Tryptophan Hydroxylase Research Articles

Neurotransmitter Gene Polymorphisms Are Associated with Symptom Clusters in Patients Undergoing Radiation Therapy

Purpose was to evaluate for associations between the severity of three distinct symptom clusters (ie, sickness-behavior, mood-cognitive, treatment-related) and polymorphisms for 16 genes involved in catecholaminergic, GABAergic, and serotonergic neurotransmission. Patients with breast and prostate cancer (n = 157) completed study questionnaires at the completion of radiation therapy. Memorial Symptom Assessment Scale was used to assess the severity of 32 common symptoms. Three distinct symptom clusters were identified using exploratory factor analysis. Associations between the symptom cluster severity scores and neurotransmitter gene polymorphisms were evaluated using regression analyses. Severity scores for the sickness-behavior symptom cluster were associated with polymorphisms for solute carrier family 6 (SLC6A) member 2 (SLC6A2), SLC6A3, SLC6A1, and 5-hydroxytryptamine receptor (HTR) 2A (HTR2A) genes. For the mood-cognitive symptom cluster, severity scores were associated with polymorphisms for adrenoreceptor alpha 1D, SLC6A2, SLC6A3, SLC6A1, HTR2A, and HTR3A. Severity scores for the treatment-related symptom cluster were associated with polymorphisms for SLC6A2, SLC6A3, catechol-o-methyltransferase, SLC6A1, HTR2A, SLC6A4, and tryptophan hydroxylase 2. Findings suggest that polymorphisms for several neurotransmitter genes are involved in the severity of sickness-behavior, mood-cognitive, and treatment-related symptom clusters in oncology patients at the completion of radiation therapy. Four genes with various associated polymorphisms were common across the three distinct symptom clusters (ie, SLC6A2, SLC6A3, SLC6A1, HTR2A) which suggest that these clusters have common underlying mechanisms.

Organic selenium ameliorates non-alcoholic fatty liver disease through 5-hydroxytryptamine/bile acid enterohepatic circulation in mice

To investigate the effects of organic selenium (L-selenocystine, L-selenomethionine, and L-selenomethylcysteine) on non-alcoholic fatty liver disease (NAFLD), the NAFLD mice model with hepatic steatosis and fibrosis was established via feeding with a Western diet and CCl4 injection. Compared with the model group, the intervention groups with organic selenium experienced a reduction in hepatic 5-hydroxytryptophan (5-HT) contents and downregulation in the expression of tryptophan hydroxylase 1 (TPH1) and 5-HT receptor 2A/2B/3A. Similar results were observed on TPH1/5-HT in the duodenum. In addition, organic selenium decreased the bile acid (BA) concentrations in gut contents, downregulated the expression of hepatic CYP7A1, and upregulated the expression of hepatic Farnesoid X‐activated receptor (FXR). In conclusion, our findings suggest that organic selenium ameliorates NAFLD through 5-HT/BA enterohepatic circulation in mice with NAFLD.

Microbiome and tryptophan metabolomics analysis in adolescent depression: roles of the gut microbiota in the regulation of tryptophan-derived neurotransmitters and behaviors in human and mice

BackgroundAdolescent depression is becoming one of the major public health concerns, because of its increased prevalence and risk of significant functional impairment and suicidality. Clinical depression commonly emerges in adolescence; therefore, the prevention and intervention of depression at this stage is crucial. Recent evidence supports the importance of the gut microbiota (GM) in the modulation of multiple functions associated with depression through the gut-brain axis (GBA). However, the underlying mechanisms remain poorly understood. Therefore, in the current study, we aimed to screen the microbiota out from healthy and depressive adolescents, delineate the association of the targeted microbiota and the adolescent depression, address the salutary effects of the targeted microbiota on anti-depressive behaviors in mice involving the metabolism of the tryptophan (Trp)-derived neurotransmitters along the GBA.ResultsHere, we found the gut microbiota from healthy adolescent volunteers, first diagnosis patients of adolescent depression, and sertraline interveners after first diagnosis displayed significant difference, the relative abundance of Faecalibacterium, Roseburia, Collinsella, Blautia, Phascolarctobacterium, Lachnospiraceae-unclassified decreased in adolescent depressive patients, while restored after sertraline treatment. Of note, the Roseburia abundance exhibited a high efficiency in predicting adolescent depression. Intriguingly, transplantation of the fecal microbiota from healthy adolescent volunteers to the chronic restraint stress (CRS)-induced adolescent depressed mice significantly ameliorated mouse depressive behaviors, in which the Roseburia exerted critical roles, since its effective colonization in the mouse colon resulted in remarkably increased 5-HT level and reciprocally decreased kynurenine (Kyn) toxic metabolites quinolinic acid (Quin) and 3-hydroxykynurenine (3-HK) levels in both the mouse brain and colon. The specific roles of the Roseburia were further validated by the target bacteria transplantation mouse model, Roseburia intestinalis (Ri.) was gavaged to mice and importantly, it dramatically ameliorated CRS-induced mouse depressive behaviors, increased 5-HT levels in the brain and colon via promoting tryptophan hydroxylase-2 (TPH2) or -1 (TPH1) expression. Reciprocally, Ri. markedly restrained the limit-step enzyme responsible for kynurenine (indoleamine2,3-dioxygenase 1, IDO1) and quinolinic acid (3-hydroxyanthranilic acid 3,4-dioxygenase, 3HAO) generation, thereby decreased Kyn and Quin levels. Additionally, Ri. administration exerted a pivotal role in the protection of CRS-induced synaptic loss, microglial activation, and astrocyte maintenance.ConclusionsThis study is the first to delineate the beneficial effects of Ri. on adolescent depression by balancing Trp-derived neurotransmitter metabolism and improving synaptogenesis and glial maintenance, which may yield novel insights into the microbial markers and therapeutic strategies of GBA in adolescent depression.5cVo2w5j9eyh76CmRyRzSQVideo

Analysis of a series of Italian APECED patients with autoimmune hepatitis and gastro-enteropathies.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) syndrome is a rare monogenic disease determined by biallelic mutations in AIRE gene, which encodes a transcription factor essential for central immune tolerance. Classic diagnosis is determined by the presence of two of the main APECED clinical diseases: chronic mucocutaneous candidiasis, chronic hypoparathyroidism, and Addison's disease. Non-endocrine autoimmunity, involving the liver, intestine, eyes, and kidneys, is generally reported in a minority of European patients, while American APECED patients have a higher tendency of developing organ-specific non-endocrine manifestations early in life. This observation led to the revision of the diagnostic criteria to permit earlier diagnosis based on the appearance of one classic triad symptom or one non-classical manifestation at a young age in the presence of IFNωAbs or AIRE mutations (Ferre-Lionakis criteria). We analyzed the clinical, genetic, and autoantibody (Ab) profiles in a series of 14 pediatric Italian APECED patients with gastrointestinal manifestations (seven male and seven female patients). Ten patients presented hepatitis (APECED-associated hepatitis (APAH)), while seven were affected by constipation, diarrhea, and malabsorption. Four patients had developed APAH before classic triad symptoms. Based on the age of appearance of non-endocrine manifestations including APAH and gastro-enteropathy, the Ferre-Lionakis criteria would have allowed an expedited diagnosis in 11/14 patients. Abs to tryptophan hydroxylase (TPHAb) and hepatic aromatic l-amino acid decarboxylase (AADC) were significantly associated with APECED patients of the present series. Abs to cP4501A2 were detectable in the serum of 4/8 patients with APAH, and Abs to cP4502A6 were detectable in 3/8 patients. AADC Abs tested positive in 5/7 patients, which is indicative of gastrointestinal dysfunction in APECED and TPHAb in 5/7 patients with gastrointestinal dysfunction. IFNAb was significantly associated with the syndrome. Although Ferre-Lionakis expanded criteria applied to the American cohorts of APECED patients would require validation in independent large cohorts of European patients, the results of this study emphasize the importance to evaluate the presence and the age of appearance of APAH and autoimmune enteropathy even in European cohorts for an earlier APECED diagnosis. An earlier APECED diagnosis would also allow the prevention of episodes of life-threatening hypocalcemic seizures and adrenal crisis, which are the main manifestations of undiagnosed APECED.

Sulfonamides (SAs) exposure causes neurobehavioral toxicity at environmentally relevant concentrations (ERCs) in early development of zebrafish

Antibiotics, due to their stability and persistence in the environment, can have chronic impacts on various ecosystems and organisms. However, the molecular mechanisms underlying antibiotic toxicity at environmental concentrations, particularly the neurotoxic effects of sulfonamides (SAs), remain poorly understood. In this study, we assessed the neurotoxicity of six SAs including the sulfadiazine (SD), sulfathiazole (ST), sulfamethoxazole (SMX), sulfisoxazole (SIZ), sulfapyridine (SPD), and sulfadimethoxine (SDM) by exposing zebrafish to environmentally relevant concentrations (ERCs). The SAs exhibited concentration-dependent effects on zebrafish behavior, including spontaneous movement, heartbeat, survival rate, and body metrics, ultimately leading to depressive-like symptoms and sublethal toxicity during early life stages. Notably, even the lowest SA concentration (0.05 μg/L) induced neurotoxicity and behavioral impairment in zebrafish. We observed a dose-dependent increase in melancholy behavior as indicated by increased resting time and decreased motor activity in zebrafish larvae. Following exposure to SAs from 4 to 120 h post-fertilization (hpf), key genes involved in folate synthesis [sepiapterin reductase a (spra), phenylalanine hydroxylase (pah), tyrosine hydroxylase (th), and tryptophan hydroxylase 1 (tryptophan 5-monooxygenase) a tryptophan hydroxylase (tph1a)] and carbonic anhydrase (CA) metabolism [carbonic anhydrase II (ca2), carbonic anhydrase IV a (ca4a), carbonic anhydrase VII (ca7), and carbonic anhydrase XIV (ca14)] were significantly downregulated or inhibited at different concentrations. Our findings demonstrate that acute exposure to six SAs at environmentally relevant concentrations induces developmental and neurotoxic effects in zebrafish, impacting folate synthesis pathways and CA metabolism. These results provide valuable insights into the potential role of antibiotics in depressive disorders and neuroregulatory pathways.

Impact of genetic variants within serotonin turnover enzymes on human cerebral monoamine oxidase A in vivo

Variants within the monoamine oxidase A (MAO-A, MAOA) and tryptophan hydroxylase 2 (TPH2) genes, the main enzymes in cerebral serotonin (5-HT) turnover, affect risk for depression. Depressed cohorts show increased cerebral MAO-A in positron emission tomography (PET) studies. TPH2 polymorphisms might also influence brain MAO-A because availability of substrates (i.e. monoamine concentrations) were shown to affect MAO-A levels. We assessed the effect of MAOA (rs1137070, rs2064070, rs6323) and TPH2 (rs1386494, rs4570625) variants associated with risk for depression and related clinical phenomena on global MAO-A distribution volume (VT) using [11C]harmine PET in 51 participants (21 individuals with seasonal affective disorder (SAD) and 30 healthy individuals (HI)). Statistical analyses comprised general linear models with global MAO-A VT as dependent variable, genotype as independent variable and age, sex, group (individuals with SAD, HI) and season as covariates. rs1386494 genotype significantly affected global MAO-A VT after correction for age, group and sex (p < 0.05, corr.), with CC homozygotes showing 26% higher MAO-A levels. The role of rs1386494 on TPH2 function or expression is poorly understood. Our results suggest rs1386494 might have an effect on either, assuming that TPH2 and MAO-A levels are linked by their common product/substrate, 5-HT. Alternatively, rs1386494 might influence MAO-A levels via another mechanism, such as co-inheritance of other genetic variants. Our results provide insight into how genetic variants within serotonin turnover translate to the cerebral serotonin system. Clinicaltrials.gov Identifier: NCT02582398. EUDAMED Number: CIV-AT-13-01-009583.

Effects of chronic combined treatment with ketanserin and fluoxetine in B6.CBA-D13Mit76C recombinant mice with abnormal 5-НТ&lt;sub&gt;1a&lt;/sub&gt; receptor functional activity

The recombinant B6.CBA-D13Mit76C mouse strain is characterized by altered sensitivity of 5-HT1A receptors and greater Htr1a gene transcription. Recently, we found that in B6.CBA-D13Mit76C mice, chronic fluoxetine treatment produced pro-depressive effect in a forced swim test. Since 5-HT2A receptor blockade may be beneficial in treatment-resistant depression, we investigated the influence of chronic treatment (14 days, intraperitoneally) with selective 5-HT2A antagonist ketanserin (0.5 mg/kg), fluoxetine (20 mg/kg), or fluoxetine + ketanserin on the behavior, functional activity of 5-HT1A and 5-HT2A receptors, serotonin turnover, and transcription of principal genes of the serotonin system in the brain of B6.CBA-D13Mit76C mice. Ketanserin did not reverse the pro-depressive effect of fluoxetine. Fluoxetine, ketanserin, and fluoxetine + ketanserin decreased functional activity of 5-HT1A receptors and Htr1a gene transcription in the midbrain and hippocampus. Additionally, all the tested drug regimens decreased mRNA levels of Slc6a4 and Maoa in the midbrain. These changes were not accompanied by a significant shift in the levels of serotonin and its metabolite 5-HIAA. Notably, ketanserin upregulated enzymatic activity of tryptophan hydroxylase 2 (TPH2). Thus, despite some benefits (reduced Htr1a, Slc6a4, and Maoa transcription and increased TPH2 activity), prolonged blockade of 5-HT2A receptors failed to ameliorate the adverse effect of fluoxetine during abnormal functioning of 5-HT1A receptors.

Maternal LPS Exposure Enhances the 5-HT Level in the Prefrontal Cortex of Autism-like Young Offspring

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by reduced social interactions, impaired communication, and stereotyped behavior. The aim of this research is to investigate the changes in serotonin (5-HT) in the medial prefrontal cortex (PFC) of autism-like offspring induced by maternal lipopolysaccharide (LPS) exposure. Pregnant Sprague-Dawley rats were intraperitoneally injected with LPS to establish an autism-like model in their offspring. Offspring prenatally exposed to LPS showed autism-like behavior. The serotonin level in the mPFC of 2-week-old offspring was noticeably increased after maternal LPS exposure. Differentially expressed genes (DEGs) were enriched in pathways related to tryptophan metabolism and the serotonin system, as shown in RNA-seq findings. Consistently, tryptophan and serotonin metabolisms were altered in 2-week-old LPS-exposed offspring. The mRNA expression levels of 5-HT catabolic enzymes were remarkably reduced or tended to decrease. Moreover, maternal LPS exposure resulted in a higher serotonin 1B receptor (5-HT1BR) expression level in the mPFC but no difference in tryptophan hydroxylase 2 (TPH2) or serotonin reuptake transporter (SERT). The concentrations of 5-HT in serum and colon were increased in LPS-exposed offspring. Meanwhile, the expression level of tryptophan hydroxylase 1 (TPH1) in the colon was increased after maternal LPS treatment, whereas SERT was reduced. Furthermore, Golgi-Cox staining showed that neuronal dendritic length and spine density were significantly reduced in the mPFC of LPS-exposed offspring. The current study reveals that maternal LPS treatment resulted in an exaltation of the 5-HT of mPFC in ASD-like young rats, which may partly be caused by the abnormal elevation of 5-HT metabolism in its colon.

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.

Inhibition of dorsal raphe GABAergic neurons blocks hyperalgesia during heroin withdrawal

Opioid withdrawal signs, such as hyperalgesia, are manifestations of opioid use disorder that may contribute to opioid seeking and taking. We have previously identified an association between dorsal raphe (DR) neurons and the expression of hyperalgesia during spontaneous heroin withdrawal. Here, we found that chemogenetic inhibition of DR neurons decreased hyperalgesia during spontaneous heroin withdrawal in male and female C57/B6 mice. By neuroanatomy, we identified three major subtypes of DR neurons expressing μ-opioid receptors (MOR) that were activated in hyperalgesia during spontaneous withdrawal, those expressing vesicular GABA transporter (VGaT), glutamate transporter 3 (VGluT3), or co-expressing VGluT3 and tryptophan hydroxylase (TPH). In contrast, we identified a small population of DR-MOR neurons expressing solely TPH, which were not activated in hyperalgesia during spontaneous withdrawal. Collectively, these findings indicate a role of the DR in hyperalgesia during spontaneous heroin withdrawal mediated, in part, by the activation of local MOR-GABAergic, MOR-glutamatergic and MOR-co-releasing glutamatergic-serotonergic neurons. We found that specific chemogenetic inhibition of DR-VGaT neurons blocked hyperalgesia during spontaneous heroin withdrawal in male and female mice. Collectively, these findings indicate that DR-GABAergic neurons play a role in the expression of hyperalgesia during spontaneous heroin withdrawal.

Glucose, Insulin and Oxygen Modulate Expression of Serotonin-Regulating Genes in Human First-Trimester Trophoblast Cell Line ACH-3P.

Serotonin signaling plays an important role in regulating development and functions of the placenta. We hypothesized that metabolic disturbances associated with maternal obesity and/or gestational diabetes mellitus (GDM) affect placental serotonin homeostasis. Therefore, we examined the effects of high glucose (25 mM) and insulin (10 nM)-two hallmarks of maternal obesity and GDM-on mRNA expression of key regulators of serotonin homeostasis, including serotonin transporter (SERT), tryptophan hydroxylase 1 (TPH1), and monoamine oxidase A (MAOA), in the first-trimester trophoblast cell line ACH-3P, focusing on oxygen levels characteristic of early human placental development. Glucose downregulated expression of SERT and MAOA independently of oxygen level and upregulated expression of TPH1 at 6.5% oxygen but not at 2.5% oxygen. Compared to 6.5% oxygen, 2.5% oxygen upregulated SERT and downregulated TPH1 expression, with no effect on MAOA expression. Insulin upregulated SERT only at 2.5% oxygen but had no effect on TPH1 and MAOA expression. These results suggest that maternal metabolic alterations in early pregnancy may be a driving force for changes in placental serotonin homeostasis.

Emerging paradigms in exploring the interactions among diet, probiotics, and cancer immunotherapeutic response

Emerging paradigms in exploring the interactions among diet, probiotics, and cancer immunotherapeutic response

Effects of Chronic Combined Treatment with Ketanserin and Fluoxetine in B6.CBA-D13Mit76C Recombinant Mice with Abnormal 5-HT1A Receptor Functional Activity.

The recombinant B6.CBA-D13Mit76C mouse strain is characterized by an altered sensitivity of 5-HT1A receptors and upregulated 5-HT1A gene transcription. Recently, we found that in B6.CBA-D13Mit76C mice, chronic fluoxetine treatment produced the pro-depressive effect in a forced swim test. Since 5-HT2A receptor blockade may be beneficial in treatment-resistant depression, we investigated the influence of chronic treatment (14 days, intraperitoneally) with selective 5-HT2A antagonist ketanserin (0.5 mg/kg), fluoxetine (20 mg/kg), or fluoxetine + ketanserin on the behavior, functional activity of 5-HT1A and 5-HT2A receptors, serotonin turnover, and transcription of principal genes of the serotonin system in the brain of B6.CBA-D13Mit76C mice. Ketanserin did not reverse the pro-depressive effect of fluoxetine, while fluoxetine, ketanserin, and fluoxetine + ketanserin decreased the functional activity of 5-HT1A receptors and Htr1a gene transcription in the midbrain and hippocampus. All tested drug regimens decreased the mRNA levels of Slc6a4 and Maoa in the midbrain. These changes were not accompanied by a significant shift in the levels of serotonin and its metabolite 5-HIAA. Notably, ketanserin upregulated enzymatic activity of tryptophan hydroxylase 2 (TPH2). Thus, despite some benefits (reduced Htr1a, Slc6a4, and Maoa transcription and increased TPH2 activity), prolonged blockade of 5-HT2A receptors failed to ameliorate the adverse effect of fluoxetine in the case of abnormal functioning of 5-HT1A receptors.

Efficient biosynthesis of high-value 5‑Hydroxytryptophan using a multienzyme cascade

5-Hydroxytryptophan (5-HTP) is a precursor of serotonin. The increasing demand for 5-HTP is driving the search for a more efficient and cost-effective production method. In this study, a new in vitro multi-enzyme cascade system (MECCS) was developed to convert L-tryptophan (L-trp) to 5-HTP in a single container while achieving the cycling and regeneration of cofactors and coenzymes. The rate-limiting enzyme tryptophan hydroxylase (TPH) was truncated to improve the overall efficiency of the cascade. After screening, the mutant M1 (NΔ143/CΔ26) showed excellent enzymatic performance, with a 2.3-fold increase in catalytic activity. Molecular dynamics simulations showed that the increase in active center binding force and the improvement of substrate tunnel in M1 improved the overall catalytic efficiency. In addition, the rigidity enhancement of the ligand binding pocket surrounding the region improved the thermal stability of the enzyme. Under optimized conditions, the MECCS converted 50 mM L-trp to 36.9 mM 5-HTP, with a conversion rate of 73.8%. This study provides an alternative pathway for the efficient production of 5-HTP.

Intense Locomotion Enhances Oviposition in the Freshwater Mollusc Lymnaea stagnalis: Cellular and Molecular Correlates.

Intense species-specific locomotion changes the behavioural and cognitive states of various vertebrates and invertebrates. However, whether and how reproductive behaviour is affected by previous increased motor activity remains largely unknown. We addressed this question using a model organism, the pond snail Lymnaea stagnalis. Intense crawling in shallow water for two hours had previously been shown to affect orienting behaviour in a new environment as well as the state of the serotonergic system in L. stagnalis. We found that the same behaviour resulted in an increased number of egg clutches and the total number of eggs laid in the following 24 h. However, the number of eggs per clutch was not affected. This effect was significantly stronger from January to May, in contrast to the September-December period. Transcripts of the egg-laying prohormone gene and the tryptophan hydroxylase gene, which codes for the rate-limiting enzyme in serotonin synthesis, were significantly higher in the central nervous system of snails that rested in clean water for two hours after intense crawling. Additionally, the neurons of the left (but not the right) caudo-dorsal cluster (CDC), which produce the ovulation hormone and play a key role in oviposition, responded to stimulation with a higher number of spikes, although there were no differences in their resting membrane potentials. We speculate that the left-right asymmetry of the response was due to the asymmetric (right) location of the male reproductive neurons having an antagonistic influence on the female hormonal system in the hermaphrodite mollusc. Serotonin, which is known to enhance oviposition in L. stagnalis, had no direct effect on the membrane potential or electrical activity of CDC neurons. Our data suggest that (i) two-hour crawling in shallow water enhances oviposition in L. stagnalis, (ii) the effect depends on the season, and (iii) the underlying mechanisms may include increased excitability of the CDC neurons and increased expression of the egg-laying prohormone gene.

RP58 knockdown contributes to hypoxia-ischemia-induced pineal dysfunction and circadian rhythm disruption in neonatal rats.

Hypoxia-ischemia (HI) of the brain not only impairs neurodevelopment but also causes pineal gland dysfunction, which leads to circadian rhythm disruption. However, the underlying mechanism of circadian rhythm disruption associated with HI-induced pineal dysfunction remains unknown. The zinc finger protein RP58 is involved in the development and differentiation of nerve cells. In this study, we established an HI model in neonatal rats to investigate the expression of RP58 and its role in pineal dysfunction and circadian rhythm disruption induced by HI. We demonstrated that RP58 was highly expressed in the pineal gland under normal conditions and significantly downregulated in the pineal gland and primary pinealocytes following HI. Knockdown of RP58 decreased the expression of enzymes in the melatonin synthesis pathway (TPH1, ASMT and AANAT) as well as clock genes (CLOCK and BMAL1), and it also reduced the production of melatonin, caused pineal cell injury, and disrupted circadian rhythms in vivo and in vitro. Similarly, HI reduced the expression of melatonin synthesis enzymes (TPH1, ASMT and AANAT) and clock genes (CLOCK and BMAL1) and caused pineal injury and circadian rhythm disruption, which were exacerbated by RP58 knockdown. The detrimental effects of RP58 knockdown on pineal dysfunction and circadian rhythm disruption was reversed by the addition of exogenous melatonin. Furthermore, exogenous melatonin reversed HI-induced pineal dysfunction and circadian rhythm disruption, as reflected by improvements in melatonin production, voluntary activity periods, and activity frequency as well as a diminished decrease in the expression of melatonin synthesis enzymes and clock genes. The present study suggests that RP58 is an endogenous source of protection against pineal dysfunction and circadian rhythm disruption after neonatal HI. This article is protected by copyright. All rights reserved.

Para-Chlorophenyl Alanine Induces Aggressive Behavior by Serotonin Depletion in Male Rats and Increases Tryptophan Hydroxylase two and GABAA α1 mRNA Expression in the Olfactory Bulb

Para-Chlorophenyl Alanine Induces Aggressive Behavior by Serotonin Depletion in Male Rats and Increases Tryptophan Hydroxylase two and GABAA α1 mRNA Expression in the Olfactory Bulb

Influence of variants in serotonin modulating genes on the risk, aggressiveness, and prognosis of oropharynx cancer.

Serotonin (5-HT) is involved in regulating tumor growth, as well as psychiatric disorders. It is synthesized by tryptophan hydroxylase (TPH) and acts through 5-HT receptors (HTRs). Single-nucleotide variations (SNVs) in TPH1 rs623580 (T>A), TPH2 rs4570625 (G>T), and HTR1D rs674386 (G>A) may affect 5-HT levels. However, the effect of these SNVs on oropharynx carcinoma (OPC) is unknown. DNA from 251 patients with OPC and 254 controls was analyzed by RT-PCR. Transcriptional activity of TPH1 rs623580 and HTR1D rs674386 was studied by luciferase assays. Multivariate statistical tests were utilized to evaluate group differences and survival outcomes. TPH1 TT was more frequent in patients than in controls (OR: 1.56, p = 0.03). Patients with HTR1D GG/GA showed invasive tumors (p = 0.01) and shorter survival (HR: 1.66, p = 0.04). TPH1 TT (0.79-fold, p = 0.03) and HTR1D GG (0.64-fold, p = 0.008) presented lower transcriptional activity. Our data suggest that SNVs in 5-HT modulating genes can influence OPC.

The Engagement of Cytochrome P450 Enzymes in Tryptophan Metabolism

Tryptophan is metabolized along three main metabolic pathways, namely the kynurenine, serotonin and indole pathways. The majority of tryptophan is transformed via the kynurenine pathway, catalyzed by tryptophan-2,3-dioxygenase or indoleamine-2,3-dioxygenase, leading to neuroprotective kynurenic acid or neurotoxic quinolinic acid. Serotonin synthesized by tryptophan hydroxylase, and aromatic L-amino acid decarboxylase enters the metabolic cycle: serotonin → N-acetylserotonin → melatonin → 5-methoxytryptamine→serotonin. Recent studies indicate that serotonin can also be synthesized by cytochrome P450 (CYP), via the CYP2D6-mediated 5-methoxytryptamine O-demethylation, while melatonin is catabolized by CYP1A2, CYP1A1 and CYP1B1 via aromatic 6-hydroxylation and by CYP2C19 and CYP1A2 via O-demethylation. In gut microbes, tryptophan is metabolized to indole and indole derivatives. Some of those metabolites act as activators or inhibitors of the aryl hydrocarbon receptor, thus regulating the expression of CYP1 family enzymes, xenobiotic metabolism and tumorigenesis. The indole formed in this way is further oxidized to indoxyl and indigoid pigments by CYP2A6, CYP2C19 and CYP2E1. The products of gut-microbial tryptophan metabolism can also inhibit the steroid-hormone-synthesizing CYP11A1. In plants, CYP79B2 and CYP79B3 were found to catalyze N-hydroxylation of tryptophan to form indole-3-acetaldoxime while CYP83B1 was reported to form indole-3-acetaldoxime N-oxide in the biosynthetic pathway of indole glucosinolates, considered to be defense compounds and intermediates in the biosynthesis of phytohormones. Thus, cytochrome P450 is engaged in the metabolism of tryptophan and its indole derivatives in humans, animals, plants and microbes, producing biologically active metabolites which exert positive or negative actions on living organisms. Some tryptophan-derived metabolites may influence cytochrome P450 expression, affecting cellular homeostasis and xenobiotic metabolism.

Genetic and neural mechanisms of sleep disorders in children with autism spectrum disorder: a review.

The incidence of sleep disorders in children with autism spectrum disorder (ASD) is very high. Sleep disorders can exacerbate the development of ASD and impose a heavy burden on families and society. The pathological mechanism of sleep disorders in autism is complex, but gene mutations and neural abnormalities may be involved. In this review, we examined literature addressing the genetic and neural mechanisms of sleep disorders in children with ASD. The databases PubMed and Scopus were searched for eligible studies published between 2013 and 2023. Prolonged awakenings of children with ASD may be caused by the following processes. Mutations in the MECP2, VGAT and SLC6A1 genes can decrease GABA inhibition on neurons in the locus coeruleus, leading to hyperactivity of noradrenergic neurons and prolonged awakenings in children with ASD. Mutations in the HRH1, HRH2, and HRH3 genes heighten the expression of histamine receptors in the posterior hypothalamus, potentially intensifying histamine's ability to promote arousal. Mutations in the KCNQ3 and PCDH10 genes cause atypical modulation of amygdala impact on orexinergic neurons, potentially causing hyperexcitability of the hypothalamic orexin system. Mutations in the AHI1, ARHGEF10, UBE3A, and SLC6A3 genes affect dopamine synthesis, catabolism, and reuptake processes, which can elevate dopamine concentrations in the midbrain. Secondly, non-rapid eye movement sleep disorder is closely related to the lack of butyric acid, iron deficiency and dysfunction of the thalamic reticular nucleus induced by PTCHD1 gene alterations. Thirdly, mutations in the HTR2A, SLC6A4, MAOA, MAOB, TPH2, VMATs, SHANK3, and CADPS2 genes induce structural and functional abnormalities of the dorsal raphe nucleus (DRN) and amygdala, which may disturb REM sleep. In addition, the decrease in melatonin levels caused by ASMT, MTNR1A, and MTNR1B gene mutations, along with functional abnormalities of basal forebrain cholinergic neurons, may lead to abnormal sleep-wake rhythm transitions. Our review revealed that the functional and structural abnormalities of sleep-wake related neural circuits induced by gene mutations are strongly correlated with sleep disorders in children with ASD. Exploring the neural mechanisms of sleep disorders and the underlying genetic pathology in children with ASD is significant for further studies of therapy.