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1.
Molecules ; 26(12)2021 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-34208700

RESUMO

Cardamonin, a naturally occurring chalcone isolated from Alpinia species has shown to possess strong anti-inflammatory and anti-nociceptive activities. Previous studies have demonstrated that cardamonin exerts antihyperalgesic and antiallodynic properties in chronic constriction injury (CCI)-induced neuropathic pain animal model. However, the mechanisms underlying cardamonin's effect have yet to be fully understood. The present study aims to investigate the involvement of the serotonergic system in cardamonin induced antihyperalgesic and antiallodynic effects in CCI-induced neuropathic pain mice model. The neuropathic pain symptoms in the CCI mice model were assessed using Hargreaves Plantar test and von-Frey filament test on day 14 post-surgery. Central depletion of serotonin along the descending serotonergic pathway was done using ρ-chlorophenylalanine (PCPA, 100 mg/kg, i.p.), an inhibitor of serotonin synthesis for four consecutive days before cardamonin treatment, and was found to reverse the antihyperalgesic and antiallodynic effect produced by cardamonin. Pretreatment of the mice with several 5-HT receptor subtypes antagonists: methiothepin (5-HT1/6/77 receptor antagonist, 0.1 mg/kg), WAY 100635 (5-HT1A receptor antagonist, 1 mg/kg), isamoltane (5-HT1B receptor antagonist, 2.5 mg/kg), ketanserin (5-HT2A receptor antagonist, 0.3 mg/kg), and ondansetron (5-HT3 receptor antagonist, 0.5 mg/kg) were shown to abolish the effect of cardamonin induced antihyperalgesic and antiallodynic effects. Further evaluation of the 5-HT1A receptor subtype protein expressions reveals that cardamonin significantly upregulated its expression in the brainstem and spinal cord. Our results suggest that the serotonergic pathway is essential for cardamonin to exert its antineuropathic effect in CCI mice through the involvement of the 5-HT1A receptor subtype in the central nervous system.


Assuntos
Chalconas/farmacologia , Neuralgia/tratamento farmacológico , Receptor 5-HT1A de Serotonina/efeitos dos fármacos , Analgésicos/farmacologia , Animais , Chalconas/metabolismo , Modelos Animais de Doenças , Hiperalgesia/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos ICR , Receptor 5-HT1A de Serotonina/metabolismo , Neurônios Serotoninérgicos/efeitos dos fármacos , Neurônios Serotoninérgicos/metabolismo , Serotonina/metabolismo , Medula Espinal/efeitos dos fármacos
2.
Int J Mol Sci ; 22(11)2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34199392

RESUMO

Coordination of four-limb movements during quadrupedal locomotion is controlled by supraspinal monoaminergic descending pathways, among which serotoninergic ones play a crucial role. Here we investigated the locomotor pattern during recovery from blockade of 5-HT7 or 5-HT2A receptors after intrathecal application of SB269970 or cyproheptadine in adult rats with chronic intrathecal cannula implanted in the lumbar spinal cord. The interlimb coordination was investigated based on electromyographic activity recorded from selected fore- and hindlimb muscles during rat locomotion on a treadmill. In the time of recovery after hindlimb transient paralysis, we noticed a presence of an unusual pattern of quadrupedal locomotion characterized by a doubling of forelimb stepping in relation to unaffected hindlimb stepping (2FL-1HL) after blockade of 5-HT7 receptors but not after blockade of 5-HT2A receptors. The 2FL-1HL pattern, although transient, was observed as a stable form of fore-hindlimb coupling during quadrupedal locomotion. We suggest that modulation of the 5-HT7 receptors on interneurons located in lamina VII with ascending projections to the forelimb spinal network can be responsible for the 2FL-1HL locomotor pattern. In support, our immunohistochemical analysis of the lumbar spinal cord demonstrated the presence of the 5-HT7 immunoreactive cells in the lamina VII, which were rarely 5-HT2A immunoreactive.


Assuntos
Locomoção/genética , Receptor 5-HT2A de Serotonina/genética , Receptores de Serotonina/genética , Traumatismos da Medula Espinal/genética , Animais , Ciproeptadina/farmacologia , Estimulação Elétrica , Eletromiografia , Membro Anterior/efeitos dos fármacos , Membro Anterior/fisiopatologia , Membro Posterior/efeitos dos fármacos , Membro Posterior/fisiopatologia , Humanos , Locomoção/efeitos dos fármacos , Região Lombossacral/fisiopatologia , Ratos , Receptor 5-HT2A de Serotonina/efeitos dos fármacos , Receptores de Serotonina/efeitos dos fármacos , Serotonina/genética , Serotonina/metabolismo , Antagonistas do Receptor 5-HT2 de Serotonina/farmacologia , Medula Espinal , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/patologia , Coluna Vertebral/efeitos dos fármacos , Coluna Vertebral/fisiopatologia
3.
Molecules ; 26(11)2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34199466

RESUMO

Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the gastrointestinal tract with an incompletely understood pathogenesis. Long-standing colitis is associated with increased risk of colon cancer. Despite the availability of various anti-inflammatory and immunomodulatory drugs, many patients fail to respond to pharmacologic therapy and some experience drug-induced adverse events. Dietary supplements, particularly saffron (Crocus sativus), have recently gained an appreciable attention in alleviating some symptoms of digestive diseases. In our study, we investigated whether saffron may have a prophylactic effect in a murine colitis model. Saffron pre-treatment improved the gross and histopathological characteristics of the colonic mucosa in murine experimental colitis. Treatment with saffron showed a significant amelioration of colitis when compared to the vehicle-treated mice group. Saffron treatment significantly decreased secretion of serotonin and pro-inflammatory cytokines, such as TNF-α, IL-1ß, and IL-6, in the colon tissues by suppressing the nuclear translocation of NF-κB. The gut microbiome analysis revealed distinct clusters in the saffron-treated and untreated mice in dextran sulfate sodium (DSS)-induced colitis by visualization of the Bray-Curtis diversity by principal coordinates analysis (PCoA). Furthermore, we observed that, at the operational taxonomic unit (OTU) level, Cyanobacteria were depleted, while short-chain fatty acids (SCFAs), such as isobutyric acid, acetic acid, and propionic acid, were increased in saffron-treated mice. Our data suggest that pre-treatment with saffron inhibits DSS-induced pro-inflammatory cytokine secretion, modulates gut microbiota composition, prevents the depletion of SCFAs, and reduces the susceptibility to colitis.


Assuntos
Bactérias/classificação , Produtos Biológicos/administração & dosagem , Colite/tratamento farmacológico , Crocus/química , Sulfato de Dextrana/efeitos adversos , Microbiota/efeitos dos fármacos , Administração Oral , Animais , Bactérias/efeitos dos fármacos , Bactérias/genética , Bactérias/isolamento & purificação , Produtos Biológicos/farmacologia , Colite/induzido quimicamente , Colite/imunologia , Colite/patologia , Citocinas/metabolismo , Modelos Animais de Doenças , Regulação para Baixo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Filogenia , Profilaxia Pré-Exposição , Serotonina/metabolismo , Resultado do Tratamento
4.
Ecotoxicol Environ Saf ; 221: 112454, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34214917

RESUMO

Pharmaceuticals are emerging pollutants of concern for aquatic ecosystems where they are occurring in complex mixtures. In the present study, the chronic toxicity of an environmentally relevant pharmaceutical mixture on juvenile rainbow trout (Oncorhynchus mykiss) was investigated. Five pharmaceuticals (paracetamol, carbamazepine, diclofenac, naproxen and irbesartan) were selected based on their detection frequency and concentration levels in the Meuse river (Belgium). Fish were exposed for 42 days to three different concentrations of the mixture, the median one detected in the Meuse river, 10-times and 100-times this concentration. Effects on the nervous, immune, antioxidant, and detoxification systems were evaluated throughout the exposure period and their response standardized using the Integrated Biomarker Response (IBRv2) index. IBRv2 scores increased over time in the fish exposed to the highest concentration. After 42 days, fish exposed to the highest concentration displayed significantly higher levels in lysozyme activity (p < 0.01). The mixture also caused significant changes in brain serotonin turnover (p < 0.05). In short, our results indicate that the subchronic waterborne exposure to a pharmaceutical mixture commonly occurring in freshwater ecosystems may affect the neuroendocrine and immune systems of juvenile rainbow trout.


Assuntos
Oncorhynchus mykiss , Poluentes Químicos da Água/toxicidade , Acetaminofen/toxicidade , Animais , Bélgica , Biomarcadores/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Carbamazepina/toxicidade , Diclofenaco/toxicidade , Irbesartana/toxicidade , Fígado/efeitos dos fármacos , Fígado/metabolismo , Lisossomos/metabolismo , Naproxeno/toxicidade , Síndromes Neurotóxicas , Rios , Serotonina/metabolismo
5.
Int J Mol Sci ; 22(9)2021 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-34063611

RESUMO

Serotonin (5-hydroxytryptamine, 5-HT) plays two important roles in humans-one central and the other peripheral-depending on the location of the 5-HT pools of on either side of the blood-brain barrier. In the central nervous system it acts as a neurotransmitter, controlling such brain functions as autonomic neural activity, stress response, body temperature, sleep, mood and appetite. This role is very important in intensive care, as in critically ill patients multiple serotoninergic agents like opioids, antiemetics and antidepressants are frequently used. High serotonin levels lead to altered mental status, deliria, rigidity and myoclonus, together recognized as serotonin syndrome. In its role as a peripheral hormone, serotonin is unique in controlling the functions of several organs. In the gastrointestinal tract it is important for regulating motor and secretory functions. Apart from intestinal motility, energy metabolism is regulated by both central and peripheral serotonin signaling. It also has fundamental effects on hemostasis, vascular tone, heart rate, respiratory drive, cell growth and immunity. Serotonin regulates almost all immune cells in response to inflammation, following the activation of platelets.


Assuntos
Estado Terminal , Inflamação/metabolismo , Síndrome da Serotonina/metabolismo , Serotonina/metabolismo , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/patologia , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/patologia , Delírio/metabolismo , Delírio/patologia , Motilidade Gastrointestinal/fisiologia , Trato Gastrointestinal/metabolismo , Trato Gastrointestinal/patologia , Humanos , Inflamação/patologia , Mioclonia/metabolismo , Mioclonia/patologia , Serotonina/biossíntese , Síndrome da Serotonina/patologia
6.
Int J Mol Sci ; 22(10)2021 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-34065591

RESUMO

Central and peripheral serotonin (5HT) have opposing functions in the regulation of energy homeostasis. Both increasing 5HT signaling in the brain and decreasing 5HT signaling in the periphery have been proposed as potential treatments for obesity. This study investigates the relationship between constitutionally high or low 5HT activity and systemic net energy balance. Two sublines of rats with high and low whole-body 5HT tone, obtained by selective breeding for platelet 5HT parameters, were examined for fat accumulation in different white adipose tissue (WAT) depots, glucose/insulin tolerance, blood metabolic parameters, and expression of various metabolic genes. High-5HT animals, unlike their low-5HT counterparts, developed widespread intra-abdominal obesity associated with glucose and insulin intolerance, which worsened with age. They also had elevated blood glucose and lipid parameters but showed no significant changes in circulating leptin, resistin, and adipsin levels. Surprisingly, adiponectin levels were increased in plasma but reduced in the WAT of high-5HT rats. A limited number of metabolic genes belonging to different functional classes showed differential expression in WAT of high-5HT compared to low-5HT rats. Overall, a constitutive increase in 5HT tone is associated with a positive energy balance acting through subtle dysregulation of a broad spectrum of metabolic pathways.


Assuntos
Homeostase/fisiologia , Serotonina/metabolismo , Adiponectina/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Encéfalo/metabolismo , Metabolismo Energético/fisiologia , Feminino , Insulina/metabolismo , Leptina/metabolismo , Lipídeos/fisiologia , Masculino , Obesidade/metabolismo , Ratos , Ratos Wistar , Transdução de Sinais/fisiologia
7.
Molecules ; 26(11)2021 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-34073226

RESUMO

Breast tumors were the first tumors of epithelial origin shown to follow the cancer stem cell model. The model proposes that cancer stem cells are uniquely endowed with tumorigenic capacity and that their aberrant differentiation yields non-tumorigenic progeny, which constitute the bulk of the tumor cell population. Breast cancer stem cells resist therapies and seed metastases; thus, they account for breast cancer recurrence. Hence, targeting these cells is essential to achieve durable breast cancer remissions. We identified compounds including selective antagonists of multiple serotonergic system pathway components required for serotonin biosynthesis, transport, activity via multiple 5-HT receptors (5-HTRs), and catabolism that reduce the viability of breast cancer stem cells of both mouse and human origin using multiple orthologous assays. The molecular targets of the selective antagonists are expressed in breast tumors and breast cancer cell lines, which also produce serotonin, implying that it plays a required functional role in these cells. The selective antagonists act synergistically with chemotherapy to shrink mouse mammary tumors and human breast tumor xenografts primarily by inducing programmed tumor cell death. We hypothesize those serotonergic proteins of diverse activity function by common signaling pathways to maintain cancer stem cell viability. Here, we summarize our recent findings and the relevant literature regarding the role of serotonin in breast cancer.


Assuntos
Neoplasias da Mama/metabolismo , Células-Tronco Neoplásicas/citologia , Serotonina/metabolismo , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular , Modelos Animais de Doenças , Docetaxel/administração & dosagem , Transição Epitelial-Mesenquimal , Feminino , Humanos , Camundongos , Metástase Neoplásica , Recidiva Local de Neoplasia/metabolismo , Transplante de Neoplasias , Fenótipo , Receptores de Serotonina/metabolismo , Indução de Remissão , Sertralina/administração & dosagem , Transdução de Sinais
8.
J Cell Sci ; 134(11)2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-34085694

RESUMO

The classical neurotransmitter serotonin or 5-hydroxytryptamine (5-HT), synthesized from tryptophan, can be produced both centrally and peripherally. Through binding to functionally distinct receptors, serotonin is profoundly implicated in a number of fundamental physiological processes and pathogenic conditions. Recently, serotonin has been found covalently incorporated into proteins, a newly identified post-translational modification termed serotonylation. Transglutaminases (TGMs), especially TGM2, are responsible for catalyzing the transamidation reaction by transferring serotonin to the glutamine residues of target proteins. Small GTPases, extracellular matrix protein fibronectin, cytoskeletal proteins and histones are the most reported substrates for serotonylation, and their functions are triggered by this post-translational modification. This Review highlights the roles of serotonylation in physiology and diseases and provides perspectives for pharmacological interventions to ameliorate serotonylation for disease treatment.


Assuntos
Proteínas Monoméricas de Ligação ao GTP , Transglutaminases , Glutamina , Processamento de Proteína Pós-Traducional , Serotonina/metabolismo , Transglutaminases/genética
9.
FASEB J ; 35(7): e21519, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34137477

RESUMO

Globally, COPD remains a major cause of disability and death. In the United States alone, it is estimated that approximately 14 million people suffer from the disease. Given the high disease burden and requirement for chronic, long-term medical care associated with COPD, it is essential that new disease modifying agents are developed to complement the symptomatic therapeutics currently available. In the present report, we have identified a potentially novel therapeutic agent through the use of a high throughput screen based on the knowledge that cigarette smoke induces the proteolytic enzyme MMP1 leading to destruction of the lung in COPD. A construct utilizing the cigarette responsive promoter element of MMP-1 was conjugated to a luciferase reporter and utilized in an in vitro assay to screen the NIH Molecular Libraries Small Molecule Repository to identify putative targets that suppressed luciferase expression in response to cigarette smoke extract (CSE). Selective serotonin reuptake inhibitors potently inhibited luciferase expression and were further validated. SSRI treatment suppressed MMP-1 production in small airway epithelial cells exposed to (CSE) in vitro as well as in smoke exposed rabbits. In addition, SSRI treatment inhibited inflammatory cytokine production while rescuing cigarette smoke induced downregulation in vivo of the anti-inflammatory lipid transporter ABCA1, previously shown by our laboratory to be lung protective. Importantly, SSRI treatment prevented lung destruction in smoke exposed rabbits as measured by morphometry. These studies support further investigation into SSRIs as a novel therapeutic for COPD may be warranted.


Assuntos
Fumar Cigarros/efeitos adversos , Células Epiteliais/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Metaloproteinase 1 da Matriz/química , Pneumonia/tratamento farmacológico , Enfisema Pulmonar/tratamento farmacológico , Inibidores de Captação de Serotonina/farmacologia , Animais , Células Cultivadas , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Feminino , Pulmão/metabolismo , Pulmão/patologia , Pneumonia/induzido quimicamente , Pneumonia/enzimologia , Pneumonia/patologia , Enfisema Pulmonar/induzido quimicamente , Enfisema Pulmonar/enzimologia , Enfisema Pulmonar/patologia , Coelhos , Serotonina/metabolismo
10.
FASEB J ; 35(7): e21701, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34143529

RESUMO

Irritable bowel syndrome (IBS) is a common functional gastrointestinal disease. Although visceral hypersensitivity (VH) and disturbed gastrointestinal motility are typical pathophysiological features of IBS, the pathological mechanisms underlying this disease remain unclear. Serotonin system abnormalities are considered to play an important role in the pathomechanisms of IBS. Here, we hypothesize that similar alterations, including VH and colonic motility, induced by serotonin transporter (SERT) knockout result from altered serotonin signaling. We sought to determine the molecular mechanism underlying VH and colonic dysmotility induced by SERT knockout. We found that female SERT (slc6a4)-knockout (KO; ie, slc6a4-/- ) rats exhibited lower pain pressure thresholds (PPTs) than wild-type (WT; ie, slc6a4+/+ ) rats in response to colorectal distension (CRD). Significantly increased fecal pellet output and reduced concentration of serum tryptophan were observed in the female SERT KO rats. The concentrations of 5-hydroxytryptamine (5-HT) in platelet-rich plasma (PRP) and serum in SERT KO rats were lower than those in WT rats, but the numbers of enterochromaffin cells (ECs) and the concentrations of 5-HT in colon of SERT KO rats were higher than those of WT rats. Finally, increased expression levels of 5-HT1B receptors, 5-HT2C receptors, 5-HT3A receptors, 5-HT3B receptors, 5-HT6 receptors, 5-HT7 receptors, and glycosylated dopamine transporters (DATs) were found in the female SERT KO rats. We concluded that alterations in the serotonin system induced by the knockout of slc6a4 might result in VH and accelerated gastrointestinal motility in female SERT KO rats, which can be used as an animal model of IBS.


Assuntos
Colo/patologia , Motilidade Gastrointestinal , Hipersensibilidade/patologia , Síndrome do Intestino Irritável/patologia , Proteínas da Membrana Plasmática de Transporte de Serotonina/fisiologia , Serotonina/metabolismo , Animais , Animais Geneticamente Modificados , Colo/metabolismo , Modelos Animais de Doenças , Feminino , Hipersensibilidade/etiologia , Hipersensibilidade/metabolismo , Síndrome do Intestino Irritável/etiologia , Síndrome do Intestino Irritável/metabolismo , Ratos , Ratos Sprague-Dawley
11.
Int J Mol Sci ; 22(9)2021 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-34064332

RESUMO

Spinal cord injury (SCI) leads to numerous chronic and debilitating functional deficits that greatly affect quality of life. While many pharmacological interventions have been explored, the current unsurpassed therapy for most SCI sequalae is exercise. Exercise has an expansive influence on peripheral health and function, and by activating the relevant neural pathways, exercise also ameliorates numerous disorders of the central nervous system (CNS). While the exact mechanisms by which this occurs are still being delineated, major strides have been made in the past decade to understand the molecular underpinnings of this essential treatment. Exercise rapidly and prominently affects dendritic sprouting, synaptic connections, neurotransmitter production and regulation, and ionic homeostasis, with recent literature implicating an exercise-induced increase in neurotrophins as the cornerstone that binds many of these effects together. The field encompasses vast complexity, and as the data accumulate, disentangling these molecular pathways and how they interact will facilitate the optimization of intervention strategies and improve quality of life for individuals affected by SCI. This review describes the known molecular effects of exercise and how they alter the CNS to pacify the injury environment, increase neuronal survival and regeneration, restore normal neural excitability, create new functional circuits, and ultimately improve motor function following SCI.


Assuntos
Exercício Físico , Regulação da Expressão Gênica , Regeneração Nervosa/genética , Plasticidade Neuronal/genética , Recuperação de Função Fisiológica/genética , Traumatismos da Medula Espinal/genética , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fator Neurotrófico Derivado de Linhagem de Célula Glial/genética , Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Humanos , Neurotrofina 3/genética , Neurotrofina 3/metabolismo , Qualidade de Vida , Receptor 5-HT2A de Serotonina/genética , Receptor 5-HT2A de Serotonina/metabolismo , Serotonina/metabolismo , Transdução de Sinais , Medula Espinal/metabolismo , Medula Espinal/patologia , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/patologia , Traumatismos da Medula Espinal/reabilitação , Simportadores/genética , Simportadores/metabolismo
12.
Int J Mol Sci ; 22(11)2021 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-34072751

RESUMO

Prevention of amyloid ß peptide (Aß) deposition via facilitation of Aß binding to its natural depot, human serum albumin (HSA), is a promising approach to preclude Alzheimer's disease (AD) onset and progression. Previously, we demonstrated the ability of natural HSA ligands, fatty acids, to improve the affinity of this protein to monomeric Aß by a factor of 3 (BBRC, 510(2), 248-253). Using plasmon resonance spectroscopy, we show here that another HSA ligand related to AD pathogenesis, serotonin (SRO), increases the affinity of the Aß monomer to HSA by a factor of 7/17 for Aß40/Aß42, respectively. Meanwhile, the structurally homologous SRO precursor, tryptophan (TRP), does not affect HSA's affinity to monomeric Aß, despite slowdown of the association and dissociation processes. Crosslinking with glutaraldehyde and dynamic light scattering experiments reveal that, compared with the TRP-induced effects, SRO binding causes more marked changes in the quaternary structure of HSA. Furthermore, molecular docking reveals distinct structural differences between SRO/TRP complexes with HSA. The disintegration of the serotonergic system during AD pathogenesis may contribute to Aß release from HSA in the central nervous system due to impairment of the SRO-mediated Aß trapping by HSA.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Serotonina/metabolismo , Albumina Sérica Humana/metabolismo , Doença de Alzheimer , Peptídeos beta-Amiloides/química , Sítios de Ligação , Humanos , Ligantes , Conformação Molecular , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Ligação Proteica , Multimerização Proteica , Serotonina/química , Albumina Sérica Humana/química , Relação Estrutura-Atividade , Temperatura
13.
Int J Mol Sci ; 22(11)2021 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-34072767

RESUMO

Substance use/abuse is one of the main causes of depressive symptoms. Cannabis and synthetic cannabinoids in particular gained significant popularity in the past years. There is an increasing amount of clinical data associating such compounds with the inflammatory component of depression, indicated by the up-regulation of pro-inflammatory cytokines. Pro-inflammatory cytokines are also well-known to regulate the enzymes of the kynurenine pathway (KP), which is responsible for metabolizing tryptophan, a precursor in serotonin synthesis. Enhanced pro-inflammatory cytokine levels may over-activate the KP, leading to tryptophan depletion and reduced serotonin levels, which can subsequently precipitate depressive symptoms. Therefore, such mechanism might represent a possible link between the endocannabinoid system (ECS) and the KP in depression, via the inflammatory and dysregulated serotonergic component of the disorder. This review will summarize the data regarding those natural and synthetic cannabinoids that increase pro-inflammatory cytokines. Furthermore, the data on such cytokines associated with KP activation will be further reviewed accordingly. The interaction of the ECS and the KP has been postulated and demonstrated in some studies previously. This review will further contribute to this yet less explored connection and propose the KP to be the missing link between cannabinoid-induced inflammation and depressive symptoms.


Assuntos
Citocinas/metabolismo , Depressão/etiologia , Depressão/metabolismo , Mediadores da Inflamação/metabolismo , Animais , Biomarcadores , Depressão/psicologia , Suscetibilidade a Doenças , Endocanabinoides/metabolismo , Humanos , Inflamação/complicações , Inflamação/etiologia , Inflamação/metabolismo , Cinurenina/metabolismo , Redes e Vias Metabólicas , Serotonina/metabolismo , Transdução de Sinais
14.
Int J Mol Sci ; 22(11)2021 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-34073933

RESUMO

Migraine and sleep disorders are common chronic diseases in the general population, with significant negative social and economic impacts. The association between both of these phenomena has been observed by clinicians for years and is confirmed by many epidemiological studies. Despite this, the nature of this relationship is still not fully understood. In recent years, there has been rapid progress in understanding the common anatomical structures of and pathogenetic mechanism between sleep and migraine. Based on a literature review, the authors present the current view on this topic as well as ongoing research in this field, with reference to the key points of the biochemical and neurophysiological processes responsible for both these disorders. In the future, a better understanding of these mechanisms will significantly expand the range of treatment options.


Assuntos
Transtornos de Enxaqueca/complicações , Transtornos de Enxaqueca/metabolismo , Transtornos do Sono-Vigília/complicações , Transtornos do Sono-Vigília/metabolismo , Tronco Encefálico/fisiopatologia , Córtex Cerebral/fisiopatologia , Dopamina/metabolismo , Humanos , Hipotálamo/fisiopatologia , Melatonina/metabolismo , Transtornos de Enxaqueca/patologia , Transtornos de Enxaqueca/fisiopatologia , Orexinas/metabolismo , Serotonina/metabolismo , Sono/fisiologia , Transtornos do Sono-Vigília/patologia , Transtornos do Sono-Vigília/fisiopatologia , Tálamo/fisiopatologia
15.
Nat Commun ; 12(1): 3525, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-34112797

RESUMO

Contrasting to the established role of the hypothalamic agouti-related protein (AgRP) neurons in feeding regulation, the neural circuit and signaling mechanisms by which they control energy expenditure remains unclear. Here, we report that energy expenditure is regulated by a subgroup of AgRP neurons that send non-collateral projections to neurons within the dorsal lateral part of dorsal raphe nucleus (dlDRN) expressing the melanocortin 4 receptor (MC4R), which in turn innervate nearby serotonergic (5-HT) neurons. Genetic manipulations reveal a bi-directional control of energy expenditure by this circuit without affecting food intake. Fiber photometry and electrophysiological results indicate that the thermo-sensing MC4RdlDRN neurons integrate pre-synaptic AgRP signaling, thereby modulating the post-synaptic serotonergic pathway. Specifically, the MC4RdlDRN signaling elicits profound, bi-directional, regulation of body weight mainly through sympathetic outflow that reprograms mitochondrial bioenergetics within brown and beige fat while feeding remains intact. Together, we suggest that this AgRP neural circuit plays a unique role in persistent control of energy expenditure and body weight, hinting next-generation therapeutic approaches for obesity and metabolic disorders.


Assuntos
Proteína Relacionada com Agouti/metabolismo , Metabolismo Energético/fisiologia , Hipotálamo/metabolismo , Condução Nervosa/fisiologia , Neurônios Serotoninérgicos/fisiologia , Tecido Adiposo Bege/metabolismo , Tecido Adiposo Marrom/metabolismo , Animais , Peso Corporal , Cromatografia Líquida , Ingestão de Alimentos/fisiologia , Metabolismo Energético/genética , Masculino , Camundongos , Condução Nervosa/efeitos dos fármacos , Condução Nervosa/efeitos da radiação , Obesidade/metabolismo , Optogenética , Receptor Tipo 4 de Melanocortina/genética , Receptor Tipo 4 de Melanocortina/metabolismo , Neurônios Serotoninérgicos/efeitos dos fármacos , Neurônios Serotoninérgicos/efeitos da radiação , Serotonina/metabolismo , Serotonina/fisiologia , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Espectrometria de Massas em Tandem , Temperatura
16.
Food Funct ; 12(9): 4142-4151, 2021 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-33977961

RESUMO

Irritable bowel syndrome (IBS) is a common chronic functional bowel disease, associated with a high risk of depression and anxiety. The brain-gut axis plays an important role in the pathophysiological changes involved in IBS; however, an effective treatment for the same is lacking. The natural compound costunolide (COS) has been shown to exert gastroprotective, enteroprotective, and neuroprotective effects, but its therapeutic effects in IBS are unclear. Our study explored the effect of COS on intestinal dysfunction and depressive behaviour in stress-induced IBS mice. Mice were subjected to chronic unpredictable mild stress to trigger IBS, and some were administered COS. Behavioural tests, histochemical assays, western blotting, and measurement of 5-hydroxytryptamine (5-HT) levels in the colon and hippocampus were applied to monitor the physiological and molecular consequences of COS treatment in IBS mice. COS administration relieved intestinal dysfunction and depression-like behaviours in IBS mice. Improvements in low-grade colon inflammation and intestinal mucosal permeability, inhibition of the activation of mast cells, upregulation of colonic Occludin expression, and downregulation of Claudin 2 expression were also observed. COS was also found to upregulate GluN2A, BDNF, p-ERK1/2, and p-CREB expression and 5-HT levels in hippocampal cells but inhibited 5-HT metabolism. Molecular docking showed that COS could form hydrogen bonds with the serotonin transporter (SERT) to affect the reuptake of 5-HT in the intercellular space. In conclusion, COS alleviates intestinal dysfunction and depressive behaviour in stress-induced IBS mice by inhibiting mast cell activation in the colon and regulating 5-HT metabolism in the central nervous system.


Assuntos
Transtorno Depressivo/tratamento farmacológico , Intestinos/fisiopatologia , Síndrome do Intestino Irritável/fisiopatologia , Síndrome do Intestino Irritável/psicologia , Mastócitos/imunologia , Serotonina/metabolismo , Sesquiterpenos/farmacologia , Animais , Barreira Hematoencefálica/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteína de Ligação a CREB/metabolismo , Colo/imunologia , Hipocampo/metabolismo , Mucosa Intestinal/fisiopatologia , Síndrome do Intestino Irritável/imunologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Permeabilidade , Receptores de N-Metil-D-Aspartato/metabolismo , Sesquiterpenos/farmacocinética , Transdução de Sinais/efeitos dos fármacos , Estresse Psicológico
17.
Int J Mol Sci ; 22(6)2021 Mar 11.
Artigo em Inglês | MEDLINE | ID: covidwho-1143517

RESUMO

The interactions at the atomic level between small molecules and the main components of cellular plasma membranes are crucial for elucidating the mechanisms allowing for the entrance of such small species inside the cell. We have performed molecular dynamics and metadynamics simulations of tryptophan, serotonin, and melatonin at the interface of zwitterionic phospholipid bilayers. In this work, we will review recent computer simulation developments and report microscopic properties, such as the area per lipid and thickness of the membranes, atomic radial distribution functions, angular orientations, and free energy landscapes of small molecule binding to the membrane. Cholesterol affects the behaviour of the small molecules, which are mainly buried in the interfacial regions. We have observed a competition between the binding of small molecules to phospholipids and cholesterol through lipidic hydrogen-bonds. Free energy barriers that are associated to translational and orientational changes of melatonin have been found to be between 10-20 kJ/mol for distances of 1 nm between melatonin and the center of the membrane. Corresponding barriers for tryptophan and serotonin that are obtained from reversible work methods are of the order of 10 kJ/mol and reveal strong hydrogen bonding between such species and specific phospholipid sites. The diffusion of tryptophan and melatonin is of the order of 10-7 cm2/s for the cholesterol-free and cholesterol-rich setups.


Assuntos
1,2-Dipalmitoilfosfatidilcolina/química , Colesterol/química , Dimiristoilfosfatidilcolina/química , Melatonina/química , Serotonina/química , Triptofano/química , 1,2-Dipalmitoilfosfatidilcolina/metabolismo , Colesterol/metabolismo , Dimiristoilfosfatidilcolina/metabolismo , Ligação de Hidrogênio , Bicamadas Lipídicas/química , Bicamadas Lipídicas/metabolismo , Melatonina/metabolismo , Simulação de Dinâmica Molecular , Serotonina/metabolismo , Soluções , Eletricidade Estática , Termodinâmica , Triptofano/metabolismo , Água/química
18.
Int J Mol Sci ; 22(9)2021 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-33925793

RESUMO

Cytoguardin was identified in the conditioned medium of fibroblasts as a tryptophan metabolite, 5-methoxytryptophan (5-MTP). It is synthesized via two enzymatic steps: tryptophan hydroxylase (TPH) and hydroxyindole O-methyltransferase (HIOMT). A truncated HIOMT isoform, HIOMT298, catalyzes 5-MTP synthesis. Cancer cells produce scarce 5-MTP due to defective HIOMT298 expression. 5-MTP inhibits cancer cell COX-2 expression and thereby reduces COX-2-mediated cell proliferation and migration. 5-MTP also inhibits MMP-9 expression and thereby reduces cancer cell invasion. 5-MTP exerts its anti-cancer effect by blocking p38 MAPK and p38-mediated NF-κB and p300 HAT activation. The stable transfection of A549 cells with HIOMT298 restores 5-MTP production which renders cancer cells less aggressive. The implantation of HIOMT-transfected A549 into subcutaneous tissues of a murine xenograft tumor model shows that HIOMT-transduced A549 cells form smaller tumors and generate fewer metastatic lung nodules than control A549 cells. HIOMT298 transfection suppresses aromatic amino acid decarboxylase (AADC) expression and serotonin production. Serotonin is a cancer-promoting factor. By restoring 5-MTP and suppressing serotonin production, HIOMT298 overexpression converts cancer cells into less malignant phenotypes. The analysis of HIOMT expression in a human cancer tissue array showed reduced HIOMT levels in a majority of colorectal, pancreatic, and breast cancer. HIOMT298 may be a biomarker of human cancer progression. Furthermore, 5-MTP has the potential to be a lead compound in the development of new therapy for the chemoprevention of certain cancers such as hepatocellular cancer.


Assuntos
Metástase Neoplásica/tratamento farmacológico , Neoplasias/tratamento farmacológico , Triptofano/análogos & derivados , Triptofano/metabolismo , Animais , Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Ciclo-Oxigenase 2/metabolismo , Fibroblastos/metabolismo , Humanos , Neoplasias Hepáticas/prevenção & controle , Metaloproteinases da Matriz/metabolismo , Camundongos , Neoplasias/metabolismo , Neoplasias/prevenção & controle , Neoplasias Pancreáticas/tratamento farmacológico , Serotonina/metabolismo , Triptofano/efeitos dos fármacos , Triptofano/farmacologia
19.
Int J Mol Sci ; 22(8)2021 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-33917107

RESUMO

Iron oxide nanoparticle (IONP) therapy has diverse health benefits but high doses or prolonged therapy might induce oxidative cellular injuries especially in the brain. Therefore, we conducted the current study to investigate the protective role of quercetin supplementation against the oxidative alterations induced in the brains of rats due to IONPs. Forty adult male albino rats were allocated into equal five groups; the control received a normal basal diet, the IONP group was intraperitoneally injected with IONPs of 50 mg/kg body weight (B.W.) and quercetin-treated groups had IONPs + Q25, IONPs + Q50 and IONPs + Q100 that were orally supplanted with quercetin by doses of 25, 50 and 100 mg quercetin/kg B.W. daily, respectively, administrated with the same dose of IONPs for 30 days. IONPs induced significant increases in malondialdehyde (MDA) and significantly decreased reduced glutathione (GSH) and oxidized glutathione (GSSG). Consequently, IONPs significantly induced severe brain tissue injuries due to the iron deposition leading to oxidative alterations with significant increases in brain creatine phosphokinase (CPK) and acetylcholinesterase (AChE). Furthermore, IONPs induced significant reductions in brain epinephrine, serotonin and melatonin with the downregulation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and mitochondrial transcription factor A (mtTFA) mRNA expressions. IONPs induced apoptosis in the brain monitored by increases in caspase 3 and decreases in B-cell lymphoma 2 (Bcl2) expression levels. Quercetin supplementation notably defeated brain oxidative damages and in a dose-dependent manner. Therefore, quercetin supplementation during IONPs is highly recommended to gain the benefits of IONPs with fewer health hazards.


Assuntos
Antioxidantes/administração & dosagem , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Nanopartículas Magnéticas de Óxido de Ferro , Estresse Oxidativo/efeitos dos fármacos , Quercetina/administração & dosagem , Animais , Biomarcadores , Epinefrina/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Imuno-Histoquímica , Nanopartículas Magnéticas de Óxido de Ferro/química , Nanopartículas Magnéticas de Óxido de Ferro/ultraestrutura , Melatonina/metabolismo , Oxirredução/efeitos dos fármacos , Tamanho da Partícula , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Ratos , Serotonina/metabolismo
20.
Molecules ; 26(5)2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33807994

RESUMO

Intestinal enteroendocrine cells (EECs) respond to fatty acids from dietary and microbial origin by releasing neurotransmitters and hormones with various paracrine and endocrine functions. Much has become known about the underlying signaling mechanisms, including the involvement of G-protein coupled receptors (GPCRs), like free fatty acids receptors (FFARs). This review focusses on two more recently emerging research lines: the roles of odorant receptors (ORs), and those of fatty acid conjugates in gut. Odorant receptors belong to a large family of GPCRs with functional roles that only lately have shown to reach beyond the nasal-oral cavity. In the intestinal tract, ORs are expressed on serotonin (5-HT) and glucagon-like-peptide-1 (GLP-1) producing enterochromaffin and enteroendocrine L cells, respectively. There, they appear to function as chemosensors of microbiologically produced short-, and branched-chain fatty acids. Another mechanism of fatty acid signaling in the intestine occurs via their conjugates. Among them, conjugates of unsaturated long chain fatty acids and acetate with 5-HT, N-acyl serotonins have recently emerged as mediators with immune-modulatory effects. In this review, novel findings in mechanisms and molecular players involved in intestinal fatty acid biology are highlighted and their potential relevance for EEC-mediated signaling to the pancreas, immune system, and brain is discussed.


Assuntos
Células Enteroendócrinas/metabolismo , Ácidos Graxos/metabolismo , Receptores Odorantes/metabolismo , Serotonina/metabolismo , Animais , Dieta , Etanolamina , Microbioma Gastrointestinal , Humanos , Fatores Imunológicos/metabolismo , Intestinos/citologia , Metabolismo dos Lipídeos , Ácidos Oleicos/fisiologia , Serotonina/química , Transdução de Sinais
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