Elevated Serotonin Levels Research Articles

P0225 Histone Serotonylation (H3Q5ser): A Novel Epigenetic Signature in Crohn’s Disease Pathogenesis

Abstract Background Serotonin, predominantly produced in the gut, regulates key processes like intestinal inflammation. Elevated serotonin levels in intestinal mucosa are linked to increased severity of Crohn’s disease (CD) (1). Despite existing serotonin-targeting drugs for CD, their efficacy is limited due to gaps in understanding serotonin's roles (2). Serotonin can covalently bind to glutamine at histone H3 position 5, forming histone serotonylation (H3Q5ser) in vitro in peripheral blood mononuclear cells (PBMCs) (3). The enzyme TGM2, crucial for this binding, is highly expressed in inflamed CD mucosa (4). Suggesting a potential H3Q5ser enrichment CD patients. Here, we aim to investigate the association between this novel epigenetic signature and CD pathogenesis. Methods To establish a causative link between serotonin and H3Q5ser in vitro set up, PBMCs isolated from buffy coats were treated with increasing concentrations of serotonin, followed by Western blot (WB) analysis using an H3Q5ser antibody. Serotonin and H3Q5ser levels in the mucosa of CD tissue and HCs (Non-CD) were assessed using immunofluorescence staining (IF) alongside with CD45 to mark immune cells. Flow cytometry (FACS) and WB were performed to assess H3Q5ser in PBMCs and compare its levels between CD patients (n=14) and HCs (n=7). FACS was also used to investigate the distribution of H3Q5ser in PBMC subtypes comparing active CD (n=5), CD in remission (n=9) and HCs. The percentage of H3Q5ser+ cells and mean fluorescence intensity was quantified in CD14+ monocytes, CD19+ B cells and CD3+ T cells. Results PBMCs treated with serotonin exhibited a dose-dependent increase in H3Q5ser. IF revealed elevated serotonin levels in CD mucosal tissues, particularly in intestinal immune and epithelial cells, with nuclear localization in some cells, suggesting a potential enrichment of H3Q5ser. H3Q5ser levels were higher in CD mucosa, with abundant H3Q5ser+CD45+ cells in inflamed mucosa. FACS and WB analyses showed high abundance of H3Q5ser in CD45+ in PBMCs, with CD14+ monocytes exhibiting significantly higher H3Q5ser levels than other PBMC subsets. The percentage of H3Q5ser+CD45+ and H3Q5ser+CD14+ cells was markedly higher in CD patients. CD patients, both active and quiescent disease, demonstrated elevated H3Q5ser levels compared to HCs. Conclusion These data suggest a causative link between serotonin and H3Q5ser levels, demonstrating its higher levels in the mucosa and PBMCs of CD patients. H3Q5ser was enriched in CD14+ monocytes, both in active and quiescent CD, suggesting its contribution to immune dysregulation in CD. Future studies are warranted to map the genomic locations of H3Q5ser and to investigate its impact on transcriptional regulation explore potential therapeutic targets for CD. References 1-Ghiboub M et al. Sustained Diet-Induced Remission in Pediatric Crohn's Disease Is Associated With Kynurenine and Serotonin Pathways. Inflamm Bowel Dis. 2023 Jan 13:izac262. doi: 10.1093/ibd/izac262. Epub ahead of print. PMID: 36637175. 2-Hatamnejad MR, Baradaran Ghavami S, Shirvani M, Asghari Ahmadabad M, Shahrokh S, Farmani M, Sherkat G, Asadzadeh Aghdaei H, Zali MR. Selective serotonin reuptake inhibitors and inflammatory bowel disease; Beneficial or malpractice. Front Immunol. 2022 Oct 6;13:980189. doi: 10.3389/fimmu.2022.980189. PMID: 36275739; PMCID: PMC9583131. 3-Farrelly LA et al. Histone serotonylation is a permissive modification that enhances TFIID binding to H3K4me3. Nature. 2019 Mar;567(7749):535-539. doi: 10.1038/s41586-019-1024-7. Epub 2019 Mar 13. PMID: 30867594; PMCID: PMC6557285. 4-Jeong EM, Son YH, Choi Y, Kim JH, Lee JH, Cho SY, Kim IG. Transglutaminase 2 is dispensable but required for the survival of mice in dextran sulfate sodium-induced colitis. Exp Mol Med. 2016 Nov 4;48(11):e267. doi: 10.1038/emm.2016.95. PMID: 27811936; PMCID: PMC5133373.

The Influence of Serotonergic Signaling on Quality of Life, Depression, Insomnia, and Hypoxia in Obstructive Sleep Apnea Patients: Cross-Sectional Study.

Background/Objectives: Serotonin and the serotonin transporter (SERT) may have a multifaceted, but not fully understood, role in obstructive sleep apnea (OSA) and its impact on mental health in this group of patients. This study aimed to investigate changes in serotonin and the serotonin transporter (SERT) and their association with depressive and insomnia symptoms. Methods: This study included 76 participants (OSA group: n = 36, control group (CG): n = 40) who underwent polysomnography, while venous blood samples (evening and morning) were analyzed for serotonin and the SERT using ELISA. SERT mRNA expression in peripheral leukocytes was measured via quantitative reverse-transcription polymerase chain reaction (qRT-PCR). Participants were evaluated for depression, insomnia, and quality of life (QoL). Results: This study found no significant differences in SERT mRNA or serotonin between the OSA group and CG. In the CG, individuals without mood disorders had higher baseline SERT levels and evening/morning SERT ratios than those with depression. Among the OSA participants, those with good QoL had elevated serotonin levels in the evening (p = 0.028) and morning (p = 0.043) compared to those with poor QoL. Baseline SERT protein levels were higher in the CG than in the OSA group for insomnia, while SERT mRNA expression was higher in the OSA group. Linear regression models showed 13.3% and 13.1% for non-rapid eye movement sleep (NREM) apnea/hypopnea index (AHI) and AHI variability, respectively, which was accounted for by the morning SERT level, while 30.8% of the arousal index variability was explained by the morning serotonin level. Conclusions: Serotonergic signaling may influence quality of life, depression, and insomnia in OSA, as well as the severity of the disease itself. Stratifying patients by clinical and laboratory phenotypes could enable more personalized treatment.

Sodium butyrate mediates the MAPK signaling pathway and apoptosis and modulates intestinal flora to alleviate glycinin-induced intestinal injury in Cyprinus carpio.

The study investigated the potential alleviating effect of sodium butyrate (SB) on intestinal injuries caused by glycinin in the diet of common carp. Fish were divided into six groups: a control group (without glycinin and SB), a Gly group (with glycinin), and four groups supplemented with different doses of SB (0.75, 1.50, 2.25, and 3.00 g/kg) based on the Gly group. All diets were isonitrogenous and isoenergetic, and the fish were fed these diets for 8 weeks. The results indicated that glycinin activated the mitogen-activated protein kinase (MAPK) signaling pathway, leading to upregulating ERK, JNK, and p38 gene expression in the intestine. However, SB2 and SB3 groups were able to inhibit this pathway. Furthermore, glycinin upregulated the expression of proapoptotic genes (Bax, Caspase-3, Caspase-8, and Caspase-9) while downregulating the antiapoptotic gene Bcl2. The SB2 and SB3 groups were found to alleviate glycinin-induced apoptosis. Additionally, dietary glycinin significantly decreased the expression of tight junction genes (ZO-1, Claudin3, Claudin7, and Occludin1) in the intestine, whereas the SB2 and SB3 groups improved intestinal barrier function. Glycinin also elevated serum levels of d-lactate, diamine oxidase, serotonin, and endothelin, resulting in intestinal damage and increased permeability. In contrast, the SB2 and SB3 groups reduced these serum levels, thereby regulating intestinal permeability. Moreover, glycinin disrupted the intestinal morphology, which was mitigated by the SB2 and SB3 groups by increasing the height and width of intestinal villi folds. Lastly, dietary glycinin altered the intestinal microecological balance by increasing Proteobacteria abundance and decreasing Clostridium and Bacteroidetes abundance. The SB2 and SB3 groups modulated the composition of dominant taxa by increasing Firmicutes and Acidobacteria abundance. Overall, SB was found to mediate the MAPK signaling pathway, apoptosis, upregulation of tight junction genes, maintenance of the intestinal physical barrier, and regulation of intestinal flora, thereby alleviating glycinin-induced intestinal damage.

The Effect of Water-Soluble Alpinia Galanga Extract on Sleep and the Activation of the GABAAergic/Serotonergic Pathway in Mice.

Background/Objectives: With increasing interest in plant-based compounds that can enhance sleep quality without the side effects of caffeine, Alpinia galanga (AG) has emerged as a promising herbal supplement for improving mental alertness. This study assessed the impact of water-soluble AG extract on sleep quality; the activity of GABAergic, glutamatergic, and serotonergic receptors; and concentrations of dopamine and serotonin in the brains of mice. Methods: The study employed two experimental models using BALB/c mice to examine the impact of pentobarbital-induced sleep and caffeine-induced insomnia. In the first model, a set of 20 mice was assigned to four groups to assess the effects of pentobarbital (42 mg/kg) or pentobarbital with AG extract on sleep induction, with observations made 45 min post-administration. In the second model, 20 mice were divided into four groups to evaluate the impact of caffeine (25 mg/kg) alone or caffeine with varying doses of AG extract (61.25 or 205.50 mg/kg administered orally) on brain activity along with additional analyses on receptor proteins and neurotransmitters. Results: A higher dose of AG extract (205.50 mg/kg) significantly increased total deep sleep duration compared to the caffeine group (p < 0.0001). Furthermore, this dose extended sleep latency and suppressed GABAergic and glutamatergic receptor activity compared to the lower AG dose (p < 0.05). Additionally, the 205.50 mg/kg dose elevated serotonin and dopamine levels compared to caffeine (p < 0.0001), suggesting improved sleep quality alongside enhanced wakefulness. Conclusions: Our data indicate that a higher dose of AG extract improved sleep latency and duration by regulating GABAergic and glutamatergic receptors through the GABAergic/serotonergic pathway in mice.

Unveiling the intricacies of irritable bowel syndrome.

Irritable bowel syndrome (IBS) remains a challenging condition both for patients and clinicians, characterized by its chronic nature and the elusive complexity of its underlying mechanisms. The multifaceted relationship between the neuroendocrine axis, gut microbiota, and inflammatory response has emerged as a focal point in recent research, offering new insights into the pathophysiology of IBS. The neuroendocrine axis plays a crucial role in maintaining the delicate balance between the brain and the gut, often referred to as the "gut-brain axis". This bidirectional communication is essential for regulating gastrointestinal function, stress responses, and overall homeostasis. Dysregulation of this axis, as highlighted by elevated cortisol and serotonin levels in IBS patients, suggests that neuroendocrine imbalances may significantly contribute to the severity of gastrointestinal symptoms. These findings underscore the need for a broader understanding of how stress and emotional factors influence IBS, potentially guiding more effective, personalized treatment approaches. Equally important is the role of the gut microbiota, a diverse and dynamic ecosystem that directly impacts gut health. This dysbiosis disrupts gut function and appears to exacerbate the neuroendocrine and inflammatory responses. These findings align with the growing recognition that gut microbiota is a critical player in IBS, influencing both the disease's onset and progression.

Complementary interventions for cognitive rehabilitation in patients with cerebral palsy: a single-center study

Abstract Background Cerebral palsy (CP) is a neuromotor disorder that impairs a person’s ability to balance, stand, maintain posture, and walk. Research has indicated that Al Fatiha and negative air ion (NAI) are beneficial for ameliorating several behavioral, spiritual, physical, and societal issues. The objective of the present study was to assess the effect of Al Fatiha and NAI interventions on cognitive skills using Lumosity software. Methods This randomized control trial was conducted et al.-Umeed Rehabilitation Association, Karachi, Pakistan, between February and April 2021, following ethical approval (Ref: IBC-2017) from the University of Karachi. CP patients who volunteered for the study were randomly assigned to either the control group or to groups receiving interventions involving Al Fatiha and NAI exposure. Due to the limited number of consents obtained, participants were selected without consideration of age, cognition level, gender, mobility, motor type, and additional impairments. While all groups continued their regular therapies, the intervention groups underwent 31 structured sessions over a period of 6 weeks. Five Lumosity games were selected to assess the cognitive performance of all inducted participants in the three groups. Statistical analysis including paired t-tests, one-way analysis of variance (ANOVA), and post hoc tests was conducted using SPSS version 28 to compare outcomes among the three groups. Results Paired t-tests showed that the Al Fatiha intervention significantly enhanced selective attention (1133.3 ± 584.8, p &lt; .05) and working memory (31,036.2 ± 4013.9, p &lt; .001), while the NAI intervention resulted in improvements in information processing (31,036.2 ± 4013.9, p &lt; .01), selective attention (1150.0 ± 705.3, p &lt; .01), spatial fluency (6830.7 ± 4720.0, p &lt; .01), and spatial reasoning (8719.3 ± 3499.5, p &lt; .01). Apart from intervention groups, only spatial reasoning was improved in the control group (9068.3 ± 3450.1, p &lt; 0.05). One-way ANOVA and Tukey’s post hoc analysis showed significant differences among the control and intervention groups at baseline in information processing, selective attention, and spatial fluency. These cognitive functions are likely attributable to increased neuronal activity in the prefrontal cortex and elevated serotonin levels. Conclusion Based on the findings, both interventions are proposed as advanced, complementary, non-pharmacological, and cost-effective cognitive rehabilitation therapies for patients with CP. We recommend further research to validate these findings through second and third-phase clinical trials.

Unveiling tryptophan dynamics and functions across model organisms via quantitative imaging

BackgroundTryptophan is an essential amino acid involved in critical cellular processes in vertebrates, serving as a precursor for serotonin and kynurenine, which are key neuromodulators to influence neural and immune functions. Systematic and quantitative measurement of tryptophan is vital to understanding these processes.ResultsHere, we utilized a robust and highly responsive green ratiometric indicator for tryptophan (GRIT) to quantitatively measure tryptophan dynamics in bacteria, mitochondria of mammalian cell cultures, human serum, and intact zebrafish. At the cellular scale, these quantitative analyses uncovered differences in tryptophan dynamics across cell types and organelles. At the whole-organism scale, we revealed that inflammation-induced tryptophan concentration increases in zebrafish brain led to elevated serotonin and kynurenine levels, prolonged sleep duration, suggesting a novel metabolic connection between immune response and behavior. Moreover, GRIT’s application in detecting reduced serum tryptophan levels in patients with inflammation symptoms suggests its potential as a high-throughput diagnostic tool.ConclusionsIn summary, this study introduces GRIT as a powerful method for studying tryptophan metabolism and its broader physiological implications, paving the way for new insights into the metabolic regulation of health and disease across multiple biological scales.

New Role of the Serotonin as a Biomarker of Gut-Brain Interaction.

Serotonin (5-hydroxytryptamine: 5-HT), a neurotransmitter that regulates mood in the brain and signaling in the gut, has receptors throughout the body that serve various functions, especially in the gut and brain. Selective serotonin reuptake inhibitors (SSRIs) are used to treat depression, but their efficacy is uncertain. Depression is often associated with early gastrointestinal symptoms. Gut disorders such as functional dyspepsia (FD), irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), are linked to elevated serotonin levels. In this review, we would like to discuss the approach of using serotonin as a biomarker for gut-brain, and body-wide organ communication may lead to the development of preventive and innovative treatments for gut-brain disorders, offering improved visibility and therapeutic monitoring. It could also be used to gauge stress intensity for self-care and mental health improvement.

Metabolomics reveals altered metabolites in cirrhotic patients with severe portal hypertension in Tibetan population.

Portal hypertension (PHT) presents a challenging issue of liver cirrhosis. This study aims to identify novel biomarkers for severe PHT (SPHT) and explore the pathophysiological mechanisms underlying PHT progression. Twenty-three Tibetan cirrhotic patients who underwent hepatic venous pressure gradient (HVPG) measurement were included. Eleven patients had an HVPG between 5 mmHg and 15 mmHg (MPHT), while 12 had an HVPG ≥16 mmHg (SPHT). Peripheral sera were analyzed using liquid chromatograph-mass spectrometer for metabolomic assessment. An additional 14 patients were recruited for validation of metabolites. Seven hundred forty-five metabolites were detected and significant differences in metabolomics between MPHT and SPHT patients were observed. Employing a threshold of p < 0.05 and a variable importance in projection score >1, 153 differential metabolites were identified. A significant number of these metabolites were lipids and lipid-like molecules. Pisumionoside and N-decanoylglycine (N-DG) exhibited the highest area under the curve (AUC) values (0.947 and 0.9091, respectively). Additional differential metabolites with AUC >0.8 included 6-(4-ethyl-2-methoxyphenoxy)-3,4,5-trihydroxyoxane-2-carboxylic acid, sphinganine 1-phosphate, 4-hydroxytriazolam, 4,5-dihydroorotic acid, 6-hydroxy-1H-indole-3-acetamide, 7alpha-(thiomethyl)spironolactone, 6-deoxohomodolichosterone, glutaminylisoleucine, taurocholic acid 3-sulfate, and Phe Ser. Enzyme-linked immunosorbent assay further confirmed elevated levels of sphinganine 1-phosphate, N-DG, and serotonin in SPHT patients. Significant disruptions in linoleic acid, amino acid, sphingolipid metabolisms, and the citrate cycle were observed in SPHT patients. Pisumionoside and N-DG are identified as promising biomarkers for SPHT. The progression of PHT may be associated with disturbances in lipid, linoleic acid, and amino acid metabolisms, as well as alterations in the citrate cycle.

Sodium oligomannate activates the enteroendocrine-vagal afferent pathways in APP/PS1 mice.

Enteroendocrine cells (EECs) and vagal afferent neurons constitute functional sensory units of the gut, which have been implicated in bottom-up modulation of brain functions. Sodium oligomannate (GV-971) has been shown to improve cognitive functions in murine models of Alzheimer's disease (AD) and recently approved for the treatment of AD patients in China. In this study, we explored whether activation of the EECs-vagal afferent pathways was involved in the therapeutic effects of GV-971. We found that an enteroendocrine cell line RIN-14B displayed spontaneous calcium oscillations due to TRPA1-mediated calcium entry; perfusion of GV-971 (50, 100 mg/L) concentration-dependently enhanced the calcium oscillations in EECs. In ex vivo murine jejunum preparation, intraluminal infusion of GV-971 (500 mg/L) significantly increased the spontaneous and distension-induced discharge rate of the vagal afferent nerves. In wild-type mice, administration of GV-971 (100 mg· kg-1 ·d-1, i.g. for 7 days) significantly elevated serum serotonin and CCK levels and increased jejunal afferent nerve activity. In 7-month-old APP/PS1 mice, administration of GV-971 for 12 weeks significantly increased jejunal afferent nerve activity and improved the cognitive deficits in behavioral tests. Sweet taste receptor inhibitor Lactisole (0.5 mM) and the TRPA1 channel blocker HC-030031 (10 µM) negated the effects of GV-971 on calcium oscillations in RIN-14B cells as well as on jejunal afferent nerve activity. In APP/PS1 mice, co-administration of Lactisole (30 mg ·kg-1 ·d-1, i.g. for 12 weeks) attenuated the effects of GV-971 on serum serotonin and CCK levels, vagal afferent firing, and cognitive behaviors. We conclude that GV-971 activates sweet taste receptors and TRPA1, either directly or indirectly, to enhance calcium entry in enteroendocrine cells, resulting in increased CCK and 5-HT release and consequent increase of vagal afferent activity. GV-971 might activate the EECs-vagal afferent pathways to modulate cognitive functions.

VAERS Vasculitis Adverse Events Retrospective Study: Etiology Model of Immune Complexes Activating Fc Receptors in Kawasaki Disease and Multisystem Inflammatory Syndromes.

Vasculitis diseases include Kawasaki disease (KD), Kawasaki disease shock syndrome (KDSS), Multisystem Inflammatory Syndrome (MIS), Henoch-Schönlein purpura (HS), or IgA vasculitis, and additional vasculitis diseases. These diseases are often preceded by infections or immunizations. Disease incidence rates are higher in children than in adults. These diseases have been extensively studied, but understanding of the disease etiology remains to be established. Many studies have failed to demonstrate an association between vasculitis diseases and vaccination; this study examines possible associations. Herein, the Vaccine Adverse Event Reporting System (VAERS) database is retrospectively examined for associations between vasculitis diseases and immunizations. For some vaccines, the number of rare cases of KD, MIS, and HS are higher than the background rates. These rare cases are predicted to occur in individuals with (1) genetic risk factors with (2) antibody titer levels above the primary immune response level. Herein, the model of humoral immune response antibodies bound to antigens (pathogen or vaccine) creating immune complexes is proposed. These immune complexes are proposed to bind Fc receptors on immune cells and platelets, resulting in cell activation and the release of inflammatory molecules including histamine and serotonin. Immune complexes and inflammatory molecules including serotonin and histamine likely trigger vasculitis. Elevated serotonin and possibly histamine drive initial vasoconstrictions, disrupting blood flow. Increased blood flow pressure from cardiac capillary vasoconstrictions is predicted to trigger coronary artery aneurysms (CAA) or lesions (CAL) in some patients. For KDSS and MIS patients, these cardiac capillary vasoconstrictions are predicted to result in ischemia followed by ventricular dysfunction. Ongoing ischemia can result in long-term cardiac damage. Cases associated with pathogens are likely to have persistent infections triggering disease onset. The proposed model of immune complexes driving disease initial disease etiology by Fc receptor activation of immune cells and platelets, resulting in elevated histamine and serotonin levels, is testable and is consistent with disease symptoms and current treatments.

Sildenafil, alone and in combination with imipramine or escitalopram, display antidepressant-like effects in an adrenocorticotropic hormone-induced (ACTH) rodent model of treatment-resistant depression

BackgroundMajor depressive disorder (MDD) represents a challenge with high prevalence and limited effectiveness of existing treatments, particularly in cases of treatment-resistant depression (TRD). Innovative strategies and alternative drug targets are therefore necessary. Sildenafil, a selective phosphodiesterase type 5 (PDE5) inhibitor, is known to exert neuroplastic, anti-inflammatory, and antioxidant properties, and is a promising antidepressant drug candidate. AimTo investigate whether sildenafil monotherapy or in combination with a known antidepressant, can elicit antidepressant-like effects in an adrenocorticotropic hormone (ACTH)-induced rodent model of TRD. MethodsACTH-naïve and ACTH-treated male Sprague-Dawley (SD) rats received various sub-acute drug treatments, followed by behavioural tests and biochemical analyses conversant with antidepressant actions. ResultsSub-chronic ACTH treatment induced significant depressive-like behaviour in rats, evidenced by increased immobility during the forced swim test (FST). Sub-acute sildenafil (10 mg/kg) (SIL-10) (but not SIL-3), and combinations of imipramine (15 mg/kg) (IMI-15) and sildenafil (3 mg/kg) (SIL-3) or escitalopram (15 mg/kg) (ESC-15) and SIL-3, exhibited significant antidepressant-like effects. ACTH treatment significantly elevated hippocampal levels of brain-derived neurotrophic factor (BDNF), serotonin, norepinephrine, kynurenic acid (KYNUA), quinolinic acid (QUINA), and glutathione. The various mono- and combined treatments significantly reversed some of these changes, whereas IMI-15 + SIL-10 significantly increased glutathione disulfide levels. ESC-15 + SIL-3 significantly reduced plasma corticosterone levels. ConclusionThis study suggests that sildenafil shows promise as a treatment for TRD, either as a stand-alone therapy or in combination with a traditional antidepressant. The neurobiological mechanism underlying the antidepressant-like effects of the different sildenafil mono- and combination therapies reflects a multimodal action and cannot be explained in full by changes in the individually measured biomarker levels.

Terpenoids derived from Semen Ziziphi Spinosae oil enhance sleep by modulating neurotransmitter signaling in mice

Semen Ziziphi Spinosae oil (SZSO) is a natural vegetable oil extracted from Semen Ziziphi Spinosae, a traditional Chinese medicine renowned for its sleep-promoting properties, while the mechanisms are still unclear. Our findings revealed that the terpenoids present in SZSO (T-SZSO) were identified as the active components responsible for promoting sleep. Network pharmacological analysis suggested that T-SZSO targeted different sleep-aid pathways to varying degrees and exhibited potential for preventing central nervous system diseases. Notably, lupeol and betulinicaldehyde exhibited more pronounced effects. Additionally, T-SZSO significantly elevated serotonin levels, enhanced gamma-aminobutyric acid (GABA) synthesis, promoted GABA A receptor expression, and decreased glutamate and norepinephrine expression levels. Moreover, T-SZSO was found to downregulate IL-1β expression while upregulating superoxide dismutase and inducible nitric oxide synthase levels. In conclusion, this study presents the first investigation into the pharmacological basis of SZSO in promoting sleep and highlights the potential of nature food in improving suboptimal health conditions.

Exploring the antidepressant potential of raspberry ketone: Behavioural and neurochemical insights in a chronic unpredictable mild stress-induced depression model

Objectives: This research investigates the potential antidepressant properties of raspberry ketone (RK) using a chronic unpredictable mild stress-induced depression model in mice. Materials and Methods: Through a comprehensive examination encompassing behavioural and neurochemical assessments, the study reveals promising outcomes. RK administration results in significant enhancements in locomotor activity, reductions in immobility time and improvements in sucrose preference, indicative of antidepressant-like effects. Results: RK treatment leads to elevated levels of dopamine and serotonin, coupled with a decrease in inflammatory cytokines, suggesting a multifaceted mechanism underlying its therapeutic potential. Conclusion: These findings underscore the promise of RK as a novel antidepressant agent, with implications for developing alternative and potentially more tolerable treatments for depression. Further, exploration into its mechanisms and clinical applicability is warranted.

Oleanolic acid-based therapeutics ameliorate rotenone-induced motor and depressive behaviors in parkinsonian male mice via controlling neuroinflammation and activating Nrf2-BDNF-dopaminergic signaling pathways

Parkinson’s disease (PD) is often accompanied by depression, which may appear before motor signs. Oleanolic acid (OA), a pentacyclic triterpenoid substance, have many pharmacological properties. However, its efficacy in treating PD-related chronic unpredictable stress (CUS) is unknown. Our study used behavioral, biochemical, and immunohistochemical techniques to assess how OA affected PDrelated CUS. Rotenone (1 mg/kg i.p. for first 21 days) was used to induce Parkinsonism, and modest psychological & environmental stresses generated CUS (from day 22 to day 43) in animals. The study included daily i.p.administration of OA (5, 10, and 20 mg/kg) from day 1 to day 57 in male swiss albino mice. Animals were evaluated for behavioral, biochemical parameters, neurotransmitters, and immunohistochemical expression following the treatment. Results of the study revealed that treatment with OA at all doses alleviated the core symptoms of CUS linked to PD and improved motor and non-motor function. OA therapy significantly lowered IL-1β, TNF-α (p < 0.01, < 0.01, < 0.001), IL-6 (p < 0.05, < 0.01, < 0.001), oxidative stress (p < 0.05, < 0.01, < 0.01), and elevated norepinephrine (p < 0.05, < 0.01, < 0.01), dopamine, and serotonin (p < 0.05, < 0.01, < 0.001) levels. Moreover, OA therapy substantially reduced α-synuclein (p < 0.05, < 0.01, < 0.01) aggregation and increased BDNF (p < 0.05, < 0.01, < 0.001) & Nrf-2 (p < 0.05, < 0.01, < 0.01) levels, which boosts neuronal dopamine survival. The study’s findings indicated that OA ameliorates depressive-like behavior persuaded by CUS in PD, decreases neuroinflammation, and improves neurotransmitter concentration via activating Nrf2-BDNF-dopaminergic pathway.

Serum melatonin and serotonin levels in long-term skilled meditators.

Melatonin and its precursor serotonin are neurochemicals that play an important role in the physiological regulation of mood, sleep, and behavior. Studies have suggested the possibility of changes in the levels of melatonin and serotonin following meditation. However, the outcome of Buddhist meditation on both these two neurochemicals collectively have not been studied yet. To assess the effect of Vipassana meditation on serum melatonin and serotonin levels in long-term meditators and to compare them with an age, gender, and education level matched, non-meditating control group. The serum melatonin and serotonin levels of long-term meditators (n=30), recruited using a validated interview, and age, gender and educational level matched control subjects (n=30) who had never practiced meditation, were determined using commercial ELISA kits (LDN, Nordhorn, Germany). The median concentration of melatonin (18.3 pg/ml) and serotonin (149.0 ng/ml) in the meditator group, were significantly higher compared to the control group; melatonin (15.6 pg/ml; p=0.006), serotonin (118.1 ng/ml; p < 0.001). The levels had no significant correlation with demographic factors but positively correlated with meditation factors in those who had meditated for <=10years (n=26, p < 0.05). The findings indicate elevated melatonin and serotonin levels in the long-term meditators with potential beneficial effects in decreasing stress and improving relaxation in individuals.

Plasma Serotonin and Cardiovascular Outcomes in Chronic Kidney Disease.

Background Platelet-poor plasma serotonin levels are associated with adverse cardiovascular outcomes. Although plasma serotonin levels increase in chronic kidney disease, the cardiovascular implications remain unknown. Methods and Results In 1114 participants from the prospective CRIC (Chronic Renal Insufficiency Cohort) Study, we evaluated the association between plasma serotonin, categorized as undetectable, intermediate, and high (≥20 ng/mL) levels, and cross-sectional findings on echocardiography, including left ventricular hypertrophy, left ventricular ejection fraction, and pulmonary hypertension. We also analyzed whether serotonin was associated with time-to-event cardiovascular outcomes, including heart failure hospitalization and atherosclerotic cardiovascular disease (ASCVD) events, in addition to mortality. Because selective serotonin reuptake inhibitors decrease plasma serotonin levels, we specifically evaluated the influence of selective serotonin reuptake inhibitor use in the relationship between serotonin and outcomes. Plasma serotonin level inversely correlated with estimated glomerular filtration rate and directly correlated with blood pressure. High plasma serotonin was associated with left ventricular hypertrophy (adjusted odds ratio, 2.74 [95% CI, 1.11-7.41]). In contrast, undetectable plasma serotonin level was associated with the highest risk of heart failure (adjusted hazard ratio [HR], 2.26 [95% CI, 1.40-3.66]) and ASCVD events (adjusted HR, 1.96 [95% CI, 1.15-3.32]). Conclusions In a large chronic kidney disease cohort, plasma serotonin levels correlated with blood pressure, and elevated serotonin levels were associated with left ventricular hypertrophy. In contrast, undetectable plasma serotonin was associated with the highest risk of heart failure and ASCVD events.

Upregulation of serotonin by sodium benzoate and sodium metabisulfite may activate caloric restriction which could enhance longevity and cognition

Sodium benzoate and sodium metabisulfite are two of the most common artificial preservatives found in processed food. Little is known about their long-term effects on the health of consumers. Studies that investigated the potential toxic effects of these compounds have also reported a side effect of lifespan extension in the animals tested. Although lifespan extension was not the main focus of these studies, it is a noteworthy observation that warrants further investigation and discussion. Several studies also reported that animals fed with sodium benzoate and sodium metabisulfite had a reduction in their appetite, which was accompanied by an improvement in their health. This suggests that caloric restriction was likely activated when the appetite was reduced, which led to the extended lifespan observed in the animals fed with sodium benzoate and sodium metabisulfite. In addition to being implicated in longevity and appetite suppression, sodium benzoate and sodium metabisulfite are also thought to augment serotonin production. Serotonin stimulates the anorexigenic pathway leading to satiety, which could trigger caloric restriction. The elevated serotonin level may also induce a nootropic action, enhancing neurocognition. We hypothesize that sodium benzoate and sodium metabisulfite could upregulate serotonin synthesis, activating caloric restriction and leading to prolonged lifespan and enhanced cognitive function.

Late-stage diagnosis of carcinoid heart disease due to lack of access to health care

Carcinoid syndrome (CS) is a unique constellation of symptoms caused by release of vasoactive substances from neuroendocrine tumors (Pandit et al., StatPearls, 2022). Neuroendocrine tumors are rare with an annual incidence of 2 in 100,000 people (Ram et al., 46:21-27, 2019). Up to 50% of patients with these tumors will develop carcinoid syndrome, which is characterized by symptoms caused by elevated levels of serotonin and most commonly include fatigue, flushing, wheezing, and non-specific gastrointestinal symptoms such as diarrhea and malabsorption (Pandit et al., StatPearls, 2022) (Fox et.al., 90:1224-1228, 2004). Over time, patients with carcinoid syndrome can develop carcinoid heart disease (CHD). CHD refers to the cardiac complications that occur when the vasoactive substances, such as serotonin, tachykinins, and prostaglandins, secreted from the carcinoid tumors. These complications most commonly include valvular abnormalities, but can also present as coronary artery damage, arrhythmias or direct myocardial injury (Ram et al., 46:21-27, 2019). While CHD is not typically an initial feature of carcinoid syndrome, it does eventually occur in up to 70% of patients with carcinoid tumors (Ram et al., 46:21-27, 2019) (Jin et.al., 146:65-73, 2021) (Macfie et.al., 224:665-669, 2022). CHD is associated with significant morbidity and mortality due to the risk of progressive heart failure (Bober et.al., 14:1179546820968101, 2020). In this case, we describe a 35-year-old Hispanic woman in South Texas with undiagnosed carcinoid syndrome for over 10 years that eventually progressed to severe CHD. In this patient’s case, we emphasize how lack of access to healthcare resulted in delay of diagnosis, appropriate treatment, and worsened prognosis in this young patient.

Pulmonary ILC2-derived serotonin mediates RSV-evoked airway hyperreactivity in mice

Abstract Respiratory syncytial virus (RSV) infection is epidemiologically linked to asthma. During RSV infection, lung epithelial cell-released IL-33 is elevated and promotes group 2 innate lymphoid cells (ILC2s) activation, leading to type 2 cytokines production and asthma development. Serotonin is a neurotransmitter involved in numerous biological functions in the central nervous system as well as peripheral tissues. Previous studies have found elevated serotonin levels in plasma and bronchoalveolar lavage fluid (BALF) from asthma patients, implying that serotonin may involve in the pathogenesis of asthma. Therefore, we aimed to elucidate the role of ILC2-released serotonin in the regulation of RSV-induced airway hyperreactivity (AHR). To investigate whether ILC2 would secrete serotonin upon activation, pulmonary ILC2s were sorted from C57BL/6 mice and then treated with IL-33 in vitro, and we found an increase in the production of serotonin from IL-33-activated ILC2s. Furthermore, elevated BALF serotonin levels were also found in RSV-infected mice. Moreover, we clarified that ILC2 as a major source of serotonin during RSV infection. Next, to determine the role of serotonin in RSV-evoked AHR, we found that the treatment of Clozapine (serotonin receptor inhibitor) significantly attenuated AHR and decreased IL-13 expression. Meanwhile, we demonstrated that the administration of exogenous serotonin exacerbated RSV-caused AHR. Furthermore, serotonin enhanced IL-5 and IL-13 production from IL-33-activated ILC2 in vitro. Taken together, our results indicated that pulmonary ILC2-derived serotonin contributes to RSV-evoked AHR and exacerbates type 2 cytokines through a positive regulation of ILC2 function.