Gut microbiota dysbiosis deteriorates immunoregulatory effects of tryptophan via colonic indole and LBP/HTR2B-mediated macrophage function.

Tryptophan (Trp) has been shown to regulate immune function by modulating gut serotonin (5-HT) metabolism and signaling. However, the mechanisms underlying the microbial modulation of gut 5-HT signaling in gut inflammation with gut microbiota dysbiosis require further investigation. Here, we investigated the effects of Trp supplementation on the composition and metabolism of the gut microbiome and 5-HT signaling-related gut immune function using a dextran sodium sulfate (DSS)-induced colitis mouse model coupled with antibiotic exposure. The results showed that antibiotic treatment before but not during DSS treatment decreased the immunoregulatory effects of Trp and aggravated gut inflammation and body weight loss in mice. Metagenomic analysis revealed that the fecal microbiota transplantation of Trp-enriched gut microbiota to recipient mice subject to antibiotic pre-exposure and DSS treatment alleviated inflammation by increasing the relative abundances of Lactobacillus and Parabacteroides and the microbial production of indole coupled with the activation of the 5-HT receptor 2B (HTR2B) in the colon. Transcriptomic analysis showed that HTR2B agonist administration strengthened the beneficial effects of Trp in DSS-induced colitis mice with antibiotic exposure by reducing gut lipopolysaccharide-binding protein (LBP) production, IκB-α/nuclear factor-κB signaling, and M1 macrophage polarization. Indole treatment reduced LBP production and M1 macrophage polarization both in mice with DSS-induced colitis and in lipopolysaccharide-treated mouse macrophages; however, the HTR2B antagonist reversed the effects of indole. Our findings provide the basis for developing new dietary and therapeutic interventions to improve gut microbiota dysbiosis-associated inflammatory gut disorders and diseases.

Targeting HTR2B suppresses non-functioning pituitary adenoma growth and sensitizes cabergoline treatment via inhibiting Gαq/PLC/PKCγ/STAT3 axis.

BACKGROUND: Managing non-functioning pituitary adenomas (NFPAs) is difficult due to limited drug treatments. Cabergoline's (CAB) effectiveness for NFPAs is debated. This study explores the role of HTR2B in NFPAs and its therapeutic potential. METHODS: We conducted screening of bulk RNA-sequencing data to analyze HTR2B expression levels in NFPA samples. In vitro and in vivo experiments were performed to evaluate the effects of HTR2B modulation on tumor growth and cell cycle regulation. Mechanistic insights into the HTR2B-mediated signaling pathway were elucidated using pharmacological inhibitors and molecular interaction assays. RESULTS: Elevated HTR2B expression was detected in NFPA samples, which was associated with increased tumor survival. Inhibition of HTR2B activity resulted in the suppression of tumor growth through modulation of the G2M cell cycle. The inhibition of HTR2B with PRX-08066 was found to block STAT3 phosphorylation and nuclear translocation by interfering with the Gαq/PLC/PKC pathway. A direct interaction between PKC-γ and STAT3 was critical for STAT3 activation. CAB was shown to activate pSTAT3 via HTR2B, reducing its therapeutic potential. However, the combination of an HTR2B antagonist with CAB significantly inhibited tumor cell proliferation in HTR2B-expressing pituitary tumor cell lines, a xenografted pituitary tumor model, and patient-derived samples. Analysis of patient-derived data indicated that a distinct molecular pattern characterized by upregulated HTR2B/PKC-γ and downregulated BTG2/GADD45A may benefit from combination treatment with CAB and PRX-08066. CONCLUSIONS: HTR2B is a potential therapeutic target for NFPAs, and its inhibition could improve CAB efficacy. A dual therapy approach may be beneficial for NFPA patients with high HTR2B expression.

SP1 transcriptionally activates HTR2B to aggravate traumatic spinal cord injury by shifting microglial M1/M2 polarization.

BACKGROUND: Spinal cord injury (SCI) can result in structural and functional damage to the spinal cord, which may lead to loss of limb movement and sensation, loss of bowel and bladder control, and other complications. Previous studies have revealed the critical influence of trans-acting transcription factor 1 (SP1) in neurological pathologies, however, its role and mechanism in SCI have not been fully studied. METHODS: The study was performed using mouse microglia BV2 stimulated using lipopolysaccharide (LPS) and male adult mice subjected to spinal hitting. Western blotting was performed to detect protein expression of SP1, 5-hydroxytryptamine (serotonin) receptor 2B (HTR2B), BCL2-associated x protein (Bax), B-cell lymphoma-2 (Bcl-2), inducible nitric oxide synthase (iNOS), clusters of differentiation 86 (CD86), Arginase 1 (Arg-1) and clusters of differentiation 206 (CD206). Cell viability and apoptosis were analyzed by MTT assay and TUNEL assay. mRNA levels of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), interleukin-4 (IL-4) and tumor necrosis factor-ß (TNF-ß) were quantified by quantitative real-time polymerase chain reaction. The association of SP1 and HTR2B was identified by chromatin immunoprecipitation assay and dual-luciferase reporter assay. HE staining assay was performed to analyze the pathological conditions of spinal cord tissues. RESULTS: LPS treatment induced cell apoptosis and inhibited microglia polarization from M1 to M2 phenotype, accompanied by an increase of Bax protein expression and a decrease of Bcl-2 protein expression, however, these effects were relieved after SP1 silencing. Mechanism assays revealed that SP1 transcriptionally activated HTR2B in BV2 cells, and HTR2B knockdown rescued LPS-induced effects on BV2 cell apoptosis and microglial M1/M2 polarization. Moreover, SP1 absence inhibited BV2 cell apoptosis and promoted microglia polarization from M1 to M2 phenotype by decreasing HTR2B expression. SCI mouse model assay further showed that SP1 downregulation could attenuate spinal hitting-induced promoting effects on cell apoptosis of spinal cord tissues and microglial M1 polarization. CONCLUSION: SP1 transcriptionally activated HTR2B to aggravate traumatic SCI by shifting microglial M1/M2 polarization.

Multiomics-based classifier to decipher immune landscape of uveal melanoma and predict patient outcomes.

Uveal melanoma (UVM) prognosis and the possibilities for targeted therapy depend on a thorough understanding of immune infiltration features and the analysis of genomic and immune signatures. Leveraging multi-omics data from The Cancer Genome Atlas and GEO datasets, we employed an unsupervised clustering algorithm to categorize UVM into immune-related subgroups. Subsequent multi-omics analysis revealed two distinct UVM subtypes, each characterized by unique genomic mutations and immune microenvironment disparities. The aggressive UMCS2 subtype exhibited higher TNM stage and poorer survival, marked by elevated metabolism and increased immune infiltration. However, UMCS2 displayed heightened tumor mutational burden and immune dysfunction, leading to reduced responsiveness to immunotherapy. Importantly, these subtypes demonstrated differential sensitivity to targeted drugs due to significant variances in metabolic and immune environments, with UMCS2 displaying lower sensitivity. We developed a robust, subtype-specific marker-based risk scoring system. This system's diagnostic accuracy was validated through ROC curves, decision curve analysis, and calibration curves, all yielding satisfactory results. Additionally, cell experiments identified the pivotal function of HTR2B, the most crucial factor in this risk model. Knocking down HTR2B significantly reduced the activity, proliferation, and invasion ability of the UVM cell line. These findings underscored the impact of gene and immune microenvironment alterations in driving distinct molecular subtypes, emphasizing the need for precise treatment strategies. The molecular subtyping-based risk assessment system not only aids in predicting patient prognosis but also guides the identification of populations suitable for combined treatment. Molecules represented by HTR2B in the model may serve as effective therapeutic targets for UVM.Communicated by Ramaswamy H. Sarma.

Htr2b Promotes M1 Microglia Polarization and Neuroinflammation after Spinal Cord Injury via Inhibition of Neuregulin-1/ErbB Signaling.

The secondary injury of spinal cord injury (SCI) is dominated by neuroinflammation, which was caused by microglia M1 polarization. This study aimed to investigate the role and mechanism of Htr2b on neuroinflammation of SCI. The BV2 and HMC3 microglia were treated with lipopolysaccharide (LPS) or interferon (IFN)-γ to simulate in vitro models of SCI. Sprague-Dawley rats were subjected to the T10 laminectomy to induce animal model of SCI. Htr2b mRNA expression was measured by qRT-PCR. The expression of Htr2b and Iba-1 was detected by western blot and immunofluorescence. The expression of inflammatory cytokines in vitro and in vivo was also measured. Kyoto Encyclopedia of Genes and Genomes (KEGG) was employed to analyze Htr2b-regulated signaling pathways. Rat behavior was analyzed by the Basso, Beattie, and Bresnahan (BBB) and inclined plane test. Rat dorsal horn tissues were stained by hematoxylin-eosin (H&E) and Nissl to measure neuron loss. Htr2b was highly expressed in LPS- and IFN-γ-treated microglia and SCI rats. SCI modeling promoted M1 microglia polarization and increased levels of inflammatory cytokines. Inhibition of Htr2b by Htr2b shRNA or RS-127445 reduced the expression of Htr2b, Iba-1, and iNOS and suppressed cytokine levels. KEGG showed that Htr2b inhibited ErbB signaling pathway. Inhibition of Htr2b increased protein expression of neuregulin-1 (Nrg-1) and p-ErbB4. Inhibition of the ErbB signaling pathway markedly reversed the effect of Htr2b shRNA on M1 microglia polarization and inflammatory cytokines. Htr2b promotes M1 microglia polarization and neuroinflammation after SCI by inhibiting Nrg-1/ErbB signaling pathway.

Variant rs17619600 in the gene encoding serotonin receptor 2B (HTR2B) increases the risk of gestational diabetes mellitus: a case-control study.

BACKGROUND: During pregnancy, the increase in maternal insulin resistance is compensated by hyperplasia and increased function of maternal pancreatic beta cells; the failure of this compensatory mechanism is associated with gestational diabetes mellitus (GDM). Serotonin participates in beta cell adaptation, acting downstream of the prolactin pathway; the blocking of serotonin receptor B (HTR2B) signaling in pregnant mice impaired beta cell expansion and caused glucose intolerance. Thus, given the importance of the serotoninergic system for the adaptation of beta cells to the increased insulin demand during pregnancy, we hypothesized that genetic variants (single nucleotide polymorphisms [SNPs]) in the gene encoding HTR2B could influence the risk of developing GDM. METHODS: This was a case-control study. Five SNPs (rs4973377, rs765458, rs10187149, rs10194776, and s17619600) in HTR2B were genotyped by real-time polymerase chain reaction in 453 women with GDM and in 443 pregnant women without GDM. RESULTS: Only the minor allele C of SNP rs17619600 conferred an increased risk for GDM in the codominant model (odds ratio [OR] 2.15; 95% confidence interval [CI] 1.53-3.09; P < 0.0001) and in the rare dominant model (OR 2.32; CI 1.61-3.37; P < 0.0001). No associations were found between the SNPs and insulin use, maternal weight gain, newborn weight, or the result of postpartum oral glucose tolerance test (OGTT). In the overall population, carriers of the XC genotype (rare dominant model) presented a higher area under the curve (AUC) of plasma glucose during the OGTT, performed for diagnostic purposes, compared with carriers of the TT genotype of rs17619600. CONCLUSIONS: SNP rs17619600 in the HTR2B gene influences glucose homeostasis, probably affecting insulin release, and the presence of the minor allele C was associated with a higher risk of GDM.

Signaling snapshots of a serotonin receptor activated by the prototypical psychedelic LSD.

Serotonin (5-hydroxytryptamine [5-HT]) 5-HT2-family receptors represent essential targets for lysergic acid diethylamide (LSD) and all other psychedelic drugs. Although the primary psychedelic drug effects are mediated by the 5-HT2A serotonin receptor (HTR2A), the 5-HT2B serotonin receptor (HTR2B) has been used as a model receptor to study the activation mechanisms of psychedelic drugs due to its high expression and similarity to HTR2A. In this study, we determined the cryo-EM structures of LSD-bound HTR2B in the transducer-free, Gq-protein-coupled, and ß-arrestin-1-coupled states. These structures provide distinct signaling snapshots of LSD's action, ranging from the transducer-free, partially active state to the transducer-coupled, fully active states. Insights from this study will both provide comprehensive molecular insights into the signaling mechanisms of the prototypical psychedelic LSD and accelerate the discovery of novel psychedelic drugs.

Environmental levels of carbaryl impair zebrafish larvae behaviour: The potential role of ADRA2B and HTR2B.

The insecticide carbaryl is commonly found in indirectly exposed freshwater ecosystems at low concentrations considered safe for fish communities. In this study, we showed that after only 24 h of exposure to environmental concentrations of carbaryl (0.066-660 ng/L), zebrafish larvae exhibit impairments in essential behaviours. Interestingly, the observed behavioural effects induced by carbaryl were acetylcholinesterase-independent. To elucidate the molecular initiating event that resulted in the observed behavioural effects, in silico predictions were followed by in vitro validation. We identified two target proteins that potentially interacted with carbaryl, the α2B adrenoceptor (ADRA2B) and the serotonin 2B receptor (HTR2B). Using a pharmacological approach, we then tested the hypothesis that carbaryl had antagonistic interactions with both receptors. Similar to yohimbine and SB204741, which are prototypic antagonists of ADRA2B and HTR2B, respectively, carbaryl increased the heart rate of zebrafish larvae. When we compared the behavioural effects of a 24-h exposure to these pharmacological antagonists with those of carbaryl, a high degree of similarity was found. These results strongly suggest that antagonism of both ADRA2B and HTR2B is the molecular initiating event that leads to adverse outcomes in zebrafish larvae that have undergone 24 h of exposure to environmentally relevant levels of carbaryl.

Contribution of the STAT Family of Transcription Factors to the Expression of the Serotonin 2B (HTR2B) Receptor in Human Uveal Melanoma.

Uveal melanoma (UM) remains the most common intraocular malignancy among diseases affecting the adult eye. The primary tumor disseminates to the liver in half of patients and leads to a 6 to 12-month survival rate, making UM a particularly aggressive type of cancer. Genomic analyses have led to the development of gene-expression profiles that can efficiently predict metastatic progression. Among these genes, that encoding the serotonin receptor 2B (HTR2B) represents the most discriminant from this molecular signature, its aberrant expression being the hallmark of UM metastatic progression. Recent evidence suggests that expression of HTR2B might be regulated through the Janus kinase/Signal Transducer and Activator of Transcription proteins (JAK/STAT) intracellular signalization pathway. However, little is actually known about the molecular mechanisms involved in the abnormally elevated expression of the HTR2B gene in metastatic UM and whether activated STAT proteins participates to this mechanism. In this study, we determined the pattern of STAT family members expressed in both primary tumors and UM cell-lines, and evaluated their contribution to HTR2B gene expression. Examination of the HTR2B promoter sequence revealed the presence of a STAT putative target site (5'-TTC (N)3 GAA3') located 280 bp upstream of the mRNA start site that is completely identical to the high affinity binding site recognized by these TFs. Gene profiling on microarrays provided evidence that metastatic UM cell lines with high levels of HTR2B also express high levels of STAT proteins whereas low levels of these TFs are observed in non-metastatic UM cells with low levels of HTR2B, suggesting that STAT proteins contribute to HTR2B gene expression in UM cells. All UM cell lines tested were found to express their own pattern of STAT proteins in Western blot analyses. Furthermore, T142 and T143 UM cells responded to interleukins IL-4 and IL-6 by increasing the phosphorylation status of STAT1. Most of all, expression of HTR2B also considerably increased in response to both IL-4 and IL-6 therefore providing evidence that HTR2B gene expression is modulated by STAT proteins in UM cells. The binding of STAT proteins to the -280 HTR2B/STAT site was also demonstrated by electrophoretic mobility shift assay (EMSA) analyses and site-directed mutation of that STAT site also abolished both IL-4 and IL-6 responsiveness in in vitro transfection analyses. The results of this study therefore demonstrate that members from the STAT family of TFs positively contribute to the expression of HTR2B in uveal melanoma.

Subtypes of Histopathologically Classical Aldosterone-Producing Adenomas Yield Various Transcriptomic Signaling and Outcomes.

[Figure: see text].

HTR2B and SLC5A3 Are Specific Markers in Age-Related Osteoarthritis and Involved in Apoptosis and Inflammation of Osteoarthritis Synovial Cells.

Objective: Osteoarthritis (OA) is a heterogeneous age-related disease, which is badly difficult to cure due to its complex regulatory networks of pathogenesis. This study explored OA-specific genes in synovial tissues and validated their roles on apoptosis and inflammation of OA synovial cells. Methods: Weighted correlation network analysis (WGCNA) was employed to explore OA-related co-expression modules in the GSE55235 and GSE55457 datasets. Then, this study screened OA-specific genes. After validation of these genes in the GSE12021 and GSE32317 datasets, HTR2B and SLC5A3 were obtained. Their expression was detected in human OA and healthy synovial tissues by RT-qPCR and western blot. OA rat models were constructed by anterior cruciate ligament transection (ACLT) operation. In OA synovial cells, HTR2B and SLC5A3 proteins were examined via western blot. After transfection with sh-HTR2B or sh-SLC5A3, apoptosis and inflammation of OA synovial cells were investigated by flow cytometry and western blot. Results: A total of 17 OA-specific DEGs were identified, which were significantly enriched in inflammation pathways. Among them, HTR2B and SLC5A3 were highly expressed in end-than early-stage OA. Their up-regulation was validated in human OA synovial tissues and ACLT-induced OA synovial cells. Knockdown of HTR2B and SLC5A3 restrained apoptosis and increased TGF-ß and IL-4 expression as well as reduced TNF-α and IL-1ß expression in OA synovial cells. Conclusion: Collectively, this study identified two OA-specific markers HTR2B and SLC5A3 and their knockdown ameliorated apoptosis and inflammation of OA synovial cells.

Serotonin receptor type 2B activation augments TNF-α-induced matrix mineralization in murine valvular interstitial cells.

Calcification, fibrosis, and chronic inflammation are the predominant features of calcific aortic valve disease, a life-threatening condition. Drugs that induce serotonin (5-hydroxytryptamine [5-HT]) are known to damage valves, and activated platelets, which carry peripheral serotonin, are known to promote calcific aortic valve stenosis. However, the role of 5-HT in valve leaflet pathology is not known. We tested whether serotonin mediates inflammation-induced matrix mineralization in valve cells. Real-time reverse transcription-polymerase chain reaction analysis showed that murine aortic valve interstitial cells (VICs) expressed both serotonin receptor types 2A and 2B (Htr2a and Htr2b). Although Htr2a expression was greater at baseline, Htr2b expression was induced several-fold more than Htr2a in response to the pro-calcific tumor necrosis factor-α (TNF-α) treatment. 5-HT also augmented TNF-α-induced osteoblastic differentiation and matrix mineralization of VIC, but 5-HT alone had no effects. Inhibition of serotonin receptor type 2B, using specific inhibitors or lentiviral knockdown in VIC, attenuated 5-HT effects on TNF-α-induced osteoblastic differentiation and mineralization. 5-HT treatment also augmented TNF-α-induced matrix metalloproteinase-3 expression, which was also attenuated by Htr2b knockdown. Htr2b expression in aortic roots and serum levels of peripheral 5-HT were also greater in the hyperlipidemic Apoe-/- mice than in control normolipemic mice. These findings suggest a new role for serotonin signaling in inflammation-induced calcific valvulopathy.

Pharmacologic inhibition of serotonin htr2b ameliorates hyperglycemia and the altered expression of hepatic FGF21, Sdf2l1, and htr2a in db/db mice and KKAy mice.

Plasma fibroblast growth factor 21 (FGF21) levels and hepatic FGF21, serotonin 2a receptor (htr2a), and stromal cell-derived factor 2 like 1 (Sdf2l1) expression are increased in insulin-resistant C57BL6J mice fed a high-fat diet. Here we show that plasma FGF21 levels and hepatic FGF21, Sdf2l1, and htr2a expression were decreased in 6-week-old db/db mice compared with C57BL6J mice, whereas they were increased in 6-week-old KKAy mice compared with KK mice. Expression of hepatic htr2b was increased in db/db mice and KKAy mice compared with controls. Treatment with the selective htr2b antagonist SB204741 suppressed the hyperglycemia in either db/db mice or KKAy mice. Treatment with SB20471 reversed the decreases in plasma FGF21 levels and hepatic FGF21, Sdf2l1, and htr2a expression in db/db mice, whereas it suppressed the increases in plasma FGF21 levels and hepatic FGF21, Sdf2l1, and htr2a expression in KKAy mice. Moreover, treatment with SB204741 increased plasma FGF21 levels and expression of hepatic FGF21, htr2a, and Sdf2l1 in C57BL6J mice, whereas it decreased plasma FGF21 levels and hepatic FGF21 expression in KK mice. These findings suggest that pharmacologic inhibition of htr2b ameliorates the hyperglycemia and altered expression of hepatic FGF21, Sdf2l1 and htr2a in obese and diabetic db/db and KKAy mice.

A positive association between a polymorphism in the HTR2B gene and cocaine-crack in a French Afro-Caribbean population.

OBJECTIVES: Cocaine dependence has a strong heritability component. The aim of this study was to investigate the putative association between the serotonin 2B receptor gene (HTR2B), crack use disorders and impulsivity. METHODS: A French Afro-Caribbean male population of patients with crack use disorders (n = 80) was compared to healthy Afro-Caribbean male controls (n = 60). Comorbid ADHD and impulsivity were assessed. Five single nucleotide polymorphisms (SNPs) in the HTR2B gene were selected: rs643700, rs6736017, rs1549339, rs17586428 and rs3806545. These SNPs were chosen to include most of the linkage disequilibrium blocks in the HTR2B gene. The French translation of the Barratt Impulsivity Scale BIS-11 was used to evaluate impulsivity. Comorbid ADHD was diagnosed using the Wender Utah Rating Scale-25 item for Attention Deficit-Hyperactivity Disorder. RESULTS: We have observed a positive association between the rs6736017 polymorphism and crack use disorders in a French Afro-Caribbean male population. CONCLUSIONS: In our population, the risk effect of HTR2B rs6736017 appeared to be specific to individuals with crack use disorders rather than being driven by impulsivity or ADHD alone.

Analysis of the proteasome activity and the turnover of the serotonin receptor 2B (HTR2B) in human uveal melanoma.

Uveal melanoma (UM), although a very rare disease, remains a particularly aggressive type of cancer as near 50% of the UM presenting patients will also develop liver metastases within 15 years from the initial diagnostic. One of the most reliable predictive markers of UM at risk of evolving toward the formation of liver lesions is an abnormally elevated level of expression of the transcript encoding the 5-Hydroxytryptamine (serotonin) receptor 2B (HTR2B). In our previous study, we demonstrated that transcription of the HTR2B gene was under the regulatory influences of two transcription factors (TFs), NFI and RUNX1. However, the action of these TFs was insufficient to explain the elevated level of the HTR2B protein in metastatic UM cells or the discrepancies we observed between its expression at the transcriptional and protein levels, therefore suggesting that additional post-translational modifications may also contribute to the altered expression of HTR2B in UM cells. In the present study, we investigated whether the turnover of HTR2B by the proteasome could account at least in part for its deregulated expression. Microarray analyses performed with UM cell lines derived from both non-metastatic and metastatic UM primary tumors revealed important alterations in the expression of some of the transcripts encoding both the E3 ubiquitin ligases and the various subunits of the proteasome, and these modifications were further exacerbated by cell passaging in culture. These alterations also correlated with significant changes in the enzymatic activity of the proteasome. However, the highest proteasome activity and amount of ubiquitinated HTR2B observed in the metastatic T142 cell line, as revealed by immunoprecipitation of ubiquitinated proteins and Western blotting using the HTR2B antibody, apparently had little impact on the total content of HTR2B protein. This contrasts with the near total disappearance of this receptor in the non-metastatic T108 cell line. Our study therefore suggests that the inability of the proteasome to degrade HTR2B in metastatic UM cells might rely on an increased stability of the ubiquitinated receptor in these cells.

Transcription of the Human 5-Hydroxytryptamine Receptor 2B (HTR2B) Gene Is under the Regulatory Influence of the Transcription Factors NFI and RUNX1 in Human Uveal Melanoma.

Because it accounts for 70% of all eye cancers, uveal melanoma (UM) is therefore the most common primary ocular malignancy. In this study, we investigated the molecular mechanisms leading to the aberrant expression of the gene encoding the serotonin receptor 2B (HTR2B), one of the most discriminating among the candidates from the class II gene signature, in metastatic and non-metastatic UM cell lines. Transfection analyses revealed that the upstream regulatory region of the HTR2B gene contains a combination of alternative positive and negative regulatory elements functional in HTR2B- but not in HTR23B⁺ UM cells. We demonstrated that both the transcription factors nuclear factor I (NFI) and Runt-related transcription factor I (RUNX1) interact with regulatory elements from the HTR2B gene to either activate (NFI) or repress (RUNX1) HTR2B expression in UM cells. The results of this study will help understand better the molecular mechanisms accounting for the abnormal expression of the HTR2B gene in uveal melanoma.

Alcohol Intoxication Moderates the Association between a Polygenic Risk Score and Unprovoked Intimate Partner Aggression.

Despite evidence that genetic variation contributes to aggression, few studies have examined how genetic variation contributes to IPA specifically. In the current study, 69 couples from a Midwestern university completed self-report measures of IPA, childhood trauma exposure, and hazardous alcohol use, and were randomly assigned to consume either a placebo or alcohol beverage before participating in an analogue aggression task against their partner. Genetic risk (i.e., association with lower transcriptional efficiency) for aggression was measured with a polygenic risk score (PRS) created from four polymorphisms (HTR1B rs13212041, HTR2B rs6437000, 5-HTTLPR, and MAOA uVNTR). Among individuals with a low PRS, individuals who consumed alcohol (BrAC = 0.07%) showed greater unprovoked IPA than individuals who consumed a placebo. Findings contribute to our limited understanding regarding the etiology of IPA and suggest that individuals who have increased transcriptional activity in certain serotonin system genes may be at higher risk of IPA when intoxicated.

Serotonergic 5HTTLPR/rs25531 s-allele homozygosity associates with violent suicides in male citalopram users.

Depressive disorders are involved as a background factor in over 50% of suicide cases. The most widely used antidepressants today are serotonin selective reuptake inhibitors (SSRIs). However, not all users benefit from SSRI medication. Although the overall number of suicides in Finland have decreased notably during the last decade, the annual rate is still relatively high, particularly in male population. In this study, we tested the hypothesis that the genetic variants associated with decreased citalopram efficiency, 5HTTLPR/rs25531, and increased impulsive behavior, MAOA-uVNTR and HTR2B Q20*, are more frequent among citalopram users committing suicide than among the citalopram users in general. Also the effect of alcohol was evaluated. The study population comprised 349 suicide victims (184 males and 165 females). Based on the suicide method used, cases were divided into two groups; violent (88 males and 49 females) and non-violent (96 males and 116 females). The control group (284; 159 males and 125 females) consisted of citalopram users who died of causes other than suicide. We found that male citalopram users with low functioning s/s genotype of 5HTTLPR/rs25531 were in increased risk to commit violent suicide (OR 2.50, 95%CI 1.15-5.42, p = 0.020). Surprisingly, high blood alcohol concentration was observed to be a risk factor only in non-violent suicides (both males and females), but not in violent ones. No association between suicides and MAOA-uVNTR and HTR2B Q20*, which have been previously connected to violent and impulsive behavior, was detected.

Serotonin Activated Hepatic Stellate Cells Contribute to Sex Disparity in Hepatocellular Carcinoma.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) occurs more frequently and aggressively in men than in women. Although sex hormones are believed to play a critical role in this disparity, the possible contribution of other factors largely is unknown. We aimed to investigate the role of serotonin on its contribution of sex discrepancy during HCC. METHODS: By using an inducible zebrafish HCC model through hepatocyte-specific transgenic krasV12 expression, differential rates of HCC in male and female fish were characterized by both pharmaceutical and genetic interventions. The findings were validated further in human liver disease samples. RESULTS: Accelerated HCC progression was observed in krasV12-expressing male zebrafish and male fish liver tumors were found to have higher hepatic stellate cell (HSC) density and activation. Serotonin, which is essential for HSC survival and activation, similarly were found to be synthesized and accumulated more robustly in males than in females. Serotonin-activated HSCs could promote HCC carcinogenesis and concurrently increase serotonin synthesis via transforming growth factor (Tgf)b1 expression, hence contributing to sex disparity in HCC. Analysis of liver disease patient samples showed similar male predominant serotonin accumulation and Tgfb1 expression. CONCLUSIONS: In both zebrafish HCC models and human liver disease samples, a predominant serotonin synthesis and accumulation in males resulted in higher HSC density and activation as well as Tgfb1 expression, thus accelerating HCC carcinogenesis in males.

Effects of Acupuncture on Expression of 5-HT Neurons in Medulla Oblongata and 5-HTR2B on Mice Models with Chloroquine-induced Pruritus / 中国中医药信息杂志

Objective To explore the effects of acupuncture on pruritic behaviors, expression of 5-HT neurons in medulla oblongata and 5-HTR2B on mice with chloroquine-induced pruritus; To discuss the mechanism of action of acupuncture in chloroquine-induced pruritus. Methods A non-histamine-dependent pruritus model was prepared by subcutaneous injection of chloroquine into the back of the neck. Forty C57B/6J mice were randomly divided into model-acupuncture group, model-non-acupuncture group, normal saline group and blank control group, with 10 mice in each group. After modeling, acupuncture was given in Xuehai, Quchi and Hegu on both sides. The plug and twist way was used to stimulate, once a day, three times. Model-non-acupuncture group received no acupuncture. Normal saline group received the neck injection of saline in the back. Blank control group received no treatment. Behavioral changes were observed, and immunofluorescence technique and Western blot were used to test the expression of 5-HT neurons and 5-HTR2B in medulla oblongata neurons. Results The number of scratches in model-acupuncture group and model-non-acupuncture group was obviously more than normal saline group and blank control group (P<0.05). The number of scratches in model-acupuncture group was lower than that of model-non-acupuncture group (P<0.05). The expression of 5-HT in medulla oblongata neurons was unclear in both normal saline group and blank control group. The expression of 5-HT neurons in medulla oblongata significantly increased in model group, which decreased after acupuncture. The expression of 5-HTR2B of model group was significant higher than normal saline group and blank control group (P<0.01). Compared with model-non-acupuncture group, the expression of 5-HTR2B in model-acupuncture group significant decreased (P<0.01). Conclusion Acupuncture can significantly inhibitscratching behaviors in mice induced by chloroquine, and the mechanism may be realized by decreasing the expression of 5-HT neurons and 5-HTR2B in medulla oblongata neurons.