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1.
Nat Commun ; 12(1): 4220, 2021 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-34244497

RESUMO

Prokineticin-2 (Prok2) is an important secreted protein likely involved in the pathogenesis of several acute and chronic neurological diseases through currently unidentified regulatory mechanisms. The initial mechanical injury of neurons by traumatic brain injury triggers multiple secondary responses including various cell death programs. One of these is ferroptosis, which is associated with dysregulation of iron and thiols and culminates in fatal lipid peroxidation. Here, we explore the regulatory role of Prok2 in neuronal ferroptosis in vitro and in vivo. We show that Prok2 prevents neuronal cell death by suppressing the biosynthesis of lipid peroxidation substrates, arachidonic acid-phospholipids, via accelerated F-box only protein 10 (Fbxo10)-driven ubiquitination, degradation of long-chain-fatty-acid-CoA ligase 4 (Acsl4), and inhibition of lipid peroxidation. Mice injected with adeno-associated virus-Prok2 before controlled cortical impact injury show reduced neuronal degeneration and improved motor and cognitive functions, which could be inhibited by Fbxo10 knockdown. Our study shows that Prok2 mediates neuronal cell deaths in traumatic brain injury via ferroptosis.


Assuntos
Lesões Encefálicas Traumáticas/patologia , Córtex Cerebral/patologia , Ferroptose , Hormônios Gastrointestinais/metabolismo , Neuropeptídeos/metabolismo , Adulto , Idoso , Animais , Lesões Encefálicas Traumáticas/cirurgia , Células Cultivadas , Córtex Cerebral/citologia , Coenzima A Ligases/metabolismo , Modelos Animais de Doenças , Proteínas F-Box/genética , Proteínas F-Box/metabolismo , Feminino , Hormônios Gastrointestinais/genética , Técnicas de Silenciamento de Genes , Humanos , Peroxidação de Lipídeos , Masculino , Camundongos , Pessoa de Meia-Idade , Mitocôndrias/patologia , Neurônios/citologia , Neurônios/patologia , Neuropeptídeos/genética , Fosfolipídeos/biossíntese , Cultura Primária de Células , Proteólise , Ubiquitinação
2.
J Med Life ; 14(2): 243-249, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34104248

RESUMO

The thyroid hormone plays a vital role in the development and maturation of the nervous system not only during prenatal and perinatal age but also in adults. "Peripheral marker hypothesis" revealed that gene expression changes in some regions of the brain are reflected into the peripheral blood lymphocytes. The objective of the study was to investigate changes in the gene expression profile of neuropeptides and their receptors in patients with different forms of thyroid pathology. One hundred fifty-three patients with thyroid pathology were enrolled in the study. They were divided into three groups: group 1 included 16 patients with postoperative hypothyroidism, group 2 included 65 patients with hypothyroidism resulting from autoimmune thyroiditis (AIT), and group 3 included 72 patients with AIT and elevated levels of anti-thyroglobulin (anti-Tg) and anti-thyroid peroxidase (anti-TPO) antibodies in the serum. We used a pathway-specific polymerase chain reaction (PCR) array (RT2 Profiler™ PCR Array Human Neurotrophins & Receptors, QIAGEN, Germany) to identify and verify neuropeptides and receptors pathway-focused gene expression in 12 individuals that were randomly selected from each group using real-time PCR. Our research identified that patients with postoperative hypothyroidism had a considerably increased expression of NPY1R, NTSR1, and NPY4R. The patients with hypothyroidism caused by autoimmune thyroiditis had considerably lower expression of NTSR1, while the expression of NPY1R increased. The mRNA levels of NPY2R and PNOC increased in the patients with elevated levels of autoantibodies anti-Tg and anti-TPO in the serum, and mRNA levels of NPY1R and NTSR1 decreased in this group of patients.


Assuntos
Neuropeptídeos/sangue , Neuropeptídeos/genética , Receptores de Neuropeptídeos/sangue , Receptores de Neuropeptídeos/genética , Glândula Tireoide/patologia , Transcrição Genética , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Alemanha , Humanos , Hipotireoidismo/sangue , Hipotireoidismo/genética , Pessoa de Meia-Idade , Neuropeptídeos/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de Neuropeptídeos/metabolismo , Tireoidite Autoimune/sangue , Tireoidite Autoimune/genética
3.
Nat Commun ; 12(1): 3519, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-34112781

RESUMO

TLR4 signaling plays key roles in the innate immune response to microbial infection. Innate immune cells encounter different mechanical cues in both health and disease to adapt their behaviors. However, the impact of mechanical sensing signals on TLR4 signal-mediated innate immune response remains unclear. Here we show that TLR4 signalling augments macrophage bactericidal activity through the mechanical sensor Piezo1. Bacterial infection or LPS stimulation triggers assembly of the complex of Piezo1 and TLR4 to remodel F-actin organization and augment phagocytosis, mitochondrion-phagosomal ROS production and bacterial clearance and genetic deficiency of Piezo1 results in abrogation of these responses. Mechanistically, LPS stimulates TLR4 to induce Piezo1-mediated calcium influx and consequently activates CaMKII-Mst1/2-Rac axis for pathogen ingestion and killing. Inhibition of CaMKII or knockout of either Mst1/2 or Rac1 results in reduced macrophage bactericidal activity, phenocopying the Piezo1 deficiency. Thus, we conclude that TLR4 drives the innate immune response via Piezo1 providing critical insight for understanding macrophage mechanophysiology and the host response.


Assuntos
Infecções Bacterianas/imunologia , Imunidade Inata , Canais Iônicos/metabolismo , Macrófagos/imunologia , Fagossomos/metabolismo , Receptor 4 Toll-Like/metabolismo , Actinas/metabolismo , Animais , Cálcio/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Citoesqueleto/genética , Citoesqueleto/metabolismo , Infecções por Escherichia coli/imunologia , Transferência Ressonante de Energia de Fluorescência , Células HEK293 , Fator de Crescimento de Hepatócito/genética , Fator de Crescimento de Hepatócito/metabolismo , Humanos , Canais Iônicos/genética , Lipopolissacarídeos/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Neuropeptídeos/genética , Neuropeptídeos/metabolismo , Fagocitose/imunologia , Fagossomos/imunologia , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Receptor 4 Toll-Like/imunologia , Proteínas rac1 de Ligação ao GTP/genética , Proteínas rac1 de Ligação ao GTP/metabolismo
4.
Cancer Sci ; 112(7): 2870-2883, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33931924

RESUMO

Wnt, PI3K-Akt-mTOR, and NF-κB pathways were reported to be involved in DNA damage repair (DDR). DDR-deficient cancers become critically dependent on backup DNA repair pathways. Neuritin 1 (NRN1) is reported to be involved in PI3K-Akt-mTOR, and its role in DDR remains unclear. Methylation-specific PCR, siRNA, flow cytometry, esophageal cancer cell lines, and xenograft mouse models were used to examine the role of NRN1 in esophageal cancer. The expression of NRN1 is frequently repressed by promoter region methylation in human esophageal cancer cells. NRN1 was methylated in 50.4% (510/1012) of primary esophageal cancer samples. NRN1 methylation is associated significantly with age (P < .001), tumor size (P < .01), TNM stage (P < .001), differentiation (P < .001) and alcohol consumption (P < .05). We found that NRN1 methylation is an independent prognostic factor for poor 5-y overall survival (P < .001). NRN1 inhibits colony formation, cell proliferation, migration, and invasion, and induces apoptosis and G1/S arrest in esophageal cancer cells. NRN1 suppresses KYSE150 and KYSE30 cells xenografts growth in nude mice. PI3K signaling is reported to activate ATR signaling by targeting CHK1, the downstream component of ATR. By analyzing the synthetic efficiency of NVP-BEZ235 (PI3K inhibitor) and VE-822 (an ATR inhibitor), we found that the combination of NVP-BEZ235 and VE-822 increased cytotoxicity in NRN1 methylated esophageal cancer cells, as well as KYSE150 cell xenografts. In conclusion, NRN1 suppresses esophageal cancer growth both in vitro and in vivo by inhibiting PI3K-Akt-mTOR signaling. Methylation of NRN1 is a novel synthetic lethal marker for PI3K-Akt-mTOR and ATR inhibitors in human esophageal cancer.


Assuntos
Biomarcadores Tumorais/metabolismo , Reparo do DNA , Neoplasias Esofágicas/metabolismo , Carcinoma de Células Escamosas do Esôfago/metabolismo , Neuropeptídeos/metabolismo , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Consumo de Bebidas Alcoólicas , Animais , Apoptose , Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células/genética , Dano ao DNA , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/mortalidade , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/mortalidade , Carcinoma de Células Escamosas do Esôfago/patologia , Feminino , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/metabolismo , Xenoenxertos , Humanos , Masculino , Metilação , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Invasividade Neoplásica , Transplante de Neoplasias , Neuropeptídeos/genética , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/uso terapêutico , Prognóstico , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pirazinas/uso terapêutico , Pirazóis/uso terapêutico , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Carga Tumoral
5.
Neuron ; 109(12): 1979-1995.e6, 2021 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-34015253

RESUMO

Nutrient sensors allow animals to identify foods rich in specific nutrients. The Drosophila nutrient sensor, diuretic hormone 44 (DH44) neurons, helps the fly to detect nutritive sugar. This sensor becomes operational during starvation; however, the mechanisms by which DH44 neurons or other nutrient sensors are regulated remain unclear. Here, we identified two satiety signals that inhibit DH44 neurons: (1) Piezo-mediated stomach/crop stretch after food ingestion and (2) Neuromedin/Hugin neurosecretory neurons in the ventral nerve cord (VNC) activated by an increase in the internal glucose level. A subset of Piezo+ neurons that express DH44 neuropeptide project to the crop. We found that DH44 neuronal activity and food intake were stimulated following a knockdown of piezo in DH44 neurons or silencing of Hugin neurons in the VNC, even in fed flies. Together, we propose that these two qualitatively distinct peripheral signals work in concert to regulate the DH44 nutrient sensor during the fed state.


Assuntos
Proteínas de Drosophila/metabolismo , Trato Gastrointestinal/fisiologia , Glucose/metabolismo , Canais Iônicos/metabolismo , Inibição Neural/fisiologia , Neurônios/metabolismo , Neuropeptídeos/metabolismo , Resposta de Saciedade/fisiologia , Animais , Drosophila , Drosophila melanogaster , Comportamento Alimentar/fisiologia , Trato Gastrointestinal/inervação , Hormônios de Inseto , Mecanotransdução Celular/fisiologia , Neurônios/fisiologia , Estômago/inervação , Estômago/fisiologia
6.
J Med Chem ; 64(11): 7555-7564, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-34008968

RESUMO

RFamide-related peptide-3 (RFRP-3) and neuropeptide FF (NPFF) target two different receptor subtypes called neuropeptide FF1 (NPFF1R) and neuropeptide FF2 (NPFF2R) that modulate several functions. However, the study of their respective role is severely limited by the absence of selective blockers. We describe here the design of a highly selective NPFF1R antagonist called RF3286, which potently blocks RFRP-3-induced hyperalgesia in mice and luteinizing hormone release in hamsters. We then showed that the pharmacological blockade of NPFF1R in mice prevents the development of fentanyl-induced hyperalgesia while preserving its analgesic effect. Altogether, our data indicate that RF3286 represents a useful pharmacological tool to study the involvement of the NPFF1R/RFRP-3 system in different functions and different species. Thanks to this compound, we showed that this system is critically involved in the development of opioid-induced hyperalgesia, suggesting that NPFF1R antagonists might represent promising therapeutic tools to improve the use of opioids in the treatment of chronic pain.


Assuntos
Analgésicos Opioides/efeitos adversos , Dipeptídeos/química , Receptores de Neuropeptídeos/antagonistas & inibidores , Animais , Cricetinae , Dipeptídeos/metabolismo , Dipeptídeos/farmacologia , Dipeptídeos/uso terapêutico , Feminino , Fentanila/efeitos adversos , Meia-Vida , Humanos , Hiperalgesia/tratamento farmacológico , Hiperalgesia/etiologia , Hormônio Luteinizante/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neuropeptídeos/química , Neuropeptídeos/metabolismo , Neuropeptídeos/farmacologia , Neuropeptídeos/uso terapêutico , Isoformas de Proteínas/química , Isoformas de Proteínas/metabolismo , Receptores de Neuropeptídeos/metabolismo , Receptores Opioides/química , Receptores Opioides/metabolismo , Relação Estrutura-Atividade
7.
Biochem Biophys Res Commun ; 555: 74-80, 2021 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-33813279

RESUMO

The engagement of the receptor for advanced glycation end-products (receptor for AGEs, RAGE) with diverse ligands could elicit chronic vascular inflammation, such as atherosclerosis. Binding of cytoplasmic tail RAGE (ctRAGE) to diaphanous-related formin 1 (Diaph1) is known to yield RAGE intracellular signal transduction and subsequent cellular responses. However, the effectiveness of an inhibitor of the ctRAGE/Diaph1 interaction in attenuating the development of atherosclerosis is unclear. In this study, using macrophages from Ager+/+ and Ager-/- mice, we validated the effects of an inhibitor on AGEs-RAGE-induced foam cell formation. The inhibitor significantly suppressed AGEs-RAGE-evoked Rac1 activity, cell invasion, and uptake of oxidized low-density lipoprotein, as well as AGEs-induced NF-κB activation and upregulation of proinflammatory gene expression. Moreover, expression of Il-10, an anti-inflammatory gene, was restored by this antagonist. These findings suggest that the RAGE-Diaph1 inhibitor could be a potential therapeutic drug against RAGE-related diseases, such as chronic inflammation and atherosclerosis.


Assuntos
Células Espumosas/metabolismo , Macrófagos Peritoneais/patologia , Receptor para Produtos Finais de Glicação Avançada/antagonistas & inibidores , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Animais , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Expressão Gênica , Inflamação/genética , Inflamação/patologia , Lipoproteínas LDL/metabolismo , Macrófagos Peritoneais/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Neuropeptídeos/metabolismo , Fosforilação/efeitos dos fármacos , Ratos , Receptor para Produtos Finais de Glicação Avançada/genética , Transdução de Sinais/efeitos dos fármacos , Proteínas rac1 de Ligação ao GTP/metabolismo
8.
Int J Mol Sci ; 22(9)2021 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-33925193

RESUMO

A high-fat diet (HFD) quickly induces obesity with insulin resistance and hyperglycemia. We previously reported that a novel hypothalamic small protein, named neurosecretory protein GL (NPGL), stimulates feeding and fat accumulation in mice. However, the effects of NPGL on insulin sensitivity and glucose homeostasis remain unknown. Hence, we subjected NPGL-precursor gene (Npgl)-overexpressing mice to the oral glucose tolerance test (OGTT) and intraperitoneal insulin tolerance test (IPITT) under normal chow (NC) and HFD conditions. Npgl overexpression promoted body mass gain and tended to increase food intake of NC-fed mice, whereas it had little effect on HFD-fed mice. The OGTT showed elevated blood glucose and insulin levels in Npgl-overexpressing NC-fed mice 15 min after glucose administration. Both the OGTT and IPITT demonstrated that Npgl overexpression decreased blood glucose levels in HFD-fed mice 60 min after glucose and insulin treatments. Notably, Npgl overexpression increased adipose tissue masses only in NC-fed mice, and it decreased blood glucose and insulin levels in HFD-fed mice at the experimental end point. It also increased the mRNA expression of galanin, one of the feeding and metabolic regulatory neuropeptides, in the hypothalamus of HFD-fed mice. Therefore, NPGL may alleviate HFD-induced hyperglycemia and insulin resistance in mice.


Assuntos
Glucose/metabolismo , Resistência à Insulina/genética , Proteínas do Tecido Nervoso/metabolismo , Animais , Glicemia/metabolismo , Dieta Hiperlipídica , Modelos Animais de Doenças , Metabolismo Energético/genética , Teste de Tolerância a Glucose , Homeostase , Insulina/metabolismo , Resistência à Insulina/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/fisiologia , Neuropeptídeos/metabolismo , Obesidade/metabolismo
9.
Int J Mol Sci ; 22(8)2021 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-33923652

RESUMO

Studies over the past 30 years have revealed that adipose tissue is the major endocrine and paracrine organ of the human body. Arguably, adiopobiology has taken its reasonable place in studying obesity and related cardiometabolic diseases (CMDs), including Alzheimer's disease (AD), which is viewed herein as a neurometabolic disorder. The pathogenesis and therapy of these diseases are multiplex at basic, clinical and translational levels. Our present goal is to describe new developments in cardiometabolic and neurometabolic adipobiology. Accordingly, we focus on adipose- and/or skeletal muscle-derived signaling proteins (adipsin, adiponectin, nerve growth factor, brain-derived neuroptrophic factor, neurotrophin-3, irisin, sirtuins, Klotho, neprilysin, follistatin-like protein-1, meteorin-like (metrnl), as well as growth differentiation factor 11) as examples of metabotrophic factors (MTFs) implicated in the pathogenesis and therapy of obesity and related CMDs. We argue that these pathologies are MTF-deficient diseases. In 1993 the "vascular hypothesis of AD" was published and in the present review we propose the "vasculometabolic hypothesis of AD." We discuss how MTFs could bridge CMDs and neurodegenerative diseases, such as AD. Greater insights on how to manage the MTF network would provide benefits to the quality of human life.


Assuntos
Adipocinas/metabolismo , Síndrome Metabólica/metabolismo , Doenças Neurodegenerativas/metabolismo , Animais , Humanos , Síndrome Metabólica/tratamento farmacológico , Terapia de Alvo Molecular/métodos , Fatores de Crescimento Neural/metabolismo , Doenças Neurodegenerativas/tratamento farmacológico , Neuropeptídeos/metabolismo , Transdução de Sinais
10.
Nat Commun ; 12(1): 2304, 2021 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-33863916

RESUMO

Mitochondria play a pivotal role in the generation of signals coupling metabolism with neurotransmitter release, but a role for mitochondrial-produced ROS in regulating neurosecretion has not been described. Here we show that endogenously produced hydrogen peroxide originating from axonal mitochondria (mtH2O2) functions as a signaling cue to selectively regulate the secretion of a FMRFamide-related neuropeptide (FLP-1) from a pair of interneurons (AIY) in C. elegans. We show that pharmacological or genetic manipulations that increase mtH2O2 levels lead to increased FLP-1 secretion that is dependent upon ROS dismutation, mitochondrial calcium influx, and cysteine sulfenylation of the calcium-independent PKC family member PKC-1. mtH2O2-induced FLP-1 secretion activates the oxidative stress response transcription factor SKN-1/Nrf2 in distal tissues and protects animals from ROS-mediated toxicity. mtH2O2 levels in AIY neurons, FLP-1 secretion and SKN-1 activity are rapidly and reversibly regulated by exposing animals to different bacterial food sources. These results reveal a previously unreported role for mtH2O2 in linking diet-induced changes in mitochondrial homeostasis with neuropeptide secretion.


Assuntos
Adaptação Fisiológica , Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/fisiologia , Peróxido de Hidrogênio/metabolismo , Mitocôndrias/metabolismo , Neuropeptídeos/metabolismo , Animais , Proteínas de Ligação a DNA/metabolismo , Comportamento Alimentar/fisiologia , Regulação da Expressão Gênica , Interneurônios/citologia , Interneurônios/metabolismo , Oxirredução , Estresse Oxidativo/fisiologia , Fatores de Transcrição/metabolismo
11.
Nat Commun ; 12(1): 2335, 2021 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-33879799

RESUMO

Current therapeutic options for treating colorectal cancer have little clinical efficacy and acquired resistance during treatment is common, even following patient stratification. Understanding the mechanisms that promote therapy resistance may lead to the development of novel therapeutic options that complement existing treatments and improve patient outcome. Here, we identify RAC1B as an important mediator of colorectal tumourigenesis and a potential target for enhancing the efficacy of EGFR inhibitor treatment. We find that high RAC1B expression in human colorectal cancer is associated with aggressive disease and poor prognosis and deletion of Rac1b in a mouse colorectal cancer model reduces tumourigenesis. We demonstrate that RAC1B interacts with, and is required for efficient activation of the EGFR signalling pathway. Moreover, RAC1B inhibition sensitises cetuximab resistant human tumour organoids to the effects of EGFR inhibition, outlining a potential therapeutic target for improving the clinical efficacy of EGFR inhibitors in colorectal cancer.


Assuntos
Neoplasias Colorretais/etiologia , Neoplasias Colorretais/metabolismo , Proteínas rac1 de Ligação ao GTP/metabolismo , Animais , Antineoplásicos Imunológicos/farmacologia , Carcinogênese , Linhagem Celular Tumoral , Cetuximab/farmacologia , Neoplasias Colorretais/genética , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neuropeptídeos/deficiência , Neuropeptídeos/genética , Neuropeptídeos/metabolismo , Transdução de Sinais , Regulação para Cima , Via de Sinalização Wnt , Proteínas rac1 de Ligação ao GTP/deficiência , Proteínas rac1 de Ligação ao GTP/genética
12.
Molecules ; 26(7)2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33915732

RESUMO

The neuropeptide galanin (GAL), which is expressed in limbic brain structures, has a strong impact on the regulation of mood and behavior. GAL exerts its effects via three G protein-coupled receptors (GAL1-3-R). Little is known about the effects of aging and loss of GAL-Rs on hippocampal-mediated processes connected to neurogenesis, such as learning, memory recall and anxiety, and cell proliferation and survival in the dorsal dentate gyrus (dDG) in mice. Our results demonstrate that loss of GAL3-R, but not GAL2-R, slowed learning and induced anxiety in older (12-14-month-old) mice. Lack of GAL2-R increased cell survival (BrdU incorporation) in the dDG of young mice. However, normal neurogenesis was observed in vitro using neural stem and precursor cells obtained from GAL2-R and GAL3-R knockouts upon GAL treatment. Interestingly, we found sub-strain differences between C57BL/6J and C57BL/6N mice, the latter showing faster learning, less anxiety and lower cell survival in the dDG. We conclude that GAL-R signaling is involved in cognitive functions and can modulate the survival of cells in the neurogenic niche, which might lead to new therapeutic applications. Furthermore, we observed that the mouse sub-strain had a profound impact on the behavioral parameters analyzed and should therefore be carefully considered in future studies.


Assuntos
Ansiedade/etiologia , Suscetibilidade a Doenças , Aprendizagem/fisiologia , Memória/fisiologia , Receptor Tipo 2 de Galanina/genética , Receptor Tipo 3 de Galanina/genética , Fatores Etários , Envelhecimento/genética , Envelhecimento/metabolismo , Envelhecimento/psicologia , Animais , Ansiedade/metabolismo , Ansiedade/psicologia , Biomarcadores , Giro Denteado/metabolismo , Modelos Animais de Doenças , Expressão Gênica , Imuno-Histoquímica , Aprendizagem em Labirinto , Camundongos , Camundongos Knockout , Neuropeptídeos/metabolismo , Receptor Tipo 2 de Galanina/metabolismo , Receptor Tipo 3 de Galanina/metabolismo , Aprendizagem Espacial , Especificidade da Espécie
13.
Int J Mol Sci ; 22(8)2021 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-33921859

RESUMO

Obesity is now a public health concern. The leading cause of obesity is an energy imbalance between ingested and expended calories. The mechanisms of feeding behavior and energy metabolism are regulated by a complex of various kinds of molecules, including anorexigenic and orexigenic neuropeptides. One of these neuropeptides, neuromedin U (NMU), was isolated in the 1980s, and its specific receptors, NMUR1 and NMUR2, were defined in 2000. A series of subsequent studies has revealed many of the physiological roles of the NMU system, including in feeding behavior, energy expenditure, stress responses, circadian rhythmicity, and inflammation. Particularly over the past decades, many reports have indicated that the NMU system plays an essential and direct role in regulating body weight, feeding behavior, energy metabolism, and insulin secretion, which are tightly linked to obesity pathophysiology. Furthermore, another ligand of NMU receptors, NMS (neuromedin S), was identified in 2005. NMS has physiological functions similar to those of NMU. This review summarizes recent observations of the NMU system in relation to the pathophysiology of obesity in both the central nervous systems and the peripheral tissues.


Assuntos
Neuropeptídeos/metabolismo , Animais , Metabolismo Energético/fisiologia , Comportamento Alimentar/fisiologia , Humanos , Obesidade/metabolismo
14.
Int J Mol Med ; 47(5)2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33693958

RESUMO

Ectodermal­neural cortex 1 (ENC1), a highly expressed protein in lung cancer tissues, was identified from the Cancer Genome Atlas (TCGA) database. The objective of the present study was to examine the effects of ENC1 on the biological functions of lung cancer cells. For this purpose, the expression of ENC1 was examined by RT­qPCR to compare mRNA expression levels between 28 lung cancer tissue samples and para­cancerous tissue samples. The association between ENC1 expression and clinicopathological features was evaluated between the 2 tissue types. Using RT­qPCR and western blot analysis, the expression of ENC1 was investigated in a normal lung cell line (16HBE) and 2 lung cancer cell lines (A549 and H1299). The effect of siRNA targeting ENC1 (si­ENC1) on the proliferation of A549 and H1299 cells was detected by CCK­8 assay at the indicated time points. Transwell assay was used to measure the migration and invasion of A549 and H1299 cells following transfection with siRNA targeting ENC1 (si­ENC1). The expression levels of several proteins related to migration and invasion were examined by western blot analysis. A mouse model of subcutaneous tumor xenotransplantation was established in nude mice to examine the effects of ENC1 downregulation on cancer cells. The results revealed that the expression of ENC1 in lung cancer tissues and lung cancer cells was significantly higher than that in para­cancerous tissues and non­cancer lung cells, respectively. The knockdown of ENC1 in the A549 and H1299 cells using si­ENC1 significantly decreased cell proliferation, migration and invasion compared with the untransfected cells. The knockdown of ENC1 significantly downregulated the levels of matrix metalloproteinase (MMP)2, MMP9, N­cadherin, p­c­Jun N­terminal kinase (JNK), p­extracellular signal­regulated kinase (ERK) and p­p38. The levels of E­cadherin were upregulated. In the mouse lung tumor model, reduced levels of ENC1 inhibited the growth of lung tumors. On the whole, the present study demonstrates that ENC1 is involved in the proliferation, migration and invasion of lung cancer cells, and may thus be an effective diagnostic target for certain cancers. The inhibition or reduction of ENC1 activity may represent a breakthrough in the treatment of lung cancer.


Assuntos
Neoplasias Pulmonares/metabolismo , Sistema de Sinalização das MAP Quinases , Proteínas dos Microfilamentos/metabolismo , Proteínas de Neoplasias/metabolismo , Neuropeptídeos/metabolismo , Proteínas Nucleares/metabolismo , Células A549 , Animais , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Nus , Proteínas dos Microfilamentos/genética , Proteínas de Neoplasias/genética , Transplante de Neoplasias , Neuropeptídeos/genética , Proteínas Nucleares/genética
15.
Nat Commun ; 12(1): 1490, 2021 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-33674568

RESUMO

The brain of mammals lacks a significant ability to regenerate neurons and is thus particularly vulnerable. To protect the brain from injury and disease, damage control by astrocytes through astrogliosis and scar formation is vital. Here, we show that brain injury in mice triggers an immediate upregulation of the actin-binding protein Drebrin (DBN) in astrocytes, which is essential for scar formation and maintenance of astrocyte reactivity. In turn, DBN loss leads to defective astrocyte scar formation and excessive neurodegeneration following brain injuries. At the cellular level, we show that DBN switches actin homeostasis from ARP2/3-dependent arrays to microtubule-compatible scaffolds, facilitating the formation of RAB8-positive membrane tubules. This injury-specific RAB8 membrane compartment serves as hub for the trafficking of surface proteins involved in astrogliosis and adhesion mediators, such as ß1-integrin. Our work shows that DBN-mediated membrane trafficking in astrocytes is an important neuroprotective mechanism following traumatic brain injury in mice.


Assuntos
Astrócitos/metabolismo , Lesões Encefálicas Traumáticas/metabolismo , Cicatriz/metabolismo , Neuropeptídeos/genética , Neuropeptídeos/metabolismo , Complexo 2-3 de Proteínas Relacionadas à Actina , Actinas/metabolismo , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Lesões Encefálicas/metabolismo , Lesões Encefálicas/patologia , Lesões Encefálicas Traumáticas/patologia , Movimento Celular , Sistema Nervoso Central/metabolismo , Modelos Animais de Doenças , Gliose/metabolismo , Gliose/patologia , Camundongos , Camundongos Knockout , Neuroproteção , Transcriptoma , Proteínas rab de Ligação ao GTP/metabolismo
16.
Int J Mol Sci ; 22(4)2021 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-33669286

RESUMO

Leucokinins (LKs) constitute a family of neuropeptides identified in numerous insects and many other invertebrates. LKs act on G-protein-coupled receptors that display only distant relations to other known receptors. In adult Drosophila, 26 neurons/neurosecretory cells of three main types express LK. The four brain interneurons are of two types, and these are implicated in several important functions in the fly's behavior and physiology, including feeding, sleep-metabolism interactions, state-dependent memory formation, as well as modulation of gustatory sensitivity and nociception. The 22 neurosecretory cells (abdominal LK neurons, ABLKs) of the abdominal neuromeres co-express LK and a diuretic hormone (DH44), and together, these regulate water and ion homeostasis and associated stress as well as food intake. In Drosophila larvae, LK neurons modulate locomotion, escape responses and aspects of ecdysis behavior. A set of lateral neurosecretory cells, ALKs (anterior LK neurons), in the brain express LK in larvae, but inconsistently so in adults. These ALKs co-express three other neuropeptides and regulate water and ion homeostasis, feeding, and drinking, but the specific role of LK is not yet known. This review summarizes Drosophila data on embryonic lineages of LK neurons, functional roles of individual LK neuron types, interactions with other peptidergic systems, and orchestrating functions of LK.


Assuntos
Proteínas de Drosophila/metabolismo , Drosophila/metabolismo , Larva/metabolismo , Neurônios/metabolismo , Neuropeptídeos/metabolismo , Animais , Ingestão de Alimentos/fisiologia , Comportamento Alimentar/fisiologia , Homeostase/fisiologia , Hormônios de Inseto/metabolismo , Transdução de Sinais/fisiologia , Sono/fisiologia , Inanição/metabolismo
17.
Arch Insect Biochem Physiol ; 106(4): e21778, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33719129

RESUMO

One representative of the order Trichoptera, namely the caddisfly Chaetopteryx villosa, was investigated along with the pygmy mole cricket Xya capensis which is a representative of the most basal superfamily of the caeliferan Orthoptera, that is, the Tridactyloidea. From both clades neuropeptides have not been biochemically characterized before this study. Here, members of the adipokinetic hormone family (AKHs) are sequenced via liquid chromatography (LC)-ion trap mass spectrometry from methanolic extracts from the corpora cardiaca of respective species. The corpora cardiaca were dissected, methanolic extracts prepared, peptides separated by liquid chromatography (LC), and AKHs detected and sequenced by ion trap mass spectrometry. Both species investigated contain an octapeptide AKH: the trichopteran species has the peptide with the sequence pGlu-Leu-Thr-Phe-Thr-Pro-Ser-Trp amide; the ambiguity of the isobaric amino acids Leu and Ile at position two was solved by comparing retention times on LC and by co-elution with the synthetic Leu2 -form. This peptide is known as Aedae-AKH and found in certain dipteran species and in an alderfly (Megaloptera). The tridactyloid species contains the peptide with the sequence pGlu-Val-Asn-Phe-Ser-Pro-Gly-Trp amide which had first been identified in a member of the order Mantophasmatodea and is called Manto-CC. Comparisons are made between the AKH complements of the sister groups Trichoptera and Lepidoptera and their possible relatedness and, on the other hand, between the AKH of X. capensis with those of closely related caeliferan superfamilies. The biology of the two studied species is used to speculate about a possible function of the elucidated hormones. Lastly, the use of a larval stage as starting material for structural neuropeptide information is discussed.


Assuntos
Gryllidae/metabolismo , Insetos/metabolismo , Neuropeptídeos , Animais , Cromatografia Líquida/métodos , Espectrometria de Massas/métodos , Neuropeptídeos/química , Neuropeptídeos/isolamento & purificação , Neuropeptídeos/metabolismo
18.
Int J Mol Sci ; 22(5)2021 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-33668086

RESUMO

The present study investigated the effect of unilateral axotomy of urinary bladder trigone (UBT)-projecting nerve fibers from the right anterior pelvic ganglion (APG) on changes in the chemical coding of their neuronal bodies. The study was performed using male pigs with immunohistochemistry and quantitative real-time PCR (qPCR). The animals were divided into a control (C), a morphological (MG) or a molecular biology group (MBG). APG neurons supplying UBT were revealed using the retrograde tracing technique with Fast Blue (FB). Unilateral axotomy resulted in an over 50% decrease in the number of FB+ neurons in both APG ganglia. Immunohistochemistry revealed significant changes in the chemical coding of FB+ cells only in the right ganglion: decreased expression of dopamine-B-hydroxylase (DBH)/tyrosine hydroxylase (TH) and up-regulation of the vesicular acetylcholine transporter (VAChT)/choline acetyltransferase (ChAT), galanin (GAL), vasoactive intestinal polypeptide (VIP) and brain nitric oxide synthase (bNOS). The qPCR results partly corresponded with immunofluorescence findings. In the APGs, genes for VAChT and ChAT, TH and DBH, VIP, and NOS were distinctly down-regulated, while the expression of GAL was up-regulated. Such data may be the basis for further studies concerning the plasticity of these ganglia under experimental or pathological conditions.


Assuntos
Gânglios Simpáticos/fisiologia , Fibras Nervosas/fisiologia , Neurônios/fisiologia , Pelve/fisiologia , Bexiga Urinária/fisiologia , Animais , Axotomia , Catecolaminas/metabolismo , Colina O-Acetiltransferase/metabolismo , Dopamina beta-Hidroxilase/metabolismo , Masculino , Vias Neurais/metabolismo , Neuropeptídeos/metabolismo , Pelve/inervação , Suínos , Tirosina 3-Mono-Oxigenase/metabolismo , Bexiga Urinária/inervação
19.
PLoS Genet ; 17(2): e1009346, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33524034

RESUMO

Ethanol is a widely used drug, excessive consumption of which could lead to medical conditions with diverse symptoms. Ethanol abuse causes dysfunction of memory, attention, speech and locomotion across species. Dopamine signaling plays an essential role in ethanol dependent behaviors in animals ranging from C. elegans to humans. We devised an ethanol dependent assay in which mutants in the dopamine autoreceptor, dop-2, displayed a unique sedative locomotory behavior causing the animals to move in circles while dragging the posterior half of their body. Here, we identify the posterior dopaminergic sensory neuron as being essential to modulate this behavior. We further demonstrate that in dop-2 mutants, ethanol exposure increases dopamine secretion and functions in a DVA interneuron dependent manner. DVA releases the neuropeptide NLP-12 that is known to function through cholinergic motor neurons and affect movement. Thus, DOP-2 modulates dopamine levels at the synapse and regulates alcohol induced movement through NLP-12.


Assuntos
Caenorhabditis elegans/efeitos dos fármacos , Neurônios Dopaminérgicos/efeitos dos fármacos , Etanol/farmacologia , Transmissão Sináptica/efeitos dos fármacos , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/fisiologia , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/fisiologia , Depressores do Sistema Nervoso Central/farmacologia , Dopamina/metabolismo , Neurônios Dopaminérgicos/fisiologia , Humanos , Locomoção/efeitos dos fármacos , Neurônios Motores/efeitos dos fármacos , Neurônios Motores/fisiologia , Mutação , Neuropeptídeos/metabolismo , Receptores de Dopamina D2/genética , Receptores de Dopamina D2/fisiologia , Transdução de Sinais/efeitos dos fármacos
20.
ACS Chem Biol ; 16(2): 251-263, 2021 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-33539706

RESUMO

Intercellular signaling events mediated by neuropeptides and peptide hormones represent important targets for both basic science and drug discovery. For many bioactive peptides, the protein receptors that transmit information across the receiving cell membrane are not known, severely limiting these signaling pathways as potential therapeutic targets. Identifying the receptor(s) for a given peptide of interest is complicated by several factors. Most notably, cell-cell signaling peptides are generated through dynamic biosynthetic pathways, can act on many different families of receptor proteins, and can participate in complex ligand-receptor interactions that extend beyond a simple one-to-one archetype. Here, we discuss recent methodological advances to identify signaling partners for bioactive peptides. Recent efforts have centered on methods to identify candidate receptors via transcript expression, methods to match peptide-receptor pairs through high throughput screening, and methods to capture direct ligand-receptor interactions using chemical probes. Future applications of the receptor identification approaches discussed here, as well as technical advancements to address their limitations, promise to lead to a greater understanding of how cells communicate to deliver complex physiologies. Importantly, such advancements will likely provide novel targets for the treatment of human diseases within the central nervous and endocrine systems.


Assuntos
Neuropeptídeos/metabolismo , Hormônios Peptídicos/metabolismo , Receptores Acoplados a Proteínas G/análise , Receptores de Neuropeptídeos/análise , Animais , Humanos , Ligantes , Aprendizado de Máquina , Sondas Moleculares/química , Receptores Acoplados a Proteínas G/química , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Neuropeptídeos/química , Receptores de Neuropeptídeos/metabolismo
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