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1.
eNeuro ; 11(2)2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38355299

RESUMO

A current hypothesis to explain the limited recovery following brain and spinal cord trauma stems from the dogma that neurons in the mammalian central nervous system lack the ability to regenerate their axons after injury. Serotonin (5-HT) neurons in the adult brain are a notable exception in that they can slowly regrow their axons following chemical or mechanical lesions. This process of regrowth occurs without intervention over several months and results in anatomical recovery that approximates the preinjured state. During development, serotonin is a trophic factor, playing a role in both cell survival and axon growth. Additionally, some studies have shown that stroke patients treated after injury with serotonin selective reuptake inhibitors (SSRIs) appeared to have improved recovery. To test the hypothesis that serotonin can influence the regrowth of 5-HT axons, mice received a high dose of para-chloroamphetamine (PCA) to induce widespread retrograde degeneration of 5-HT axons. Then, after a short rest period to avoid any interaction with the acute injury phase, SSRIs were administered daily for 6 or 10 weeks. Using immunohistochemistry in 5-HT transporter-GFP BAC transgenic mice, we determined that while PCA led to a rapid initial decrease in total 5-HT axon length in the somatosensory cortex, visual cortex, or area CA1 of the hippocampus, treatment with either fluoxetine or sertraline (two different SSRIs) did not affect the recovery of axon length. These results suggest that chronic SSRI treatment does not affect the regrowth of 5-HT axons and argue against SSRIs as a potential therapy following brain injury.


Assuntos
Inibidores Seletivos de Recaptação de Serotonina , Serotonina , Humanos , Adulto , Camundongos , Animais , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Anfetamina , Fluoxetina/farmacologia , Axônios/fisiologia , Prosencéfalo , Camundongos Transgênicos , Mamíferos
2.
Pharmacol Res Perspect ; 12(1): e1175, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38339883

RESUMO

The aim of this study was to investigate the functional role of phosphodiesterase enzymes (PDE) in the isolated porcine ureter. Distal ureteral strips were mounted in organ baths and pre-contracted with 5-HT (100 µM). Upon generation of stable phasic contractions, PDE-4 and PDE-5 inhibitors were added cumulatively to separate tissues. PDE-4 inhibitors, such as rolipram (10 nM and greater) and roflumilast (100 nM and greater), resulted in significant attenuation of ureteral contractile responses, while a higher concentration of piclamilast (1 µM and greater) was required to induce a significant depressant effect. The attenuation effect by rolipram was abolished by SQ22536 (100 µM). PDE-5 inhibitors, such as sildenafil and tadalafil, were not nearly as effective and were only able to suppress the 5-HT-induced contractions at higher concentrations of 1 µM. Rolipram significantly enhanced the depressant effect of forskolin, while sodium nitroprusside-induced attenuation of contractile responses remained unchanged in the presence of tadalafil. In summary, our study demonstrates that PDE-4 inhibitors are effective in attenuating 5-HT-induced contractility in porcine distal ureteral tissues, while PDE-5 inhibitors are less effective. These findings suggest that PDE-4 inhibitors, such as rolipram, may hold promise as potential therapeutic agents for the treatment of ureteral disorders attributable to increased intra-ureteral pressure.


Assuntos
Inibidores da Fosfodiesterase 4 , Ureter , Animais , Suínos , Rolipram/farmacologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4 , Isoenzimas , Inibidores da Fosfodiesterase 5/farmacologia , Inibidores da Fosfodiesterase 4/farmacologia , Ureter/fisiologia , Serotonina/farmacologia , Tadalafila
3.
Amino Acids ; 56(1): 13, 2024 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-38340185

RESUMO

Behavioral and functional studies describe hemispheric asymmetry in anxiety and metabolic behaviors in responses to stress. However, no study has reported serotonergic receptor (the 5-HT1A receptor) lateralization in the basolateral amygdala (BLA) in vivo on anxiety and metabolic behaviors under stress. In the present study, the effect of unilateral and bilateral suppression of the 5-HT1A receptor in the BLA on anxiety, and metabolic responses to chronic restraint stress was assessed. Male Wistar rats 7 days after cannulation into the BLA received chronic restraint stress for 14 consecutive days. 20 minutes before induction of stress, WAY-100-635 (selective 5-HT1A antagonist) or sterile saline (vehicle) was administered either uni- or bi-laterally into the BLA. Behavioral (elevated plus maze; EPM, and open field test), and metabolic parameter studies were performed. Results showed that stress causes a significant increase in weight gain compared to control. In the non-stress condition, the left and bilaterally, and in the stress condition the right, left, and both sides, inhibition of 5-HT1A in the BLA reduced weight gain. In the restraint stress condition, only inhibition of the 5-HT1A receptor in the left BLA led to decreased food intake compared to the control group. In stress conditions, inhibition of the 5-HT1A receptor on the right, left, and bilateral BLA increased water intake compared to the stress group. Inhibition of the 5-HT1A receptor on the left side of the BLA by WAY-100-635 induced anxiety-like behaviors in stressed rats. Similarly, WAY-100-635 on the left BLA effectively caused anxiety-like behaviors in both EPM and open field tests in the control animals. In conclusion, it seems that 5-HT1A receptors in the left BLA are more responsible for anxiety-like behaviors and metabolic changes in responses to stress.


Assuntos
Complexo Nuclear Basolateral da Amígdala , Ratos , Masculino , Animais , Complexo Nuclear Basolateral da Amígdala/metabolismo , Serotonina/metabolismo , Receptor 5-HT1A de Serotonina/metabolismo , Ratos Wistar , Ansiedade , Aumento de Peso
4.
Int J Mol Sci ; 25(3)2024 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-38338762

RESUMO

Serotonin or 5-hydroxytryptamine (5-HT) is a ubiquitous neuro-modulator-transmitter that acts in the central nervous system, playing a major role in the control of breathing and other physiological functions. The midbrain, pons, and medulla regions contain several serotonergic nuclei with distinct physiological roles, including regulating the hypercapnic ventilatory response, upper airway patency, and sleep-wake states. Obesity is a major risk factor in the development of sleep-disordered breathing (SDB), such as obstructive sleep apnea (OSA), recurrent closure of the upper airway during sleep, and obesity hypoventilation syndrome (OHS), a condition characterized by daytime hypercapnia and hypoventilation during sleep. Approximately 936 million adults have OSA, and 32 million have OHS worldwide. 5-HT acts on 5-HT receptor subtypes that modulate neural control of breathing and upper airway patency. This article reviews the role of 5-HT in SDB and the current advances in 5-HT-targeted treatments for SDB.


Assuntos
Síndromes da Apneia do Sono , Apneia Obstrutiva do Sono , Humanos , Serotonina , Síndromes da Apneia do Sono/complicações , Obesidade/complicações , Sono , Hipercapnia
5.
J Phys Chem Lett ; 15(6): 1711-1718, 2024 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-38319949

RESUMO

The structure and dynamics of the lipid membrane can affect the activity of membrane proteins. Therefore, small lipophilic molecules that alter membrane properties (such as the neurotransmitter serotonin) can potentially modulate receptor activity without binding to the receptor. Here, we investigated how the activity of neuropeptide Y type 4 receptor (Y4R, reconstituted in lipid bicelles) is modulated by serotonin, which has no known interaction with Y4R. We found a serotonin-concentration-dependent decrease (down to 0.1 mM of serotonin) in the ligand affinity of Y4R. This effect correlates with a serotonin-induced reduction of the resistance of the bilayer to indentation (measured by atomic force microscopy) and bilayer thickness (measured by solid state NMR) in two different types of zwitterionic lipid bicelles. Our findings indicate a "membrane-mediated allosteric effect" of serotonin on the activation of Y4R and suggest the potential for developing pharmacophores, which can modulate cellular signaling without directly interacting with any receptor.


Assuntos
Receptores Acoplados a Proteínas G , Serotonina , Receptores de Neuropeptídeo Y/metabolismo , Proteínas de Membrana/química , Lipídeos , Bicamadas Lipídicas/química
6.
PeerJ ; 12: e16858, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38313029

RESUMO

A multitude of species engages in social interactions not only with their conspecifics but also with other species. Such interspecific interactions can be either positive, like helping, or negative, like aggressive behaviour. However, the physiological mechanisms of these behaviours remain unclear. Here, we manipulated the serotonin system, a well-known neurohormone for regulating intraspecific aggressive behaviour, to investigate its role in interspecific aggression. We tested whether serotonin blockade affects the aggressive behaviour of a coral reef fish species (Ctenochaetus striatus) that engages in mutualistic interactions with another species, the cleaner fish (Labroides dimidiatus). Although this mutualistic cleaning relationship may appear positive, cleaner fish do not always cooperate and remove ectoparasites from the other coral reef fish ("clients") but tend to cheat and bite the client's protective layer of mucus. Client fish thus often apply control mechanisms, like chasing, to deter their cleaner fish partners from cheating. Our findings show that blocking serotonin receptors 5-HT2A and 5-HT2C with ketanserin reduced the client fish's aggressive behaviour towards cleaner fish, but in the context where the latter did not cheat. These results are evidence of the involvement of serotonin in regulating aggressive behaviour at the between-species social interactions level. Yet, the direction of effect we found here is the opposite of previous findings using a similar experimental set-up and ecological context but with a different client fish species (Scolopsis bilineatus). Together, it suggests that serotonin's role in aggressive behaviour is complex, and at least in this mutualistic ecological context, its function is species-dependent. This warrants, to some extent, careful interpretations from single-species studies looking into the physiological mechanisms of social behaviour.


Assuntos
Perciformes , Serotonina , Humanos , Animais , Ketanserina/farmacologia , Serotonina/farmacologia , Agressão , Interação Social , Recifes de Corais , Peixes/parasitologia , Perciformes/fisiologia
7.
Sci Rep ; 14(1): 2651, 2024 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-38302683

RESUMO

Cardiovascular disease (CVD) represents one of the main causes of mortality worldwide and nearly a half of it is related to ischemic heart disease (IHD). The article represents a comprehensive study on the diagnostics of IHD through the targeted metabolomic profiling and machine learning techniques. A total of 112 subjects were enrolled in the study, consisting of 76 IHD patients and 36 non-CVD subjects. Metabolomic profiling was conducted, involving the quantitative analysis of 87 endogenous metabolites in plasma. A novel regression method of age-adjustment correction of metabolomics data was developed. We identified 36 significantly changed metabolites which included increased cystathionine and dimethylglycine and the decreased ADMA and arginine. Tryptophan catabolism pathways showed significant alterations with increased levels of serotonin, intermediates of the kynurenine pathway and decreased intermediates of indole pathway. Amino acid profiles indicated elevated branched-chain amino acids and increased amino acid ratios. Short-chain acylcarnitines were reduced, while long-chain acylcarnitines were elevated. Based on these metabolites data, machine learning algorithms: logistic regression, support vector machine, decision trees, random forest, and gradient boosting, were used for IHD diagnostic models. Random forest demonstrated the highest accuracy with an AUC of 0.98. The metabolites Norepinephrine; Xanthurenic acid; Anthranilic acid; Serotonin; C6-DC; C14-OH; C16; C16-OH; GSG; Phenylalanine and Methionine were found to be significant and may serve as a novel preliminary panel for IHD diagnostics. Further studies are needed to confirm these findings.


Assuntos
Doenças Cardiovasculares , Isquemia Miocárdica , Humanos , Serotonina , Aminoácidos , Metabolômica/métodos , Aminoácidos de Cadeia Ramificada/metabolismo , Isquemia Miocárdica/complicações , Doenças Cardiovasculares/etiologia
8.
BMC Microbiol ; 24(1): 48, 2024 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-38302874

RESUMO

BACKGROUND: Pediatric chronic intestinal pseudo-obstruction (PIPO) is a rare disease characterized by symptoms and radiological signs suggestive of intestinal obstruction, in the absence of lumen-occluding lesions. It results from an extremely severe impairment of propulsive motility. The intestinal endocrine system (IES) jointly with the enteric nervous system (ENS) regulates secreto-motor functions via different hormones and bioactive messengers/neurotransmitters. The neurotransmitter 5-hydroxytryptamine (5-HT) (or serotonin) is linked to intestinal peristalsis and secretory reflexes. Gut microbiota and its interplay with ENS affect 5-HT synthesis, release, and the subsequent serotonin receptor activation. To date, the interplay between 5-HT and gut microbiota in PIPO remains largely unclear. This study aimed to assess correlations between mucosa associated microbiota (MAM), intestinal serotonin-related genes expression in PIPO. To this purpose, biopsies of the colon, ileum and duodenum have been collected from 7 PIPO patients, and 7 age-/sex-matched healthy controls. After DNA extraction, the MAM was assessed by next generation sequencing (NGS) of the V3-V4 region of the bacterial RNA 16 S, on an Illumina Miseq platform. The expression of genes implicated in serotoninergic pathway (TPH1, SLC6A4, 5-HTR3 and 5-HTR4) was established by qPCR, and correlations with MAM and clinical parameters of PIPO have been evaluated. RESULTS: Our results revealed that PIPO patients exhibit a MAM with a different composition and with dysbiosis, i.e. with a lower biodiversity and fewer less connected species with a greater number of non-synergistic relationships, compared to controls. qPCR results revealed modifications in the expression of serotonin-related intestinal genes in PIPO patients, when compared to controls. Correlation analysis do not reveal any kind of connection. CONCLUSIONS: For the first time, we report in PIPO patients a specific MAM associated to underlying pathology and an altered intestinal serotonin pathway. A possible dysfunction of the serotonin pathway, possibly related to or triggered by an altered microbiota, may contribute to dysmotility in PIPO patients. The results of our pilot study provide the basis for new biomarkers and innovative therapies targeting the microbiota or serotonin pathways in PIPO patients.


Assuntos
Microbioma Gastrointestinal , Pseudo-Obstrução Intestinal , Humanos , Criança , Serotonina/metabolismo , Projetos Piloto , Intestinos , Pseudo-Obstrução Intestinal/genética , Pseudo-Obstrução Intestinal/diagnóstico , Proteínas da Membrana Plasmática de Transporte de Serotonina
9.
Chem Biol Drug Des ; 103(2): e14479, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38361139

RESUMO

Depression is not similar to daily mood fluctuations and temporary emotional responses to day-to-day activities. Depression is not a passing problem; it is an ongoing problem. It deals with different episodes consisting of several symptoms that last for at least 2 weeks. It can be seen for several weeks, months, or years. At its final stage, or can say, in its worst condition, it can lead to suicide. Antidepressants are used to inhibit the reuptake of the neurotransmitters by some selective receptors, which increase the concentration of specific neurotransmitters around the nerves in the brain. Drugs that are currently being used for the management of various types of depression include selective serotonin reuptake inhibitors, tricyclic antidepressants, atypical antidepressants, serotonin, noradrenaline reuptake inhibitors, etc. In this review, we have outlined different symptoms, causes, and recent advancements in nitrogen-containing heterocyclic drug candidates for the management of depression. This article highlights the various structural features along with the structure-activity relationship (SAR) of nitrogen-containing heterocyclics that play a key role in binding at target sites for potential antidepressant action. The in silico studies were carried out to determine the binding interactions of the target ligands with the receptor site to determine the potential role of substitution patterns at core pharmacophoric features. This article will help medicinal chemists, biochemists, and other interested researchers in identifying the potential pharmacophores as lead compounds for further development of new potent antidepressants.


Assuntos
Antidepressivos , Depressão , Humanos , Depressão/tratamento farmacológico , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Antidepressivos Tricíclicos , Inibidores Seletivos de Recaptação de Serotonina , Serotonina
10.
Skin Res Technol ; 30(2): e13606, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38363081

RESUMO

BACKGROUND: Dopamine (D) and serotonin (5-HT) pathways contribute to psoriasis pathobiology. Disruptions incite increased inflammatory mediators, keratinocyte activation and deterioration, and worsening symptoms. Brilaroxazine (RP5063), which displays potent high binding affinity to D2/3/4 and 5-HT1A/2A/2B/7 receptors and a moderate affinity to serotonin transporter (SERT), may affect the underlying psoriasis pathology. METHODS: An imiquimod-induced psoriatic mouse model (BALB/c) evaluated brilaroxazine's activity in a topical liposomal-aqueous gel (Lipogel) formulation. Two of the three groups (n = 6 per) underwent induction with 5% imiquimod, and one group received topical brilaroxazine Lipogel (Days 1-11). Assessments included (1) Psoriasis Area and Severity Index (PASI) scores (Days 1-12), skin histology for Baker score based on H&E stained tissue (Day 12), and serum blood collection for serum cytokine analysis (Day 12). One-way ANOVA followed by post hoc Dunnett's t-test evaluated significance (p < 0.05). RESULTS: Imiquimod-induced animal Baker scores were higher versus Sham non-induced control's results (p < 0.001). Brilaroxazine Lipogel had significantly (p = 0.003) lower Baker scores versus the induced Psoriasis group. Brilaroxazine PASI scores were lower (p = 0.03) versus the induced Psoriasis group (Days 3-12), with the greatest effect in the last 3 days. The induced Psoriasis group showed higher Ki-67 and TGF-ß levels versus non-induced Sham controls (p = 0.001). The brilaroxazine Lipogel group displayed lower levels of these cytokines versus the induced Psoriasis group, Ki-67 (p = 0.001) and TGF-ß (p = 0.008), and no difference in TNF-α levels versus Sham non-induced controls. CONCLUSION: Brilaroxazine Lipogel displayed significant activity in imiquimod-induced psoriatic animals, offering a novel therapeutic strategy.


Assuntos
Fármacos Dermatológicos , Psoríase , Animais , Camundongos , Imiquimode/efeitos adversos , Antígeno Ki-67/metabolismo , Serotonina/metabolismo , Serotonina/farmacologia , Serotonina/uso terapêutico , Psoríase/induzido quimicamente , Psoríase/tratamento farmacológico , Pele/patologia , Fármacos Dermatológicos/farmacologia , Citocinas/metabolismo , Citocinas/farmacologia , Citocinas/uso terapêutico , Fator de Crescimento Transformador beta/metabolismo , Fator de Crescimento Transformador beta/farmacologia , Fator de Crescimento Transformador beta/uso terapêutico , Modelos Animais de Doenças
11.
J Mol Neurosci ; 74(1): 21, 2024 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-38363395

RESUMO

The conventional method of one drug being used for one target has not yielded therapeutic solutions for Lewy body dementia (LBD), which is a leading progressive neurological disorder characterized by significant loss of neurons. The age-related disease is marked by memory loss, hallucinations, sleep disorder, mental health deterioration, palsy, and cognitive impairment, all of which have no known effective cure. The present study deploys a network medicine pipeline to repurpose drugs having considerable effect on the genes and proteins related to the diseases of interest. We utilized the novel SAveRUNNER algorithm to quantify the proximity of all drugs obtained from DrugBank with the disease associated gene dataset obtained from Phenopedia and targets in the human interactome. We found that most of the 154 FDA-approved drugs predicted by SAveRUNNER were used to treat nervous system disorders, but some off-label drugs like quinapril and selegiline were interestingly used to treat hypertension and Parkinson's disease (PD), respectively. Additionally, we performed gene set enrichment analysis using Connectivity Map (CMap) and pathway enrichment analysis using EnrichR to validate the efficacy of the drug candidates obtained from the pipeline approach. The investigation enabled us to identify the significant role of the synaptic vesicle pathway in our disease and accordingly finalize 8 suitable antidepressant drugs from the 154 drugs initially predicted by SAveRUNNER. These potential anti-LBD drugs are either selective or non-selective inhibitors of serotonin, dopamine, and norepinephrine transporters. The validated selective serotonin and norepinephrine inhibitors like milnacipran, protriptyline, and venlafaxine are predicted to manage LBD along with the affecting symptomatic issues.


Assuntos
Doença por Corpos de Lewy , Doença de Parkinson , Humanos , Doença por Corpos de Lewy/tratamento farmacológico , Doença por Corpos de Lewy/genética , Doença por Corpos de Lewy/complicações , Serotonina/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Antidepressivos/uso terapêutico , Norepinefrina
12.
Handb Clin Neurol ; 199: 17-42, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38307644

RESUMO

The advent of the triptans revolutionized acute migraine treatment. The older migraine-specific drugs, the ergot alkaloids (ergotamine and dihydroergotamine), also relieve migraine attacks through agonism at the 5-HT1B and 5-HT1D receptors, but the triptans have much greater specificity for these receptors. Unlike the ergot alkaloids, the triptans do not activate many other receptor types, and therefore are much better tolerated. This reduction in side effects greatly enhanced their clinical utility as it allowed a far greater proportion of patients to take a full therapeutic dose. As a result, the clinical use of ergotamine is minimal today, although dihydroergotamine still has a significant clinical role. There is extensive evidence that the seven triptans available today, sumatriptan, zolmitriptan, rizatriptan, eletriptan, naratriptan, almotriptan, and frovatriptan, are effective in the acute treatment of migraine. Available formulations include oral tablets, orally dissolving tablets, subcutaneous injections, nasal sprays, and in some countries, rectal suppositories. For optimal benefit, therapy needs to be individualized for a given patient both regarding the triptan chosen and the formulation. This chapter discusses the ergot alkaloids and the triptans, including mechanism of action, evidence for efficacy, clinical use, and adverse effects.


Assuntos
Ergotamina , Transtornos de Enxaqueca , Agonistas do Receptor 5-HT1 de Serotonina , Humanos , Di-Hidroergotamina/uso terapêutico , Ergotamina/uso terapêutico , Transtornos de Enxaqueca/tratamento farmacológico , Serotonina/uso terapêutico , Triptaminas/uso terapêutico , Agonistas do Receptor 5-HT1 de Serotonina/uso terapêutico
13.
Int J Mol Sci ; 25(3)2024 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-38338923

RESUMO

The aetiology of acute appendicitis (AA), the most frequent abdominal surgical emergency, is still unclarified. Recent epidemiologic, clinical and laboratorial data point to an allergic component in the pathophysiology of AA. Mastocytes participate in the Th2 immune response, releasing inflammatory mediators from their granules upon stimulation by IgE-specific antigens. Among the well-known mediators are histamine, serotonin and tryptase, which are responsible for the clinical manifestations of allergies. We conducted a prospective single-centre study to measure histamine and serotonin (commercial ELISA kit) and tryptase (ImmunoCAP System) concentrations in appendicular lavage fluid (ALF) and serum. Consecutive patients presenting to the emergency department with a clinical diagnosis of AA were enrolled: 22 patients with phlegmonous AA and 24 with gangrenous AA The control group was composed of 14 patients referred for colectomy for colon malignancy. Appendectomy was performed during colectomy. Tryptase levels were strikingly different between histological groups, both in ALF and serum (p < 0.001); ALF levels were higher than serum levels. Tryptase concentrations in ALF were 109 times higher in phlegmonous AA (APA) (796.8 (194.1-980.5) pg/mL) and 114 times higher in gangrenous AA (AGA) (837.4 (272.6-1075.1) pg/mL) than in the control group (7.3 (4.5-10.3) pg/mL. For the diagnosis of AA, the discriminative power of serum tryptase concentration was good (AUC = 0.825), but discriminative power was weak (AUC = 0.559) for the differential diagnosis between APA and AGA. Mastocytes are involved in AA during clinical presentations of both phlegmonous and gangrenous appendicitis, and no significant differences in concentration were found. No differences were found in serum and ALF concentrations of histamine and serotonin between histological groups. Due to their short half-lives, these might have elapsed by the time the samples were collected. In future research, these determinations should be made immediately after appendectomy. Our findings confirm the hypersensitivity type I reaction as an event occurring in the pathogenesis of AA: tryptase levels in ALF and serum were higher among patients with AA when compared to the control group, which is in line with a Th2 immune response and supports the concept of the presence of an allergic reaction in the pathogenesis of acute appendicitis. Our results, if confirmed, may have clinical implications for the treatment of AA.


Assuntos
Apendicite , Hipersensibilidade , Humanos , Apendicite/diagnóstico , Apendicite/cirurgia , Apendicite/etiologia , Triptases , Histamina , Estudos Prospectivos , Serotonina , Hipersensibilidade/complicações
14.
Nat Commun ; 15(1): 1368, 2024 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-38365905

RESUMO

Serotonin (5-HT) imbalances in the developing prefrontal cortex (PFC) are linked to long-term behavioral deficits. However, the synaptic mechanisms underlying 5-HT-mediated PFC development are unknown. We found that chemogenetic suppression and enhancement of 5-HT release in the PFC during the first two postnatal weeks decreased and increased the density and strength of excitatory spine synapses, respectively, on prefrontal layer 2/3 pyramidal neurons in mice. 5-HT release on single spines induced structural and functional long-term potentiation (LTP), requiring both 5-HT2A and 5-HT7 receptor signals, in a glutamatergic activity-independent manner. Notably, LTP-inducing 5-HT stimuli increased the long-term survival of newly formed spines ( ≥ 6 h) via 5-HT7 Gαs activation. Chronic treatment of mice with fluoxetine, a selective serotonin-reuptake inhibitor, during the first two weeks, but not the third week of postnatal development, increased the density and strength of excitatory synapses. The effect of fluoxetine on PFC synaptic alterations in vivo was abolished by 5-HT2A and 5-HT7 receptor antagonists. Our data describe a molecular basis of 5-HT-dependent excitatory synaptic plasticity at the level of single spines in the PFC during early postnatal development.


Assuntos
Fluoxetina , Serotonina , Camundongos , Animais , Serotonina/farmacologia , Fluoxetina/farmacologia , Células Piramidais/fisiologia , Córtex Pré-Frontal/fisiologia , Sinapses/fisiologia
15.
Biopharm Drug Dispos ; 45(1): 43-57, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38305087

RESUMO

The renal tubular organic cation transporter 2 (OCT2) and multidrug and toxin extrusion protein 1 (MATE1) mediate the vectorial elimination of many drugs and toxins from the kidney, and endogenous biomarkers for vectorial transport (OCT2-MATE1) would allow more accurate drug dosing and help to characterize drug-drug interactions and toxicity. Human serum uptake in OCT2-overexpressing cells and metabolomics analysis were carried out. Potential biomarkers were verified in vitro and in vivo. The specificity of biomarkers was validated in renal transporter overexpressing cells and the sensitivity was investigated by Km . The results showed that the uptake of thiamine, histamine, and 5-hydroxytryptamine was significantly increased in OCT2-overexpressing cells. In vitro assays confirmed that thiamine, histamine, and 5-hydroxytryptamine were substrates of both OCT2 and MATE1. In vivo measurements indicated that the serum thiamine level was increased significantly in the presence of the rOCT2 inhibitor cimetidine, and the level in renal tissue was increased significantly by the rMATE1 inhibitor pyrimethamine. There were no significant changes in the uptake or efflux of thiamine in cell lines overexpressed OAT1, OAT2, OAT3, MRP4, organic anion transporting polypeptide 4C1, P-gp, peptide transporter 2, urate transporter 1, and OAT4. The Km for thiamine with OCT2 and MATE1 were 71.2 and 10.8 µM, respectively. In addition, the cumulative excretion of thiamine at 2 and 4 h was strongly correlated with metformin excretion (R2  > 0.6). Thus, thiamine is preferentially secreted by the OCT2 and MATE1 in renal tubules and can provide a reference value for evaluating the function of the renal tubular OCT2-MATE1.


Assuntos
Proteínas de Transporte de Cátions Orgânicos , Transportador 1 de Cátions Orgânicos , Humanos , Transportador 1 de Cátions Orgânicos/metabolismo , Proteínas de Transporte de Cátions Orgânicos/genética , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Histamina/metabolismo , Serotonina/metabolismo , Rim/metabolismo , Tiamina/metabolismo , Células HEK293
16.
BMJ Case Rep ; 17(1)2024 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-38176752

RESUMO

Serotonin syndrome (SS) is an iatrogenic, drug-induced clinical syndrome caused by an increase in the intrasynaptic concentration of serotonin. Serotonin plays a significant role in the pathophysiology of migraines. Upregulation of 5-HT2A receptors is found in medication-overuse headache (MOH). Several migraine medications, both preventative and abortive drugs, act on serotonin receptors. We report two patients with chronic migraine who developed MOH. Besides headache, patients had frequent attacks of dizziness, restlessness, irritability, insomnia, excessive sweating, abdominal discomforts and tremors. These symptoms were suggestive of withdrawal headache. However, on physical examinations, we elicited hyperreflexia, hypertonia, clonus, tachycardia, hypertension, mydriasis and hyperactive bowel sound. Both patients also met the criteria for SS. Cyproheptadine was started. All features, including headaches, got better after cyproheptadine administration within 24 hours. In 7 days, there was practically total improvement. Both patients continued to take cyproheptadine as a preventative medicine, and migraine frequency was under control.


Assuntos
Transtornos da Cefaleia Secundários , Transtornos de Enxaqueca , Síndrome da Serotonina , Humanos , Ciproeptadina/uso terapêutico , Cefaleia , Transtornos da Cefaleia Secundários/diagnóstico , Transtornos da Cefaleia Secundários/induzido quimicamente , Transtornos de Enxaqueca/diagnóstico , Serotonina , Síndrome da Serotonina/induzido quimicamente , Síndrome da Serotonina/diagnóstico , Síndrome da Serotonina/complicações
17.
Clin Nucl Med ; 49(2): 157-159, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38178372

RESUMO

ABSTRACT: Carcinoid heart disease (Hedinger syndrome) is a long-term consequence in hormone-active neuroendocrine tumors with hepatic metastases and carcinoid syndrome. Because of serotonin, excess multiple cardiac and pulmonary symptoms evolve, which are further complicated by a patent foramen ovale due to right-left shunting. We present a 53-year-old man with an ileum-neuroendocrine tumor including gross liver metastases and long-term stable disease who subsequently developed Hedinger syndrome. Initially experiencing progressive dyspnea, he eventually experienced severe hypoxemia due to patent foramen ovale. 99mTc-MAA lung perfusion scintigraphy quantitatively identified the right-left shunting, whereas 68Ga-FAPI-46 PET/CT characterized the typical fibrous heart valve thickening due to serotonin-induced fibroblast proliferative properties.


Assuntos
Doença Cardíaca Carcinoide , Forame Oval Patente , Medicina Nuclear , Humanos , Masculino , Pessoa de Meia-Idade , Valva Aórtica , Doença Cardíaca Carcinoide/complicações , Doença Cardíaca Carcinoide/diagnóstico por imagem , Forame Oval Patente/complicações , Forame Oval Patente/diagnóstico por imagem , Hipóxia/complicações , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Serotonina
18.
J Transl Med ; 22(1): 34, 2024 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-38191373

RESUMO

OBJECTIVES: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a significant medical challenge, with no indisputable pathophysiological mechanism identified to date. METHODS: Based on clinical clues, we hypothesized that 5-hydroxytryptamine (5-HT) hyperactivation is implicated in the pathogenic causes of ME/CFS and the associated symptoms. We experimentally evaluated this hypothesis in a series of mouse models. RESULTS: High-dose selective serotonin reuptake inhibitor (SSRI) treatment induced intra- and extracellular serotonin spillover in the dorsal raphe nuclei of mice. This condition resulted in severe fatigue (rota-rod, fatigue rotating wheel and home-cage activity tests) and ME/CFS-associated symptoms (nest building, plantar and open field test), along with dysfunction in the hypothalamic-pituitary-adrenal (HPA) axis response to exercise challenge. These ME/CFS-like features induced by excess serotonin were additionally verified using both a 5-HT synthesis inhibitor and viral vector for Htr1a (5-HT1A receptor) gene knockdown. CONCLUSIONS: Our findings support the involvement of 5-HTergic hyperactivity in the pathophysiology of ME/CFS. This ME/CFS-mimicking animal model would be useful for understanding ME/CFS biology and its therapeutic approaches.


Assuntos
Síndrome de Fadiga Crônica , Animais , Camundongos , Serotonina , Modelos Animais de Doenças , Técnicas de Silenciamento de Genes , Sistema Hipotálamo-Hipofisário
19.
ACS Appl Bio Mater ; 7(1): 472-484, 2024 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-38166214

RESUMO

In this study, we demonstrated the fabrication of multicontact hierarchical probes for the in vitro detection of serotonin levels. The basic three-dimensional (3D) bendable prototypes with 3 (C1), 6 (C2), or 9 (C3) contact surfaces were printed from polymeric resin via the digital light processing (DLP) technique. We chose ultrasonicated carbon fiber strands to transform these designs into multicontact carbon fiber electrodes (MCCFEs). The exposed carbon fiber (CF) surfaces were modified with aminopropyl alkoxysilane (APTMS), followed by the subsequent loading of palladium nanoclusters (PdNPs) to build active recording sites. CF functionalization with PdNPs was achieved by the wet chemical reduction of Pd(II) to Pd(0). The MCCFE configurations demonstrated an enhancement in the electroactive surface area and an improved voltammetric response toward 5-HT oxidation by increasing the points of the contacts (i.e., from C1 to C3). These MCCFEs are comparable to 3D-protruding electrodes as they can enable multipoint analyte detection. Along with the electrode patterns, morphological irregularities associated with both Pd-doped and undoped CFs supported the creation of proximal diffusion layers for facile mass transfer. Low detection limits of 0.8-10 nM over a wide concentration range, from 0.005 nM to 1 mM, were demonstrated. The MCCFE sensors had a relatively low standard deviation value of ∼2%. This type of sensitive and cost-effective electrochemical sensor may prove useful for collecting electrical impulses and long-term monitoring of 5-HT in vivo in addition to in vitro testing.


Assuntos
Nanoestruturas , Serotonina , Fibra de Carbono , Oxirredução , Eletrodos
20.
Transl Psychiatry ; 14(1): 24, 2024 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-38225222

RESUMO

Fear-induced bradycardia, a transient heartbeat deceleration following exposure to threat, is a physiological index observable in humans, especially in fear conditioning experiments. While gaining interest in recent years, it is still currently underemployed in neuroscientific research compared to more popular physiological indices. Besides its use in research, it could also constitute a valuable resource in a clinical psychiatry setting, as many disorders are also characterized by altered heart rate responses. However, differences in fear-induced bradycardia may also be subtended by genetic interindividual differences, thus suggesting precaution when recommending its use in the clinical setting. Here, we discussed the first endeavors that aimed at clarifying the genetic underpinnings of heart rate variations, which suggest that individual genetic differences have a role in defining the characteristics of heart rate responses. Given this, translating heart rate measurements in the clinical setting must be implemented with caution. Future endeavors in this field will aim at identifying these differences even further, thus allowing for more precise clinical interventions.


Assuntos
Bradicardia , Dopamina , Humanos , Bradicardia/induzido quimicamente , Bradicardia/genética , Serotonina , Medo/fisiologia , Encéfalo
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