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1.
Int J Mol Sci ; 21(1)2019 Dec 25.
Artigo em Inglês | MEDLINE | ID: mdl-31881740

RESUMO

The G protein-coupled cannabinoid receptors type 1 (CB1R) and type 2 (CB2R), and their endocannabinoid (eCBs) ligands, have been implicated in several aspects of brain wiring during development. Here we aim to assess whether interfering with CB1R affects development, neuritogenesis and pathfinding of GnRH and AgRP neurons, forebrain neurons that control respectively reproduction and appetite. We pharmacologically and genetically interfered with CB1R in zebrafish strains with fluorescently labeled GnRH3 and the AgRP1 neurons. By applying CB1R antagonists we observed a reduced number of GnRH3 neurons, fiber misrouting and altered fasciculation. Similar phenotypes were observed by CB1R knockdown. Interfering with CB1R also resulted in a reduced number, misrouting and poor fasciculation of the AgRP1 neuron's axonal projections. Using a bioinformatic approach followed by qPCR validation, we have attempted to link CB1R functions with known guidance and fasciculation proteins. The search identified stathmin-2, a protein controlling microtubule dynamics, previously demonstrated to be coexpressed with CB1R and now shown to be downregulated upon interference with CB1R in zebrafish. Together, these results raise the likely possibility that embryonic exposure to low doses of CB1R-interfering compounds could impact on the development of the neuroendocrine systems controlling sexual maturation, reproduction and food intake.


Assuntos
Proteína Relacionada com Agouti/metabolismo , Axônios/metabolismo , Hormônio Liberador de Gonadotropina/metabolismo , Ácido Pirrolidonocarboxílico/análogos & derivados , Receptor CB1 de Canabinoide/metabolismo , Proteínas de Peixe-Zebra/metabolismo , Peixe-Zebra/metabolismo , Animais , Benzoxazinas/farmacologia , Embrião não Mamífero/efeitos dos fármacos , Embrião não Mamífero/metabolismo , Desenvolvimento Embrionário/efeitos dos fármacos , Morfolinas/farmacologia , Morfolinos/metabolismo , Naftalenos/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Ácido Pirrolidonocarboxílico/metabolismo , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptor CB1 de Canabinoide/genética , Peixe-Zebra/crescimento & desenvolvimento , Proteínas de Peixe-Zebra/antagonistas & inibidores , Proteínas de Peixe-Zebra/genética
2.
Nature ; 574(7779): 559-564, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31645735

RESUMO

Although glucose-sensing neurons were identified more than 50 years ago, the physiological role of glucose sensing in metazoans remains unclear. Here we identify a pair of glucose-sensing neurons with bifurcated axons in the brain of Drosophila. One axon branch projects to insulin-producing cells to trigger the release of Drosophila insulin-like peptide 2 (dilp2) and the other extends to adipokinetic hormone (AKH)-producing cells to inhibit secretion of AKH, the fly analogue of glucagon. These axonal branches undergo synaptic remodelling in response to changes in their internal energy status. Silencing of these glucose-sensing neurons largely disabled the response of insulin-producing cells to glucose and dilp2 secretion, disinhibited AKH secretion in corpora cardiaca and caused hyperglycaemia, a hallmark feature of diabetes mellitus. We propose that these glucose-sensing neurons maintain glucose homeostasis by promoting the secretion of dilp2 and suppressing the release of AKH when haemolymph glucose levels are high.


Assuntos
Encéfalo/metabolismo , Drosophila melanogaster/citologia , Drosophila melanogaster/metabolismo , Glucagon/metabolismo , Glucose/metabolismo , Insulina/metabolismo , Neurônios/metabolismo , Animais , Axônios/metabolismo , Encéfalo/anatomia & histologia , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/anatomia & histologia , Glucose/análise , Hormônios de Inseto/metabolismo , Masculino , Inibição Neural , Vias Neurais , Neuropeptídeos/química , Neuropeptídeos/metabolismo , Neurotransmissores/metabolismo , Oligopeptídeos/metabolismo , Ácido Pirrolidonocarboxílico/análogos & derivados , Ácido Pirrolidonocarboxílico/metabolismo
3.
Int J Mol Sci ; 20(19)2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31557968

RESUMO

Among various homing devices, gonadotropin-releasing hormone-III (GnRH-III) peptide represents a suitable targeting moiety for drug delivery systems. The anti-tumor activity of the previously developed GnRH-III-[4Lys(Bu),8Lys(Dau=Aoa)] conjugate and the novel synthesized GnRH-III-[2ΔHis,3d-Tic,4Lys(Bu),8Lys(Dau=Aoa)] conjugate, containing the anti-cancer drug daunorubicin, were evaluated. Here, we demonstrate that both GnRH-III-Dau conjugates possess an efficient growth inhibitory effect on more than 20 cancer cell lines, whereby the biological activity is strongly connected to the expression of gonadotropin-releasing hormone receptors (GnRH-R). The novel conjugate showed a higher in vitro anti-proliferative activity and a higher uptake capacity. Moreover, the treatment with GnRH-III-Dau conjugates cause a significant in vivo tumor growth and metastases inhibitory effect in three different orthotopic models, including 4T1 mice and MDA-MB-231 human breast carcinoma, as well as HT-29 human colorectal cancer bearing BALB/s and SCID mice, while toxic side-effects were substantially reduced in comparison to the treatment with the free drug. These findings illustrate that our novel lead compound is a highly promising candidate for targeted tumor therapy in both colon cancer and metastatic breast cancer.


Assuntos
Antineoplásicos/farmacologia , Daunorrubicina/análogos & derivados , Daunorrubicina/farmacologia , Hormônio Liberador de Gonadotropina , Ácido Pirrolidonocarboxílico/análogos & derivados , Animais , Antineoplásicos/química , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Daunorrubicina/química , Modelos Animais de Doenças , Feminino , Expressão Gênica , Hormônio Liberador de Gonadotropina/química , Humanos , Masculino , Camundongos , Estrutura Molecular , Ácido Pirrolidonocarboxílico/química , RNA Mensageiro/genética , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , Testes de Toxicidade , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Arch Insect Biochem Physiol ; 102(4): e21611, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31471923

RESUMO

Seventeen species of the coleopteran series Cucujiformia are investigated for the presence and sequence of putative adipokinetic hormones (AKHs). Cucujiformia includes species from the major superfamilies, that is, Chrysomeloidea, Curculionoidea, Cucujoidea, and Tenebrionoidea. The clade Phytophaga in which the Chrysomeloidea and Curculionoidea reside, harbor very detrimental species for agriculture and forestry. Thus, this study aims not only to demonstrate the structural biodiversity of AKHs in these beetle species and possible evolutionary trends but also to determine whether the AKHs from harmful pest species can be used as lead substances for a future putative insecticide that is harmless to beneficial insects. Sequence analysis of AKHs is achieved by liquid chromatography coupled to mass spectrometry. Most of the investigated species contain AKH octapeptides in their corpora cardiaca, although previously published work also found a few decapeptides, which we comment on. The signature and sole AKH in cerambycidae Chrysomeloidea and Curculionoidea is Peram-CAH-I (pEVNFSPNW amide), which is also found in the majority of chrysomelidae Chrysomeloidea and in the one investigated species of Cucujoidea albeit in a few cases associated with a second AKH which can be either Peram-CAH-II (pELTFTPNW amide), Emppe-AKH (pEVNFTPNW amide), or Micvi-CC (pEINFTPNW amide). The most often encountered AKH in Tenebrionoidea, family Meloidae as well as family Tenebrionidae, is Tenmo-HrTH (pELNFSPNW amide) followed by Pyrap-AKH (pELNFTPNW amide) and a Tenmo-HrTH extended decapeptide (in Meloidae). Finally, we examine AKH sequences from 43 species of cucujiform beetles, including the superfamily Coccinelloidea for a possible lead compound for producing a cucujiform-specific pesticide.


Assuntos
Besouros/química , Hormônios de Inseto/química , Oligopeptídeos/química , Ácido Pirrolidonocarboxílico/análogos & derivados , Sequência de Aminoácidos , Animais , Cromatografia Líquida , Corpora Allata/química , Hormônios de Inseto/análise , Espectrometria de Massas , Oligopeptídeos/análise , Peptídeos/análise , Peptídeos/química , Ácido Pirrolidonocarboxílico/análise , Ácido Pirrolidonocarboxílico/química
5.
Artigo em Inglês | MEDLINE | ID: mdl-31386905

RESUMO

Gonadotropin-releasing hormones (GnRH) regulate gonadal growth of teleosts. Benzo(a)pyrene (BaP) functions as a reproductive endocrine disruptor. Furthermore, endocrine regulation on brood pouch growth of Syngnathidaes is elusive. To better understand the role of GnRH in brood pouch growth and effects of BaP on reproductive endocrine in lined seahorse (Hippocampus erectus), gnrh2 and gnrh3 genes were identified. Results showed that lined seahorse GnRH2 and GnRH3 precursors included the conservative tripartite structure and their transcripts highly expressed in brain as other teleosts. Expression profiles of gnrh2 and gnrh3 transcripts were detected during brood pouch growth. Results indicated that brain gnrh2 transcripts remarkably increased at the middle-stage and late-stage of brood pouch growth, while brain gnrh3 transcripts significantly raised at the early-stage and middle-stage. These suggested that GnRH2 and GnRH3 regulated brood pouch growth at different stages. Short-term BaP exposure in lined seahorse was performed. Transcripts of gnrh2 and gnrh3 remarkably increased in females and males exposed to BaP. Besides, plasma 17-beta estradiol (E2) levels presented a reduced trend during female fish exposed to BaP. This revealed that BaP functioned as anti-estrogenic effects and it may result in high expression of gnrh mRNA. However, plasma 11-ketone testosterone (11-KT) levels showed an increased trend during male fish exposed to BaP. Taken together, these indicated interesting results of BaP on reproduction in each sex of seahorse. These observations contribute to provide novel information of regulation on brood pouch growth and effects of BaP on reproductive endocrine in Syngnathidaes.


Assuntos
Benzo(a)pireno/farmacologia , Estradiol/metabolismo , Hormônio Liberador de Gonadotropina/metabolismo , Gônadas/metabolismo , Ácido Pirrolidonocarboxílico/análogos & derivados , Smegmamorpha/metabolismo , Testosterona/análogos & derivados , Animais , Feminino , Masculino , Ácido Pirrolidonocarboxílico/metabolismo , RNA Mensageiro/metabolismo , Reprodução/fisiologia , Testosterona/metabolismo
6.
Arch Insect Biochem Physiol ; 101(4): e21586, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31180597

RESUMO

This study examined the effect of two natural toxins (a venom from the parasitic wasp Habrobracon hebetor and destruxin A from the entomopathogenic fungus Metarhizium anisopliae), and one pathogen (the entomopathogenic fungus Isaria fumosorosea) on the activity of basic digestive enzymes in the midgut of the cockroach Periplaneta americana. Simultaneously, the role of adipokinetic hormones (AKH) in the digestive processes was evaluated. The results showed that all tested toxins/pathogens elicited stress responses when applied into the cockroach body, as documented by an increase of AKH level in the central nervous system. The venom from H. hebetor showed no effect on digestive enzyme activities in the ceca and midgut in vitro. In addition, infection by I. fumosorosea caused a decrease in activity of all enzymes in the midgut and a variable decrease in activity in the ceca; application of AKHs did not reverse the inhibition. Destruxin A inhibited the activity of all enzymes in the midgut but none in the ceca in vitro; application of AKHs did reverse this inhibition, and no differences between both cockroach AKHs were found. Overall, the results demonstrated the variable effect of the tested toxins/pathogens on the digestive processes of cockroaches as well as the variable ability of AKH to counteract these effects.


Assuntos
Depsipeptídeos/toxicidade , Hormônios de Inseto/farmacologia , Oligopeptídeos/farmacologia , Periplaneta/efeitos dos fármacos , Ácido Pirrolidonocarboxílico/análogos & derivados , Venenos de Vespas/toxicidade , Animais , Ativação Enzimática , Trato Gastrointestinal/enzimologia , Periplaneta/enzimologia , Ácido Pirrolidonocarboxílico/farmacologia
7.
Amino Acids ; 51(7): 1023-1028, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31073692

RESUMO

It is known for almost 25 years that the corpora cardiaca (neurosecretory glands) of cicadas synthesize two isobaric peptides with hypertrehalosaemic activity denominated Placa-HrTH-I and II. Both decapeptides have the same amino acid sequence (pGlu-Val-Asn-Phe-Ser-Pro-Ser-Trp-Gly-Asn amide) and mass, but differ in their chromatographic retention time. The slightly more hydrophobic peptide, Placa-HrTH-II, co-elutes with the synthetic peptide of the same sequence and is less active in biological assays than Placa-HrTH-I. Ion mobility separation in conjunction with high-resolution mass spectrometry detected the differing structural feature between both peptides in the region Pro6-Ser7-Trp8. Here, it was shown that Placa-HrTH-I co-eluted with a synthetic peptide containing D-Pro in position 6, while dextrorotatory amino acid residues in positions 7 and 8 could be excluded in this way. Amino acid hydrolysis followed by chiral analysis using a relative of Marfey's reagent was then used to validate the presence of D-Pro in Placa-HrTH-I. Interestingly, this experiment unambiguously proved both the absence of D-Pro and the presence of L-Pro in Placa-HrTH-I. Racemization as a reason for the structural differences of the twin adipokinetic hormones was hence ruled out and cis-trans isomerism as the likely alternative came into focus. It remains to be investigated if Pro6 in cis-conformation is indeed present and responsible for the increased bioactivity of Placa-HrTH-I.


Assuntos
Hemípteros/química , Hormônios de Inseto/química , Neuropeptídeos/química , Oligopeptídeos/química , Ácido Pirrolidonocarboxílico/análogos & derivados , Sequência de Aminoácidos , Aminoácidos , Animais , Isomerismo , Espectrometria de Massas , Conformação Molecular , Peptídeos/química , Ácido Pirrolidonocarboxílico/química , Estereoisomerismo
8.
Zoolog Sci ; 36(2): 167-171, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-31120653

RESUMO

The two-pore domain potassium ion (K + ) channel-related K + (TREK) channel and melatonin receptors play roles in the regulation of reproduction in zebrafish. Since reproduction is regulated by diurnal rhythms, the TREK family and melatonin receptors may exhibit diurnal rhythms in expression. In this study, we aimed to investigate diurnal variations of the gene expressions of TREK family and melatonin receptors and their associations with kisspeptin and gonadotrophin-releasing hormone (GnRH). Diurnal variations of trek1b, trek2a, trek2b, mt1, mt2, mel1a, kiss2 and gnrh3 expressions were examined by real-time PCR. For reproduction-related genes, kiss2 and gnrh3 exhibited diurnal rhythms. trek2a revealed a diurnal rhythm in the TREK family. mt2 and mel1c exhibited diurnal rhythms in the melatonin receptors. Since Trek2a regulates gnrh3 expression, the diurnal rhythm of gnrh3 expression suggests to be regulated by the diurnal rhythm of trek2a expression.


Assuntos
Ritmo Circadiano/genética , Hormônio Liberador de Gonadotropina/metabolismo , Canais de Potássio de Domínios Poros em Tandem/metabolismo , Ácido Pirrolidonocarboxílico/análogos & derivados , Peixe-Zebra/metabolismo , Animais , Ritmo Circadiano/fisiologia , Regulação da Expressão Gênica/fisiologia , Hormônio Liberador de Gonadotropina/genética , Kisspeptinas/metabolismo , Masculino , Canais de Potássio de Domínios Poros em Tandem/genética , Ácido Pirrolidonocarboxílico/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Receptores de Melatonina/genética , Receptores de Melatonina/metabolismo , Peixe-Zebra/genética
9.
Toxins (Basel) ; 11(4)2019 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-30959738

RESUMO

Amphibians have developed successful defensive strategies for combating predators and invasive microorganisms encountered in their broad range of environments, which involve secretion of complex cocktails of noxious, toxic and diverse bioactive molecules from the skins. In recent years, amphibian skin secretions have been considered as an extraordinary warehouse for the discovery of therapeutic medicines. In this study, through bioactivity screening of the Hylarana latouchii skin secretion-derived fractions, a novel peptide belonging to ranatensin subfamily (ranatensin-HLa) was discovered, and structurally and pharmacologically-characterised. It consists of 15 amino acid residues, pGlu-NGDRAPQWAVGHFM-NH2, and its synthetic replicate was found to exhibit pharmacological activities on increasing the contraction of the in vitro rat bladder and uterus smooth muscles. Corresponding characteristic sigmoidal dose-response curves with EC50 values of 7.1 nM and 5.5 nM were produced, respectively, in bladder and uterus. Moreover, the precursor of ranatensin-HLa showed a high degree of similarity to those of bombesin-like peptides from Odorrana grahami and Odorrana schmackeri. Hylarana latouchii skin continues to serve as a storehouse with diverse lead compounds for the development of therapeutically effective medicines.


Assuntos
Músculo Liso/efeitos dos fármacos , Oligopeptídeos/farmacologia , Ácido Pirrolidonocarboxílico/análogos & derivados , Bexiga Urinária/efeitos dos fármacos , Sequência de Aminoácidos , Animais , Sequência de Bases , Clonagem Molecular , DNA Complementar/genética , Feminino , Técnicas In Vitro , Músculo Liso/fisiologia , Oligopeptídeos/química , Oligopeptídeos/genética , Ácido Pirrolidonocarboxílico/química , Ácido Pirrolidonocarboxílico/farmacologia , Ranidae/metabolismo , Ratos Wistar , Pele/metabolismo , Bexiga Urinária/fisiologia
10.
Int J Food Sci Nutr ; 70(8): 959-969, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31010351

RESUMO

There is increasing interest in the potential role of epigallocatechin gallate (EGCG) in changing body composition to lower body fat with increased lean mass. In this study, we examined the sex-dependent effect of EGCG on body composition, locomotion, feeding behaviour, sugar levels, and transcription levels of key regulators in lipid, carbohydrate, and energy metabolisms in Drosophila melanogaster. EGCG had no effects on body weights in both females and males, but decreased fat accumulation in females compared to the control, accompanied by a reduction in food intake. EGCG treatments increased lean mass and locomotor activity, and downregulated transcription levels of brummer (bmm), adipokinetic hormone (akh), and Drosophila insulin-like peptide 2 (dilp2), and upregulated spargel (srl) in males. In addition, EGCG decreased sugar levels in both females and males. In conclusion, EGCG promotes lean phenotype in D. melanogaster via sex-specific metabolic regulations.


Assuntos
Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Catequina/análogos & derivados , Drosophila melanogaster/efeitos dos fármacos , Drosophila melanogaster/metabolismo , Animais , Antioxidantes/farmacologia , Composição Corporal/efeitos dos fármacos , Peso Corporal , Catequina/farmacologia , Regulação para Baixo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Metabolismo Energético , Feminino , Homeostase , Hormônios de Inseto/genética , Hormônios de Inseto/metabolismo , Lipase/genética , Lipase/metabolismo , Masculino , Neuropeptídeos/genética , Neuropeptídeos/metabolismo , Oligopeptídeos/genética , Oligopeptídeos/metabolismo , Fator B de Elongação Transcricional Positiva/genética , Fator B de Elongação Transcricional Positiva/metabolismo , Ácido Pirrolidonocarboxílico/análogos & derivados , Ácido Pirrolidonocarboxílico/metabolismo , Fatores Sexuais
11.
Pest Manag Sci ; 75(6): 1750-1759, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30734498

RESUMO

BACKGROUND: Neuropeptides are regulators of critical life processes in insects and, due to their high specificity, represent potential targets in the development of greener insecticidal agents. Fundamental to this drive is understanding neuroendocrine pathways that control key physiological processes in pest insects and the screening of potential analogues. The current study investigated neuropeptide binding sites of kinin and CAPA (CAPA-1) in the aphids Myzus persicae and Macrosiphum rosae and the effect of biostable analogues on aphid fitness under conditions of desiccation, starvation and thermal (cold) stress. RESULTS: M. persicae and M. rosae displayed identical patterns of neuropeptide receptor mapping along the gut, with the gut musculature representing the main target for kinin and CAPA-1 action. While kinin receptor binding was observed in the brain and VNC of M. persicae, this was not observed in M. rosae. Furthermore, no CAPA-1 receptor binding was observed in the brain and VNC of either species. CAP2b/PK analogues (with CAPA receptor cross-activity) were most effective in reducing aphid fitness under conditions of desiccation and starvation stress, particularly analogues 1895 (2Abf-Suc-FGPRLa) and 2129 (2Abf-Suc-ATPRIa), which expedited aphid mortality. All analogues, with the exception of 2139-Ac, were efficient at reducing aphid survival under cold stress, although were equivalent in the strength of their effect. CONCLUSION: In demonstrating the effects of analogues belonging to the CAP2b neuropeptide family and key analogue structures that reduce aphid fitness under stress conditions, this research will feed into the development of second generation analogues and ultimately the development of neuropeptidomimetic-based insecticidal agents. © 2019 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.


Assuntos
Afídeos/efeitos dos fármacos , Afídeos/fisiologia , Cininas/química , Cininas/farmacologia , Neuropeptídeos/química , Neuropeptídeos/farmacologia , Oligopeptídeos/química , Oligopeptídeos/farmacologia , Ácido Pirrolidonocarboxílico/análogos & derivados , Estresse Fisiológico/efeitos dos fármacos , Animais , Sítios de Ligação , Resposta ao Choque Térmico/efeitos dos fármacos , Cininas/metabolismo , Neuropeptídeos/metabolismo , Oligopeptídeos/metabolismo , Ácido Pirrolidonocarboxílico/química , Ácido Pirrolidonocarboxílico/metabolismo , Ácido Pirrolidonocarboxílico/farmacologia , Receptores de Neuropeptídeos/metabolismo
12.
Br Poult Sci ; 60(3): 187-194, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30686025

RESUMO

1. Two candidate genes, namely, Gonadotropin releasing hormone I (GnRHI) and Gonadotropin releasing hormone II (GnRHII) play pivotal roles in ovulation and egg production in chicken. The objective of this study was to explore polymorphism in these genes and to estimate the effects of polymorphism of these two genes on egg production and egg quality traits in White Leghorn laying hens. 2. Single strand conformation polymorphism followed by sequencing was performed to detect polymorphism in these genes. 3. The coding regions of the GnRHI and GnRHII genes were found to be polymorphic. In the GnRH1 gene, 12 haplotypes were determined, of which the h1 haplotype was predominant and the h5, h9 and h11 haplotypes were the least frequent ones. In the GnRHII gene, eight haplotypes were found, of which the h1 haplotype was the most frequent and the h6 was the least frequent haplotype in the White Leghorn population. 4. The haplogroups of GnRHI had a significant effect on body weight and egg production up to 64 weeks of age, yolk content, Haugh units and egg shell parameters. The h1h2 haplogroup of the GnRHI gene showed the highest egg production, with 211.0 ± 24.3 eggs up to 64 weeks of age, while the highest yolk content and Haugh unit was found in h3h10 haplogrouped birds. The haplogroups of GnRHII had a significant effect on age at sexual maturity (ASM) where the shortest ASM was found in the h1h4 birds (147.3 ± 5.9 d) and the longest ASM was observed in the h1h3 birds (160.6 ± 23.4 d). 5. It was concluded that GnRHI and GnRHII genes are polymorphic and have a significant effect on body weight, egg production and egg quality traits in White Leghorn laying hens.


Assuntos
Proteínas Aviárias/genética , Galinhas/fisiologia , Ovos/análise , Hormônio Liberador de Gonadotropina/análogos & derivados , Óvulo/fisiologia , Ácido Pirrolidonocarboxílico/análogos & derivados , Animais , Proteínas Aviárias/metabolismo , Galinhas/genética , Feminino , Hormônio Liberador de Gonadotropina/genética , Hormônio Liberador de Gonadotropina/metabolismo , Fases de Leitura Aberta , Polimorfismo Conformacional de Fita Simples , Ácido Pirrolidonocarboxílico/metabolismo , Análise de Sequência de DNA/veterinária
13.
Neurotoxicology ; 71: 31-38, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30521821

RESUMO

Gonadotropin releasing hormone (GnRH) neurons in the brain are the main controllers of reproduction and reproductive behavior in most vertebrates, and are susceptible to endocrine disruption by different bisphenols. While the endocrine disrupting properties of bisphenol A have been well documented, commonly used analogues such as bisphenol F (BPF) are not as well studied. In this study we examined the effects of early, low-dose, chronic BPF exposure on the development of the GnRH neural system in the zebrafish embryo. Using a transgenic zebrafish model system with GnRH3 neurons tagged with green fluorescent protein (GFP), developing GnRH neurons in both the terminal nerve (TN) and preoptic area (POA) were observed. These are neuronal populations with the former associated with allied reproductive behaviors and the latter associated with pituitary-gonadal axis control. Embryos were exposed in vitro to 0.25, 0.5 and 1 µM BPF from fertilization to 3 days post fertilization (dpf). At 0.25 µM BPF exposure, both POA- and TN- GnRH3 neurons showed significant reductions in neural area at 2 dpf that did not persist to 3 dpf. The higher BPF doses did not show neuron size differences at 2 dpf, but showed reduction in TN-GnRH3 neuron area at 3 dpf. These effects of BPF were closely mimicked by different doses of estradiol. An estrogen antagonist, ICI, mitigated BPF effects on the embryo. This is the first study to show that BPF affects the developing GnRH neural system via an estrogen-mediated pathway.


Assuntos
Compostos Benzidrílicos/toxicidade , Desenvolvimento Embrionário/efeitos dos fármacos , Disruptores Endócrinos/toxicidade , Estradiol/fisiologia , Hormônio Liberador de Gonadotropina/fisiologia , Neurônios/efeitos dos fármacos , Fenóis/toxicidade , Ácido Pirrolidonocarboxílico/análogos & derivados , Animais , Animais Geneticamente Modificados , Embrião não Mamífero/efeitos dos fármacos , Estradiol/administração & dosagem , Feminino , Masculino , Neurônios/patologia , Neurônios/fisiologia , Peixe-Zebra , Proteínas de Peixe-Zebra/fisiologia
14.
Int Immunopharmacol ; 67: 35-45, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30530167

RESUMO

OBJECTIVES: Recurrent respiratory tract infections (RRTIs) remain a great challenge to pediatricians, because they can increase the risk of various complications and there is no confirmed effective treatment. In the present study, we aimed to assess the effectiveness and safety of pidotimod (PDT), an immunostimulant, in treatment of RRTIs in children aged 14 years and under. METHODS: PubMed, EMBASE, Web of Science, Cochrane Library, ClinicalTrials.gov, CBM and CNKI were searched from their inception up to February 2018. All randomized controlled trials (RCTs) using PDT with various treatment durations and enrolling participants <14 years of age were included in the present review. The interventions were PDT plus conventional treatment (e.g. anti-bacterial and antiviral therapy) or PDT alone versus the conventional treatment plus placebo or conventional treatment alone. RESULTS: A total of 29 RCTs consisting of 4344 pediatric patients were included in this meta-analysis. Ten RCTs were published from Italy, Russia or Greece, and 19 RCTs were published by Chinese groups. However, appropriate randomization methods were only used in 15 trials. Only one study had explicit allocation concealment. Since only eight RCTs were double-blind and placebo controlled, the evidence was not assessed as high quality. The meta-analysis indicates that treatment with PDT resulted in a significant increase in the proportion of participants who had lower RTIs (RR 1.59; 95% CI 1.45-1.74, p < 0.00001) compared with the conventional treatment. PDT could significantly decrease the duration of cough and fever. The number of patients in using antibiotics was also remarkably decreased in the PDT treatment group. Moreover, PDT administration improved the levels of serum immunoglobulin (IgG, IgA, or IgM) and T-lymphocyte subtypes (CD3+, CD4+). Besides, PDT administration did not increase the risk of adverse events of any cause (RR = 1.05, 95% CI 0.72-1.54, p = 0.80). CONCLUSIONS: PDT showed a good efficacy and safety in treatment of pediatric RRTIs. Further high-quality and large-scale RCTs are still required to provide confirmatory evidence. TRIAL REGISTRATION: The protocol of this study can be found at PROSPERO with the registration number of CRD42018093541.


Assuntos
Adjuvantes Imunológicos/uso terapêutico , Ácido Pirrolidonocarboxílico/análogos & derivados , Infecções Respiratórias/tratamento farmacológico , Subpopulações de Linfócitos T/imunologia , Linfócitos T/imunologia , Tiazolidinas/uso terapêutico , Criança , Pré-Escolar , Humanos , Imunidade Celular/efeitos dos fármacos , Imunidade Humoral/efeitos dos fármacos , Imunoglobulinas/sangue , Lactente , Recém-Nascido , Ácido Pirrolidonocarboxílico/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Recidiva
15.
J Endocrinol ; 240(2): R47-R72, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30475219

RESUMO

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder in the elderly population. Numerous epidemiological and experimental studies have demonstrated that patients who suffer from obesity or type 2 diabetes mellitus have a higher risk of cognitive dysfunction and AD. Several recent studies demonstrated that food intake-lowering (anorexigenic) peptides have the potential to improve metabolic disorders and that they may also potentially be useful in the treatment of neurodegenerative diseases. In this review, the neuroprotective effects of anorexigenic peptides of both peripheral and central origins are discussed. Moreover, the role of leptin as a key modulator of energy homeostasis is discussed in relation to its interaction with anorexigenic peptides and their analogs in AD-like pathology. Although there is no perfect experimental model of human AD pathology, animal studies have already proven that anorexigenic peptides exhibit neuroprotective properties. This phenomenon is extremely important for the potential development of new drugs in view of the aging of the human population and of the significantly increasing incidence of AD.


Assuntos
Doença de Alzheimer/prevenção & controle , Metabolismo Energético/efeitos dos fármacos , Leptina/metabolismo , Oligopeptídeos/farmacologia , Ácido Pirrolidonocarboxílico/análogos & derivados , Doença de Alzheimer/metabolismo , Animais , Depressores do Apetite/metabolismo , Depressores do Apetite/farmacologia , Modelos Animais de Doenças , Homeostase/efeitos dos fármacos , Humanos , Fármacos Neuroprotetores/farmacologia , Oligopeptídeos/metabolismo , Ácido Pirrolidonocarboxílico/metabolismo , Ácido Pirrolidonocarboxílico/farmacologia
16.
J Neurosci ; 38(42): 8976-8988, 2018 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-30185461

RESUMO

Neurons in the central pattern-generating circuits in the crustacean stomatogastric ganglion (STG) release neurotransmitter both as a graded function of presynaptic membrane potential that persists in TTX and in response to action potentials. In the STG of the male crab Cancer borealis, the modulators oxotremorine, C. borealis tachykinin-related peptide Ia (CabTRP1a), red pigment concentrating hormone (RPCH), proctolin, TNRNFLRFamide, and crustacean cardioactive peptide (CCAP) produce and sustain robust pyloric rhythms by activating the same modulatory current (I MI), albeit on different subsets of pyloric network targets. The muscarinic agonist oxotremorine, and the peptides CabTRP1a and RPCH elicited rhythmic triphasic intracellular alternating fluctuations of activity in the presence of TTX. Intracellular waveforms of pyloric neurons in oxotremorine and CabTRP1a in TTX were similar to those in the intact rhythm, and phase relationships among neurons were conserved. Although cycle frequency was conserved in oxotremorine and TTX, it was altered in CabTRP1a in the presence of TTX. Both rhythms were primarily driven by the pacemaker kernel consisting of the Anterior Burster and Pyloric Dilator neurons. In contrast, in TTX the circuit remained silent in proctolin, TNRNFLRFamide, and CCAP. These experiments show that graded synaptic transmission in the absence of voltage-gated Na+ current is sufficient to sustain rhythmic motor activity in some, but not other, modulatory conditions, even when each modulator activates the same ionic current. This further demonstrates that similar rhythmic motor patterns can be produced by qualitatively different mechanisms, one that depends on the activity of voltage-gated Na+ channels, and one that can persist in their absence.SIGNIFICANCE STATEMENT The pyloric rhythm of the crab stomatogastric ganglion depends both on spike-mediated and graded synaptic transmission. We activate the pyloric rhythm with a wide variety of different neuromodulators, all of which converge on the same voltage-dependent inward current. Interestingly, when action potentials and spike-mediated transmission are blocked using TTX, we find that the muscarinic agonist oxotremorine and the neuropeptide CabTRP1a sustain rhythmic alternations and appropriate phases of activity in the absence of action potentials. In contrast, TTX blocks rhythmic activity in the presence of other modulators. This demonstrates fundamental differences in the burst-generation mechanisms in different modulators that would not be suspected on the basis of their cellular actions at the level of the targeted current.


Assuntos
Potenciais de Ação/fisiologia , Geradores de Padrão Central/fisiologia , Gânglios dos Invertebrados/fisiologia , Neurotransmissores/fisiologia , Transmissão Sináptica , Animais , Braquiúros , Geradores de Padrão Central/efeitos dos fármacos , Gânglios dos Invertebrados/diagnóstico por imagem , Masculino , Agonistas Muscarínicos/administração & dosagem , Neuropeptídeos/administração & dosagem , Neuropeptídeos/fisiologia , Neurotransmissores/administração & dosagem , Oligopeptídeos/administração & dosagem , Oligopeptídeos/fisiologia , Oxotremorina/administração & dosagem , Piloro/fisiologia , Ácido Pirrolidonocarboxílico/administração & dosagem , Ácido Pirrolidonocarboxílico/análogos & derivados , Bloqueadores dos Canais de Sódio/administração & dosagem , Tetrodotoxina/administração & dosagem
17.
Insect Biochem Mol Biol ; 101: 94-107, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30165105

RESUMO

Hylobius abietis (Linnaeus), or large pine weevil (Coleoptera, Curculionidae), is a pest of European coniferous forests. In order to gain understanding of the functional physiology of this species, we have assembled a de novo transcriptome of H. abietis, from sequence data obtained by Next Generation Sequencing. In particular, we have identified genes encoding neuropeptides, peptide hormones and their putative G-protein coupled receptors (GPCRs) to gain insights into neuropeptide-modulated processes. The transcriptome was assembled de novo from pooled paired-end, sequence reads obtained from RNA from whole adults, gut and central nervous system tissue samples. Data analysis was performed on the transcripts obtained from the assembly including, annotation, gene ontology and functional assignment as well as transcriptome completeness assessment and KEGG pathway analysis. Pipelines were created using Bioinformatics tools and techniques for prediction and identification of neuropeptides and neuropeptide receptors. Peptidomic analysis was also carried out using a combination of MALDI-TOF as well as Q-Exactive Orbitrap mass spectrometry to confirm the identified neuropeptide. 41 putative neuropeptide families were identified in H. abietis, including Adipokinetic hormone (AKH), CAPA and DH31. Neuropeptide F, which has not been yet identified in the model beetle T. castaneum, was identified. Additionally, 24 putative neuropeptide and 9 leucine-rich repeat containing G protein coupled receptor-encoding transcripts were determined using both alignment as well as non-alignment methods. This information, submitted to the NCBI sequence read archive repository (SRA accession: SRP133355), can now be used to inform understanding of neuropeptide-modulated physiology and behaviour in H. abietis; and to develop specific neuropeptide-based tools for H. abietis control.


Assuntos
Proteínas de Insetos/genética , Neuropeptídeos/genética , Receptores Acoplados a Proteínas-G/genética , Receptores de Neuropeptídeos/genética , Transcriptoma , Gorgulhos/genética , Sequência de Aminoácidos , Animais , Sistema Nervoso Central/metabolismo , Biologia Computacional , Feminino , Agricultura Florestal , Trato Gastrointestinal/metabolismo , Regulação da Expressão Gênica , Ontologia Genética , Sequenciamento de Nucleotídeos em Larga Escala , Hormônios de Inseto/genética , Hormônios de Inseto/metabolismo , Proteínas de Insetos/classificação , Proteínas de Insetos/metabolismo , Masculino , Redes e Vias Metabólicas/genética , Anotação de Sequência Molecular , Neuropeptídeos/classificação , Neuropeptídeos/metabolismo , Oligopeptídeos/genética , Oligopeptídeos/metabolismo , Filogenia , Pinus/parasitologia , Ácido Pirrolidonocarboxílico/análogos & derivados , Ácido Pirrolidonocarboxílico/metabolismo , Receptores Acoplados a Proteínas-G/classificação , Receptores Acoplados a Proteínas-G/metabolismo , Receptores de Neuropeptídeos/classificação , Receptores de Neuropeptídeos/metabolismo , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Gorgulhos/classificação , Gorgulhos/metabolismo
18.
Curr Protein Pept Sci ; 19(12): 1201-1213, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30091409

RESUMO

Despite much research on the insect immune system, hormonal regulation of its activity is not well-understood. Previous research on insect neuroendocrinology suggests that neuropeptides may play an important role in the regulation of the insect immune system. Especially recent studies dealing for example with adipokinetic hormones, bursicon or insulin-like peptides provided deeper insights on this issue showing that neuropeptides can modulate various aspects of insect immune responses, both at the molecular and cellular level. The presented review summarizes the current knowledge about the role of neuropeptides regulating the insect immune system activity. Based on structural and functional homology of some vertebrate and insect neuropeptide families, several propositions of insect neuropeptides that might also possess immunotropic activities, but have not been examined for this aspect, are discussed.


Assuntos
Sistema Imunitário/metabolismo , Insetos/metabolismo , Neuropeptídeos/metabolismo , Animais , Combinação de Medicamentos , Hormônios de Inseto/metabolismo , Insetos/imunologia , Hormônios de Invertebrado/metabolismo , Mamíferos , Neuropeptídeos/química , Neuropeptídeos/imunologia , Oligopeptídeos/metabolismo , Pirimidinas/metabolismo , Ácido Pirrolidonocarboxílico/análogos & derivados , Ácido Pirrolidonocarboxílico/metabolismo , Transdução de Sinais , Sulfametazina/metabolismo
19.
Artigo em Inglês | MEDLINE | ID: mdl-30110658

RESUMO

The role of adipokinetic hormone (Drome-AKH) in maintaining the levels of basic nutrients, under starvation conditions, was studied using Drosophila melanogaster mutants with AKH deficiency (Akh1) and AKH abundance (EE-Akh). Our results showed lipids as the main energy reserve in Drosophila, and their physiological level and metabolism were shown to be under the control of AKH. AKH abundance in the body resulted in lower levels of triacylglycerols and diacylglycerols than in the controls, probably due to a more intensive metabolism; interestingly, there was a disproportional representation of fatty acids in triacylglycerols and diacylglycerols in Drosophila. Lower level of glycogen and its partial control by AKH suggest its lesser role as the storage substance. However, maintenance of free carbohydrate level in Drosophila seemed to be critical; when glycogen stores are exhausted, carbohydrates are synthesized from other sources. Protein levels and their alterations, under starvation, did not seem controlled by AKH. AKH-deficient flies were more resistant while AKH-abundant flies were more sensitive to starvation; females were found to be more resistant than males, regardless of the AKH level, probably due to higher body mass and higher amount of nutrients. However, in accordance with the level of all nutrients, that of AKH also gradually decreased with prolonged starvation.


Assuntos
Metabolismo dos Carboidratos , Proteínas de Drosophila/metabolismo , Metabolismo Energético , Hormônios de Inseto/metabolismo , Metabolismo dos Lipídeos , Oligopeptídeos/metabolismo , Ácido Pirrolidonocarboxílico/análogos & derivados , Inanição/metabolismo , Animais , Animais Geneticamente Modificados , Cruzamentos Genéticos , Diglicerídeos/metabolismo , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Ensaio de Imunoadsorção Enzimática , Feminino , Deleção de Genes , Glicogênio/metabolismo , Hormônios de Inseto/genética , Masculino , Oligopeptídeos/genética , Ácido Pirrolidonocarboxílico/metabolismo , Distribuição Aleatória , Reprodutibilidade dos Testes , Caracteres Sexuais , Análise de Sobrevida , Triglicerídeos/metabolismo
20.
Bioorg Med Chem ; 26(16): 4644-4649, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-30119995

RESUMO

A series of l-pyroglutamic acid analogues from natural product lead were designed and synthesized, as well as their antifungal activities against Phytophthora infestans, neuritogenic activities, antibacterial activities and anti-inflammatory activities are described. The bioassays and SAR study showed that the majority of l-pyroglutamic acid esters have a significant antifungal activity against P. infestans, especially 2d and 2j demonstrated the best activities with EC50 values of 1.44 and 1.21 µg mL-1, which were about seven times that of commercial azoxystrobin (7.85 µg mL-1). Moreover, compounds 2e, 2g and 4d displayed anti-inflammatory activity against LPS-induced NO production in BV-2 microglial cells; neuritogenic activity in NGF-induced PC-12 cells is the same activity. This study demonstrates that compounds 2d and 2j are potential drugs to control P. infestans.


Assuntos
Antifúngicos/síntese química , Produtos Biológicos/química , Ácido Pirrolidonocarboxílico/análogos & derivados , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Antifúngicos/química , Antifúngicos/farmacologia , Linhagem Celular , Lipopolissacarídeos/farmacologia , Camundongos , Microglia/citologia , Microglia/efeitos dos fármacos , Microglia/metabolismo , Óxido Nítrico/metabolismo , Células PC12 , Phytophthora infestans/efeitos dos fármacos , Ácido Pirrolidonocarboxílico/síntese química , Ácido Pirrolidonocarboxílico/farmacologia , Ratos , Relação Estrutura-Atividade
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