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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]

[Display omitted] • MOE ameliorates depressive behaviors by modulating the microbiota-gut-brain axis. • MOE restored sucrose preference in depressed mice. • MOE reversed CUMS-induced 5-HT reduction in the prefrontal cortex and hippocampus. • MOE increased gut lactobacilli in stressed mice. The gut microbiota has been posited as a target for the treatment of major depressive disorder. Herein, we investigated the effect of the hydroethanolic leaf extract of Mallotus oppositifolius (MOE) on the gut microbiota of mice and how this contributes to its known antidepressant-like effect. A 6-week chronic unpredictable mild stress (CUMS) procedure was employed in 7 groups of mice to induce depression. From the third week, oral MOE treatments (10, 30, 100 mg/kg) and two reference drugs, fluoxetine (12 mg/kg) and minocycline (40 mg/kg), known to affect the gut microbiota, were administered. The sixth and seventh groups were the vehicle stressed (VEH-S) and non-stressed groups (VEH-NS). Changes in depressive-like behaviors were assessed using sucrose preference test while the forced swimming test (FST) was used to assess sustained antidepressant-effect after treatment discontinuation. Moreover, changes in prefrontal cortex (PFC) and hippocampal serotonin (5-HT) levels were evaluated using enzyme-linked immunosorbent assay (ELISA). The effect of treatment on the profile of the gut microbiota of the groups was elucidated using 16S rRNA Oxford Nanopore sequencing. MOE and reference drugs reversed the depression-associated reduction in sucrose preference when compared to VEH-S. MOE (with peak effect at 30 mg/kg) reduced immobility while increasing swimming and climbing behaviors. MOE reversed CUMS-induced reduction of 5-HT concentration in PFC and hippocampus. The behavioral effects of MOE were associated with shifts in the gut microbiota of CUMS-exposed mice. The study has provided seminal evidence that MOE ameliorates CUMS-induced depressive symptoms by modulating gut microbiota and increasing brain 5-HT levels. [ABSTRACT FROM AUTHOR]

Background and Purpose Experimental Approach Key Results Conclusions and Implications In male rats, the serotonergic system modulates sympathetic outflow at vascular levels, causing sympatho‐inhibition and sympatho‐excitation, mainly via 5‐HT1D/1A and 5‐HT3 receptors, respectively. However, sex influence on vascular serotonergic regulation has not yet been elucidated. This study aimed to analyse the 5‐HT sympatho‐modulatory role in female rats, characterising the 5‐HT receptors involved.Female Wistar (14‐ to 16‐week‐old) rats were prepared for sympathetic stimulation. Mean blood pressure (MBP) and heart rate (HR) were continuously measured. Vasopressor responses were obtained by electrical stimulation of the sympathetic outflow (0.1–5 Hz) or i.v. noradrenaline (0.01–0.5 μg·kg−1). 5‐HT‐related drug effects on adrenergic system were determined. Age‐matched male rats were used as control.Basal MBP in females was lower than in male rats, whereas electrical‐induced increases in MBP were similar. In females, 5‐HT exerted a dose‐dependent inhibition on the sympathetic‐evoked vasoconstrictions, that was reproduced by some agonists; 5‐CT (5‐HT1/5/7) and L‐694,247 (5‐HT1D), whereas the selective 5‐HT2A/2B/2C (α‐methyl‐5‐HT) and 5‐HT3 agonist (1‐PBG) increased the electrically‐produced vasopressor responses. None of the other drugs tested (targeting 5‐HT1A/1B/1F, 5‐HT2B/2C, 5‐HT4, 5‐HT5A or 5‐HT7) modified these vasoconstrictions. Only 1‐PBG (5‐HT3) modified the vasoconstrictions induced by exogenous noradrenaline.In female rats, vascular serotonergic sympatholytic effects are due to prejunctional 5‐HT1D receptor activation, whereas pre and/or postjunctional 5‐HT3 and prejunctional 5‐HT2A receptor activation is involved in the potentiating effect of vascular sympathetic neurotransmission. These findings may open novel sex‐differential therapeutic strategies for treating cardiovascular conditions. [ABSTRACT FROM AUTHOR]

Background: Current treatment of major depressive disorder is facing challenges, including a low remission rate, late onset of efficacy, and worsening severity due to comorbid symptoms such as psychosis and cognitive dysfunction. Serotonin (5-HT) neurotransmission is involved in a wide variety of psychiatric diseases and its potential as a drug target continues to attract attention. Objectives: The present study elucidates the effects of a novel 5-HT modulator, DSP-6745, on depression and its comorbid symptoms. Results: In vitro radioligand binding and functional assays showed that DSP-6745 is a potent inhibitor of 5-HT transporter and 5-HT2A, 5-HT2C, and 5-HT7 receptors. In vivo, DSP-6745 (6.4 and 19.1 mg/kg as free base, p.o.) increased the release of not only 5-HT, norepinephrine, and dopamine, but also glutamate in the medial prefrontal cortex. The results of in vivo mouse phenotypic screening by SmartCube® suggested that DSP-6745 has a behavioral signature combined with antidepressant-, anxiolytic-, and antipsychotic-like signals. A single oral dose of DSP-6745 (6.4 and 19.1 mg/kg) showed rapid antidepressant-like efficacy in the rat forced swim test, even at 24 h post-dosing, and anxiolytic activity in the rat social interaction test. Moreover, DSP-6745 (12.7 mg/kg, p.o.) led to an improvement in the apomorphine-induced prepulse inhibition deficit in rats. In the marmoset object retrieval with detour task, which is used to assess cognitive functions such as attention and behavioral inhibition, DSP-6745 (7.8 mg/kg, p.o.) enhanced cognition. Conclusions: These data suggest that DSP-6745 is a multimodal 5-HT receptor antagonist and a 5-HT transporter inhibitor and has the potential to be a rapid acting antidepressant with efficacies in mitigating the comorbid symptoms of depression. [ABSTRACT FROM AUTHOR]

Background: The traditional herbal medicine Atractylodes macrocephala Koidz. (A. macrocephala) is commonly utilized for alleviating symptoms associated with spleen deficiency, abdominal distension, diarrhea, and constipation. These pharmacological effects are attributed to a variety of active constituents. However, the specific bioactive compounds responsible for promoting defecation and gastrointestinal transit in A. macrocephala remain unidentified. Methods: The primary polysaccharide characteristics of PAMK was elucidated by HPLC, FT‐IR, and HGPGC. Efficacy of PAMK (0.07, 0.14, and 0.28 mg/g) on mice was evaluated in a spleen deficiency constipation mouse model by analyzing stool parameters, constipation‐related physiological indexes, and SCFAs. The expression levels of 5‐HT3R, 5‐HT4R, and related receptor genes were examined by RT‐qPCR, and neurotransmitters were examined using ELISA. Finally, the diversity of gut microbiota was analyzed with 16S rDNA sequencing. Key Results: The results showed that PAMK significantly reduced the gastrointestinal transport time and increased the number of fecal pellets and fecal water content in spleen deficiency constipation model mice. PAMK kept the balance of 5‐HT, SCFAs, TPH‐1, SERT, CgA, and neurotransmitter levels (VIP, SP, MTL) in mice colon. In addition, PAMK could regulate the abundance of gut microbiota such as Alistopes, Bacteroides, and Odoribacter in spleen deficiency constipation model mice gut. Conclusions and Inferences: It can be concluded that PAMK effectively ameliorated the symptoms of spleen deficiency constipation in mice by modulating the expression of 5‐HT and its associated receptors. The underlying mechanism was elucidated, providing a solid theoretical foundation for the therapeutic application of A. macrocephala in treating spleen deficiency constipation and offering potential for developing novel approaches to address this condition. [ABSTRACT FROM AUTHOR]

Purpose: Our study aimed to explore the efficacy of Bifidobacterium breve 207-1 on specific neurotransmitters and hormones and the ability to regulate lifestyle behaviors in healthy adults. Methods: In total, 120 healthy adults with high mental stress, overweight, insomnia, and constipation were randomly assigned to receive low-dose B. breve 207-1 (LD, n = 40), high-dose B. breve 207-1 (HD, n = 40), or placebo (n = 40) for 28 days. Fecal and blood samples were collected and questionnaires were answered before and after the trial. Neurotransmitters and serum hormones were detected using enzyme-linked immunosorbent assay. The gut microbiota composition was assessed using 16 S rRNA sequencing. Short–chain fatty acids (SCFAs) concentrations were determined via gas chromatography–mass spectrometry (GC–MS). Results: The primary outcome of our study was changes in mental wellness, including neurotransmitters, the hypothalamic–pituitary–adrena (HPA) axis hormones, and the psychological scales. The results showed that γ-aminobutyric acid (GABA) increased significantly and the HPA axis hormones were suppressed overall in the probiotic groups while 5-hydroxytryptamine (5-HT) did not change significantly. However, there was no significant change in mood scale scores. The secondary outcome focused on the ability of 207-1 to regulate the body and lifestyle of healthy adults (e.g., sleep, diet, exercise, etc.). The PSQI scores in the probiotics groups significantly decreased, indicating improved sleep quality. Meanwhile, the probiotic groups had a slight increase in exercise consumption while dietary intake stabilized. By physical examination, the participants showed weight loss although no statistically significant difference was observed between the groups. Then, validated by gut microbiota, changes in the gut microbiota were observed under the effective intervention of 207-1 while short-chain fatty acids (SCFAs) increased in the LD group, particularly acetic and propionic acids. There was a slight decrease in alpha–diversity in the HD group. Conclusion: Bifidobacterium breve 207-1 entered the organism and affected neurotransmitter and the HPA axis hormone levels via the microbiome-gut-brain axis. Meanwhile, 207-1 supplementation improved daily lifestyle behaviors in healthy adults, which may in turn lead to changes in their bodies (e.g. weight and lipid metabolism). However, this study did not find significant mood-modulating efficacy. The mechanism of the overall study is unclear, but we hypothesize that SCFAs may be the key pathway, and more experiments are needed for validation in the future. Trial registration: This trial was retrospectively registered in the Chinese Clinical Trial Registry under the accession number ChiCTR2300069453 on March 16, 2023. [ABSTRACT FROM AUTHOR]

Cerebral dopamine neurotrophic factor (CDNF) is an unconventional neurotrophic factor because it does not bind to a known specific receptor on the plasma membrane and functions primarily as an unfolded protein response (UPR) regulator in the endoplasmic reticulum. Data on the effects of CDNF on nonmotor behavior and monoamine metabolism are limited. Here, we performed the intracerebroventricular injection of a recombinant CDNF protein at doses of 3, 10, and 30 μg in C57BL/6 mice. No adverse effects of the CDNF injection on feed and water consumption or locomotor activity were observed for 3 days afterwards. Decreases in body weight and sleep duration were transient. CDNF-treated animals demonstrated improved performance on the operant learning task and a substantial decrease in anxiety and behavioral despair. CDNF in all the doses enhanced serotonin (5-HT) turnover in the murine frontal cortex, hippocampus, and midbrain. This alteration was accompanied by changes in the mRNA levels of the 5-HT1A and 5-HT7 receptors and in monoamine oxidase A mRNA and protein levels. We found that CDNF dramatically increased c-Fos mRNA levels in all investigated brain areas but elevated the phosphorylated-c-Fos level only in the midbrain. Similarly, enhanced CREB phosphorylation was found in the midbrain in experimental animals. Additionally, the upregulation of a spliced transcript of XBP1 (UPR regulator) was detected in the midbrain and frontal cortex. Thus, we can hypothesize that exogenous CDNF modulates the UPR pathway and overall neuronal activation and enhances 5-HT turnover, thereby affecting learning and emotion-related behavior. [ABSTRACT FROM AUTHOR]

Introduction: Major depressive disorder (MDD) is a common and disabling mental health condition; the currently available treatments for MDD are insufficient to meet clinical needs due to their limited efficacy and slow onset of action. Hypidone hydrochloride (YL-0919) is a sigma-1 receptor agonist and a novel fast-acting antidepressant that is currently under clinical development. Methods: To further understand the fast-acting antidepressant activity of YL-0919, this study focused on the role of 5-HTergic neurons in the dorsal raphe nucleus (DRN) in mice. Using fiber photometry to assess neural activity in vivo and two behavioral assays (tail suspension test and forced swimming test) to evaluate antidepressant-like activity. Results: It was found that 3 or 7 days of YL-0919 treatment significantly activated serotonin (5-HT) neurons in the DRN and had significant antidepressant-like effects on mouse behaviors. Chemogenetic inhibition of 5-HTergic neurons in the DRN significantly blocked the antidepressant-like effect of YL-0919. In addition, YL-0919 treatment significantly increased the 5-HT levels in the prefrontal cortex (PFC). These changes were drastically different from those of the selective serotonin reuptake inhibitor (SSRI) fluoxetine, which suggested that the antidepressant-like effects of the two compounds were mechanistically different. Conclusion: Together, these results reveal a novel role of 5-HTergic neurons in the DRN in mediating the fast-acting antidepressant-like effects of YL-0919, revealing that these neurons are potential novel targets for the development of fast-acting antidepressants for the clinical management of MDD. [ABSTRACT FROM AUTHOR]

Background and Purpose Experimental approach Key Results Conclusion and Implications The emerging antidepressant effects of ketamine have inspired tremendous interest in its underlying neurobiological mechanisms, although the involvement of 5‐HT in the antidepressant effects of ketamine remains unclear.The chronic restraint stress procedure was performed to induce depression‐like behaviours in mice. OFT, FST, TST, and NSFT tests were used to evaluate the antidepressant‐like effects of ketamine. Tph2 knockout or depletion of 5‐HT by PCPA and 5,7‐DHT were used to manipulate the brain 5‐HT system. ELISA and fibre photometry recordings were used to measure extracellular 5‐HT levels in the brain.60 min after injection, ketamine (10 mg·kg−1, i.p.) produced rapid antidepressant‐like effects and increased brain 5‐HT levels. After 24 h, ketamine significantly reduced immobility time in TST and FST tests and increased brain 5‐HT levels, as measured by ELISA and fibre photometry recordings. The sustained (24 h) but not rapid (60 min) antidepressant‐like effects of ketamine were abrogated by PCPA and 5,7‐DHT, or by Tph2 knockout. Importantly, NBQX (10 mg·kg−1, i.p.), an AMPA receptor antagonist, significantly inhibited the effect of ketamine on brain 5‐HT levels and abolished the sustained antidepressant‐like effects of ketamine in naïve or CRS‐treated mice.This study confirms the requirement of serotonergic neurotransmission for the sustained antidepressant‐like effects of ketamine, which appears to involve AMPA receptors, and provides avenues to search for antidepressant pharmacological targets. [ABSTRACT FROM AUTHOR]

5-Hydroxytryptamine (5-HT) plays a substantial role in mitigating depression and anxiety. However, the potential effects of 5-HT against posttraumatic stress disorder (PTSD) and its underlying mechanisms remain unclear. Elevated plus maze test evaluates anxiety-related behaviors, and the open field test is used to assess overall activity levels and anxiety. Inflammatory cytokine levels were determined using ELISA. The levels of 5-HT and dopamine were measured using HPLC. mRNA and protein levels were examined by PCR and Western blot, respectively. Rats exposed to single prolonged stress (SPS) exhibited typical PTSD-like phenotypes, with decreased levels of 5-HT in the hippocampus and significant reductions in its downstream targets, brain-derived neurotrophic factor (BDNF) and TrkB. In addition, it was discovered that the autophagy signaling pathway might be involved in regulating hippocampal BDNF in rats exposed to SPS. Subsequent treatment with an intracerebral injection of sh-SERT significantly inhibited anxiety and cognitive dysfunction in rats. Moreover, sh-SERT treatment was observed to substantially reverse the increase in autophagy signaling protein expression and consequently improve the expression of BDNF and TrkB proteins, which had been reduced. The current study demonstrates that sh-SERT exhibits significant anti-PTSD effects, potentially mediated in part through the reduction of cellular autophagy to enhance hippocampal synaptic plasticity. NEW & NOTEWORTHY: The study demonstrated that sh-SERT exhibits significant anti-posttraumatic stress disorder (PTSD) effects, potentially mediated in part through the reduction of cellular autophagy to enhance hippocampal synaptic plasticity. [ABSTRACT FROM AUTHOR]

A dual-template molecularly imprinted electrochemical sensor was developed for the simultaneous detection of serotonin (5-HT) and glutamate (Glu). First, amino-functionalized reduced graphene oxide (NRGO) was used as the modification material of a GCE to increase its electrical conductivity and specific surface area, using Glu and 5-HT as dual-template molecules and o-phenylenediamine (OPD) with self-polymerization ability as functional monomers. Through self-assembly and electropolymerization, dual-template molecularly imprinted polymers were formed on the electrode. After removing the templates, the specific recognition binding sites were exposed. The amount of NRGO, polymerization parameters, and elution parameters were further optimized to construct a dual-template molecularly imprinted electrochemical sensor, which can specifically recognize double-target molecules Glu and 5-HT. The differential pulse voltammetry (DPV) technique was used to achieve simultaneous detection of Glu and 5-HT based on their distinct electrochemical activities under specific conditions. The sensor showed a good linear relationship for Glu and 5-HT in the range 1 ~ 100 μM, and the detection limits were 0.067 μM and 0.047 μM (S/N = 3), respectively. The sensor has good reproducibility, repeatability, and selectivity. It was successfully utilized to simultaneously detect Glu and 5-HT in mouse serum, offering a more dependable foundation for objectively diagnosing and early warning of depression. Additionally, the double signal sensing strategy also provides a new approach for the simultaneous detection of both electroactive and non-electroactive substances. [ABSTRACT FROM AUTHOR]

Zebrafish (Danio rerio) are unusual in having two paralogues of the serotonin re-uptake transporter (Sert), slc6a4a (serta) and slc6a4b (sertb), the transporter that serves in serotonin re-uptake from a synapse into the pre-synaptic cell or in serotonin uptake from the extracellular milieu into cells in the peripheral tissues. To address a knowledge gap concerning the specific roles of these paralogues, we used CRISPR/Cas9 technology to generate zebrafish knockout lines predicted to lack functional expression of Serta or Sertb. The consequences of loss-of-function of Serta or Sertb were assessed at the gene expression level, focusing on the serotonergic signalling pathway, and at the behaviour level, focusing on aggression. Whereas serta mRNA was expressed in all tissues examined, with high expression in the heart, gill and brain, only the brain displayed substantial sertb mRNA expression. In both serta−/− and sertb−/− fish, changes in transcript abundances of multiple components of the serotonin signalling pathway were detected, including proteins involved in serotonin synthesis (tph1a, tph1b, tph2, ddc), packaging (vmat2) and degradation (mao), and serotonin receptors (htr1aa, htr1ab). Using a mirror aggression test, serta−/− male but not female fish exhibited greater aggression than wildtype fish. However, both male and female sertb−/− fish displayed less aggression than their wildtype counterparts. These differences in behaviour between serta−/− and sertb−/− individuals hold promise for increasing our understanding of the neurophysiological basis of aggression in zebrafish. [ABSTRACT FROM AUTHOR]

Objectives: Acute and chronic orofacial pain are very common and remain a vexing health problem that has a negative effect on the quality of life. Serotonin (5‐HydroxyTryptamine, 5‐HT) is a kind of monoamine neurotransmitter that is involved in many physiological and pathological processes. However, its role in orofacial pain remains inconclusive. Therefore, this review aims to summarize the recent advances in understanding the effect exerted by 5‐HT on the modulation of orofacial pain. Subjects and Methods: An extensive search was conducted on PubMed and Web of Science for pertinent studies focusing on the effects of 5‐HT on the modulation of orofacial pain. Results: In this review, we concisely review how 5‐HT mediates orofacial pain, how 5‐HT is regulated and how we can translate these findings into clinical applications for the prevention and/or treatment of orofacial pain. Conclusions: 5‐HT plays a key role in the modulation of orofacial pain, implying that 5‐HT modulators may serve as effective treatment for orofacial pain. However, further research on the precise mechanisms underlying the modulation of orofacial pain is still warranted. [ABSTRACT FROM AUTHOR]

The roles of brain asymmetry in Drosophila are diverse, encompassing the regulation of behavior, the creation of memory, neurodevelopment, and evolution. A comprehensive examination of the Drosophila brain has the potential to enhance our understanding of the functional significance of brain asymmetry in cognitive and behavioral processes, as well as its role in evolutionary perspectives. This study explores the influence of brain asymmetry on interval timing behaviors in Drosophila, with a specific focus on the asymmetric body (AB) structure. Despite being bilaterally symmetric, the AB exhibits functional asymmetry and is located within the central complex of the fly brain. Interval timing behaviors, such as rival-induced prolonged mating duration: longer mating duration behavior (LMD) and sexual experience-mediated shorter mating duration behavior (SMD), are essential for Drosophila. We utilize genetic manipulations to selectively activate or inhibit AB neurons and evaluates their impact on LMD and SMD behaviors. The results indicate that specific populations of AB neurons play unique roles in orchestrating these interval timing behaviors. Notably, inhibiting GAL4R38D01-labeled AB neurons disrupts both LMD and SMD, while GAL4R42C09 neuron inhibition affects only LMD. Moreover, hyperexcitation of GAL4R72A10-labeled AB neurons perturbs SMD. Our study identifies NetrinB (NetB) and Abdominal-B (Abd-B) are important genes for AB neurons in LMD and highlights the role of 5-HT1B neurons in generating LMD through peptidergic Pigment-dispersing factor (PDF) signaling. In summary, this study underscores the importance of AB neuron asymmetry in mediating interval timing behaviors and provides insights into the underlying mechanisms of memory formation and function in Drosophila. [ABSTRACT FROM AUTHOR]

Serotonin syndrome is a rare, life-threatening toxidrome caused by serotonergic agents. This syndrome classically presents with a combination of mental status changes, autonomic hyperactivity, and neuromuscular abnormalities. However, diagnosing the condition is difficult because of its variable symptoms at presentation. As a result, serotonin syndrome often is underreported, making it harder to understand, recognize, and treat. Patients with this condition may present to primary or urgent care or an ED, and may become acutely symptomatic during an inpatient admission. Clinicians must be able to identify at-risk patients and intervene to prevent potentially lethal complications. [ABSTRACT FROM AUTHOR]

The synthesized compound 1-(2-chlorophenyl) 6-7-dimethoxy-3-methyl-3,4-dihydroisoquinoline (DIQ) was investigated as a biological agent. Its potential to affect muscle contractility was predicted through in silico PASS analysis. Based on the in silico analysis, its capabilities were experimentally investigated. The study aimed to investigate the effects of DIQ on the ex vivo spontaneous contractile activity (CA) of smooth muscle (SM) tissue. DIQ was observed to reduce the strength of Ca2+-dependent contractions in SM preparations (SMP), possibly by increasing cytosolic Ca2+ levels through the activation of a voltage-gated L-type Ca2+ channel. DIQ potently affected calcium currents by modulating the function of muscarinic acetylcholine receptors (mAChRs) and 5-hydroxytryptamine (5-HT) receptors at a concentration of 50 μM. Immunohistochemical tests showed a 47% reduction in 5-HT2A and 5-HT2B receptor activity in SM cells and neurons in the myenteric plexus (MP), further confirming the effects of DIQ. Furthermore, a significant inhibition of neuronal activity was observed when the compound was co-administered with 5-HT to SM tissues. The conducted experiments confirm the ability of the isoquinoline analog to act as a physiologically active molecule to control muscle contractility and related physiological processes. [ABSTRACT FROM AUTHOR]

Introduction: Since the discovery of gonadotropin-inhibitory hormone (GnIH), it has been found to play a critical role in reproduction in vertebrates. Recently, a regulatory role of GnIH in appetite and energy metabolism has emerged, although its precise physiological mechanisms remain unknown. Methods: Thus, the present study evaluated the effects of a single or long-term intraperitoneal GnIH treatment on the food intake, weight, and glucolipid metabolism of chickens, as well as investigating the possible neuroendocrinology factors and mechanisms involved in GnIH-induced obesity and glucolipid metabolism disorder. Results: Our results show that the intraperitoneal administration of GnIH to chickens resulted in a marked body mass increase, hyperlipidemia, hyperglycemia, and glucose intolerance. Subsequently, the results of metabolomics studies and the pharmacological inhibition of the 5-HT2C receptor revealed that blocking the 5-HT2C receptor reinforced the effects of GnIH on food intake, body weight, and blood glucose and lipid levels, resulting in even worse cases of GnIH-induced hyperglycemia, hyperlipidemia, and hepatic lipid deposition. This suggests that, via the 5-HT2C receptor, peripheral 5-HT may act as a negative feedback regulator to interplay with GnIH and jointly control energy balance homeostasis in chickens. Discussion: Our present study provides evidence of cross-talk between GnIH and 5-HT in food intake and energy metabolism at the in vivo pharmacological level, and it proposes a molecular basis for these interactions, suggesting that functional interactions between GnIH and 5-HT may open new avenues for understanding the mechanism of the neuroendocrine network involved in appetite and energy metabolism, as well as providing a new therapeutic strategy to prevent obesity, diabetes, and metabolic disorders. [ABSTRACT FROM AUTHOR]

Background and Aims: Vitamin D deficiency impacts a significant proportion of the world's population, and this deficiency has been linked to various conditions characterized by imbalanced serotonin regulation. The objective of this systematic review and meta‐analysis was to evaluate the effect of vitamin D supplementation on serum serotonin levels. Methods: We conducted a comprehensive search of PubMed, Scopus, Cochrane Central for Randomized Clinical Trials, and Web of Science up to September 2022, without any language restrictions. The effect sizes were calculated using the standard mean difference (SMD) and 95% confidence interval (CI). Results: Six randomized clinical trials involving 356 participants were included in the analysis. Our findings indicated no significant changes in serotonin levels between the intervention and control groups (SMD: 0.24 ng/mL, 95% CI: −0.28, 0.75, p > 0.10). Subgroup analysis also did not reveal any significant changes in serotonin levels among children, participants with autism spectrum disorders, interventions lasting 10 weeks or longer, or those receiving vitamin D doses below 4000 IU/day. Conclusion: Although the results obtained in this systematic review are inconclusive, they support the need for further well‐designed randomized trials to assess the potential role of vitamin D supplementation in regulating serotonin levels and potentially ameliorating depression and related disorders. [ABSTRACT FROM AUTHOR]

Light plays an essential role in a variety of physiological processes, including vision, mood, and glucose homeostasis. However, the intricate relationship between light and an animal's feeding behavior has remained elusive. Here, we found that light exposure suppresses food intake, whereas darkness amplifies it in male mice. Interestingly, this phenomenon extends its reach to diurnal male Nile grass rats and healthy humans. We further show that lateral habenula (LHb) neurons in mice respond to light exposure, which in turn activates 5-HT neurons in the dorsal Raphe nucleus (DRN). Activation of the LHb5-HTDRN circuit in mice blunts darkness-induced hyperphagia, while inhibition of the circuit prevents light-induced anorexia. Together, we discovered a lightresponsive neural circuit that relays the environmental light signals to regulate feeding behavior in mice. [ABSTRACT FROM AUTHOR]

Objective To investigate the relationships between the serum 5-hydroxytryptamine (5-HT) and nerve growth factor (NGF) levels and recurrence after selective resection of the dorsal nerve of the penis in patients with primary premature ejaculation. Methods Totally 200 patients who underwent selective resection of the dorsal nerve of the penis were selected as the study subjects. Six months after surgery, they were divided into the recurrent group (n=23) and nonrecurrent group (n=177) based on whether the patients had recurrence or not. The clinical data, serum levels of 5-HT and NGF were compared between two groups. The correlations between 5-HT and NGF with the Chinese Index of Premature Ejaculation-5 questionnaire (CIPE-5), International Index of Erectile Function-5（IIEF-5) score, and ejaculation latency time (IELT) were analyzed. Factors affecting postoperative recurrence were analyzed, and we constructed a nomogram model to evaluate the consistency between the postoperative recurrence predicted by model containing serum indicators and the actual observation, and used the decision curve to evaluate the clinical benefit of the model. Results The serum 5- HT level, IELT, and CIPE-5 score in the recurrent group were lower than those in the non-recurrent group at 3 months after surgery, while the NGF level was higher than that in the non-recurrent group (all P<0. 05) . The serum 5-HT level was positively correlated with CIPE-5 score and IELT in patients with primary premature ejaculation before surgery, 1 months after surgery, and 3 months after surgery (all P<0. 05), but was not related to IIEF-5 score (P>0. 05) ； the serum NGF level was negatively correlated with CIPE-5 score and IELT (all P<0. 05), but was not related to IIEF-5 score (P>0. 05) .IELT, CIPE-5 score, serum 5-HT, and NGF levels at 3 months after surgery were independent influencing factors for postoperative recurrence in patients with primary premature ejaculation (all P<0. 05) . The consistency index of the nomogram model in predicting postoperative recurrence related factors in patients with primary premature ejaculation was 0. 775 (95% CI=0. 674-0. 802) . The decision curve showed that when the model containing serum indicators predicted postoperative recurrence in patients with primary premature ejaculation in the range of 0. 2-0. 85, it could provide additional clinical benefits. Conclusion The serum 5-HT level decreases and NGF level increases 3 months after selective resection of the dorsal penile nerve, which has certain reference value for predicting postoperative recurrence in patients with primary premature ejaculation [ABSTRACT FROM AUTHOR]

Inflammatory bowel disease (IBD) encompasses several debilitating chronic gastrointestinal (GI) inflammatory disorders, including Crohn's disease and ulcerative colitis. In both conditions, mucosal inflammation is a key clinical presentation associated with altered serotonin (5-hydroxytryptamine or 5-HT) signaling. This altered 5-HT signaling is also found across various animal models of colitis. Of the 14 known receptor subtypes, 5-HT receptor type 7 (5-HT7) is one of the most recently discovered. We previously reported that blocking 5-HT signaling with either a selective 5-HT7 receptor antagonist (SB-269970) or genetic ablation alleviated intestinal inflammation in murine experimental models of colitis. Here, we developed novel antagonists, namely, MC-170073 and MC-230078, which target 5-HT7 receptors with high selectivity. We also investigated the in vivo efficacy of these antagonists in experimental colitis by using dextran sulfate sodium (DSS) and the transfer of CD4+CD45RBhigh T cells to induce intestinal inflammation. Inhibition of 5-HT7 receptor signaling with the antagonists, MC-170073 and MC-230078, ameliorated intestinal inflammation in both acute and chronic colitis models, which was accompanied by lower histopathological damage and diminished levels of proinflammatory cytokines compared with vehicle-treated controls. Together, the data reveal that the pharmacological inhibition of 5-HT7 receptors by these selective antagonists ameliorates the severity of colitis across various experimental models and may, in the future, serve as a potential treatment option for patients with IBD. In addition, these findings support that 5-HT7 is a viable therapeutic target for IBD. NEW & NOTEWORTHY: This study demonstrates that the novel highly selective 5-HT7 receptor antagonists, MC-170073 and MC-230078, significantly alleviated the severity of colitis across models of experimental colitis. These findings suggest that inhibition of 5-HT7 receptor signaling by these new antagonists may serve as an alternative mode of treatment to diminish symptomology in those with inflammatory bowel disease. [ABSTRACT FROM AUTHOR]

Most HIV-antiretroviral drugs have adverse effects. Efavirenz (EFV) is an example of a drug with neuropsychiatric effects, such as anxiety, depression, and suicidal thoughts, in people living with HIV (PLWH). The mechanisms by which EFV causes neuropsychiatric alterations in PLWH are complex, multifactorial, and not fully understood, although several studies in animals have reported changes in brain energy metabolism, alterations in monoamine turnover, GABA, and glutamate levels, and changes in 5-HT receptors. In this report, we studied the effects of EFV on the serotonergic system in healthy mice, specifically, whether EFV results in alterations in the levels of the tryptophan hydroxylase 2 (Tph2) gene in the brain. EFV (10 mg/kg) and distilled water (1.5 µL/kg) (control group) were orally administered to the mice for 36 days. At the end of the treatment, Tph2 expression levels in mouse brains were measured, and mood was evaluated by three trials: the forced swim test, elevated plus maze, and open field test. Our results revealed dysregulation of Tph2 expression in the brainstem, amygdala, and hypothalamus in the EFV group, and 5-HT levels increased in the amygdala in the EFV group. In the behavioral tests, mice given EFV exhibited a passive avoidance response in the forced swim test and anxiety-like behavior in the elevated plus maze, and they lost weight. Herein, for the first time, we showed that EFV triggered dysregulation of the Tph2 gene in the three serotonergic areas studied; and 5-HT levels increased in the amygdala using the ELISA method. However, further studies will be necessary to clarify the increase of 5-HT in the amygdala as well as understand the paradoxical decrease in body weight with the simultaneous increase in food consumption. It will also be necessary to measure 5-HT by other techniques different from ELISA, such as HPLC. [ABSTRACT FROM AUTHOR]

Purpose: To determine the effect of J147 on depression, anxiety, and gut malfunction triggered by stress in a mouse model exhibiting symptoms of irritable bowel syndrome (IBS). Methods: An IBS mouse model was established by chronic/acute combined stress and housed individually. The stressed mouse was exposed to 21 consecutive days of random chronic unpredictable stress and received 3 h of acute restraint stress on day 2. Forced swimming test (FST) and elevated plus-maze test were used to evaluate depressive and anxiety behaviour, respectively. The intestinal motility and visceral sensitivity of mouse were measured by abdominal withdrawal reflex test (AWR). Also, 8-OH-DPAT (a 5-HT1A receptor agonist) and NAN-190 hydrobromide (a 5-HT1A receptor antagonist) were used in combination with different doses of J147 (2 and 10 mg/kg) for three weeks and AWR test was done. Furthermore, IBS-related protein expression (PKA, pCREB, BDNF) in the hippocampus, colon and ileum was determined by western blotting. Results: After CACS induction, mice showed depression/anxiety-like behaviour along with intestinal allergy, and altered levels of 5-hydroxytryptamine (5-HT) in both the hippocampus and gut. Furthermore, J147 significantly alleviated depression, anxiety, intestinal motility disorders, and intestinal hypersensitivity. Additionally, it normalized abnormal levels of brain-gut 5-HT neurotransmitters observed in IBS mice. Pre-treatment with NAN-190 reversed the effect of J147, whereas the addition of 8-OH-DPAT, augmented the effect of low dose J147 (2 mg/kg) on behavioural abnormalities associated with CACS. Furthermore, J147 significantly increased expression levels of IBS-related proteins in the hippocampus, and decreased their levels in the ileum and colon. Conclusion: J147 inhibits IBS-like depression, anxiety, and visceral hypersensitivity by modulating the 5-HT1A-dependent PKA-CREB-BDNF signaling pathway. Thus, there is need for further studies on the development of J147 in the treatment of irritable bowel syndrome. [ABSTRACT FROM AUTHOR]

BackgroundAutism spectrum disorder (ASD) is often linked to gastrointestinal issues and altered serotonin metabolism. Emerging evidence suggests gut microbiota influence both, with fecal microbiota transplantation (FMT) offering a potential therapeutic approach. However, its impact on serotonin metabolism and ASD symptoms is not well understood. In this study, we aimed to evaluate the clinical effects of FMT and examine changes in specific urinary metabolites in children with ASD.MethodsA randomized double-blind controlled trial was performed to evaluate the clinical effects of FMT on GI and ASD-related symptoms. Gastrointestinal symptoms were assessed using the Gastrointestinal Symptom Rating Scale (GSRS), and the ASD-related symptoms were assessed using the Childhood Autism Rating Scale (CARS), Aberrant Behavior Checklist (ABC), and Social Responsiveness Scale (SRS) scores. Urinary metabolites were analyzed by homogeneous enzyme immunoassay using commercially available kits.ResultsSignificant improvements in GI and core ASD symptoms were observed following FMT intervention. The average GSRS scores decreased from 30.17 (before) to 19 (after; p

Abstract Background Methylation of serotonin-related genes has been proposed as a plausible gene-by-environment link which may mediate environmental stress, depressive and anxiety symptoms. DNA methylation is often measured in blood cells, but little is known about the association between this peripheral epigenetic modification and brain serotonergic architecture. Here, we evaluated the association between whole-blood-derived methylation of four CpG sites in the serotonin transporter (SLC6A4) and six CpG sites of the tryptophan hydroxylase 2 (TPH2) gene and in-vivo brain levels of serotonin transporter (5-HTT) and serotonin 4 receptor (5-HT4) in a cohort of healthy individuals (N = 254) and, for 5-HT4, in a cohort of unmedicated patients with depression (N = 90). To do so, we quantified SLC6A4/TPH2 methylation using bisulfite pyrosequencing and estimated brain 5-HT4 and 5-HTT levels using positron emission tomography. In addition, we explored the association between SLC6A4 and TPH2 methylation and measures of early life and recent stress, depressive and anxiety symptoms on 297 healthy individuals. Results We found no statistically significant association between peripheral DNA methylation and brain markers of serotonergic neurotransmission in patients with depression or in healthy individuals. In addition, although SLC6A4 CpG2 (chr17:30,236,083) methylation was marginally associated with the parental bonding inventory overprotection score in the healthy cohort, statistical significance did not remain after accounting for blood cell heterogeneity. Conclusions We suggest that findings on peripheral DNA methylation in the context of brain serotonin-related features should be interpreted with caution. More studies are needed to rule out a role of SLC6A4 and TPH2 methylation as biomarkers for environmental stress, depressive or anxiety symptoms.

Cognitive dysfunction is a core symptom common in psychiatric disorders including depression that is primarily managed by antidepressants lacking efficacy in improving cognition. In this study, we report a novel dual serotonin transporter and voltage-gated potassium Kv7/KCNQ/M-channel inhibitor D01 (a 2-methyl-3-aryloxy-3-heteroarylpropylamines derivative) that exhibits both anti-depression effects and improvements in cognition. D01 inhibits serotonin transporters (Ki = 30.1 ± 6.9 nmol/L) and M channels (IC50 = 10.1 ± 2.4 μmol/L). D01 also reduces the immobility duration in the mouse FST and TST assays in a dose-dependent manner without a stimulatory effect on locomotion. Intragastric administrations of D01 (20 and 40 mg/kg) can significantly shorten the immobility time in a mouse model of chronic restraint stress (CRS)-induced depression-like behavior. Additionally, D01 dose-dependently improves the cognitive deficit induced by CRS in Morris water maze test and increases the exploration time with novel objects in normal or scopolamine-induced cognitive deficits in mice, but not fluoxetine. Furthermore, D01 reverses the long-term potentiation (LTP) inhibition induced by scopolamine. Taken together, our findings demonstrate that D01, a dual-target serotonin reuptake and M channel inhibitor, is highly effective in the treatment-resistant depression and cognitive deficits, thus holding potential for development as therapy of depression with cognitive deficits.

Background: Methylation of serotonin-related genes has been proposed as a plausible gene-by-environment link which may mediate environmental stress, depressive and anxiety symptoms. DNA methylation is often measured in blood cells, but little is known about the association between this peripheral epigenetic modification and brain serotonergic architecture. Here, we evaluated the association between whole-blood-derived methylation of four CpG sites in the serotonin transporter (SLC6A4) and six CpG sites of the tryptophan hydroxylase 2 (TPH2) gene and in-vivo brain levels of serotonin transporter (5-HTT) and serotonin 4 receptor (5-HT4) in a cohort of healthy individuals (N = 254) and, for 5-HT4, in a cohort of unmedicated patients with depression (N = 90). To do so, we quantified SLC6A4/TPH2 methylation using bisulfite pyrosequencing and estimated brain 5-HT4 and 5-HTT levels using positron emission tomography. In addition, we explored the association between SLC6A4 and TPH2 methylation and measures of early life and recent stress, depressive and anxiety symptoms on 297 healthy individuals. Results: We found no statistically significant association between peripheral DNA methylation and brain markers of serotonergic neurotransmission in patients with depression or in healthy individuals. In addition, although SLC6A4 CpG2 (chr17:30,236,083) methylation was marginally associated with the parental bonding inventory overprotection score in the healthy cohort, statistical significance did not remain after accounting for blood cell heterogeneity. Conclusions: We suggest that findings on peripheral DNA methylation in the context of brain serotonin-related features should be interpreted with caution. More studies are needed to rule out a role of SLC6A4 and TPH2 methylation as biomarkers for environmental stress, depressive or anxiety symptoms. [ABSTRACT FROM AUTHOR]

Serotonin (5 hydroxytryptamine, 5-HT) is a biogenic amine of ancient origin that is widespread among animals. It plays multiple roles during development and in adults as neurotransmitter at synaptic level and neuro hormone controlling complex behaviors in both vertebrates and invertebrates. Tunicates occupy a key phylogenetic position to understand the evolution of serotonin functions since they are the sister group of vertebrates. The presence of serotonin in tunicates was first reported in adults of the ascidian Ciona robusta (formerly Ciona intestinalis) in the 1946. Since then, serotonin systems have been in many tunicate species and its functions during embryogenesis and metamorphosis explored. We reviewed the current knowledge about serotonin in these animals first by comparing its presence and localization in larvae and adults of different species. Then, we focused on the model organism Ciona for which data regarding sequences and expression patterns of genes involved in serotonin synthesis and function have been reported. Overall, we provided a comprehensive overview of serotonergic machinery in tunicates and gave hints for future studies in this field. [ABSTRACT FROM AUTHOR]

Cognitive dysfunction is a core symptom common in psychiatric disorders including depression that is primarily managed by antidepressants lacking efficacy in improving cognition. In this study, we report a novel dual serotonin transporter and voltage-gated potassium Kv7/KCNQ/M-channel inhibitor D01 (a 2-methyl-3-aryloxy-3-heteroarylpropylamines derivative) that exhibits both anti-depression effects and improvements in cognition. D01 inhibits serotonin transporters (K i = 30.1 ± 6.9 nmol/L) and M channels (IC 50 = 10.1 ± 2.4 μmol/L). D01 also reduces the immobility duration in the mouse FST and TST assays in a dose-dependent manner without a stimulatory effect on locomotion. Intragastric administrations of D01 (20 and 40 mg/kg) can significantly shorten the immobility time in a mouse model of chronic restraint stress (CRS)-induced depression-like behavior. Additionally, D01 dose-dependently improves the cognitive deficit induced by CRS in Morris water maze test and increases the exploration time with novel objects in normal or scopolamine-induced cognitive deficits in mice, but not fluoxetine. Furthermore, D01 reverses the long-term potentiation (LTP) inhibition induced by scopolamine. Taken together, our findings demonstrate that D01, a dual-target serotonin reuptake and M channel inhibitor, is highly effective in the treatment-resistant depression and cognitive deficits, thus holding potential for development as therapy of depression with cognitive deficits. Compound D01, a novel dual serotonin transporter and M-channel inhibitor, is effective in alleviating depression and improving cognitive function, thus holding developmental potential for therapy of depression with cognitive deficits. [Display omitted] [ABSTRACT FROM AUTHOR]

objective: To investigate the effect of sea cucumber cooking liquid (SCCL) dry powder on chronic constipation in mice. Methods: Loperamide hydrochloride was administered intragastrically to establish the chronic constipation model. To evaluate the positive effect of SCCL in intestinal motility of constipation mice, the defecation situation, intestinal ink transit rate and mRNA expression levels of intestinal motility related neurotransmitters and receptors were detected. Result: Compared with the model control group, the intestine ink transit rate of mice in the high-dose SCCL group was significantly increased (P<0.05), the time of first black faeces was significantly shortened (P<0.01), and the number and weight of faeces in 6 hours in the low-dose and high-dose SCCL groups were significantly increased (P<0.05); The number of goblet cells and the content of mucin in the colon of mice were improved significantly (P<0.05); The mRNA expression levels of M2AChR, M3AChR, 5-HT3R, 5-HT4R and C-Kit in colon tissue were significantly increased (P<0.05). Conclusion: SCCL alleviated constipation by regulating intestinal peristalsis related neurotransmitters such as ACh, 5-HT and its downstream signaling pathways, eventually increased the number of ICC cells, improved intestinal motility and promoted intestinal peristalsis. [ABSTRACT FROM AUTHOR]

Novelty detection, crucial to episodic memory formation, is impaired in epileptic patients with mesial temporal lobe resection. Mismatch novelty detection, that activates the hippocampal CA1 area in humans and is vital for memory reformulation and reconsolidation, is also impaired in patients with hippocampal lesions. In this work, we investigated the response to mismatch novelty, as occurs with the new location of known objects in a familiar environment, in the Li2+-pilocarpine rat model of TLE and its correlation with hippocampal monoaminergic markers. Animals showing spontaneous recurrent seizures (SRSs) for at least 4 weeks at the time of behavioural testing showed impaired spatial learning in the radial arm maze, as described. Concurrently, SRS rats displayed impaired exploratory responses to mismatch novelty, yet novel object recognition was not significantly affected in SRS rats. While the levels of serotonin and dopamine transporters were mildly decreased in hippocampal membranes from SRS rats, the levels on the norepinephrine transporter, tyrosine hydroxylase and dopamine-β-hydroxylase were enhanced, hinting for an augmentation, rather than an impairment in noradrenergic function in SRS animals. Altogether, this reveals that mismatch novelty detection is particularly affected by hippocampal damage associated to the Li2+-pilocarpine model of epilepsy 4–8 weeks after the onset of SRSs and suggests that deficits in mismatch novelty detection may substantially contribute to cognitive impairment in MTLE. As such, behavioural tasks based on these aspects of mismatch novelty may prove useful in the development of cognitive therapy strategies aiming to rescue cognitive deficits observed in epilepsy. [ABSTRACT FROM AUTHOR]

Abstract Background and Aims Vitamin D deficiency impacts a significant proportion of the world's population, and this deficiency has been linked to various conditions characterized by imbalanced serotonin regulation. The objective of this systematic review and meta‐analysis was to evaluate the effect of vitamin D supplementation on serum serotonin levels. Methods We conducted a comprehensive search of PubMed, Scopus, Cochrane Central for Randomized Clinical Trials, and Web of Science up to September 2022, without any language restrictions. The effect sizes were calculated using the standard mean difference (SMD) and 95% confidence interval (CI). Results Six randomized clinical trials involving 356 participants were included in the analysis. Our findings indicated no significant changes in serotonin levels between the intervention and control groups (SMD: 0.24 ng/mL, 95% CI: −0.28, 0.75, p > 0.10). Subgroup analysis also did not reveal any significant changes in serotonin levels among children, participants with autism spectrum disorders, interventions lasting 10 weeks or longer, or those receiving vitamin D doses below 4000 IU/day. Conclusion Although the results obtained in this systematic review are inconclusive, they support the need for further well‐designed randomized trials to assess the potential role of vitamin D supplementation in regulating serotonin levels and potentially ameliorating depression and related disorders.

Aging often accompanies cognitive and mood disturbances. Emerging evidence indicates that specific probiotics mitigate cognitive and mood dysfunctions. Strains within Lactococcus, a subgroup of probiotics, including Lactococcus lactis and Lactococcus cremoris are shown beneficial effects on brain functions via the gut microbiota-brain axis (GBA). Our previous study identified two Lactococcus strains (L. lactis WHH2078 and L. cremoris WHH2080) with the ability to promote the secretion of gut 5-hydroxytryptophan (5-HTP), the precursor of the GBA mediator 5-hydroxytryptamine (5-HT). In this study, the modulatory effects of WHH2078 and WHH2080 on cognitive and mood alternations were investigated in aged mice. Oral administration of WHH2078 and WHH2080 (1 × 109 CFU/mL/day) in aged mice (12-month-old) for 12 weeks significantly improved cognitive and depressive-and anxiety-like behaviors. The neuronal loss, the 5-HT metabolism dysfunction, and the neuroinflammation in the hippocampus of aged mice were restored by WHH2078 and WHH2080. the disturbances in the serum tryptophan metabolism in aged mice were unveiled by metabolomics, notably with decreased levels of 5-HT and 5-HTP, and increased levels of kynurenine, 3-hydroxykynurenine, and indolelactic acid, which were reversed by WHH2078 and WHH2080. Regarding the gut microbial community, WHH2078 and WHH2080 restored the increased abundance of Firmicutes, Desulfobacterota, and Deferribacterota and the decreased abundance of Bacteroidota and Actinobacteriota in aged mice. The beneficial effects of the two strains were linked to the modulation of 5-HT metabolism and gut microbiota. Our findings point to the potential role of Lactococcus strains with 5-HTP-promoting abilities as therapeutic approaches for age-related cognitive and mood disorders.

The aim of this study is to investigate the role of estrogen receptor β (ERβ) in nonylphenol (NP) - induced depression - like behavior in rats and its impact on the regulation of the TPH2/5-HT pathway. In the in vitro experiment, rat basophilic leukaemia cells (RBL-2H3) cells were divided into the four groups: blank group, NP group (20 μM), ERβ agonist group (0.01 μM), and NP＋ERβ agonist group (20 μM＋0.01 μM). For the in vivo experiment, 72 adult male Sprague-Dawley rats were randomly divided into following six groups: the Control, NP (40 mg/kg) group, ERβ agonist (2 mg/kg, Diarylpropionitrile (DPN)) group, ERβ inhibitor (0.1 mg/kg, 4-(2-phenyl-5,7-bis(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl) phenol (PHTPP)) group, NP+ERβ agonist (40 mg/kg NP ＋ 2 mg/kg DPN) group, and NP+ERβ inhibitor (40 mg/kg NP + 0.1 mg/kg PHTPP) group, with 12 rats in each group. Each rat in drug group were given NP by gavage and/or received a single intraperitoneal injection of DPN 2 mg/kg or PHTPP 0.1 mg/kg. Both in vivo and in vitro, NP group showed a decrease in the expression levels of ERβ, tryptophan hydroxylase (TPH1), and tryptophan hydroxylase-2 (TPH2) genes and proteins, and reduced levels of DA, NE, and 5-hydroxytryptophan (5-HT) neurotransmitters. RBL-2H3 cells showed signs of cell shrinkage, with rounded cells, increased suspension and more loosely arranged cells. The effectiveness of the ERβ agonist stimulation exhibited an increase exceeding 60% in RBL-2H3 cells. The application of ERβ agonist resulted in an alleviation the aforementioned alterations. ERβ agonist activated the TPH2/5-HT signaling pathways. Compared to the control group, the NP content in the brain tissue of the NP group was significantly increased. The latency to eat for the rats was longer and the amount of food consumed was lower, and the rats had prolonged immobility time in the behavioral experiment of rats. The expression levels of ERβ, TPH1, TPH2, 5-HT and 5-HITT proteins were decreased in the NP group, suggesting NP-induced depression-like behaviours as well as disturbances in the secretion of serum hormones and monoamine neurotransmitters. In the NP group, the midline raphe nucleus showed an elongated nucleus with a dark purplish-blue colour, nuclear atrophy, displacement and pale cytoplasm. ERβ might ameliorate NP-induced depression-like behaviors, and secretion disorders of serum hormones and monoamine neurotransmitters via activating TPH2/5-HT signaling pathways.

Anxiety-like conditions can interfere with daily activities as the adaptive mechanism fails to cope with stress. These conditions are often linked with increased oxidative stress, and abrupt neurotransmission and electroencephalography (EEG) wave pattern. Geraniol, a monoterpenoid, has antioxidant and anti-inflammatory activities, as well as brain-calming effects. Therefore, in this study, geraniol was tested for the potential anxiolytic effects in a rat model of anxiety. The rats were exposed to an electric foot shock (1 mA for 1 s) to develop anxiety-like symptoms. Treatment was carried out using geraniol (10 and 30 mg/kg) and the standard diazepam drug. The behavior of the rats was analyzed using the open field test, light-dark test, and social interaction test. Afterward, the rats were decapitated to collect samples for neurochemical and biochemical analyses. The cortical-EEG wave pattern was also obtained. The study revealed that the electric foot shock induced anxiety-like symptoms, increased oxidative stress, and altered hippocampal neurotransmitter levels. The power of low-beta and high-beta was amplified with the increased coupling of delta-beta waves in anxiety group. However, the treatment with geraniol and diazepam normalized cortical-EEG wave pattern and hippocampal serotonin and catecholamines profile which was also reflected by reduced anxious behavior and normalized antioxidant levels. The study reports an anxiolytic potential of geraniol, which can be further explored in future.

Abstract The association between capsaicin, the major natural pungent compound of chili peppers, and gastric cancer progression has engendered conflicting findings. In this work, we sought to explore the character of a high capsaicin diet in gastric cancer metastasis and its possible mechanism. The impact of high capsaicin consumption on gastric cancer metastasis was investigated in vivo (xenograft mouse and zebrafish models) and in vitro (biochemical and molecular assays). It was demonstrated that high diet of capsaicin gave rise to accelerate tumor metastasis, which was partially mediated by elevating the expression of transient receptor potential vanilloid 1 (TRPV1) in gastric cancer cells. Importantly, we found that genetic depletion of TRPV1 could reduce gastric cancer metastasis by diminishing the motility of tumor cells in vitro, but acted poorly in xenograft mouse model. Considering the distribution of capsaicin in vivo, 16S rRNA sequencing and fecal microbiota transplantation (FMT) were used to appraise whether the gut microbiota involved in the high capsaicin diet induced metastasis. It was demonstrated that the level of Firmicutes and Clostridiales was expressively boosted following the high consumption of capsaicin. This microbial shift contributed to the increased peripheral 5-hydroxytryptamine (5-HT) levels, yielding the aggravated metastatic burden. Collectively, our findings highlighted the potential risk of high capsaicin diet in promoting gastric cancer metastasis by virtue of modulating TRPV1 expression and gut microbiota composition, indicating the importance of controlled consumption of chili peppers for patients with gastric cancer. Video Abstract

Abstract Background Broilers have a robust metabolism and high body temperature, which make them less tolerant to high-temperature (HT) environments and more susceptible to challenges from elevated temperatures. Gut microbes, functioning as symbionts within the host, possess the capacity to significantly regulate the physiological functions and environmental adaptability of the host. This study aims to investigate the effects of gut microbial intervention on the body temperature and thermogenesis of broilers at different ambient temperatures, as well as the underlying mechanism involving the "gut-brain" axis. Methods Broilers were subjected to gut microbiota interference with or without antibiotics (control or ABX) starting at 1 day of age. At 21 day of age, they were divided into 4 groups and exposed to different environments for 7 d: The control and ABX groups at room temperature (RT, 24 ± 1 °C, 60% relative humidity (RH), 24 h/d) and the control-HT and ABX-HT groups at high temperature (HT, 32 ± 1 °C, 60% RH, 24 h/d). Results The results demonstrated that the antibiotic-induced gut microbiota intervention increased body weight and improved feed conversion in broiler chickens (P < 0.05). Under HT conditions, the microbiota intervention reduced the rectal temperature of broiler chickens (P < 0.05), inhibited the expression of avUCP and thermogenesis-related genes in breast muscle and liver (P < 0.05), and thus decreased thermogenesis capacity. Furthermore, the gut microbiota intervention blunted the hypothalamic‒pituitary‒adrenal axis and hypothalamic–pituitary–thyroid axis activation induced by HT conditions. By analyzing the cecal microbiota composition of control and ABX chickens maintained under HT conditions, we found that Alistipes was enriched in control chickens. In contrast, antibiotic-induced gut microbiota intervention resulted in a decrease in the relative abundance of Alistipes (P < 0.05). Moreover, this difference was accompanied by increased hypothalamic 5-hydroxytryptamine (5-HT) content and TPH2 expression (P < 0.05). Conclusions These findings underscore the critical role of the gut microbiota in regulating broiler thermogenesis via the gut-brain axis and suggest that the hypothalamic 5-HT pathway may be a potential mechanism by which the gut microbiota affects thermoregulation in broilers. Graphical Abstract

Lin Sheng,1– 4,&ast; Yumeng Wei,1,3,&ast; Chao Pi,1,3,&ast; Ju Cheng,3,4 Zhilian Su,1– 4 Yuanyuan Wang,1,5 Tao Chen,1– 4 Jie Wen,1– 4 Yuxun Wei,1– 4 Jingwen Ma,1– 4 Jia Tang,1– 4 Huiyang Liu,1– 4 Zerong Liu,6,7 Hongping Shen,8 Ying Zuo,9 Wenwu Zheng,10 Ling Zhao2– 4 1Key Laboratory of Medical Electrophysiology, Ministry of Education, School of Pharmacy of Southwest Medical University, Luzhou, People’s Republic of China; 2Luzhou Key Laboratory of Traditional Chinese Medicine for Chronic Diseases Jointly Built by Sichuan and Chongqing, the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China; 3Key Laboratory of Medical Electrophysiology, Ministry of Education, Development Planning Department of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China; 4Central Nervous System Drug Key Laboratory of Sichuan Province, School of Pharmacy of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China; 5Department of Clinical Pharmacy, West China Hospital, Sichuan University, Chengdu, People’s Republic of China; 6Central Nervous System Drug Key Laboratory of Sichuan Province, Sichuan Credit Pharmaceutical CO., Ltd. Luxian County, Luzhou City, People’s Republic of China; 7Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400030, People’s Republic of China; 8Clinical Trial Center, the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China; 9Department of Comprehensive Medicine, the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China; 10Department of cardiology, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wenwu Zheng, Department of Cardiology, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, People’s Republic of China, Tel/Fax +86 830 3165311, Email zhengwenwu888@163.com Ling Zhao, Luzhou Key Laboratory of Traditional Chinese Medicine for Chronic Diseases Jointly Built by Sichuan and Chongqing, the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, No. 182, Chunhui Road, Longmatan District, Luzhou, Sichuan, 646000, People’s Republic of China, Tel/Fax +86 830 3160093, Email zhaoling@swmu.edu.cnPurpose: The early stage of this study verified that a turmeric extract (TUR) including 59% curcumin (CU), 22% demethoxycurcumin (DMC), and 18% bisdemethoxycurcumin (BDMC), could enhance the stability of CU and had greater antidepressant potential in vitro. The objective of the study was to develop a nano-delivery system containing TUR (TUR-NE) to improve the pharmacokinetic behavior of TUR and enhance its antidepressant effect.Methods: The antidepressant potential of TUR was explored using ABTS, oxidative stress-induced cell injury, and a high-throughput screening model. TUR-NE was fabricated, optimized and characterized. The pharmacokinetic behaviors of TUR-NE were evaluated following oral administration to normal rats. The antidepressant effect of TUR-NE was assessed within chronic unpredictable mild stress model (CUMS) mice. The behavioral and biochemical indexes of mice were conducted.Results: The results depicted that TUR had 3.18 and 1.62 times higher antioxidant capacity than ascorbic acid and CU, respectively. The inhibition effect of TUR on ASP+ transport was significantly enhanced compared with fluoxetine and CU. TUR-NE displayed a particle size of 116.0 ± 0.31 nm, polydispersity index value of 0.121 ± 0.007, an encapsulation rate of 98.45%, and good release and stability in cold storage. The results of pharmacokinetics indicated the AUC(0-t) of TUR-NE was 8.436 and 4.495 times higher than that of CU and TUR, while the Cmax was 9.012 and 5.452 times higher than that of CU and TUR, respectively. The pharmacodynamic study confirmed that the superior antidepressant effect of TUR-NE by significantly improving the depressant-like behaviors and elevating the content of 5-hydroxytryptamine in plasma and brain in CUMS mice. TUR-NE showed good safety with repeated administration.Conclusion: TUR-NE, which had small and uniform particle size, enhanced the bioavailability and antidepressant effect of TUR. It could be a promising novel oral preparation against depression.Keywords: turmeric extract, curcuminoids, nanoemulsion, stability, antidepressant effect, 5-hydroxytryptamine

Cerebral dopamine neurotrophic factor (CDNF) is an unconventional neurotrophic factor because it does not bind to a known specific receptor on the plasma membrane and functions primarily as an unfolded protein response (UPR) regulator in the endoplasmic reticulum. Data on the effects of CDNF on nonmotor behavior and monoamine metabolism are limited. Here, we performed the intracerebroventricular injection of a recombinant CDNF protein at doses of 3, 10, and 30 μg in C57BL/6 mice. No adverse effects of the CDNF injection on feed and water consumption or locomotor activity were observed for 3 days afterwards. Decreases in body weight and sleep duration were transient. CDNF-treated animals demonstrated improved performance on the operant learning task and a substantial decrease in anxiety and behavioral despair. CDNF in all the doses enhanced serotonin (5-HT) turnover in the murine frontal cortex, hippocampus, and midbrain. This alteration was accompanied by changes in the mRNA levels of the 5-HT1A and 5-HT7 receptors and in monoamine oxidase A mRNA and protein levels. We found that CDNF dramatically increased c-Fos mRNA levels in all investigated brain areas but elevated the phosphorylated-c-Fos level only in the midbrain. Similarly, enhanced CREB phosphorylation was found in the midbrain in experimental animals. Additionally, the upregulation of a spliced transcript of XBP1 (UPR regulator) was detected in the midbrain and frontal cortex. Thus, we can hypothesize that exogenous CDNF modulates the UPR pathway and overall neuronal activation and enhances 5-HT turnover, thereby affecting learning and emotion-related behavior.

Background: The serotonergic neurotransmitter system is involved in many ethanol‐induced changes, including many behavioural alterations, as well as contributing to alcohol dependence and its withdrawal. Aims: This review has evaluated microdialysis studies where alterations in the serotonin system, that is, serotonin, 5‐HT, or its metabolite 5‐hydroxyindoleacetic acid, 5‐HIAA, have been reported during different ethanol intoxication states, as well as in animals showing alcohol preference or not. Changes in 5‐HT receptors and the 5‐HT transporter are briefly reviewed to comprehend the significance of changes in microdialysate 5‐HT concentrations. Materials and methods: Changes in 5‐HT content following acute, chronic and during ethanol withdrawal states are evaluated. In addition, the serotoninergic system was assessed in animals that have been genetically selected for alcohol preference to ascertain whether changes in this monoamine microdialysate content may contribute to alcohol preference. Results and discussion: Changes occurred in 5‐HT signalling in the limbic brain regions, increasing after acute ethanol administration in specific brain regions, particularly at higher doses, while chronic alcohol exposure essentially decreased serotonergic transmission. Such changes may play a pivotal role in emotion‐driven craving and relapse. Depending on the dosage, mode of administration and consumption rate, ethanol affects specific brain regions in different ways, enhancing or reducing 5‐HT microdialysate content, thereby inducing behavioural and cognitive functions and enhancing ethanol consumption. Conclusion: Microdialysis studies demonstrated that ethanol induces several alterations in 5‐HT content as well as its metabolites, 5‐HIAA and 5‐HTOL, not only in its release from a specific brain region but also in the modifications of its different receptor subtypes and its transporter. [ABSTRACT FROM AUTHOR]

Background: Serotonin (5-hydroxytryptamine, 5-HT) signaling is involved in neurodevelopment, mood regulation, energy metabolism, and other physiological processes. DNA methylation plays a significant role in modulating the expression of genes responsible for maintaining 5-HT balance, such as 5-HT transporter (SLC6A4), monoamine oxidase A (MAOA), and 5-HT receptor type 2A (HTR2A). Maternal metabolic health can influence long-term outcomes in offspring, with DNA methylation mediating these effects. We investigated associations between maternal metabolic parameters—pre-pregnancy body mass index (pBMI), gestational weight gain (GWG), and glucose tolerance status (GTS), i.e., gestational diabetes mellitus (GDM) versus normal glucose tolerance (NGT)—and cord blood methylation of SLC6A4, MAOA, and HTR2A in participants from our PlaNS birth cohort. CpG sites (15, 9, and 2 in each gene, respectively) were selected based on literature and in silico data. Methylation levels were quantified by bisulfite pyrosequencing. We also examined the stability of methylation patterns in these genes in circulating blood cells from birth to adolescence using longitudinal DNA methylation data from the ARIES database. Results: None of the 203 PlaNS mothers included in this study had preexisting diabetes, 99 were diagnosed with GDM, and 104 had NGT; all neonates were born at full term by planned Cesarean section. Methylation at most CpG sites differed between male and female newborns. SLC6A4 methylation correlated inversely with maternal pBMI and GWG, while methylation at HTR2A site -1665 correlated positively with GWG. None of the maternal metabolic parameters statistically associated with MAOA methylation. DNA methylation data in cord blood and peripheral blood at ages 7 and 15 years were available for 808 participants from the ARIES database; 4 CpG sites (2 in SLC6A4 and 2 in HTR2A) overlapped between the PlaNS and ARIES cohorts. A positive correlation between methylation levels in cord blood and peripheral blood at 7 and 15 years of age was observed for both SLC6A4 and HTR2A CpG sites. Conclusions: Methylation of 5-HT regulating genes in cord blood cells is influenced by neonatal sex, with maternal metabolism playing an additional role. Inter-individual variations present in circulating blood cells at birth are still pronounced in childhood and adolescence. [ABSTRACT FROM AUTHOR]

Anxiety and depression have been associated with imbalances in the gut microbiota and bile acid metabolism. Takeda G protein-coupled receptor 5 (TGR5) , a bile acid receptor involved in metabolism, is influenced by the gut microbiota. This study aimed to investigate the relationship between anxiety, depression, and microbiota using TGR5 knockout mice. We employed the following methods: (1) Assessment of behavioral changes, (2) Measurement of 5-HT levels and protein expression, (3) Analysis of stool samples, (4) Utilization of gene sequencing and statistical analysis to identify microbial signatures, (5) Examination of correlations between microbial signatures and 5-HT levels, and (6) Fecal microbiota transplantation experiments of TGR5 −/− mice. The deletion of TGR5 was found to result in increased anxiety- and depression-like behaviors in mice. TGR5 knockout mice exhibited significant reductions in 5-hydroxytryptamine (5-HT) levels in both serum and hippocampus, accompanied by a decrease in the expression of 5-HT1A receptor in the hippocampus. Moreover, TGR5 deficiency was associated with a decrease in the species richness of the gut microbiota. Specifically, the gut microbiota compositions of TGR5 knockout mice displayed distinct differences compared to their littermates, characterized by higher abundances of Anaeroplasma , Prevotella , Staphylococcus , Jeotgalicoccus , and Helicobacter , and a lower abundance of Bifidobacterium. Notably, a strong association between Jeotgalicoccus as well as Staphylococcus and serum 5-HT levels was observed in co-occurrence network. Furthermore, mice that received fecal microbiota transplants from TGR5 −/− mice displayed anxiety and depression -like behaviors, accompanied by alterations in 5-HT levels in the hippocampus and serum. Study limitations for gut bacteria were analyzed at the genus level only. TGR5 deletion in mice induces anxiety and depression-like behaviors, linked to reduced 5-HT levels in serum and the hippocampus. Gut microbiota changes play a direct role in these behaviors and serotonin alterations. This implicates TGR5 and gut bacteria in mood regulation, with potential therapeutic implications. • TGR5 knockout mice exhibit anxiety and depression -like behaviors. • TGR5 knockout mice have lower hippocampal and serum 5-HT levels and reduced 5-HT1AR protein expression. • TGR5 knockout mice display an altered gut microbiota composition. • Jeotgalicoccus and Staphylococcus in TGR5 knockout mice exhibit a strong correlation with serum 5-HT levels. • Mice with TGR5 knockout fecal transplants show anxiety, depression, and altered hippocampal and serum 5-HT levels. [ABSTRACT FROM AUTHOR]

Balneotherapy has demonstrated clinical efficacy in the management of pathologies involving low-grade inflammation and stress. In rheumatic conditions such as osteoarthritis (OA), this therapy presents anti-inflammatory properties and potential to improve psychological well-being. Although the neurohormones serotonin and dopamine are known to be involved in these processes, surprisingly they have not been studied in this context. The objective was to evaluate the effect of a cycle of balneotherapy with peloids (pelotherapy) on circulating serotonin and dopamine concentrations in a group of aged individuals with OA, after comparing their basal state to that of an age-matched control group. In our pilot study, a pelotherapy program (10 days) was carried out in a group of 16 elderly patients with OA, evaluating its effects on circulating serotonin and dopamine concentrations (measured by ELISA). Individuals with OA showed higher levels of serotonin and lower dopamine levels, in line with the inflammatory roles of these mediators. After pelotherapy, serotonin concentrations significantly decreased, potentially contributing to the previously reported anti-inflammatory effects of balneotherapy. [ABSTRACT FROM AUTHOR]

Serotonergic neurons constitute one of the main systems of neuromodulators, whose diffuse projections regulate the functions of the cerebral cortex. Serotonin (5-HT) is known to play a crucial role in the differential modulation of cortical activity related to behavioral contexts. Some features of the 5-HT signaling organization suggest its possible participation as a modulator of activity-dependent synaptic changes during the critical period of the primary visual cortex (V1). Cells of the serotonergic system are among the first neurons to differentiate and operate. During postnatal development, ramifications from raphe nuclei become massively distributed in the visual cortical area, remarkably increasing the availability of 5-HT for the regulation of excitatory and inhibitory synaptic activity. A substantial amount of evidence has demonstrated that synaptic plasticity at pyramidal neurons of the superficial layers of V1 critically depends on a fine regulation of the balance between excitation and inhibition (E/I). 5-HT could therefore play an important role in controlling this balance, providing the appropriate excitability conditions that favor synaptic modifications. In order to explore this possibility, the present work used in vitro intracellular electrophysiological recording techniques to study the effects of 5-HT on the E/I balance of V1 layer 2/3 neurons, during the critical period. Serotonergic action on the E/I balance has been analyzed on spontaneous activity, evoked synaptic responses, and long-term depression (LTD). Our results pointed out that the predominant action of 5-HT implies a reduction in the E/I balance. 5-HT promoted LTD at excitatory synapses while blocking it at inhibitory synaptic sites, thus shifting the Hebbian alterations of synaptic strength towards lower levels of E/I balance. [ABSTRACT FROM AUTHOR]

Background: Broilers have a robust metabolism and high body temperature, which make them less tolerant to high-temperature (HT) environments and more susceptible to challenges from elevated temperatures. Gut microbes, functioning as symbionts within the host, possess the capacity to significantly regulate the physiological functions and environmental adaptability of the host. This study aims to investigate the effects of gut microbial intervention on the body temperature and thermogenesis of broilers at different ambient temperatures, as well as the underlying mechanism involving the "gut-brain" axis. Methods: Broilers were subjected to gut microbiota interference with or without antibiotics (control or ABX) starting at 1 day of age. At 21 day of age, they were divided into 4 groups and exposed to different environments for 7 d: The control and ABX groups at room temperature (RT, 24 ± 1 °C, 60% relative humidity (RH), 24 h/d) and the control-HT and ABX-HT groups at high temperature (HT, 32 ± 1 °C, 60% RH, 24 h/d). Results : The results demonstrated that the antibiotic-induced gut microbiota intervention increased body weight and improved feed conversion in broiler chickens (P < 0.05). Under HT conditions, the microbiota intervention reduced the rectal temperature of broiler chickens (P < 0.05), inhibited the expression of avUCP and thermogenesis-related genes in breast muscle and liver (P < 0.05), and thus decreased thermogenesis capacity. Furthermore, the gut microbiota intervention blunted the hypothalamic‒pituitary‒adrenal axis and hypothalamic–pituitary–thyroid axis activation induced by HT conditions. By analyzing the cecal microbiota composition of control and ABX chickens maintained under HT conditions, we found that Alistipes was enriched in control chickens. In contrast, antibiotic-induced gut microbiota intervention resulted in a decrease in the relative abundance of Alistipes (P < 0.05). Moreover, this difference was accompanied by increased hypothalamic 5-hydroxytryptamine (5-HT) content and TPH2 expression (P < 0.05). Conclusions: These findings underscore the critical role of the gut microbiota in regulating broiler thermogenesis via the gut-brain axis and suggest that the hypothalamic 5-HT pathway may be a potential mechanism by which the gut microbiota affects thermoregulation in broilers. [ABSTRACT FROM AUTHOR]

The association between capsaicin, the major natural pungent compound of chili peppers, and gastric cancer progression has engendered conflicting findings. In this work, we sought to explore the character of a high capsaicin diet in gastric cancer metastasis and its possible mechanism. The impact of high capsaicin consumption on gastric cancer metastasis was investigated in vivo (xenograft mouse and zebrafish models) and in vitro (biochemical and molecular assays). It was demonstrated that high diet of capsaicin gave rise to accelerate tumor metastasis, which was partially mediated by elevating the expression of transient receptor potential vanilloid 1 (TRPV1) in gastric cancer cells. Importantly, we found that genetic depletion of TRPV1 could reduce gastric cancer metastasis by diminishing the motility of tumor cells in vitro, but acted poorly in xenograft mouse model. Considering the distribution of capsaicin in vivo, 16S rRNA sequencing and fecal microbiota transplantation (FMT) were used to appraise whether the gut microbiota involved in the high capsaicin diet induced metastasis. It was demonstrated that the level of Firmicutes and Clostridiales was expressively boosted following the high consumption of capsaicin. This microbial shift contributed to the increased peripheral 5-hydroxytryptamine (5-HT) levels, yielding the aggravated metastatic burden. Collectively, our findings highlighted the potential risk of high capsaicin diet in promoting gastric cancer metastasis by virtue of modulating TRPV1 expression and gut microbiota composition, indicating the importance of controlled consumption of chili peppers for patients with gastric cancer. CLQ_5di4C7NjAvrz19eKZi Video Abstract [ABSTRACT FROM AUTHOR]

The mud crab Scylla olivacea is widely cultured for its economic value, but reproduction issues limit its production. Vitellogenesis-inhibiting hormone (VIH), serotonin (5-HT), and gonadotropin-releasing hormone (GnRH) are important neurohormones that control reproduction in crustaceans. Mimicking crab hormone stimulation during reproduction has scarcely been reported. Comparison of the single hormone and multiple hormone approaches to crab hormonal control in S. olivacea is limited. In situ hybridization showed that injection of dsRNA-VIH could abolish its gene expression in neuronal clusters of female S. olivacea eyestalks, potentially reducing its inhibitory effects on ovarian maturation. This was confirmed by assessing the ovarian gonadosomatic index (GSI), hemolymph vitellogenin (Vg), an indicator of vitellogenesis, and gonad histology using dsRNA-VIH and 5-HT/GnRH combinations. Based on our findings, we demonstrated that administration of dsRNA-VIH significantly increased the gonadosomatic index (GSI) on days 14 and 28 post-treatment. The combination cocktail, however, consisting of 5-HT + GnRH + dsRNA-VIH on days 14 and 28, and GnRH + dsRNA-VIH on day 28, was the most efficacious in increasing GSI and enhancing crab ovarian maturation. Upregulation of hemolymph Vg levels was observed solely on the 28th day following treatment with dsRNA-VIH, 5-HT + GnRH + dsRNA-VIH, and GnRH + dsRNA-VIH. Differential gene expression analysis using quantitative RNA-sequencing of the neural tissues (brain and ventral nerve cord), revealed a significant upregulation of certain receptors (5-HTR, GnRHR, LHR, and FSHR), neuropeptides (sNPF, NPF1, NPF2, SIFamide, AKH/Crz, CHH, and RPCH), downstream reproductive-related genes (FAMeT, ESULT, progesterone-like protein), and prostanoid-related genes (phospholipase A and C, COX, Thromboxane A synthase, prostaglandin D, E, and F synthases) following treatment, particularly dsRNA-VIH + GnRH and/or 5-HTinjected individuals. Upregulation of prostaglandin E synthase and estrogen sulfotransferase genes was confirmed by real-time PCR. Since the construction and propagation of dsRNA-VIH is costly, its lower dose application supplemented with synthetic GnRH and/or 5-HT may be an alternative approach to ensure that female S. olivacea attain sufficient reproductive fecundity in aquaculture. Furthermore, we propose that the administration of multiple hormones in crabs may better emulate the physiological conditions of crustaceans in their natural habitat. [ABSTRACT FROM AUTHOR]

Aims: Migraine is a common neurological disorder with high incidence in population. This study aimed to investigate the therapeutic efficacy of Tibetan medicine Ratanasampil (RNSP) and to identify the serum biomarkers for diagnosis and response assessment.Materials and methods: We prospectively recruited 108 migraine patients living at high altitude (2,260 m), including 40 patients for RNSP group, 40 patients for flunarizine (FLZ) group, and 28 patients for placebo group. Serum levels of 5-hydroxytryptamine (5-HT), brain-derived neurotrophic factor (BDNF), calcitonin gene related peptide (CGRP), nerve growth factor (NGF) and β-endorphin (β-EP) before and after therapy were measured.Results: In comparison with placebo, both FLZ and RNSP significantly reduced the migraine days, HIT-6 score and verbal rating scale, headache intensity, duration, accompanying symptoms and headache score in four and eight weeks treatment. RNSP showed no significant difference to FLZ in the above parameters after four weeks treatment, but showed significantly better relief after eight weeks treatment. The overall effective rate of RNSP (92.5%) was also significantly higher than FLZ (74.4%, p < 0.05), mainly due to significantly higher ratio of patients with full recovery. The serum levels of biomarkers, including 5-HT, BDNF, NGF and β-EP, significantly elevated after eight weeks of treatment with RNSP, whereas the level of CGRP significantly decreased. The serum level of 5-HT exhibited significantly bigger percentage changes than other markers.Conclusion: In conclusion, RNSP was more effective than FLZ in relieving migraine after eight weeks continuous treatment. Serum 5-HT, BDNF, CGRP, NGF and β-EP were effective markers reflecting the response to RNSP and FLZ therapy. [ABSTRACT FROM AUTHOR]

The neurotransmitter serotonin (5-HT) is involved in several key processes in the central nervous system. But the great majority of serotonin is produced by intestinal enterochromaffin cells of the gastrointestinal (GI) tract and circulating blood platelets, which work independently of the central nervous system. The mediating pathway through which serotonin transmits its effects is the 5-HT receptor (5-HTR) superfamily, which consists of at least 14 members with extensive characterizations. Having been discovered as the final member of the 5-HTR family, 5-HT7 receptors have specific roles in the neurological, GI, circulatory, and immune systems. Due to their extensive distribution, these receptors' stimulation and repression are of importance during the therapy process, even if their exact mechanism of action in disease has not been fully understood. This review establishes the functions of 5-HT7Rs in systems and discusses how these receptors may be used therapeutically to treat peripheral diseases. [ABSTRACT FROM AUTHOR]