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1.
PLoS Genet ; 18(9): e1010371, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36048889

RESUMO

The regulation of ribosome function is a conserved mechanism of growth control. While studies in single cell systems have defined how ribosomes contribute to cell growth, the mechanisms that link ribosome function to organismal growth are less clear. Here we explore this issue using Drosophila Minutes, a class of heterozygous mutants for ribosomal proteins. These animals exhibit a delay in larval development caused by decreased production of the steroid hormone ecdysone, the main regulator of larval maturation. We found that this developmental delay is not caused by decreases in either global ribosome numbers or translation rates. Instead, we show that they are due in part to loss of Rp function specifically in a subset of serotonin (5-HT) neurons that innervate the prothoracic gland to control ecdysone production. We find that these effects do not occur due to altered protein synthesis or proteostasis, but that Minute animals have reduced expression of synaptotagmin, a synaptic vesicle protein, and that the Minute developmental delay can be partially reversed by overexpression of synaptic vesicle proteins in 5-HTergic cells. These results identify a 5-HT cell-specific role for ribosomal function in the neuroendocrine control of animal growth and development.


Assuntos
Proteínas de Drosophila , Drosophila , Animais , Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Ecdisona/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Larva , Proteínas Ribossômicas/genética , Proteínas Ribossômicas/metabolismo , Neurônios Serotoninérgicos/metabolismo , Serotonina/genética , Serotonina/metabolismo
2.
Cell ; 185(18): 3390-3407.e18, 2022 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-36055200

RESUMO

Chemical synapses between axons and dendrites mediate neuronal intercellular communication. Here, we describe a synapse between axons and primary cilia: the axo-ciliary synapse. Using enhanced focused ion beam-scanning electron microscopy on samples with optimally preserved ultrastructure, we discovered synapses between brainstem serotonergic axons and the primary cilia of hippocampal CA1 pyramidal neurons. Functionally, these cilia are enriched in a ciliary-restricted serotonin receptor, the 5-hydroxytryptamine receptor 6 (5-HTR6). Using a cilia-targeted serotonin sensor, we show that opto- and chemogenetic stimulation of serotonergic axons releases serotonin onto cilia. Ciliary 5-HTR6 stimulation activates a non-canonical Gαq/11-RhoA pathway, which modulates nuclear actin and increases histone acetylation and chromatin accessibility. Ablation of this pathway reduces chromatin accessibility in CA1 pyramidal neurons. As a signaling apparatus with proximity to the nucleus, axo-ciliary synapses short circuit neurotransmission to alter the postsynaptic neuron's epigenetic state.


Assuntos
Axônios/fisiologia , Cromatina/química , Cílios , Sinapses , Núcleo Celular/metabolismo , Cromatina/metabolismo , Cílios/metabolismo , Hipocampo/citologia , Hipocampo/fisiologia , Serotonina/metabolismo , Transdução de Sinais , Sinapses/fisiologia
3.
World J Microbiol Biotechnol ; 38(12): 222, 2022 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-36100774

RESUMO

Intestinal peristalsis is essential for gastrointestinal function, which could maintain the appropriate progression and digestion of food and reduce bacterial aggregation through mixing function. Even though certain ingredients of foodstuff are known to increase or decrease intestinal peristalsis, the role of environmental pollutants on intestinal peristalsis is relatively unknown. Therefore, the effects of four typical environmental pollutants (oxytetracycline, arsenic, polychlorinated biphenyls and chlorpyrifos) on intestinal peristalsis in the zebrafish model and then tested the recovery effect of the constipation-resistant probiotic. The results showed that 4-day environmental pollutants exposures on the zebrafish embryos at 1 day post fertilization clearly decreased the intestinal peristalsis through decreasing the serotonin (5-HT) production and down-regulating the expression of key genes involved in 5-HT synthesis. Pollutants-evoked change of gut motility could be normalized in the presence of Lactobacillus rhamnosus GG (LGG) via increasing 5-HT secretion. Exogenous 5-hydroxytryptophan (100 µg/L) could also rescue the dysfunction of gut motility in pollutants-treated zebrfish. The data identified that LGG normalized disorder of intestinal peristalsis induced by environmental pollutants through increasing 5-HT level. The stimulant effect of LGG on peristalsis may be associated with 5-HT system, which could provide references for the application of probiotics in regulation of gut dysmotility.


Assuntos
Poluentes Ambientais , Lactobacillus rhamnosus , Animais , Poluentes Ambientais/metabolismo , Poluentes Ambientais/toxicidade , Lactobacillus rhamnosus/genética , Lactobacillus rhamnosus/metabolismo , Larva , Serotonina/metabolismo , Peixe-Zebra
4.
Biomed Pharmacother ; 154: 113627, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36058152

RESUMO

Constipation has become an epidemic enteric medical problem, accompanied with increasing long-term sequelae. Gut microbiota and serotonin (5-HT) have been believed as predominant player in the treatment of constipation. In clinical practices, Shouhui Tongbian Capsule (SHTB) was found to effectively improve constipation symptoms and promote gastrointestinal motility. However, the specific mechanism of SHTB is not clearly elucidated. Our current study aims to explore the therapeutic effects of SHTB against the development of constipation and the underlying mechanisms related to gut bacterial and 5-HT. We established loperamide hydrochloride (LH)-induced experimental constipation mouse model to evaluate the effect of SHTB. 16S RNA sequencing, fecal microbiota transplants (FMT), high performance liquid chromatograph, and molecular biological analysis were performed to investigate the potential mechanisms of SHTB. Our data demonstrated that SHTB significantly ameliorated LH-induced experimental constipation and accelerated enteric motility via promoting 5-HT biosynthesis in enterochromaffin cells and enteric neuron growth of the enteric nervous system (ENS) in both the small intestine and colon. Additionally, SHTB significantly modulated gut microbiota dysbiosis and potentially altered microbiota metabolites to enhance intestinal 5-HT production. Finally, FMT study confirmed that the effects of SHTB on 5-HT production and constipation are dependent on modulating intestinal microbiota dysbiosis. In conclusion, our current study deciphered therapeutic mechanism of SHTB in the treatment of experimental constipation from perspectives of gut microbiota-5-HT-intetinal motility axis and provides novel insights into the appropriate and safe application of SHTB in the clinic.


Assuntos
Microbioma Gastrointestinal , Animais , Constipação Intestinal/induzido quimicamente , Constipação Intestinal/tratamento farmacológico , Disbiose , Motilidade Gastrointestinal/fisiologia , Loperamida/uso terapêutico , Camundongos , Serotonina/metabolismo
5.
Int J Mol Sci ; 23(17)2022 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-36077360

RESUMO

In recent decades, neuropsychiatric disorders such as major depressive disorder, schizophrenia, bipolar, etc., have become a global health concern, causing various detrimental influences on patients. Tryptophan is an important amino acid that plays an indisputable role in several physiological processes, including neuronal function and immunity. Tryptophan's metabolism process in the human body occurs using different pathways, including the kynurenine and serotonin pathways. Furthermore, other biologically active components, such as serotonin, melatonin, and niacin, are by-products of Tryptophan pathways. Current evidence suggests that a functional imbalance in the synthesis of Tryptophan metabolites causes the appearance of pathophysiologic mechanisms that leads to various neuropsychiatric diseases. This review summarizes the pharmacological influences of tryptophan and its metabolites on the development of neuropsychiatric disorders. In addition, tryptophan and its metabolites quantification following the neurotransmitters precursor are highlighted. Eventually, the efficiency of various biomarkers such as inflammatory, protein, electrophysiological, genetic, and proteomic biomarkers in the diagnosis/treatment of neuropsychiatric disorders was discussed to understand the biomarker application in the detection/treatment of various diseases.


Assuntos
Transtorno Depressivo Maior , Triptofano , Humanos , Cinurenina/metabolismo , Proteômica , Serotonina/metabolismo , Triptofano/metabolismo
6.
Artigo em Inglês | MEDLINE | ID: mdl-36078631

RESUMO

As a major neonicotinoid insecticide, thiacloprid (THCP) is frequently detected in aquatic environments worldwide due to its heavy use, posing potential threats to aquatic organisms. In this study, zebrafish (Danio rerio) embryos were exposed to THCP (1, 10, 100, 1000 and 10,000 µg/L) for 5 days and then recovered in THCP-free water for 20 days to investigate the effects of early-stage THCP exposure on the development, antioxidant defense, and neurotransmitter systems of zebrafish, and explore their recovery mechanism. The results show that THCP exposure induced developmental toxicity and oxidative stress in zebrafish. The hypoactivity, behavioral alterations (decreased avoidance and edge preference behaviors) and neurotoxicity were found throughout the exposure-recovery experiments. THCP exposure altered the expression of γ-aminobutyric acid (GABA)- and serotonin (5-HT)-related genes accompanied by the decrease in GABA and 5-HT contents. However, after recovery, GABA content returned to the control level, but 5-HT did not, indicating that only the serotonergic system was persistently disrupted. Overall, our results suggest that the disruption of the serotonergic system and oxidative stress may aggravate neurotoxicity and that the former was the main reason for the depressive-like behavior. This study could help to unravel the mechanisms of the behavioral alterations induced by early-stage THCP exposure in zebrafish.


Assuntos
Poluentes Químicos da Água , Peixe-Zebra , Animais , Embrião não Mamífero , Neonicotinoides/toxicidade , Estresse Oxidativo , Serotonina/metabolismo , Tiazinas , Poluentes Químicos da Água/metabolismo , Peixe-Zebra/metabolismo , Ácido gama-Aminobutírico/metabolismo
7.
BMC Psychiatry ; 22(1): 590, 2022 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-36064335

RESUMO

Depression is a mental disease involving complex pathophysiological mechanisms, and there are many ways to establish depressive mouse models. The purpose of this study is to comprehensively compare the behavioral changes and its mechanism induced by two different models. This study established two depressive mouse models by maternal separation (MS) or lipopolysaccharide (LPS) administration, and added fluoxetine treatment group respectively for comparison. MS induced more apparent anxiety-like behavior while LPS induced more apparent depressive-like behavior. LPS increased peripheral inflammatory factors more apparent, which were mitigated by fluoxetine. MS inhibited the 5-HT system more obviously and was relieved by fluoxetine. LPS triggered stronger immune response in the hippocampus and prefrontal cortex (PFC). MS significantly reduced the expression of neurotrophic proteins and was alleviated by fluoxetine. Overall, LPS induced stronger system inflammation, while MS impaired the function of HPA axis and 5-HT system. Our results will contribute to a deeper understanding of the pathophysiology of different stress-induced depression and will also help researchers select appropriate models of depression for their own needs.


Assuntos
Fluoxetina , Lipopolissacarídeos , Animais , Depressão/metabolismo , Modelos Animais de Doenças , Fluoxetina/farmacologia , Fluoxetina/uso terapêutico , Hipocampo/metabolismo , Humanos , Sistema Hipotálamo-Hipofisário/metabolismo , Inflamação/metabolismo , Privação Materna , Camundongos , Sistema Hipófise-Suprarrenal/metabolismo , Serotonina/metabolismo
8.
Molecules ; 27(17)2022 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-36080227

RESUMO

Alzheimer's disease (AD) is a neurodegenerative disease associated with memory impairment and other central nervous system (CNS) symptoms. Two myrtenal-adamantane conjugates (MACs) showed excellent CNS potential against Alzheimer's models. Adamantane is a common pharmacophore for drug design, and myrtenal (M) demonstrated neuroprotective effects in our previous studies. The aim of this study is to evaluate the MACs' neuroprotective properties in dementia. METHODS: Scopolamine (Scop) was applied intraperitoneally in Wistar rats for 11 days, simultaneously with MACs or M as a referent, respectively. Brain acetylcholine esterase (AChE) activity, noradrenaline and serotonin levels, and oxidative brain status determination followed behavioral tests on memory abilities. Molecular descriptors and docking analyses for AChE activity center affinity were performed. RESULTS: M derivatives have favorable physicochemical parameters to enter the CNS. Both MACs restored memory damaged by Scop, showing significant AChE-inhibitory activity in the cortex, in contrast to M, supported by the modeling analysis. Moderate antioxidant properties were manifested by glutathione elevation and catalase activity modulation. MACs also altered noradrenaline and serotonin content in the hippocampus. CONCLUSION: For the first time, neuroprotective properties of two MACs in a rat dementia model were observed. They were stronger than the natural M effects, which makes the substances promising candidates for AD treatment.


Assuntos
Adamantano , Doença de Alzheimer , Doenças Neurodegenerativas , Fármacos Neuroprotetores , Acetilcolinesterase/metabolismo , Adamantano/farmacologia , Doença de Alzheimer/tratamento farmacológico , Animais , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Monoterpenos Bicíclicos , Aprendizagem em Labirinto , Doenças Neurodegenerativas/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Norepinefrina , Estresse Oxidativo , Ratos , Ratos Wistar , Escopolamina/farmacologia , Serotonina/metabolismo
9.
Neuroreport ; 33(14): 612-616, 2022 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-36062511

RESUMO

The monoamine neurotransmitter serotonin (5-HT) is important for the regulation of behavior, and aberrations in 5-HT signaling are linked to several neuropsychiatric and neurodevelopmental disorders. 5-HT signaling is dependent on and tightly regulated by the functional activity of the 5-HT transporter (SERT). Neurotrauma is known to structurally and functionally impact 5-HT neuronal tracts and 5-HT signaling; however, the extent to which various forms of neurotrauma alter homeostatic 5-HT signaling through the modulation of SERT expression and/or functional uptake capacity is currently not well characterized. We aimed to better characterize the protein expression and uptake activity of SERT following mild traumatic brain injury (mTBI). A murine model of blast-induced mTBI was utilized to characterize alterations in SERT expression and function following injury. mTBI was found to decrease (≈26%) the protein levels of SERT 3 days postinjury (DPI) in the dorsal raphe nucleus (DRN), the primary locale of 5-HT neuronal cell bodies within the central nervous system. Concomitant reductions in midbrain SERT-dependent radiolabeled 5-HT uptake were observed 3 DPI (≈24%). No alterations in SERT expression were observed 10 DPI in the DRN. Additionally, no alterations in SERT expression or function were observed in prefrontal cortex samples at any time point observed. This data reveals time- and location-dependent alterations in SERT expression and function following mTBI. These studies illustrate the critical importance of ongoing research efforts to characterize the molecular effects of various forms of neurotrauma on SERT protein expression and function, which may yield novel drug targets within 5-HT systems.


Assuntos
Concussão Encefálica , Proteínas da Membrana Plasmática de Transporte de Serotonina , Animais , Núcleo Dorsal da Rafe , Camundongos , Neurônios/metabolismo , Serotonina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo
10.
Cell Rep ; 40(12): 111368, 2022 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-36130487

RESUMO

Quorum sensing fundamentally alters the interaction of Vibrio cholerae with aquatic environments, environmental hosts, and the human intestine. At high cell density, the quorum-sensing regulator HapR represses not only expression of cholera toxin and the toxin co-regulated pilus, virulence factors essential in human infection, but also synthesis of the Vibrio polysaccharide (VPS) exopolysaccharide-based matrix required for abiotic and biotic surface attachment. Here, we describe a feature of V. cholerae quorum sensing that shifts the host-pathogen interaction toward commensalism. By repressing pathogen consumptive anabolic metabolism and, in particular, tryptophan uptake, V. cholerae HapR stimulates host intestinal serotonin production. This, in turn, activates host intestinal innate immune signaling to promote host survival.


Assuntos
Vibrio cholerae , Proteínas de Bactérias/metabolismo , Contagem de Células , Toxina da Cólera , Regulação Bacteriana da Expressão Gênica , Humanos , Imunidade Inata , Intestinos , Polissacarídeos/metabolismo , Percepção de Quorum , Serotonina/metabolismo , Triptofano/metabolismo , Vibrio cholerae/metabolismo , Fatores de Virulência/metabolismo
11.
Psychopharmacology (Berl) ; 239(10): 3355-3366, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36063206

RESUMO

RATIONALE: Serotonin (5-HT) is a monoamine neuromodulator that plays a key role in the organization of the central nervous system. 5-HT alterations may be associated to the emergence of social deficits and psychiatric disorders, including anxiety, depression, and substance abuse disorders. Notably, disruption of the 5-HT system during sensitive periods of development seems to exert long-term consequences, including altered anxiety responses and problematic use of alcohol. OBJECTIVE: We analyzed, in mice, the effects of transient 5-HT depletion at gestation (a developmental stage when medial prefrontal cortex (mPFC) 5-HT levels depend exclusively on placental 5-HT availability) on 5-HT central synthesis and reuptake at weaning. We also explored if 5-HT disruption at the embryonic stage influences behavioral outcomes that may serve as a proxy for autistic- or anxiety-like phenotypes. METHODS: C57/BL6 male and female mice, born from dams treated with a 5-HT synthesis inhibitor (PCPA; 4-Chloro-DL-phenylalanine methyl ester hydrochloride) at gestational days (G)13.5-16.5, were subjected to a behavioral battery that assesses social preference and novelty, compulsive behavior, stereotypies, and ethanol's anti-anxiety effects, at postnatal days (P) 21-28. Afterwards, expression of the genes that encode for 5-HT synthesis (Tph2) and SERT (5-HT transporter) were analyzed in mPFC via real-time RT-PCR. Dopamine 2 receptor (D2R) expression was also analyzed via RT-PCR to further explore possible effects of PCPA on dopaminergic transmission. RESULTS: Transient 5-HT disruption at G13.5-16.5 reduced Tph2 expression of both male and female mice in mPFC at P23. Notably, female mice also exhibited higher SERT expression and reduced D2R expression in mPFC. Mice derived from 5-HT depleted dams displayed heightened compulsive behavior at P21, when compared to control mice. Alcohol anti-anxiety effects at early adolescence (P28) were exhibited by mice derived from 5-HT depleted dams, but not by control counterparts. No social deficits or stereotyped behaviors were observed. CONCLUSION: Transient 5-HT inhibition at gestation resulted in altered expression of genes involved in 5-HT synthesis and reuptake in mPFC at weaning, a period in which the 5-HT system is still developing. These alterations may exert lingering effects, which translate to significant compulsivity and heightened sensitivity to the anxiolytic effects of alcohol at early adolescence.


Assuntos
Ansiolíticos , Serotonina , Animais , Ansiolíticos/farmacologia , Comportamento Animal , Dopamina/metabolismo , Etanol/farmacologia , Feminino , Fenclonina/farmacologia , Humanos , Masculino , Camundongos , Placenta/metabolismo , Gravidez , Piridinolcarbamato , Serotonina/metabolismo , Desmame
12.
Compr Physiol ; 12(4): 1-16, 2022 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-36036567

RESUMO

Serotonin is often referred to as a "happy hormone" as it maintains good mood, well-being, and happiness. It is involved in communication between nerve cells and plays a role in sleeping and digestion. However, too much serotonin can have pathogenic effects and serotonin synthesis is elevated in pulmonary artery endothelial cells from patients with pulmonary arterial hypertension (PAH). PAH is characterized by elevated pulmonary pressures, right ventricular failure, inflammation, and pulmonary vascular remodeling; serotonin has been shown to be associated with these pathologies. The rate-limiting enzyme in the synthesis of serotonin in the periphery of the body is tryptophan hydroxylase 1 (TPH1). TPH1 expression and serotonin synthesis are elevated in pulmonary artery endothelial cells in patients with PAH. The serotonin synthesized in the pulmonary arterial endothelium can act on the adjacent pulmonary arterial smooth muscle cells (PASMCs), adventitial macrophages, and fibroblasts, in a paracrine fashion. In humans, serotonin enters PASMCs cells via the serotonin transporter (SERT) and it can cooperate with the 5-HT1B receptor on the plasma membrane; this activates both contractile and proliferative signaling pathways. The "serotonin hypothesis of pulmonary hypertension" arose when serotonin was associated with PAH induced by diet pills such as fenfluramine, aminorex, and chlorphentermine; these act as indirect serotonergic agonists causing the release of serotonin from platelets and cells through the SERT. Here the role of serotonin in PAH is reviewed. Targeting serotonin synthesis or signaling is a promising novel alternative approach which may lead to novel therapies for PAH. © 2022 American Physiological Society. Compr Physiol 12: 1-16, 2022.


Assuntos
Hipertensão Pulmonar , Proliferação de Células , Células Endoteliais/metabolismo , Humanos , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Artéria Pulmonar , Serotonina/metabolismo , Serotonina/farmacologia , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/farmacologia
13.
Int J Mol Sci ; 23(16)2022 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-36012419

RESUMO

(1) Background: Tryptophan metabolism is known to be one of the important mechanisms used by cancer to evade immune surveillance. Altered tryptophan metabolism was studied in patients with pigmented malignant melanoma confirmed histologically by the anatomic stage grouping for cutaneous melanoma using clinical staging on the basis of the Breslow thickness of the melanoma, the degree of spread to regional lymph nodes, and by the presence of distant metastasis. (2) Methods: Urinary tryptophan metabolites were detected by RP-HPLC method. (3) Results: In the present work, we provided evidence of altered metabolism of all tryptophan pathways in melanoma patients. (4) Conclusions: Knowledge of the shifted serotonin pathway toward DHICA formation and kynurenine pathway shifted toward NAD+ production could serve in the early detection of the disease and the initiation of early treatment of malignant melanoma.


Assuntos
Melanoma , Neoplasias Cutâneas , Humanos , Indóis , Cinurenina/metabolismo , Serotonina/metabolismo , Triptofano/metabolismo
14.
Nutrients ; 14(16)2022 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-36014776

RESUMO

L-tryptophan (Trp) contributes to regulating bilateral communication of the gut-brain axis. It undergoes three major metabolic pathways, which lead to formation of kynurenine, serotonin (5-HT), and indole derivatives (under the control of the microbiota). Metabolites from the principal Trp pathway, kynurenic acid and quinolinic acid, exhibit neuroprotective activity, while picolinic acid exhibits antioxidant activity, and 5-HT modulates appetite, sleep cycle, and pain. Abnormality in Trp plays crucial roles in diseases, including depression, colitis, ulcer, and gut microbiota-related dysfunctions. To address these diseases, the use of natural products could be a favorable alternative because they are a rich source of compounds that can modulate the activity of Trp and combat various diseases through modulating different signaling pathways, including the gut microbiota, kynurenine pathway, and serotonin pathway. Alterations in the signaling cascade pathways via different phytochemicals may help us explore the deep relationships of the gut-brain axis to study neuroprotection. This review highlights the roles of natural products and their metabolites targeting Trp in different diseases. Additionally, the role of Trp metabolites in the regulation of neuroprotective and gastroprotective activities is discussed. This study compiles the literature on novel, potent neuroprotective agents and their action mechanisms in the gut-brain axis and proposes prospective future studies to identify more pharmaceuticals based on signaling pathways targeting Trp.


Assuntos
Produtos Biológicos , Fármacos Neuroprotetores , Eixo Encéfalo-Intestino , Depressão , Cinurenina/metabolismo , Serotonina/metabolismo , Triptofano/metabolismo
15.
Pestic Biochem Physiol ; 186: 105152, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35973757

RESUMO

Chemical or drug treatments are successfully used to treat parasitic nematode infections that impact human, animal and plant health. Many of these exert their effects through modifying neural function underpinning behaviours essential for parasite viability. Selectivity against the parasite may be achieved through distinct pharmacological properties of the parasite nervous system, as exemplified by the success of the ivermectin which target a glutamate-gated chloride channel found only in invertebrates. Despite the success of the ivermectins, emerging resistance and concerns around eco-toxicity are driving the search for new nematocidal chemicals or drugs. Here, we describe the potential of a 5-HT-gated chloride channel MOD-1, which is involved in vital parasite behaviours with constrained distribution in the invertebrate phyla. This ion channel has potential pharmacophores that could be targeted by new nematocidal chemicals and drugs. We have developed a microtiter based bioassay for MOD-1 pharmacology based on its ectopic expression in the Caenorhabditis elegans essential neuron M4. We have termed this technology 'PhaGeM4' for 'Pharmacogenetic targeting of M4 neuron'. Exposure of transgenic worms harbouring ectopically expressed MOD-1 to 5-HT results in developmental arrest. By additional expression of a fluorescence marker in body wall muscle to monitor growth we demonstrate that this assay is suitable for the identification of receptor agonists and antagonists. Indeed, the developmental progression is a robustly quantifiable bioassay that resolves MOD-1 activation by quipazine, 5-carboxyamidotryptamine and fluoxetine and highlight methiothepin as a potent antagonist. This assay has the intrinsic ability to highlight compounds with optimal bioavailability and furthermore to filter out off-target effects. It can be extended to the investigation of other classes of membrane receptors and modulators of neuronal excitation. This approach based on heterologous modulation of the essential M4 neuron function offers a route to discover new effective and selective anthelmintics potentially less confounded by disruptive environmental impact.


Assuntos
Caenorhabditis elegans , Canais de Cloreto , Neurônios , Animais , Antinematódeos/farmacologia , Caenorhabditis elegans/genética , Canais de Cloreto/antagonistas & inibidores , Canais de Cloreto/genética , Ivermectina/farmacologia , Neurônios/fisiologia , Farmacogenética , Serotonina/metabolismo
16.
Neurochem Res ; 47(9): 2890-2898, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35951201

RESUMO

Chronic fatigue and central fatigue with malaise significantly impair quality of life. Inattention caused by central fatigue is closely related to attention deficit/hyperactivity disorder (ADHD) symptoms, but the neurochemical mechanism of central fatigue remains hypothetical. The serotonin hypothesis of central fatigue was proposed first, serving as the central dogma for the molecular and neural mechanisms of central fatigue, and underpinning many studies. The tryptophan hypothesis was proposed because tryptophan released into the synaptic cleft of neurons in the brain coincides with and responds sensitively to development of fatigue. Tryptophan is highly bioactive, with brain concentrations of 50 to 200 times that of serotonin. The tryptophan-kynurenic acid-synergy hypothesis posits that central fatigue is not monocausal but a synergistic effect between tryptophan itself and its catabolite kynurenic acid. Central fatigue is associated with mental health problems and is a cause of inattention, thereby warranting scrutiny for its relationship with ADHD. Fatigability in ADHD is mediated by tryptophan, in which abnormal enhancement of the tryptophan-kynurenine-kynurenic acid pathway causes an imbalance in monoamine nervous system function. Notably, noradrenergic neuronal dysfunction is associated with the characteristic inattention of ADHD. Neutral amino acids such as branched-chain amino acids (BCAAs) can assist recovery from attentional and cognitive decline caused by central fatigue. Since they are transported by the same L-amino acid transporter as tryptophan, BCAAs compete with tryptophan to inhibit its brain uptake. Controlling central fatigue this way may improve attentional cognitive performance.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Aminoácidos de Cadeia Ramificada/metabolismo , Transtorno do Deficit de Atenção com Hiperatividade/metabolismo , Cognição , Humanos , Ácido Cinurênico , Qualidade de Vida , Serotonina/metabolismo , Triptofano/metabolismo
17.
J Phys Chem B ; 126(35): 6682-6690, 2022 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-35973070

RESUMO

G protein-coupled receptors (GPCRs) are signaling hubs in cell membranes that regulate a wide range of physiological processes and are popular drug targets. Serotonin1A receptors are important members of the GPCR family and are implicated in neuropsychiatric disorders. Cholesterol is a key constituent of higher eukaryotic membranes and is believed to contribute to the segregated distribution of membrane constituents into domains. To explore the role of cholesterol in lateral dynamics of GPCRs, we utilized single particle tracking (SPT) to monitor diffusion of serotonin1A receptors under acute and chronic cholesterol-depleted conditions. Our results show that the short-term diffusion coefficient of the receptor decreases upon cholesterol depletion, irrespective of the method of cholesterol depletion. Analysis of SPT trajectories revealed that relative populations of receptors undergoing various modes of diffusion change upon cholesterol depletion. Notably, in cholesterol-depleted cells, we observed an increase in the confined population of the receptor accompanied by a reduction in diffusion coefficient for chronic cholesterol depletion. These results are supported by our recent work and present observations that show polymerization of G-actin in response to chronic cholesterol depletion. Taken together, our results bring out the interdependence of cholesterol and actin cytoskeleton in regulating diffusion of GPCRs in membranes.


Assuntos
Receptor 5-HT1A de Serotonina , Serotonina , Membrana Celular/metabolismo , Colesterol/metabolismo , Difusão , Receptor 5-HT1A de Serotonina/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Serotonina/metabolismo , Imagem Individual de Molécula
18.
Ecotoxicol Environ Saf ; 243: 113978, 2022 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-36007322

RESUMO

Epidemiological studies have shown that prenatal triphenyl phosphate (TPhP) exposure is related to abnormal neurobehavior in children. However, the neurodevelopmental toxicity of TPhP in mammals is limited. To study the neurodevelopmental toxicity of TPhP in mammals and investigate the underlying mechanism, we used a mouse intrauterine TPhP exposure model. We measured the inflammatory factors (IL-6, TNFα) and NFκB levels, and tryptophan metabolism in placentae, detected the fetal brain transcriptome, hippocampal neuron development and neurobehavioral in the male offspring. The results showed that the protein level of IL-6, TNFα and NFκB in the placenta of the TPhP treatment group (1, 5 mg/kg) were significantly increased. Change of the protein level of these pro-inflammatory factors in maternal serum or fetal brain was not observed. Expression of genes along tryptophan-serotonin metabolism pathway were significantly decreased. While, the concentration of 5-HT levels in the placenta or fetal brain were significantly increased. Consistent with the increased 5-HT, the Nissl body was reduced in the hippocampus of treatment group. The expression of serotonergic neuron gene markers including Tph2, Htr1A, Htr2A, Pet1 and Lmx1b in the hippocampus of treatment group was significantly decreased. The neurobehavioral test showed that TPhP decreased center time that represent anxiety-like behavior, and reduced learning and memory in male offspring. Meanwhile, expression of genes along tryptophan-kynurenine metabolism pathway were significantly increased. The result of the transcriptome analysis of fetal brain showed that the differentially expressed genes are mainly involved in the transcription regulation of DNA as a template in the nucleus, and the enriched pathways are mainly signal pathways regulated by axon guidance and neurotrophic factors, dopaminergic and cholinergic synapses, suggest that not only serotonergic neuronal was affected. Overall, this study demonstrates that TPhP has the potential to induce placental inflammatory response in the placenta, disturb placental tryptophan metabolism, compromise the neuronal development and synaptic transmission, and cause abnormal neurobehavior in male offspring.


Assuntos
Placenta , Triptofano , Animais , Feminino , Interleucina-6/metabolismo , Masculino , Mamíferos/metabolismo , Camundongos , Organofosfatos/toxicidade , Placenta/metabolismo , Gravidez , Serotonina/metabolismo , Triptofano/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
19.
Cells ; 11(15)2022 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-35954298

RESUMO

Selective serotonin reuptake inhibitors (SSRIs) are less efficacious in treating depression in children than in adults. SSRIs block serotonin uptake via the high-affinity, low-capacity serotonin transporter. However, the low-affinity, high-capacity organic cation transporter 3 (OCT3) and plasma membrane monoamine transporter (PMAT) are emerging as important players in serotonin uptake. We hypothesized that OCT3 and/or PMAT are functionally upregulated in juveniles, thereby buffering SSRIs' ability to enhance serotonergic neurotransmission. Unlike in adult mice, we found the OCT/PMAT blocker, decynium-22, to have standalone antidepressant-like effects in juveniles. Using in vivo high-speed chronoamperometry, we found that juveniles clear serotonin from the CA3 region of the hippocampus ~2-fold faster than adult mice. Cell density did not differ between ages, suggesting that faster serotonin clearance in juveniles is unrelated to faster diffusion through the extracellular matrix. Western blot and immunohistochemistry showed that juvenile mice have modestly greater expression of PMAT than adults, whereas OCT3 expression in the CA3 region of the hippocampus was similar between ages. Together, these data suggest that faster serotonin clearance and antidepressant-like effects of decynium-22 in juvenile mice may be due to functionally upregulated PMAT. Faster serotonin clearance via PMAT in juveniles may contribute to reduced therapeutic efficacy of SSRIs in children relative to adults.


Assuntos
Antidepressivos , Serotonina , Animais , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Membrana Celular/metabolismo , Hipocampo/metabolismo , Camundongos , Serotonina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Inibidores de Captação de Serotonina/farmacologia
20.
Int J Mol Sci ; 23(15)2022 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-35955633

RESUMO

Depression is a common and serious disorder, characterized by symptoms like anhedonia, lack of energy, sad mood, low appetite, and sleep disturbances. This disease is very complex and not totally elucidated, in which diverse molecular and biological mechanisms are involved, such as neuroinflammation. There is a high need for the development of new therapies and gaining new insights into this disease is urgent. One important player in depression is the amino acid tryptophan. This amino acid can be metabolized in two important pathways in the context of depression: the serotonin and kynurenine pathways. These metabolic pathways of tryptophan are crucial in several processes that are linked with depression. Indeed, the maintenance of the balance of serotonin and kynurenine pathways is critical for the human physiological homeostasis. Thus, this narrative review aims to explore tryptophan metabolism (particularly in the serotonin and kynurenine pathways) in depression, starting with a global overview about these topics and ending with the focus on these pathways in neuroinflammation, stress, microbiota, and brain-derived neurotrophic factor regulation in this disease. Taken together, this information aims to clarify the metabolism of tryptophan in depression, particularly the serotonin and kynurenine pathways.


Assuntos
Cinurenina , Serotonina , Depressão/metabolismo , Humanos , Cinurenina/metabolismo , Redes e Vias Metabólicas , Serotonina/metabolismo , Triptofano/metabolismo
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