4) and 35.2 μmol/L (<LOD-67.6) for 5-HIAA and HVA, respectively. These results suggest that the quantification of the urinary metabolites possibly does not reflect the interference of manganese in the metabolism of DA and 5-HA in the central nervous system.

Prenatal SAMe Treatment Changes via Epigenetic Mechanism/s USVs in Young Mice and Hippocampal Monoamines Turnover at Adulthood in a Mouse Model of Social Hierarchy and Depression.

The role of hippocampal monoamines and their related genes in the etiology and pathogenesis of depression-like behavior, particularly in impaired sociability traits and the meaning of changes in USVs emitted by pups, remains unknown. We assessed the effects of prenatal administration of S-adenosyl-methionine (SAMe) in Sub mice that exhibit depressive-like behavior on serotonergic, dopaminergic and noradrenergic metabolism and the activity of related genes in the hippocampus (HPC) in adulthood in comparison to saline-treated control Sub mice. During postnatal days 4 and 8, we recorded and analyzed the stress-induced USVs emitted by the pups and tried to understand how the changes in the USVs' calls may be related to the changes in the monoamines and the activity of related genes. The recordings of the USVs showed that SAMe induced a reduction in the emitted flat and one-frequency step-up call numbers in PND4 pups, whereas step-down type calls were significantly increased by SAMe in PND8 pups. The reduction in the number of calls induced by SAMe following separation from the mothers implies a reduction in anxiety, which is an additional sign of decreased depressive-like behavior. Prenatal SAMe increased the concentrations of serotonin in the HPC in both male and female mice without any change in the levels of 5HIAA. It also decreased the level of the dopamine metabolite DOPAC in females. There were no changes in the levels of norepinephrine and metabolites. Several changes in the expression of genes associated with monoamine metabolism were also induced by prenatal SAMe. The molecular and biochemical data obtained from the HPC studies are generally in accordance with our previously obtained data from the prefrontal cortex of similarly treated Sub mice on postnatal day 90. The changes in both monoamines and their gene expression observed 2-3 months after SAMe treatment are associated with the previously recorded behavioral improvement and seem to demonstrate that SAMe is effective via an epigenetic mechanism.

Effects of the Combination of the C1473G Mutation in the Tph2 Gene and Lethal Yellow Mutations in the Raly-Agouti Locus on Behavior, Brain 5-HT and Melanocortin Systems in Mice.

Tryptophan hydroxylase 2 (TPH2) is the key and rate-limited enzyme of serotonin (5-HT) synthesis in the brain. The C1473G mutation in the Tph2 gene results in a two-fold decrease in enzyme activity in the mouse brain. The lethal yellow (AY) mutation in the Raly-Agouti locus results in the overexpression of the Agouti gene in the brain and causes obesity and depressive-like behavior in mice. Herein, the possible influences of these mutations and their combination on body mass, behavior, brain 5-HT and melanocortin systems in mice of the B6-1473CC/aa. B6-1473CC/AYa, B6-1473GG/aa are investigated. B6-1473GG/AYa genotypes were studied. The 1473G and AY alleles increase the activity of TPH2 and the expression of the Agouti gene, respectively, but they do not alter 5-HT and 5-HIAA levels or the expression of the genes Tph2, Maoa, Slc6a4, Htr1a, Htr2a, Mc3r and Mc4r in the brain. The 1473G allele attenuates weight gain and depressive-like immobility in the forced swim test, while the AY allele increases body weight gain and depressive-like immobility. The combination of these alleles results in hind limb dystonia in the B6-1473GG/AYa mice. This is the first evidence for the interaction between the C1473G and AY mutations.

Cerebrospinal fluid levels of 5-HIAA and dopamine in people with HIV and depression.

Depression is a common illness in people with HIV (PWH) and is associated with substantial morbidity and mortality. The mechanisms that underpin depression in PWH remain incompletely elucidated, and more research is therefore needed to develop effective treatments. One hypothesis is that neurotransmitter levels may be altered. These levels could be influenced by the chronic inflammation and viral persistence that occurs in PWH. We examined a panel of cerebrospinal fluid (CSF) neurotransmitters in PWH on suppressive antiretroviral therapy (ART), many of whom had a current depression diagnosis. CSF monoamine neurotransmitters and their metabolites were measured from participants in studies at the Emory Center for AIDS Research (CFAR). Only participants on stable ART with suppressed HIV RNA from both plasma and CSF were analyzed. Neurotransmitter levels were measured with high-performance liquid chromatography (HPLC). Neurotransmitters and their metabolites included dopamine (DA), homovanillic acid (HVA, a major metabolite of dopamine), serotonin (5-HT), 5-hydroxyindole-3-acetic acid (5-HIAA, a major metabolite of serotonin), and 4-hydroxy-3-methoxyphenylglycol (MHPG, a major metabolite of norepinephrine). Multivariable logistic regression was used to evaluate factors associated with depression. There were 79 PWH with plasma and CSF HIV RNA levels < 200 copies/mL at the time of the visit, and 25 (31.6%) carried a current diagnosis of depression. Participants with depression were significantly older (median age 53years versus 47years, P = 0.014) and were significantly less likely to be African American (48.0% versus 77.8%, P = 0.008). Participants with depression had significantly lower dopamine levels (median 0.49ng/mL versus 0.62ng/mL, P = 0.03) and significantly lower 5-HIAA levels (median 12.57ng/mL versus 15.41ng/mL, P = 0.015). Dopamine and 5-HIAA were highly correlated. In the multivariable logistic regression models, lower 5-HIAA was significantly associated with the depression diagnosis when accounting for other significant demographic factors. The associations between lower 5-HIAA, lower dopamine, and depression in PWH suggest that altered neurotransmission may contribute to these comorbid conditions. However, the effects of antidepressants on neurotransmitters cannot be ruled out as a factor in the 5-HIAA results.

English

The objective of this study is to study the sedative and hypnotic effects of the compatibility of Schisandra chinensis (SC) and Polygala tenuifolia (PT) on insomnia mice and its mechanisms. The 160 SPF KM mice were divided into 8 groups with 20 each group (10 female and 10 male mice), including control, model, estazolam, SC, PT, SC-PT 1:1, SC-PT 1:2, and SC-PT 2:1 group. Insomnia mice model was established with intraperitoneal injection of P-chlorophenylalanine (PCPA) for 3 days. The mice were investigated by the sleep time of mice induced by pentobarbital sodium, the levels of GABA, DA, 5-HT and 5-HIAA in hypothalamus by enzyme-linked immunosorbent assay, and the GABA&alpha;1 and DRD2 mRNA expression in hypothalamus by quantitative real-time polymerase chain reaction (RT-qPCR). SC-PT reduced the sleep latency of insomnia mice and prolonged the Pentobarbital-sodium induced sleep time than model group. SC-PT 2:1 group increased the levels of 5-hydroxytryptamine (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), &gamma;-Aminobutyric acid (GABA) and the expression of GABAAR&alpha;1 and decreased the levels of dopamine (DA) and the expression of DRD2 in the hypothalamus of insomnia mice. The compatibility of SC and PT can enhance the function of sedation and hypnosis than single group. This study provides a basis for the compatibility of SC and PT in the insomnia treatment. Key words: Schisandra chinensis, Polygala tenuifolia, mice, sedative, hypnotic, &gamma;-Aminobutyric acid, dopamine.

Carcinoid Heart Disease Management: A Multi-Disciplinary Collaboration.

Carcinoid heart disease (CaHD) is an important complication among patients with metastatic neuroendocrine tumors and carcinoid syndrome (CS). CS patients (25%-65%) eventually develop CaHD; these patients face a significantly increased risk of morbidity and mortality. Guidance papers (eg, clinical practice guidelines, consensus guidelines, and expert statements) have been established by major organizations across the disciplines of cardiology and oncology; however, these recommendations are not routinely implemented. The aim of this article is to encourage the integration of current recommendations from national societies into clinical practice. Early screening upon recognition of CS and prior to the development of CaHD symptoms is paramount, as no existing therapies are approved to reverse the fibrotic damage to the heart once it occurs. Valvular replacement is the only definitive treatment for CaHD once it has developed. When patients are noted to have urinary 5-hydroxyindoleacetic acid (5-HIAA) levels ≥300 µmol/24 h and/or serum N-terminal pro B-type natriuretic peptide (NT-proBNP) levels >260 pg/mL, echocardiography is recommended. Systemic approaches to control tumor growth and hormonal secretion include somatostatin analogs (SSAs), followed by options including peptide receptor radiotherapy (PRRT), everolimus and liver embolization. Telotristat is the primary choice for control of diarrhea refractory to SSA. Diuretics are the mainstay of heart failure symptom management for patients who develop CaHD. Considerations for future research are discussed, including the ongoing TELEHEART (TELotristat Ethyl in a HEART biomarker study) trial involving telotristat and not yet activated CHARRT (Carcinoid Heart disease And peptide Receptor Radiotargetted Therapy) study involving PRRT with lutetium 177 (177Lu) dotatate.