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AbstractThe term serotonin syndrome (SS) is a potentially life-threatening devastating condition triggered by the excessive accumulation of serotonin, often due to an overdose or the concurrent use of multiple serotonergic drugs. Lavandula angustifolia (lavender), a known plant from the Lamiaceae family, is very rich in essential oils, minerals, and tannins. This study aimed to elucidate the detrimental effects of SS on the brain and to evaluate the neuroprotective potential of L. angustifolia essential oil. Male rats were randomly divided into the following groups: control (Group 1); L. angustifolia-treated (Group 2); ondansetron-treated high-dose (Group 3); sertraline-treated high-dose (Group 4); low-dose ondansetron + sertraline-treated (Group 5); high-dose ondansetron + sertraline-treated (Group 6); low-dose ondansetron + sertraline + L. angustifolia-treated (Group 7); and high-dose ondansetron + sertraline + L. angustifolia-treated (Group 8). Neurotransmitter levels, dopamine metabolites, and expressed cytokines were quantified. Additionally, histological assessment of the hippocampus was performed. The results revealed significant disruptions in neurotransmitter and amino acid levels within the hippocampus across the treated groups. Notably, the high-dose ondansetron + sertraline group presented pronounced increases in serotonin, 5-HIAA, and proinflammatory cytokines, resulting in neurotoxicity and pronounced alterations in the hippocampus. Conversely, treatment with L. angustifolia significantly attenuated these neurotoxic effects. The findings suggest that L. angustifolia confers neuroprotection against the deleterious effects of SS, particularly by counteracting the neurotoxic impact of combined serotonin 5-HT3 receptor antagonists and serotonin reuptake inhibitors within the hippocampus. These findings highlight the potential of L. angustifolia as a natural therapeutic agent for mitigating SS-induced neurotoxicity. [ABSTRACT FROM AUTHOR]

[Display omitted] • Fluoxetine enhances survival and cognitive recovery in meningitis through the 5-HT 7 R/CCR5 pathway. • 5-HT 7 R signaling induces CCR5 ubiquitination and degradation via the E3 ligase STUB1. • 5-HT 7 R recruits STUB1 to CCR5 and initiates K48-linked ubiquitination at Lys138 and Lys322. Excessive immune activation induces tissue damage during infection. Compared to external strategies to reconstruct immune homeostasis, host balancing ways remain largely unclear. Here we found a neuroimmune way that prevents infection-induced tissue damage. By FACS and histopathology analysis of brain Streptococcus pneumonia meningitis infection model and behavioral testing. Western blot, co-immunoprecipitation, and ubiquitination analyze the Fluoxetine initiate 5-HT7R-STUB1-CCR5 K48-linked ubiquitination degradation. Fluoxetine, a selective serotonin reuptake inhibitor, or the agonist of serotonin receptor 5-HT 7 R, protects mice from meningitis by inhibiting CCR5-mediated excessive immune response and tissue damage. Mechanistically, the Fluoxetine-5-HT 7 R axis induces proteasome-dependent degradation of CCR5 via mTOR signaling, and then recruits STUB1, an E3 ubiquitin ligase, to initiate K48-linked polyubiquitination of CCR5 at K138 and K322, promotes its proteasomal degradation. STUB1 deficiency blocks 5-HT 7 R-mediated CCR5 degradation. Our results reveal a neuroimmune pathway that balances anti-infection immunity via happiness neurotransmitter receptor and suggest the 5-HT 7 R-CCR5 axis as a potential target to promote neuroimmune resilience. [ABSTRACT FROM AUTHOR]

Copyright of Shipin Kexue/ Food Science is the property of Food Science Editorial Department and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background: Hepatocellular carcinoma (HCC) has a poor prognosis, partly due to resistance to treatments like sorafenib. The 5-hydroxytryptamine receptor 1D (HTR1D) is involved in cancer progression through the PI3K/Akt pathway, but its role in HCC is not well understood. This study investigates HTR1D's expression, function, and potential as a prognostic marker in HCC. Methods: First, the correlation between HTR1D and hepatocellular carcinoma was analyzed using the TCGA database, and the expression level of HTR1D in clinical samples was detected by qPCR. Then the siRNA was transfected into Huh-7 and Hep3B cells, and the cell proliferation ability, colony formation ability, migration and invasion ability were detected with or without sorafenib. And the expression of the PI3K/Akt pathway was detected by Western Blot. Finally, the potential of HTR1D as a predictive marker for patient prognosis was evaluated by immunohistochemistry. Results: Analysis of TCGA data showed that methylation of the HTR1D gene was associated with cancer status. Clinical samples confirmed significant differences in HTR1D expression between HCC and adjacent tissues, with higher expression correlating with poorer patient prognosis. Interference with HTR1D gene expression demonstrated its role in promoting HCC proliferation, migration, and drug resistance through the PI3K/Akt pathway. These findings were validated in a mouse model. Immunohistochemical analysis of clinicopathological samples suggested that HTR1D could be a valuable prognostic marker for HCC. Conclusion: HTR1D is highly expressed in hepatocellular carcinoma tissues, and it can influence hepatocellular carcinoma development and resistance to sorafenib by regulating the PI3K/Akt signaling pathway. In addition, HTR1D has potential as a prognostic indicator. [ABSTRACT FROM AUTHOR]

The hormone and neurotransmitter serotonin regulates numerous physiological functions within the central nervous system and in the periphery upon binding to specific receptors. In the periphery, the serotonin receptor 7 (5-HT7R) is expressed on different immune cells including monocytes and macrophages. To investigate the impact of 5-HT7R-mediated signaling on macrophage properties, we used human THP-1 cells and differentiated them into pro-inflammatory M1- and anti-inflammatory M2-like macrophages. Pharmacological 5-HT7R activation with the specific agonist LP-211 especially modulates morphology of M1-like macrophages by increasing the number of rounded cells. Furthermore, 5-HT7R stimulation results in significantly reduced phagocytic and migratory ability of M1-like macrophages. Noteworthy, LP-211 treatment leads to changes in secretory properties of all macrophage types with the highest effects obtained for M0- and M2c-like macrophages. Finally, the importance of 5-HT7R for regulation of phagocytosis was confirmed in human primary CD14+ cells. These results indicate that 5-HT7R activation selectively impairs basic functions of macrophages and might thus be a new access point for the modulation of macrophage responses in the future treatment of inflammatory diseases. [ABSTRACT FROM AUTHOR]

Botanical dietary supplements are widely used, but issues of authenticity, consistency, safety, and efficacy that complicate their poorly understood mechanism of action have prompted questions and concerns in the popular and scientific literature. Black cohosh (Actaea racemosa L., syn. Cimicifuga racemosa, Nutt., Ranunculaceae) is a multicomponent botanical therapeutic used as a popular remedy for menopause and dysmenorrhea and explored as a treatment in breast and prostate cancer. However, its use and safety are controversial. A. racemosa tissues contain the bioactive serotonin analog N-methylserotonin, which is thought to contribute to the serotonergic activities of black cohosh–containing preparations. A. racemosa has several TDC-like genes hypothesized to encode tryptophan decarboxylases (TDCs) converting L-tryptophan to tryptamine, a direct serotonin precursor in plants. Expression of black cohosh TDC1, TDC2, and TDC3 in Saccharomyces cerevisiae resulted in the production of tryptamine. TDC1 and TDC3 had approximately fourfold higher activity than TDC2, which was attributable to a variable Cys/Ser active site residue identified by site-directed mutagenesis. Co-expression in yeast of the high-activity black cohosh TDCs with the next enzyme in serotonin biosynthesis, tryptamine 5-hydroxylase (T5H), from rice (Oryza sativa) resulted in the production of serotonin, whereas co-expression with low-activity TDCs did not, suggesting that TDC activity is a rate-limiting step in serotonin biosynthesis. Two T5H-like sequences were identified in A. racemose, but their co-expression with the high-activity TDCs in yeast did not result in serotonin production. TDC expression was detected in several black cohosh tissues, and phytochemical analysis using LC-MS revealed several new tryptamines, including tryptamine and serotonin, along with N-methylserotonin and, interestingly, N-N-dimethyl-5-hydroxytryptamine (bufotenine), which may contribute to hepatotoxicity. Incubation of A. racemosa leaves with tryptamine and N-methyltryptamine resulted in increased concentrations of serotonin and N-methylserotonin, respectively, suggesting that methylation of tryptamine precedes hydroxylation in the biosynthesis of N-methylserotonin. This work indicates a significantly greater variety of serotonin derivatives in A. racemosa than previously reported. Moreover, the activities of the TDCs underscore their key role in the production of serotonergic compounds in A. racemosa. Finally, it is proposed that tryptamine is first methylated and then hydroxylated to form the black cohosh signature compound N-methylserotonin. [ABSTRACT FROM AUTHOR]

• Neuroinflammation is a principle mechanism in the pathogenesis of Alzheimer's disease. • Psychedelics by 5HT2AR activation can inhibit neuroinflammation. • Psychedelics offer new possibilities in the treatment of Alzheimer's disease. Dementia is an increasing disorder, and Alzheimer's disease (AD) is the cause of 60% of all dementia cases. Despite all efforts, there is no cure for stopping dementia progression. Recent studies reported potential effects of psychedelics on neuroinflammation during AD. Psychedelics by 5HT 2A R activation can reduce proinflammatory cytokine levels (TNF-α, IL-6) and inhibit neuroinflammation. In addition to neuroinflammation suppression, psychedelics induce neuroplasticity by increasing Brain-derived neurotrophic factor (BDNF) levels through Sigma-1R stimulation. This review discussed the effects of psychedelics on AD from both neuroinflammatory and neuroplasticity standpoints. [ABSTRACT FROM AUTHOR]

Rising cases of type 2 diabetes (T2D) in India, especially in metropolitan cities is an increasing concern. The individuals that were most affected are young professionals working in the corporate sector. However, the corporate sector has remained the least explored for T2D risk predisposition. Considering corporate employees' lifestyles and the role of gene-environment interaction in T2D susceptibility, the study aims to find genetic variants associated with T2D predisposition. In this first kind of study, 680 young professionals (284 T2D cases, and 396 controls) were diagnosed and screened for 2658 variants on an array designed explicitly for the CoGsI study. The variant filtering was done at Bonferroni p-value of 0.000028. The genetic data was analysed using PLINK v1.09, SPSS, R programming, VEP tool, and FUMA GWAS tool. Interestingly, 42 variants were associated with the T2D risk. Out of 42, three missense variants (rs1402467, rs6050, and rs713598) in Sulfotransferase family 1 C member 4 (SULT1C4), Fibrinogen Alpha Chain (FGA), and Taste 2 Receptor Member 38 (TAS2R38) and two untranslated region (UTR) variants (rs1063320 and rs6296) in Major Histocompatibility Complex, Class I, G (HLA-G) and 5-Hydroxytryptamine Receptor 1B (HTR1B) were associated with the T2D risk. CoGsI identified potential genomic markers increasing susceptibility to the early onset of T2D. Present findings provide insights into mechanisms underlying T2D manifestation in corporate professionals due to genetics interacting with occupational stress and urban lifestyles. [ABSTRACT FROM AUTHOR]

To elucidate the potential roles of presynaptic and postsynaptic serotonergic activity in impulsivity traits, we investigated the relationship between self-reported impulsiveness and serotonin transporter (5-HTT) and 5-HT2A receptors in healthy individuals. In this study, 26 participants completed 3-Tesla magnetic resonance imaging and positron emission tomography with [11C]DASB and [11C]MDL100907. To quantify 5-HTT and 5-HT2A receptor availability, the binding potential (BPND) of [11C]DASB and [11C]MDL100907 was derived using the simplified reference tissue model with cerebellar gray matter as the reference region. The participants' impulsivity levels were assessed using the Barratt Impulsiveness Scale-11 (BIS-11). The region of interest (ROI)-based partial correlation analysis with age, sex, and temperament traits as covariates revealed a significant positive correlation between non-planning impulsiveness and [11C]MDL100907 BPND in the caudate (CAU) at Bonferroni-corrected p < 0.0045. Non-planning impulsiveness was also positively correlated with [11C]MDL100907 BPND in the prefrontal cortex (PFC), ventromedial PFC, orbitofrontal cortex (OFC), insula (INS), amygdala (AMYG), putamen, ventral striatum, and thalamus, and the total score of BIS-11 was positively correlated with [11C]MDL100907 BPND in the OFC, INS, AMYG, and CAU at uncorrected p < 0.05. Motor impulsiveness had a positive correlation with [11C]DASB BPND in the CAU at uncorrected p < 0.05. Our results suggest that impulsivity traits, characterized by focusing on the present moment without considering future consequences, may be involved in serotonergic neurotransmission, particularly 5-HT2A receptor-mediated postsynaptic signaling in the CAU, which plays an important role in cognitive processes related to executive function, judgment of alternative outcomes, and inhibitory control. [ABSTRACT FROM AUTHOR]

Spinal cord injury (SCI) results in functional deficits below the injured spinal level. The descending serotonergic system in the spinal cord is critically involved in the control of motor and autonomic functions. Specifically, SCI damages the projections of serotonergic fibers, which leads to reduced serotonin inputs and increased amounts of spinal serotonergic receptors. Our previous pharmacological study demonstrated that brief administration of a highly selective 5-HT1A receptor agonist, NLX-112, improves lower urinary tract (LUT) function at the termination stage of thoracic 8 (T8) contusive SCI in rats. However, whether chronic activation of serotonin 5-HT1A receptors by NLX-112 after SCI is beneficial remains an unanswered question. Here, we evaluated the efficacy of long-term NLX-112 intervention starting from two weeks post-T8 contusive SCI for an additional six weeks. We evaluated locomotion, LUT function, bladder morphology, and the number of spinal 5-HT1A receptors in both L4 and L6/S1 spinal cord segments. Our results indicate that NLX-112 treatment significantly improves locomotion in a dose-dependent fashion, improves LUT function, reduces bladder weight and bladder wall thickness, and reduces the SCI-upregulated spinal 5-HT1A receptors compared to vehicle-treated SCI animals. These data suggest promising therapeutic potential for long-term NLX-112 activation of 5-HT1A receptors to treat SCI. [ABSTRACT FROM AUTHOR]

Schizophrenia is a complex heterogenous disorder thought to be caused by interactions between genetic and environmental factors. The theories developed to explain the etiology of schizophrenia have focused largely on the dysfunction of neurotransmitters such as dopamine, serotonin and glutamate with their receptors, although research in the past several decades has indicated strongly that other factors are also involved and that the role of neuroglial cells in psychotic disorders including schizophrenia should be given more attention. Although glia were originally thought to be present in the brain only to support neurons in a physical, metabolic and nutritional capacity, it has become apparent that these cells have a variety of important physiological roles and that abnormalities in their function may make significant contributions to the symptoms of schizophrenia. In the present paper, we review the interactions of brain microglia, astrocytes and oligodendroglia with aspects such as transmitter dysregulation, neuro-inflammation, oxidative stress, synaptic function, the gut microbiome, myelination and the blood–brain barrier that appear to affect the cause, development and treatment of schizophrenia. We also review crosstalk between microglia, astrocytes and oligodendrocytes and the effects of antipsychotics on neuroglia. Problems associated with studies on specific biomarkers for glia in schizophrenia are discussed. [ABSTRACT FROM AUTHOR]

Background: Perturbations of intestinal serotonergic neurotransmission seem to be involved in bowel dysmotility associated with irritable bowel syndrome (IBS) with diarrhea. Oral administration of probiotics is an emerging strategy to improve IBS symptoms, possibly via influencing local serotonin metabolism and neurotransmission. In the present study, we evaluated the effects of the yeast Saccharomyces boulardii CNCM I-745 (S. boulardii) on intestinal motility and serotonergic receptors. Methods: Isolated rat ileum was contracted in a cumulative concentration way by serotonin (5-HT), various 5-HT agonists or by acetylcholine to determine their effective concentration 50% (EC50). Single concentrations of S. boulardii or 5-HT antagonists were added before agonists to identify the receptors targeted by S. boulardii. Results: The serotonin antagonists 5-HT1A WAY100635, 5-HT2A ketanserin and 5-HT4 GR113808 inhibited 5-HT-induced contractions in a concentration-dependent manner. S. boulardii between 0.05 and 1.5 mg/mL increased the EC50 value of 5-HT suggesting an inhibitory effect against serotonin-induced contraction. Ileum contractions induced by the serotonin agonist 5-HT1 carboxamidotryptamine or by the serotonin agonist 5-HT2 alpha-methyl-5-HT were significantly reduced by S. boulardii at 1.5 mg/mL. The yeast did not affect acetylcholine-induced ileum contraction. Conclusion: S. boulardii CNCM I-745 possesses relaxant properties on the rat ileum involving the inhibition of 5-HT and more specifically 5-HT1A and 5-HT2A/2B/2C receptor-induced contractions. These data suggest that the attenuation of 5-HT-induced ileal contractions by S. boulardii represents a probable mechanism of action sustaining its efficacy in patients affected by IBS with diarrhea. [ABSTRACT FROM AUTHOR]

Background: Both depressive symptoms and neurotransmitter changes affect the characteristics of functional brain networks in clinical patients. We sought to explore how brain functional grading is organized among patients with mild cognitive impairment and depressive symptoms (D-MCI) and whether changes in brain organization are related to neurotransmitter distribution. Methods: Using 3 T magnetic resonance imaging (MRI) we acquired functional MRI (fMRI) data from patients with D-MCI, patients with mild cognitive impairment without depression (nD-MCI), and healthy controls. We used resting-state fMRI and diffusion embedding to examine the pattern of functional connectivity gradients. We used analysis of covariance and post hoc t tests to compare the difference in functional connectivity gradients among the 3 groups. We examined the correlation between variations in functional connectivity gradients and neurotransmitter maps using the JuSpace toolbox. Results: We included 105 participants, including 31 patients with D-MCI, 40 patients with nD-MCI, and 34 healthy controls. Compared with healthy controls, both the nD-MCI and D-MCI groups showed abnormalities in the principal unimodal–transmodal gradient pattern. Compared with controls, the D-MCI group showed an increased secondary gradient in the default mode network. Differences in the functional connectivity gradients between the D-MCI and nD-MCI groups were significantly correlated with the distribution of 5-hydroxytryptamine receptor subtype 1A. Limitations: The small sample size affects the generalizability of the results, and the neurotransmitter template is based on healthy participants, not patients. Conclusion: Our results suggest that depressive symptoms cause abnormalities in the hierarchical segregation of functional brain organization among patients with MCI. Such abnormal changes may be related to the distribution of neurotransmitters. [ABSTRACT FROM AUTHOR]

NLX-112 (i.e., F13640, befiradol) exhibits nanomolar affinity, exceptional selectivity and full agonist efficacy at serotonin 5-HT1A receptors. NLX-112 shows efficacy in rat, marmoset and macaque models of L-DOPA induced dyskinesia (LID) in Parkinson's disease and has shown clinical efficacy in a Phase 2a proof-of-concept study for this indication. Here we investigated, in rats, its pharmacodynamic, pharmacokinetic (PK) and brain 5-HT1A receptor occupancy profiles, and its PK properties in the absence and presence of L-DOPA. Total and free NLX-112 exposure in plasma, CSF and striatal ECF was dose-proportional over the range tested (0.04, 0.16 and 0.63 mg/kg i.p.). NLX-112 exposure increased rapidly (Tmax 0.25–0.5h) and exhibited approximately threefold longer half-life in brain than in plasma (1.1 and 3.6h, respectively). At a pharmacologically relevant dose of 0.16 mg/kg i.p., previously shown to elicit anti-LID activity in parkinsonian rats, brain concentration of NLX-112 was 51–63 ng/g from 0.15 to 1h. In microPET imaging experiments, NLX-112 showed dose-dependent reduction of 18F-F13640 (i.e., 18F-NLX-112) brain 5-HT1A receptor labeling in cingulate cortex and striatum, regions associated with motor control and mood, with almost complete inhibition of labeling at the dose of 0.63 mg/kg i.p.. Co-administration of L-DOPA (6 mg/kg s.c., a dose used to elicit LID in parkinsonian rats) together with NLX-112 (0.16 mg/kg i.p.) did not modify PK parameters in rat plasma and brain of either NLX-112 or L-DOPA. Here, we demonstrate that NLX-112's profile is compatible with 'druggable' parameters for CNS indications, and the results provide measures of brain concentrations and 5-HT1A receptor binding parameters relevant to the anti-dyskinetic activity of the compound. [ABSTRACT FROM AUTHOR]

Background: Maintaining gut microbial homeostasis is crucial for human health, as imbalances in the gut microbiota (GM) can lead to various diseases, including metabolic syndrome (MS), exacerbated by the use of antipsychotic medications such as olanzapine (OLZ). Understanding the role of the GM in OLZ-induced MS could lead to new therapeutic strategies. This study used metagenomic analysis to explore the impact of OLZ on the GM composition and examined how probiotics can mitigate its adverse effects in a rat model. Changes in weight, blood pressure, and lipid levels, which are key parameters defining MS, were assessed. Additionally, this study investigated serotonin, dopamine, and histopathological changes to explore their possible link with the microbiota-gut-brain axis (MGBA). Results: OLZ had an antagonistic effect on serotonin and dopamine receptors, and it was consistently found to alter the composition of the GM, with an increase in the relative abundance (RA) of the Firmicutes/Bacteroidetes phyla ratio and TM7 genera, indicating that the anticommonsal action of OLZ affects appetite and energy expenditure, contributing to obesity, dyslipidemia and increased blood pressure, which are core components of MS. Hepatic steatosis and intestinal damage in OLZ-treated rat tissues further indicate its role in MS. Conversely, the administration of probiotics, either alone or in combination with OLZ, was found to mitigate these OLZ-induced symptoms of MS by altering the GM composition. These alterations included increases in the abundances of the taxa Bacteroidetes, Actinobacteria, Prevotella, Blautia, Bacteroides, Bacteroidales, and Ruminococcaceae and a decrease in Firmicute abundance. These changes helped maintain gut barrier integrity and modulated neurotransmitter levels, suggesting that probiotics can counteract the adverse metabolic effects of OLZ by restoring the GM balance. Moreover, this study highlights the modulation of the MGBA by OLZ as a potential mechanism through which probiotics modulate serotonin and dopamine levels, influencing metabolic health. Conclusion: These findings emphasise the significant impact of OLZ on the GM and its contribution to MS. These findings suggest that interventions targeting the GM, such as probiotics, could mitigate the metabolic side effects of OLZ. Future research should focus on developing integrative treatment approaches that consider the health of the gut microbiome in managing antipsychotic-induced adverse effects. [ABSTRACT FROM AUTHOR]

ackground and purpose: The serotonin receptor (5-HTR) family includes seven distinct members, with the serotonin seven receptor (5-HT7R) being the newest addition to this family. The 5-HT7R contributes to different physiological and pathological processes including glioblastoma multiforme (GBM). The standard treatment for GBM involves a combination of surgery, radiotherapy and chemotherapy. However, GBM tumors are highly diffuse and exhibit a significant risk of recurrence. As a result, the use of advanced monitoring techniques, such as nuclear medicine imaging, is essential. This study aims to develop an effective radiotracer for imaging 5-HT7R overexpression in GBM by utilizing a radiolabeled aryl piperazine derivative (99mTc(CO)3-[5]). Materials and methods: In this experimental study, compound 5 1-(3-nitropyridin-2-yl) piperazine was designed, synthesized, and characterized, then radiolabeled with fac-[99mTc(CO)3(H2O)3]+ to produce 99mTc(CO)3-[5]. Quality control tests, including high-حperformance liquid chromatography (HPLC) and thin-layer chromatography (TLC) were performed to determine the radiochemical purity. The specific binding study was performed using various cell lines, including U-87 MG, MCF-7, SKBR3, HT-29, and A549. The affinity of 99mTc(CO)3-[5] for 5-HT7R was evaluated using the U87-MG cell line and the maximum binding capacity (Bmax,) and dissociation constant (Kd) were calculated. Results: The initial radiochemical purity of 99mTc(CO)3-[5] was greater than 95% (RCP>95%). This radiotracer displayed moderate affinity for the U87-MG cell line’s 5-HT7R and lower affinity for MCF-7, SKBR3, HT-29, and A549 cell lines. The calculated Bmax, and Kd of the radioligands were 48±9.23nM and 2.94±0.09×105. Conclusion: Compound 5 can be quantitatively radiolabeled with fac-[99mTc(CO)3(H2O)3]+  resulting in the radiotracer (99mTc(CO)3-[5]). The initial radiochemical purity of this radiotracer is approximately 95%; however, its stability decreases over time. 99mTc(CO)3-[5] recognizes the  5-HT7R on the surface of U87-MG cells and binds to this receptor with moderate affinity. [ABSTRACT FROM AUTHOR]

[Display omitted] • Long-term blockade of A2AR and 5-HTRs may have therapeutic efficacy in SH-SY5Ys. • Short and long-term blockade of A2AR and 5-HTR have different effects on miR-27b-3p. • The long-term blockade of A2AR and 5-HTRs increase miR-27b-3p in SH-SY5Y cells. • MSX3 and SB269970 increase apoptosis and reduce proliferation in SH-SY5Ys. • MSX3 and SB269970 combinations may be promising therapeutic in NB patients. The first of our aims in this study was to investigate the effects of 5-HT2AR, 5-HT7R, and A2AR blockades on miR-27b-3p expression in the short and long-term in neuroblastoma cells. Our second aim was to reduce the expression of pERK and suppress proliferation by blocking the 5-HT2AR with ketanserin. Our third aim was to reduce the expression of pAKT and induce apoptosis by blocking the A2AR and 5-HT7R with MSX3 and SB269970. Thus, we aimed to investigate the therapeutic efficacy of ketanserin, MSX3 and SB269970, individually or in combination, on neuroblastoma cells. We found that short and long-term blockades of A2A, 5-HT2A, and 5-HT7 receptors had different effects on miR-27b-3p expression. Blockade of A2AR and 5-HT7R with MSX3 and SB269970 decreased miR-27b-3p expression in the short term while increasing it in the long term. Ketanserin increased miR-27b-3p expression in both the short and long term. When 5-HT2AR was blocked with ketanserin, no significant difference was observed in pERK expression and proliferation in the short term. In contrast, a substantial decrease in pERK expression and proliferation was detected in the long term. Our findings show that the MSX3 + SB269970 dual combination and ketanserin + MSX3 + SB269970 triple combination are especially critical in suppressing pAKT expression in the long term. These findings showed that pAKT protein expression induced apoptosis due to decreased in neuroblastoma cells. Our study provides the first evidence for the relationships between ketanserin/miR-27b-3p/pERK, MSX3/miR-27b-3p/pAKT, and SB269970/miR-27b-3p/pAKT in neuroblastoma cells. Ketanserin, MSX3, and SB269970 drug combinations may be promising therapeutic agents in neuroblastoma cells. [ABSTRACT FROM AUTHOR]

Early life adversity is a risk factor for psychopathology and is associated with epigenetic alterations in the 5-HT 1A receptor gene promoter. The 5-HT 1A receptor mediates neurotrophic effects, which could affect brain structure and function. We examined relationships between self-reported early childhood abuse, 5-HT 1A receptor promoter DNA methylation, and gray matter volume (GMV) in Major Depressive Disorder (MDD). Peripheral DNA methylation of 5-HT 1A receptor promoter CpG sites −681 and −1007 was assayed in 50 individuals with MDD, including 18 with a history of childhood abuse. T1-weighted structural magnetic resonance imaging (MRI) was performed. Voxel-based morphometry (VBM) was quantified in amygdala, hippocampus, insula, occipital lobe, orbitofrontal cortex, temporal lobe, parietal lobe, and at the voxel level. No relationship was observed between DNA methylation and history of childhood abuse. We observed regional heterogeneity comparing −681 CpG site methylation and GMV (p = 0.014), with a positive relationship to GMV in orbitofrontal cortex (p = 0.035). Childhood abuse history was associated with higher GMV considering all ROIs simultaneously (p < 0.01). In whole-brain analyses, childhood abuse history was positively correlated with GMV in multiple clusters, including insula and orbitofrontal cortex (p FWE = 0.005), and negatively in intracalcarine cortex (p FWE = 0.001). Small sample size, childhood trauma assessment instrument used, and assay of peripheral, rather than CNS, methylation. These cross-sectional findings support hypotheses of 5-HT 1A receptor-related neurotrophic effects, and of increased regional GMV as a potential regulatory mechanism in the setting of childhood abuse. Orbitofrontal cortex was uniquely associated with both childhood abuse history and 5-HT 1A receptor methylation. • Methylation positively correlated with orbitofrontal cortex gray matter volume • Supports neurotrophic effects of serotonin 1A receptors in major depressive disorder • Orbitofrontal cortex may be susceptible to stress-associated epigenetic changes • History of childhood abuse associated with higher gray matter volume • May be compensatory response after childhood adversity [ABSTRACT FROM AUTHOR]

Copyright of Basic & Clinical Andrology is the property of BioMed Central and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The potential of natural phytochemicals in mitigating depression has been supported by substantial evidence. This study evaluated a total of 88 natural phytochemicals with potential antidepressant properties by targeting serotonin (5-HT) receptors (5-HT1A, 5-HT4, and 5-HT7) using molecular docking, ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) analysis, internal coordinates normal mode analysis (NMA), molecular dynamics simulation (MDS), and free energy calculation. Five evaluated compounds (Genistein, Kaempferol, Daidzein, Peonidin, and glycitein) exhibited favorable pharmacokinetic properties and improved binding scores, indicating their potential as effective antidepressants. Redocking and superimposition analysis of 5-HT with cocrystal structures validated these findings. Furthermore, NMA, MDS, and free energy calculations confirmed the stability and deformability of the ligand-receptor complexes, suggesting that these phytochemicals can effectively interact with 5-HT receptors to modulate depressive symptoms. These powerful phytochemicals, abundantly found in soybeans, fruits, vegetables, and herbs, represent a promising avenue for developing natural treatments for depression. Further in vitro and in vivo studies are warranted to explore their efficacy in alleviating stress and depression through their interactions with 5-HT receptors. [ABSTRACT FROM AUTHOR]

AbstractConvenient multiday dosing of antiemetic regimens for the prevention of chemotherapy-induced nausea and vomiting (CINV) are needed in pediatric patients, who are more likely than adults to be treated with emetogenic chemotherapy over multiple consecutive days. Intravenous (IV) fosaprepitant is approved for the prevention of CINV in children aged 6 months and older. This open-label, single-arm study assessed the safety and tolerability of a 3-day fosaprepitant regimen (consecutive daily IV administration on days 1–3) plus a serotonin receptor antagonist with or without dexamethasone in pediatric patients (6 months to 17 years) receiving emetogenic chemotherapy. Study treatment was initiated at the start of a chemotherapy cycle (cycle 1); patients completing cycle 1 could participate in optional cycles 2 and 3. Primary endpoints included adverse events (AEs) and AE-related discontinuation during cycle 1.98/100. Patients completed cycle 1; 69 participated in optional cycles 2 and 3. The AE profile during cycle 1 was typical of cancer patients receiving emetogenic chemotherapy; 80/100 (80.0%) patients experienced ≥1 AE. AE rates were generally similar between patients aged 6 months to <2 years (11/15 patients [73.3%]), 2 to <6 years (22/30 [73.3%]), 6 to <12 years (24/25 [96.0%]), and 12–17 years (23/30 [76.7%]). Rates of drug-related AEs (4/100 [4.0%]) and AE-related discontinuations (2/100 [2.0%]) were low. Similar trends in safety outcomes were observed during cycles 2 and 3. No deaths were reported. The 3-day IV fosaprepitant regimen for the prevention of CINV was generally well tolerated in pediatric patients receiving emetogenic chemotherapy. [ABSTRACT FROM AUTHOR]

Bipolar disorder, a psychiatric condition identified by significant mood changes and a considerable genetic connection with schizophrenia, needs continuous and extensive management due to its common onset in adolescence and significant impact on psychosocial activities. While traditional mood stabilizers continue to be widely used, the pursuit of more effective treatments remains ongoing, with the current research targeting various stages of the disorder. This study provides a thorough examination of new pharmacological treatments for bipolar disorder, which are currently in Phase II and Phase III clinical trials up to 22 April 2024. A systematic search was conducted using the NIH National Library of Medicine, focusing on both repurposed and innovative drugs now in advanced stages of testing. The study identifies several promising therapeutic agents, including those intended for severe mood disorders with suicidal tendencies, and others aimed at treating mood-related neuroinflammation. Drugs that enhance dopamine stabilization and those that act on serotonin receptor activities were found notable. We also explored the strategic repurposing of already existing medications for broader therapeutic uses and looked into the potential of new formulations designed for the immediate management of symptoms. Our analysis highlights two main strategies for tackling bipolar disorder: finding new uses for existing drugs and developing new medications with unique actions. This approach shows continuous improvement in drug treatments, helping patients manage their condition better and addressing the complicated nature of bipolar disorder. [ABSTRACT FROM AUTHOR]

Assays of behavior in model organisms play an important role in genetic screens, drug testing, and the elucidation of gene-behavior relationships. We have developed an automated, high-throughput imaging and analysis method for assaying behaviors of the nematode Caenorhabditis elegans. We use high-resolution optical imaging to longitudinally record the behaviors of 96 animals at a time in multi-well plates, and computer vision software to quantify the animals' locomotor activity, behavioral states, and egg-laying events. To demonstrate the capabilities of our system, we used it to examine the role of serotonin in C. elegans behavior. We found that egg-laying events are preceded by a period of reduced locomotion, and that this decline in movement requires serotonin signaling. In addition, we identified novel roles of serotonin receptors SER-1 and SER-7 in regulating the effects of serotonin on egg laying across roaming, dwelling, and quiescent locomotor states. Our system will be useful for performing genetic or chemical screens for modulators of behavior. [ABSTRACT FROM AUTHOR]

Selective serotonin reuptake inhibitors (SSRIs) are prescribed in 15% of pregnancies in the United States for depression. Maternal use of SSRIs has been linked to an increased risk of congenital heart defects, but the exact mechanism of pathogenesis is unknown. SSRIs, including sertraline, are permeable to the placenta and can produce direct fetal exposure. Previously, we have shown decreased cardiomyocyte proliferation, left ventricle size, and cardiac expression of the serotonin receptor 5-HT2B in the offspring of mice exposed to the SSRI sertraline relative to the offspring of saline-exposed mice. Using a mouse model of in utero plus neonatal sertraline exposure, we observed lengthened peak-to-peak time of calcium oscillation (saline 784 ± 76 ms; sertraline 1,121 ± 130 ms, P < 0.001) and decreased expression of critical genes in calcium regulation. We also observed significant upregulation of specific microRNAs (miRNAs) that modulate serotonin signaling in neonatal cardiac tissues (Slc6a4: miR-223-5p, miR-92a-2-5p, miR-182-5p; Htr2a: miR-34b-5p, miR-182-5p; Htr2b: miR-223-5p, miR-92a-2-5p, miR-337-5p) (P < 0.05) with corresponding levels of the target mRNAs downregulated (Slc6a4 0.73 ± 0.05; Htr2a 0.67 ± 0.04; Htr2b 0.72 ± 0.03; all P < 0.01), resulting in decreased production of the cognate proteins. Adult mice at 10 wk showed altered cardiac parameters including decreased heart rates in males (saline 683 ± 8 vs. sertraline 666 ± 6 beats/min, P < 0.05) and ejection fraction in females (saline 83.9 ± 0.6% vs. sertraline 80.6 ± 1.1%, P < 0.05). These findings raise the question of whether sertraline exposure during development may increase the potential risk for cardiac disease when subjected to stress. NEW & NOTEWORTHY: Sertraline exposure during development decreased the expression of critical genes in calcium regulation and lengthened periods in calcium oscillation in neonatal cardiomyocytes. Sertraline upregulated specific microRNAs that may modulate serotonin signaling in neonatal cardiac tissues, which corresponded with a decrease in the levels of the corresponding target mRNAs. Although the echocardiograms in our adult mice suggest a mild phenotype associated with sertraline exposure, these upregulated microRNAs (miRNAs) have been linked to adult cardiovascular disease and heart failure. [ABSTRACT FROM AUTHOR]

Background/Objectives: Rodents provide a useful translational model of fear- and anxiety-related behaviors. Previously stressed animals exhibit physiological and behavioral stress responses that parallel those observed in anxious humans. Patients diagnosed with post-traumatic stress disorder (PTSD) present with a spectrum of debilitating anxiety symptoms that result from exposure to one or more traumatic events, with individuals exposed to early adverse experiences and women having increased vulnerability for diagnoses; however, the mechanisms of this increased vulnerability remain unknown. PTSD involves a complex network of highly interconnected brain regions, including the bed nucleus of the stria terminalis (BNST). Serotonin (5-HT) release into the BNST yields an increased expression of both fear and anxiety, specifically through 5-HT2C receptor signaling. The present experiment addressed whether 5-HT2C receptor signaling in the BNST is necessary for the acquisition of early-life stress (ELS)-induced enhancements in adult contextual fear learning. Methods: Rats received 0 or 15 footshocks on postnatal day 17, an established model of acute ELS (aELS) that yields enhanced adult fear learning. In adulthood, rats received bilateral infusions of a vehicle, a 5-HT2C receptor antagonist (RS-102221), or a 5-HT2C receptor agonist (MK-212) into the BNST 15 min prior to one-footshock contextual fear conditioning in a novel context. The next day, rats were returned to the fear-conditioning context to assess their fear memory (freezing). Results: Females demonstrated aELS-induced enhancement in contextual fear learning, while males did not. BNST infusions of RS-102221 reduced contextual fear conditioning, independent of aELS condition and sex. Infusions of MK-212 had no effect. Conclusions: Taken together, these data suggest that serotonergic signaling through 5-HT2C receptors in the BNST contributes to contextual fear conditioning, but not aELS-induced stress-enhanced fear learning (SEFL). [ABSTRACT FROM AUTHOR]

Background: Firstly, 5-hydroxytryptamine G-protein-coupled receptors (HTGPCRs) are a family of 13 genes associated with cancer progression. Nevertheless, a comprehensive understanding of HTGPCRs in cancer remains largely lacking. Method: We tested the gene expression levels and prognostic values for the HTGPCRs in relation to pan-cancer. A subsequent analysis examined the relationships among HTGPCR expression and clinical characteristics, immune subtypes, stemness scores, tumor microenvironments (TMEs), single-cell analyses, and drug sensitivity. Result: A significant difference in HTGPCR expression was found between normal tissues and tumors. HTR1D/2C expressed higher levels in breast invasive carcinoma (BRCA), colon adenocarcinoma, and liver hepatocellular carcinoma. HTGPCR gene expression was correlated with prognosis in many cancers. HTR1D/2C were associated with poorer overall survival for head and neck squamous cell carcinoma. In addition, HTGPCR expression correlated significantly with the stemness scores of RNA and DNA, TMB, and MSI, as well as stromal and immune scores of pan-cancer patients. Additionally, the expression of HTR2A/2B/7 was correlated significantly with immune cells and immune checkpoint genes in a variety of cancers, such as BRCA, brain lower-grade glioma, and lung adenocarcinoma. Immune regulation and TME were both regulated by HTGPCRs. Using single-cell analysis, we found that the gene set of HTGPCRs correlated with many cancer-related functional states in retinoblastoma. Moreover, drug sensitivity and HTR4 were significantly correlated. Furthermore, we validated results in breast cancer and found knockdown of HTR1D inhibited breast cancer cell growth and metastasis. Conclusion: As prognostic indicators, HTGPCRs hold considerable promise and offer insights into the therapeutic targets for malignancy. [ABSTRACT FROM AUTHOR]

Serotonin (5-HT), a versatile signaling molecule, plays a variety of roles in both neurotransmission and tissue regulation. The influence of serotonin on early development was first studied in marine invertebrate embryos and has since been documented in a variety of vertebrate species, including mammals. The present study investigates the expression and functional activity of serotonin components in mouse embryos, focusing on key receptors and transporters. Transcriptomic analyses revealed that mRNA transcripts related to serotonin show marked expression during the oogenesis and preimplantation stages. The results of the immunohistochemical studies show the presence of serotonin, the vesicular monoamine transporter VMAT2, and several membrane receptors (5-HT1B, 5-HT1D, 5-HT2B, 5-HT7) in the early stages of development. A functional analysis performed with the VMAT inhibitor reserpine revealed the crucial role of vesicular transport in the maintenance of serotonin signaling. The findings presented here support the hypothesis that serotonin plays a significant role in oocyte maturation and embryonic development, as well as in interblastomere interactions. [ABSTRACT FROM AUTHOR]

FKBP51, also known as FK506‐binding protein 51, is a molecular chaperone and scaffolding protein with significant roles in regulating hormone signaling and responding to stress. Genetic variants in FKBP5, which encodes FKBP51, have been implicated in a growing number of neuropsychiatric disorders, which has spurred efforts to target FKBP51 therapeutically. However, the molecular mechanisms and sub‐anatomical regions influenced by FKBP51 in these disorders are not fully understood. In this study, we aimed to examine the impact of Fkbp5 ablation using circadian phenotyping and molecular analyses. Our findings revealed that the lack of FKBP51 did not significantly alter circadian rhythms, as detected by wheel‐running activity, but did offer protection against stress‐mediated disruptions in rhythmicity in a sex‐dependent manner. Protein changes in Fkbp5 KO mice, as measured by histology and proteomics, revealed alterations in a brain region‐ and sex‐dependent manner. Notably, regardless of sex, aged Fkbp5 KOs showed elevated MYCBP2, FBXO45, and SPRYD3 levels, which are associated with neuronal‐cell adhesion and synaptic integrity. Additionally, pathways such as serotonin receptor signaling and S100 family signaling were differentially regulated in Fkbp5 KO mice. Weighted protein correlation network analysis identified protein networks linked with synaptic transmission and neuroinflammation. The information generated by this work can be used to better understand the molecular changes in the brain during aging and in the absence of Fkbp5, which has implications for the continued development of FKBP51‐focused therapeutics for stress‐related disorders. [ABSTRACT FROM AUTHOR]

Introduction: The Hong Kong Poison Information Centre (HKPIC) has been providing consultation services to healthcare professionals and collecting epidemiological data on poisoning in Hong Kong since 2005. Objective: To analyse and report the poisoning data from HKPIC in 2021. Methods: A retrospective review was conducted on all poisoning cases recorded in the Poison Information and Clinical Management System of HKPIC in 2021. Results: A total of 3973 poisoning cases were analysed. There was an increase of approximately 10% in total poisoning cases compared to 2020, bringing the total caseload back to the pre‐COVID era. Teenage (13–19 years) poisoning incidence continued to rise, reaching a recorded high of 16.2% of total poisoning cases. Notably, poisoning cases involving selective serotonin receptor inhibitors showed a significant increase, along with the use of the antidote cyproheptadine. The majority of these cases involved individuals under the age of 20 presenting with suspected self‐harm. Compared to 2020, the number of poisoning‐related deaths decreased by 25%, from 48 to 36 deaths in 2021, resulting in a case fatality rate of 1.0%. Additionally, six interesting cases and two poisoning clusters were discussed. Conclusions: The 16th annual report provides valuable information on poisoning patterns in Hong Kong during the second year of the COVID‐19 pandemic, highlighting significant changes compared to previous reports. [ABSTRACT FROM AUTHOR]

Objectives: Antidepressants used by patients with bipolar disorder have been associated with destabilization with an increase in mania, depression, and cycling. The most commonly proposed mechanism, that antidepressants 'overshoot' their antidepressant effect to create a manic or mixed state, is unlikely since antidepressants have actually been found to be ineffective in treating bipolar depression. Beginning with known bipolar‐specific pathophysiologic abnormalities provides the greatest likelihood of insight. Methods: PubMed was queried with 'bipolar', 'sodium', 'intracellular sodium', 'serotonin 3', '5HT3', '5‐hydroxytryptamine type 3 receptors', and 'antidepressant' either individually or in combination. Results: Pathologic mood states (both mania and depression) are associated with increased intracellular sodium (Na) concentrations that depolarize the resting membrane potential to increase cellular excitability (mania) or cause depolarization block (depression). Stimulation of the serotonin (5HT) receptors depolarizes the post‐synaptic neuron. Stimulation of 5HT3 may be of particular importance since it is coupled to a cation channel that directly depolarizes the membrane. These effects directly impact the physiology of patients with bipolar disorder to alter neuronal excitability in a fashion that worsens both mania and depression. Proposed Concept: The most consistently observed biological abnormality in individuals going through mania or bipolar depression involves a decline in Na pump activity, with consequent elevation of intracellular Na levels. Antidepressant treatment potentiates this, particularly by activation of 5HT3. This hypothesis can be tested by coadministering a 5HT3 antagonist (e.g., vortioxetine or ondansetron) to achieve blockade of that receptor while treating bipolar depression with a serotoninergic antidepressant. [ABSTRACT FROM AUTHOR]

The claustrum is a small but densely interconnected brain structure that is innervated by axons containing serotonin (5-HT), a neuromodulator that has been implicated in control of sleep and in the actions of psychedelic drugs. However, little is known about how 5-HT influences the claustrum. We have combined whole-cell patch-clamp measurements of ionic currents, flash photolysis, and receptor pharmacology to characterize the 5-HT responses of individual claustral projection neurons (PNs) in mouse brain slices. Serotonin application elicited a long-lasting outward current in claustral PNs. This current was due to an increase in membrane permeability to K+ ions and was mediated mainly by the type 1A 5-HT receptor (5-HTR-1A). The 5-HT-induced K+ current hyperpolarized, and thereby inhibited, the PNs by reducing action potential firing. Focal uncaging of 5-HT revealed that inhibitory 5-HTR-1As were located at both the soma and dendrites of PNs. We conclude that 5-HT creates a net inhibition in the claustrum, an action that should decrease claustrum sensitivity to excitatory input from other brain areas and thereby contribute to 5-HT action in the brain. [ABSTRACT FROM AUTHOR]

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Long regarded as illicit substances with no clinical value, N-dimethylated tryptamines—such as N,N-dimethyltryptamine, 5-methoxy-N,N-dimethyltryptamine, and bufotenine—have been found to produce naturally in a wide variety of species, including humans. Known for their psychoactive effects through serotonin receptors (5-HTRs), N-dimethylated tryptamines are currently being reinvestigated clinically for their long-term benefits in mental disorders. Endogenous tryptamine is methylated by indolethylamine-N-methyltransferase (INMT), which can then serve as an agonist to pro-survival pathways, such as sigma non-opioid intracellular receptor 1 (SIGMAR1) signaling. Fibrogenic diseases, like metabolic-associated fatty liver disease (MAFLD), steatohepatitis (MASH), and chronic kidney disease (CKD) have shown changes in INMT and SIGMAR1 activity in the progression of disease pathogenesis. At the cellular level, endothelial cells and fibroblasts have been found to express INMT in various tissues; however, little is known about tryptamines in endothelial injury and fibrosis. In this review, I will give an overview of the biochemistry, molecular biology, and current evidence of INMT's role in hepatic fibrogenesis. I will also discuss current pre-clinical and clinical findings of N-methylated tryptamines and highlight new and upcoming therapeutic strategies that may be adapted for mitigating fibrogenic diseases. Finally, I will mention recent findings for mutualistic gut bacteria influencing endogenous tryptamine signaling and metabolism. [ABSTRACT FROM AUTHOR]

Objective: To investigate the hemostatic effect of modified Sijunzi Granules (MSG) in primary immune thrombocytopenia (ITP) zebrafish model and explore the potential mechanism. Methods: AB strain wild type zebrafish were treated with simvastatin (6 µmol/L) for 24 h to establish the hemorrhage model (model control group). The zebrafish were treated with MSG at different doses (55.6, 167, and 500 µg/mL), respectively. The hemostatic effect was assessed by examining the intestinal bleeding and hemostatic rate. 5-Hydroxytryptamine (5-HT) content was determined using enzyme-linked immunosorbent assay (ELISA) assay. The expressions of 5-HT2aR, 5-HT2bR, and SERT genes were detected by quantitative real-time polymerase chain reaction(PCR). The protein expressions of protein kinase B (Akt), p-Akt, extracellular regulated protein kinases (Erk), and p-Erk were examined using Western blot analysis. Results: The intestinal bleeding rate was 37%, 40%, and 80% in the 55.6, 167, and 500 µg/mL dose of MSG, respectively, in which 55.6 and 167 µg/mL MSG dose groups were associated with significantly decreased intestinal bleeding rate when compared with the model control group (70%, P<0.05). Significantly higher hemostatic rates were also observed in the 55.6 (54%) and 167 (52%) µg/mL MSG dose groups (P<0.05). MSG increased the 5-HT content and mRNA expression levels of 5-HT2aR, 5-HT2bR, and SERT (P<0.05). In addition, caspase3/7 activity was inhibited (P<0.05). Significant increase in p-Akt and p-Erk was also detected after treatment with MSG (P<0.05). Conclusions: MSG could reduce the incidence and severity of intestinal bleeding in zebrafish by activating MAPK/Erk and PI3K/Akt signal pathways through regulating the levels of 5-HT and its receptors, which may provide evidence for the treatment of ITP. [ABSTRACT FROM AUTHOR]

BACKGROUND: Previous studies found that Semen Ziziphi Spinosae extract prolongs slow-wave sleep and promotes growth hormone secretion in mice by increasing the expression of brain tissue serotonin 1A receptor (5-HT1AR), which binds to serotonin, thus leading to bone growth. Serotonin 1A receptor acts as a protein, and its expression abundance is regulated by miRNAs. The authors hypothesized that Semen Ziziphi Spinosae extract may regulate the expression of 5-HT1AR through miRNAs and thus exert drug effects. OBJECTIVE: To observe the effect of Semen Ziziphi Spinosae extract on bone growth by regulating the miR-7b-3p/5-HT1AR pathway in mouse brain tissue. METHODS: (1) Kunming mice were divided into a normal control group, a drug administration group (gavage administration of Semen Ziziphi Spinosae extract 0.320 mg/g), a positive control group (gavage administration of jujuboside 0.013 mg/g), a Semen Ziziphi Spinosae extract+5-HT1AR selective inhibitor group (8 μg of P-MPPF, a 5-HTIAR selective inhibitor, was injected into the lateral ventricle every day for the last 3 days during the gavage administration of Semen Ziziphi Spinosae extract). After 25 days, the effects of Semen Ziziphi Spinosae extract on bone growth, serum growth hormone level and brain 5-HT1AR expression were observed. (2) Then the chip method was used to observe differentially expressed miRNAs in the brain tissues of growing mice and ordinary mice. PCR validation and dual luciferase reporter gene assay confirmed the regulatory relationship between the screened Mir-7B-3p and 5-HT1AR. (3) Mouse cerebral cortical cells were cultured and identified in vitro, and the effect of Semen Ziziphi Spinosae extract on 5-HT1AR expression in cerebral cortical cells was observed using western blot. (4) Kunming mice were divided into a normal control group, a medication group, a miR-7b-3p inhibitor group, a medication +5-HT1AR inhibitor group, and a positive control group. The expression of 5-HT1AR in brain tissues of mice and the binding activity of 5-HT and 5-HT1AR were observed. (5) Sprague-Dawley rats were divided into a normal control group, a medication group, a miR-7b-3p inhibitor group, a medication+miR-7b-3p mimics group and a positive control group. Changes in slow wave sleep in mice were observed. RESULTS AND CONCLUSION: (1) Semen Ziziphi Spinosae extract could promote the growth of body length and tibia, growth hormone secretion, and brain tissue 5-HT1AR level in mice. (2) The number of differentially expressed miRNAs screened by GeneChip was 16, of which 13 were up-regulated and 3 were down-regulated. Bioinformatics results predicted that down-regulation of miR-7b-3p could regulate 5-HT1AR expression, and dual-luciferase reporter gene experiments confirmed a direct regulatory relationship between the two. (3) Semen Ziziphi Spinosae extract and silencing of miR-7b-3p expression in cerebral cortical cells could cause high expression of 5-HT1AR. After silencing of miR-7b-3p, 5-HT1AR expression, binding activity of serotonin and 5-HT1AR and growth hormone secretion in mouse brain tissue were all elevated. After overexpression of miR-7b-3p, 5-HT1AR expression, binding activity of serotonin and 5-HT1AR and growth hormone secretion were all reduced. Accordingly, the slow-wave sleep period in mice was also prolonged or shortened. To conclude, Semen Ziziphi Spinosae extract can reduce the level of miR-7b-3p and increase the expression of 5-HT1AR in brain tissue to prolong slow wave sleep and promote the secretion of growth hormone, thereby playing a postive effect on bone growth. These findings provide a scientific basis for the use of Semen Ziziphi Spinosae extract as a potential measure to promote bone growth. [ABSTRACT FROM AUTHOR]

Background: Homo- and heteromerization of G protein-coupled receptors (GPCRs) plays an important role in the regulation of receptor functions. Recently, we demonstrated an interaction between the serotonin receptor 7 (5-HT7R), a class A GPCR, and the cell adhesion molecule CD44. However, the functional consequences of this interaction on 5-HT7R-mediated signaling remained enigmatic. Methods: Using a quantitative FRET (Förster resonance energy transfer) approach, we determined the affinities for the formation of homo- and heteromeric complexes of 5-HT7R and CD44. The impact of heteromerization on 5-HT7R-mediated cAMP signaling was assessed using a cAMP responsive luciferase assay and a FRET-based cAMP biosensor under basal conditions as well as upon pharmacological modulation of the 5-HT7R and/or CD44 with specific ligands. We also investigated receptor-mediated G protein activation using BRET (bioluminescence resonance energy transfer)-based biosensors in both, homo- and heteromeric conditions. Finally, we analyzed expression profiles for 5-HT7R and CD44 in the brain during development. Results: We found that homo- and heteromerization of the 5-HT7R and CD44 occur at similar extent. Functionally, heteromerization increased 5-HT7R-mediated cAMP production under basal conditions. In contrast, agonist-mediated cAMP production was decreased in the presence of CD44. Mechanistically, this might be explained by increased Gαs and decreased GαoB activation by 5-HT7R/CD44 heteromers. Unexpectedly, treatment of the heteromeric complex with the CD44 ligand hyaluronic acid boosted constitutive 5-HT7R-mediated cAMP signaling and receptor-mediated transcription, suggesting the existence of a transactivation mechanism. Conclusions: Interaction with the hyaluronan receptor CD44 modulates both the constitutive activity of 5-HT7R as well as its agonist-mediated signaling. Heteromerization also results in the transactivation of 5-HT7R-mediated signaling via CD44 ligand. [ABSTRACT FROM AUTHOR]

Somatic symptom disorder (SSD) is characterized by persistent physical symptoms that cause significant distress and functional impairment. Despite the widespread use of serotonin reuptake inhibitors (SRIs) in treating SSD, some patients experience insufficient response, necessitating alternative therapeutic approaches. We report two cases of SSD that demonstrated significant improvement with vortioxetine, a novel antidepressant with multimodal serotonergic receptor activity. In Case 1, an 88-year-old female with throat discomfort and cough experienced an insufficient response to an SRI. After switching to vortioxetine, she achieved significant symptom relief within 10 days, with no relapse observed over the following four months. In Case 2, a 29-year-old female presenting with widespread somatic pain and palpitations, unresponsive to analgesics, achieved symptom resolution within two weeks with the initial use of vortioxetine. The therapeutic effects of vortioxetine were rapid and well-tolerated. These cases highlight the potential of vortioxetine for treating SSD, particularly in cases of insufficient response to SRIs, and suggest a possible overlap between SSD and obsessive-compulsive spectrum disorders through its action on serotonergic pathways. [ABSTRACT FROM AUTHOR]

There has been a recent renewal of interest in the therapeutic potential of serotonergic psychedelics. Here, we uncover the essential role of ventral hippocampus (vHpc) GABAergic interneurons in the anxiolytic effect evoked by the serotonergic psychedelic 2,5-dimethoxy-4-iodoamphetamine (DOI). Integrating anatomical, pharmacological, and genetic approaches, we show that 5-HT 2A receptors in the CA1/subiculum (CA1/sub) region of the vHpc are required for the anxiolytic action of DOI. In vivo electrophysiology and opto-tagging experiments indicate that DOI enhances the firing rate of hippocampal fast-spiking parvalbumin (PV)-positive interneurons, most of which express the 5-HT 2A receptors. Restoration of 5-HT 2A receptors in PV-positive interneurons in a loss-of-function background reinstated the anxiolytic responses evoked by DOI in the vHpc CA1/sub region. Collectively, our results localize the acute anxiolytic action of a serotonergic psychedelic to 5-HT 2A receptors in the ventral hippocampus and specifically identify PV-positive fast-spiking cells as a cellular trigger for the psychedelic-induced relief of anxiety-like behavior. [Display omitted] • The psychedelic DOI evokes acute anxiolytic effects in rodent models via the vHpc • DOI enhances the firing rate of a fast-spiking neuron subpopulation in the vHpc • Opto-tagging reveals that DOI recruits PV-positive inhibitory interneurons in the vHpc • Agonism of 5-HT 2A receptors on PV neurons in the vHpc mediate evoked anxiolysis Tiwari et al. identify the discrete neural circuit underlying the acute anxiolytic actions of the serotonergic psychedelic DOI, demonstrating that DOI recruits 5-HT 2A receptors on parvalbumin-positive, fast-spiking inhibitory interneurons in the ventral hippocampal CA1/subiculum region to drive its acute anxiolytic effects. [ABSTRACT FROM AUTHOR]

Honey bee, Apis mellifera L. (Hymenoptera: Apidae), colonies and individuals respond variably to disturbances. The response depends on perception and interpretation of stimuli requiring both neural modulation and use of energy. In this study, we examined the role of neural modulation and brain metabolism in constitutive and experience‐dependent differences in defensive response. For constitutive differences, we compared brain gene expression in bees from gentle and defensive colonies identified in a standard colony‐level assay. For experience‐dependent changes in defensiveness response, we compared brain gene expression in control bees and bees that responded by sting extension to electric shock in a standardized individual behavioral assay. In both experiments, for neuromodulation, we examined membrane receptor genes for the biogenic amines dopamine (DopR2), octopamine (OA1), and serotonin (5HT2a), as well the gene for the enzyme responsible for serotonin synthesis (THR). For neural metabolism, we examined the expression of two Oxidative Phosphorylation Pathway “OXPHOS” genes (ND51 and ND20‐LIKE). Bees collected from defensive colonies had a significantly lower expression of amine receptor, synthesis gene, and OXPHOS genes. However, bees responding to noxious stimuli (i.e., electric shock) showed greater gene expression for both OXPHOS and neuromodulation genes, except for 5HT2a. We discuss the intriguing intersection of neuromodulation and neural metabolism in defensive response both for constitutive differences, and contrasting experience dependent or adaptive differences. [ABSTRACT FROM AUTHOR]

The 5-hydroxytryptamine (5-HT) and dopamine (DA) receptors have emerged as significant targets for therapeutic intervention in psychiatric disorders. Currently, the efficacy of psychiatric drugs is limited by challenges in achieving desired outcomes, the occurrence of adverse effects, dependence, and withdrawal reactions. Consequently, there is a pressing need for the development of safe and effective therapeutic agents for psychiatric disorders. To explore the potential effects of natural product extracts as therapeutic agents for psychiatric disorders, 73 active ingredients from natural medicine extracts were screened to identify potential inhibitors of the serotonin 2A receptor (5-HT2AR) and dopamine D2 receptor (DRD2) using computerized virtual molecular docking. The most effective inhibitor of 5-HT2AR and DRD2 among these natural extracts was then evaluated for its drug-like properties using ADMET analysis, and its mechanisms of antagonism on DRD2 and 5-HT2AR were studied through molecular dynamics simulation. Risperidone was used as a positive control drug. The results showed that ruscogenin (RUS) was the most effective inhibitor of 5-HT2AR and DRD2, possessing favorable drug-like properties (most values of ADMET analysis were within the optimal range). When compared to risperidone, RUS exhibited more stable root mean square deviation (RMSD) plots, lower root mean square fluctuation (RMSF) values from residues 50 to 260, stronger hydrogen bonding interactions, higher compactness, a smaller solvent-accessible surface area (SASA) value, and lower binding free energy (-43.81 kcal/mol vs. -35.68 kcal/mol). RUS also demonstrated inhibitory effects on DRD2, as indicated by stable RMSD plots, low RMSF values from residues 50 to 250, strong hydrogen bonding interactions, high compactness, a small SASA value, and low binding free energy (-35.00 kcal/mol). Consequently, this research suggests that RUS, a natural pharmaceutical extract, is a promising candidate for further validation through clinical studies, representing a potential development of a therapeutic agent targeting psychiatric disorders. [ABSTRACT FROM AUTHOR]

Psychedelics hold promise as alternate treatments for neuropsychiatric disorders. However, the neural mechanisms by which they drive adaptive behavioral effects remain unclear. We isolated the specific neurons modulated by a psychedelic to determine their role in driving behavior. Using a light- and calcium-dependent activity integrator, we genetically tagged psychedelic-responsive neurons in the medial prefrontal cortex (mPFC) of mice. Single-nucleus RNA sequencing revealed that the psychedelic drove network-level activation of multiple cell types beyond just those expressing 5-hydroxytryptamine 2A receptors. We labeled psychedelic-responsive mPFC neurons with an excitatory channelrhodopsin to enable their targeted manipulation. We found that reactivation of these cells recapitulated the anxiolytic effects of the psychedelic without driving its hallucinogenic-like effects. These findings reveal essential insight into the cell-type-specific mechanisms underlying psychedelic-induced behavioral states. [ABSTRACT FROM AUTHOR]

Substance use disorder (SUD) is a chronic condition, with maintained abuse of a substance leading to physiological and psychological alterations and often changes in cognitive and social behaviours. Current therapies include psychotherapy coupled with medication; however, high relapse rates reveal the shortcomings of these therapies. The signalling, expression profile, and neurological function of the serotonin 2C receptor (5‐HT2C receptor) make it a candidate of interest for the treatment of SUD. Recently, psychedelics, which broadly act at 5‐HT2 receptors, have indicated potential for the treatment of SUD, implicating the 5‐HT2C receptor. The modern psychedelic movement has rekindled interest in the 5‐HT2C receptor, resulting in many new studies, especially structural analyses. This review explores the structural, molecular and cellular mechanisms governing 5‐HT2C receptor function in the context of SUD. This provides the basis of the preclinical and clinical evidence for their role in SUD and highlights the potential for future exploration. [ABSTRACT FROM AUTHOR]

Simple Summary: Supernumerary teats (SNTs) refer to developmental anomalies that occur during the embryonic period and are commonly found around the mammary line. We performed a genome-wide selective sweep analysis on 37 goats using copy number variants, and identified multiple genes involved in embryonic mammary gland development and the biological process of breast cancer. Our findings can be used as a reference for the further investigation of SNT phenotypic candidate genes. Supernumerary teats (SNTs) or nipples often emerge around the mammary line. This study performed a genome-wide selective sweep analysis (GWS) at the copy number variant (CNV) level using two selected signal calculation methods (VST and FST) to identify candidate genes associated with SNTs in goats. A total of 12,310 CNVs were identified from 37 animals and 123 CNVs, with the top 1% VST values including 84 candidate genes (CDGs). Of these CDGs, minichromosome maintenance complex component 3, ectodysplasin A receptor associated via death domain, and cullin 5 demonstrated functions closely related to mammary gland development. In addition, 123 CNVs with the top 1% FST values were annotated to 97 CDGs. 5-Hydroxytryptamine receptor 2A, CCAAT/enhancer-binding protein alpha, and the polymeric immunoglobulin receptor affect colostrum secretion through multiple signaling pathways. Two genes, namely, RNA-binding motif protein 46 and β-1,3-galactosyltransferase 5, showed a close relation to mammary gland development. Six CNVs were identified and annotated to five genes by intersecting the top 1% of candidate CNVs with both parameters. These genes include LOC102185621, LOC102190481, and UDP-glucose pyrophosphorylase 2, which potentially affect the occurrence of BC through multiple biological processes, such as cell detoxification, glycogen synthesis, and phospholipid metabolism. In conclusion, we discovered numerous genes related to mammary development and breast cancer (BC) through a GWS, which suggests the mechanism of SNTs in goats and a certain association between mammary cancer and SNTs. [ABSTRACT FROM AUTHOR]

Plants possess a complex signaling system that enables them to sense and adapt to various environmental stressors, including abiotic factors like extreme temperatures, drought, salinity, and toxic heavy metals. While the roles of hormones and signaling molecules in plant stress responses are well established, the involvement of neurotransmitters—traditionally linked to animal nervous systems—in plant stress physiology is a relatively underexplored area. Recent findings indicate that neurotransmitters such as gamma-aminobutyric acid, glutamate, serotonin, and dopamine play crucial roles in several physiological processes within plants. They regulate ion channels, adjust stomatal movements, modulate the production of reactive oxygen species, and influence gene expression. Evidence suggests that these neurotransmitters enhance antioxidant defense mechanisms and regulate stress-responsive pathways vital for plant stress tolerance. Additionally, under stressful conditions, neurotransmitters have been shown to impact plant growth, development, and reproductive activities. This review aims to illuminate the emerging understanding of neurotransmitters as key biomediators in plant responses to abiotic stress. [ABSTRACT FROM AUTHOR]

Aims Methods and results Conclusions Oesophageal adenocarcinoma (EAC) is a glandular or mucinous epithelial malignancy that can show immunohistochemical evidence of neuroendocrine differentiation (NED) and express the hormone serotonin. The objective of this study was to correlate the presence of NED and serotonin with clinicopathological characteristics and patient outcome after neoadjuvant chemoradiation.A retrospective cohort of patients treated between 2002 and 2021 was established and included 218 oesophagectomy specimens with residual tumour. Representative full‐face sections of tumour were stained for synaptophysin, chromogranin‐A and serotonin by immunohistochemistry, and staining results were correlated with disease‐free survival (DFS) and overall survival (OS). In total, 129 (59%) tumours showed evidence of NED, defined as immunohistochemical expression of synaptophysin or chromogranin‐A, while 40 (18%) showed evidence of NED and expressed serotonin. Patients with neuroendocrine‐positive tumours had significantly shorter median OS compared to those with neuroendocrine‐negative tumours (22.5 versus 48.8 months, P = 0.006), but similar median DFS (13.3 versus 17.8 months, P = 0.34). Using Cox regression, the association between NED and OS was significant in univariate [hazard ratio (HR) = 1.68, 95% confidence interval (CI) = 1.16–2.45] and multivariate (HR = 1.65, 95% CI = 1.08–2.52) analysis. Patients with serotonin‐expressing tumours had similar median OS (21.7 versus 25.9 months, P = 0.24) and DFS (7.3 versus 15.6 months, P = 0.12) compared to those with NED but lacking serotonin. Using Cox regression, serotonin expression was associated with reduced OS in univariate (HR = 1.62, 95% CI = 1.06–2.47) but not multivariate (HR = 1.03, 95% CI = 0.64–1.65) analysis.Our findings support NED as independent predictor of OS in EAC after neoadjuvant chemoradiation. While a subset of tumours with NED expressed serotonin, this did not provide additional prognostic information. [ABSTRACT FROM AUTHOR]

Background: Chemotherapy-induced nausea and vomiting (CINV) are common side effects, classified according to timing and severity. Conventional agents such as dexamethasone are effective but have various side effects. For moderately emetogenic chemotherapy, dexamethasone-sparing antiemetic therapies have been developed to minimize these side effects. This systematic review evaluated the efficacy and safety of dexamethasone-sparing antiemetic therapy for highly emetogenic chemotherapy (HEC). Methods: We performed a thorough literature search for studies related to dexamethasone-sparing antiemetic therapy with neurokinin-1 antagonists (NK1RA) for HEC using the PubMed, Cochrane Library, and Ichushi-Web databases. A qualitative analysis of the combined data was performed and risk differences with confidence intervals were calculated. Results: Two reviewers independently assessed the 425 records and 12 full-text articles were evaluated for eligibility. Two studies were included in the qualitative and meta-analyses. These studies included anthracycline-cyclophosphamide (AC) regimens and cisplatin-based regimens, with palonosetron as the serotonin receptor antagonist. In the two studies, no difference was found in the prevention of vomiting (delayed complete response). However, non-inferiority was not demonstrated in the subgroup that received cisplatin-containing regimens. Delayed complete control showed different results for nausea prevention; however, there was no significant difference in the meta-analysis. Only one report has shown non-inferiority for delayed total control. Although the strength of evidence for individual outcomes varied, there was no difference in the duration of dexamethasone administration. Conclusions: This systematic review and meta-analysis revealed that dexamethasone-sparing antiemetic therapy with NK1RA and palonosetron can be used to prevent CINV in HEC, limited to AC combination therapy. [ABSTRACT FROM AUTHOR]