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1.
Talanta ; 209: 120506, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31892084

RESUMO

Abstractly, in this study, an aptasensor is introduced based on a platform consisting of the gold nanorod (AuNR) on a screen printed carbon electrode (SPCE) surface. The aptasensor is applied for detection of the ß-casomorphin (BCM-7) as a promising biomarker of autism disorder. The NH2-Apt sequence is directly immobilized onto the AuNR/SPCE surface by formation of a chemisorption bond between the amine-Au groups. By incubation of the BCM-7 onto the aptasensor surface, the aptasensor directed against BCM-7 and cleverly formed a target/Apt complex to produce a measurable electrical current change. The aptasensor shows linearity over the range of 1 fmol L-1 to 25 nmol L-1 with a limit of detection (LOD) of 334 amol L-1. Furthermore, the function of the aptasensor in real samples such as human urine and plasma samples is evaluated. The achieved satisfactory results are mainly due to three main reasons including (1) the large specific surface area of the AuNR which forms a 3D network on the SPCE surface to capture more Apt sequences at the sensing interface, (2) utilizing Apt as the BCM-7 receptor with inherent unique properties to produce a synergetic effect with the AuNR, and finally, (3) effective using screen printing technology with the fantastic capability to less cost of the aptasensor preparation. There is hope that miniaturization of the proposed aptasensor may aid future efforts to detect autism symptoms as early as infancy under clinical conditions in real-world.


Assuntos
Aptâmeros de Nucleotídeos/química , Transtorno Autístico/diagnóstico , Endorfinas/sangue , Endorfinas/urina , Nanopartículas Metálicas/química , Sequência de Bases , Biomarcadores/sangue , Biomarcadores/urina , Técnicas Biossensoriais/métodos , Carbono/química , Técnicas Eletroquímicas/instrumentação , Técnicas Eletroquímicas/métodos , Eletrodos , Ouro/química , Humanos , Limite de Detecção , Reprodutibilidade dos Testes
2.
Food Chem ; 314: 126176, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31962282

RESUMO

Pasteurized donor human milk (PDHM) for preterm infant nutrition is fortified with hydrolyzates of cow's milk proteins, which have been poorly investigated in relation to heat-damage and occurrence of the bioactive peptides ß-casomorphins (BCMs). Therefore, thermal protein modifications of three commercial fortifiers were assessed by measuring well-recognized indexes of heat load. The fortifiers did not contain pyrraline, whereas furosine and lysinoalanine levels roughly overlapped the lowest values reported for liquid formulas addressed to term infant nutrition. Bovine BCMs 3 to 7 and human BCMs 3 to 9 were searched. Bovine BCMs 3, 4, 6 and 7 were found in the undigested fortifiers. Following in vitro digestion simulating the digestive conditions of premature infant, bovine BCMs still occurred in fortified PDHM; the human BCMs 3, 7, 8 and 9 formed. Overall, these results better address the nutritional features of protein fortifiers and fortified PDHM intended for nutrition of preterm infants.


Assuntos
Endorfinas/análise , Alimentos Fortificados , Proteínas do Leite/química , Leite Humano/química , Animais , Bovinos , Digestão , Endorfinas/química , Feminino , Alimentos Fortificados/análise , Temperatura Alta , Humanos , Fenômenos Fisiológicos da Nutrição do Lactente , Recém-Nascido , Recém-Nascido Prematuro , Lisina/análogos & derivados , Lisina/análise , Lisinoalanina/análise , Norleucina/análogos & derivados , Norleucina/análise , Pasteurização , Pirróis/análise
3.
Yakugaku Zasshi ; 139(11): 1403-1415, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31685737

RESUMO

For my Ph.D. research topic, I isolated endogenous morphine-like analgesic dipeptide, kyotorphin, which mediates Met-enkephalin release, and discovered kyotorphin synthetase, a putative receptor and antagonist. Furthermore, I succeeded in purifying µ-opioid receptor and functional reconstitution with purified G proteins. After receiving my full professor position at Nagasaki University in 1996, I worked on two topics of research, molecular mechanisms of chronic pain through lysophosphatidic acid (LPA) and identification and characterization of neuroprotective protein, prothymosin α. In a series of studies, we have shown that LPA signaling defines the molecular mechanisms of neuropathic pain and fibromyalgia in terms of development and maintenance. Above all, the discovery of feed-forward system in LPA production and pain memory may contribute to better understanding of chronic pain and future analgesic drug discovery. Regarding prothymosin α, we first discovered it as neuronal necrosis-inhibitory molecule through two independent mechanisms, such as toll-like receptor and F0/F1 ATPase, both which protect neurons through indirect mechanisms. Prothymosin α is released by non-classical and non-vesicular mechanisms on various stresses, such as ischemia, starvation, and heat-shock. Thus it may be called a new type of neuroprotective damage-associated molecular patterns (DAMPs)/Alarmins. Heterozygotic mice showed a defect in memory-learning and neurogenesis as well as anxiogenic behaviors. Small peptide, P6Q derived from prothymosin α retains neuroprotective actions, which include blockade of cerebral hemorrhage caused by late treatment with tissue plasminogen activator in the stroke model in mice.


Assuntos
Dor Crônica/etiologia , Dor Crônica/genética , Fármacos Neuroprotetores , Precursores de Proteínas , Receptores de Ácidos Lisofosfatídicos/fisiologia , Transdução de Sinais/fisiologia , Timosina/análogos & derivados , Animais , Endorfinas , Humanos , Camundongos , Precursores de Proteínas/metabolismo , ATPases Translocadoras de Prótons , Receptores de Ácidos Lisofosfatídicos/metabolismo , Receptores Opioides , Acidente Vascular Cerebral , Timosina/metabolismo , Receptores Toll-Like
4.
Amino Acids ; 51(10-12): 1501-1513, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31520285

RESUMO

The established decrease in the level of endogenous kyotorphin (KTP) into the cerebrospinal fluid of patients with an advanced stage of Alzheimer's disease (AD) and the found neuroprotective activity of KTP suggested its participation in the pathophysiology of the disease. We aimed to study the effects of subchronic intracerebroventricular (ICV) treatment (14 days) with KTP on the behavioral, biochemical and histological changes in rats with streptozotocin (STZ-ICV)-induced model of sporadic AD (sAD). Three months after the administration of STZ-ICV, rats developed increased locomotor activity, decreased level of anxiety, impaired spatial and working memory. Histological data from the STZ-ICV group demonstrated decreased number of neurons in the CA1 and CA3 subfields of the hippocampus. The STZ-ICV group was characterized with a decrease of total protein content in the hippocampus and the prefrontal cortex as well as increased levels of the carbonylated proteins in the hippocampus. KTP treatment of STZ-ICV rats normalized anxiety level and regained object recognition memory. KTP abolished the protein loss in prefrontal cortex and decrease the neuronal loss in the CA3 subfield of the hippocampus. STZ-ICV rats, treated with KTP, did not show significant changes in the levels of the carbonylated proteins in specific brain structures or in motor activity and spatial memory compared to the saline-treated STZ-ICV group. Our data show a moderate and selective protective effect of a subchronic ICV administration of the dipeptide KTP on the pathological changes induced by an experimental model of sAD in rats.


Assuntos
Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/tratamento farmacológico , Modelos Animais de Doenças , Endorfinas/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Estreptozocina/administração & dosagem , Doença de Alzheimer/patologia , Doença de Alzheimer/fisiopatologia , Animais , Ansiedade/prevenção & controle , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Masculino , Atividade Motora/efeitos dos fármacos , Ratos , Ratos Wistar , Memória Espacial/efeitos dos fármacos , Resultado do Tratamento
5.
Vitam Horm ; 111: 247-279, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31421703

RESUMO

More than 40years ago, the endogenous opioids were first described. Their role as important neuromodulators of pain and their influence on a variety of neuroendocrine control systems within the central nervous system has been recognized. More recently, endogenous opioids and their receptor have been identified in a variety of reproductive and non-reproductive tissues outside the central nervous system. What role the opioid system plays in these peripheral tissues and organs is not completely understood and thus the subjects of current research. In the central nervous system, endogenous opioids inhibit pulsatile Gonadotropin Releasing Hormone (GnRH) release, affecting the release of gonadotropins from the pituitary, and thus mediating stress response within the central nervous-pituitary-gonadal axes in both women and men-Peripherally, endogenous opioids have been demonstrated to be present-among other organs-in the pancreas and in the ovary, where they are produced by granulosa cells and may influence oocyte maturation. In men, endogenous opioids play a role in sperm production within the testis. Opioid antagonists such as naltrexone have been used to restore cyclicity in women through improvement in insulin resistance, GnRH-pulsatility and hyperandrogenemia stemming from specific pathophysiological conditions such as hypothalamic amenorrhea, polycystic ovarian syndrome, hyperinsulinemia, ovarian hyperstimulation syndrome. Opioid antagonists have also been used to treat male sexual disorders and male infertility. In summary, endogenous opioids exert a variety of actions within the reproductive system which are reviewed in this chapter.


Assuntos
Analgésicos Opioides/farmacologia , Peptídeos Opioides/fisiologia , Reprodução/efeitos dos fármacos , Reprodução/fisiologia , Amenorreia/etiologia , Amenorreia/fisiopatologia , Animais , Endorfinas/fisiologia , Feminino , Humanos , Doenças Hipotalâmicas/complicações , Doenças Hipotalâmicas/fisiopatologia , Masculino , Peptídeos Opioides/antagonistas & inibidores , Ocitocina/fisiologia , Síndrome do Ovário Policístico/fisiopatologia , Gravidez , Prolactina/fisiologia , Receptores Opioides/fisiologia
6.
J Dairy Sci ; 102(10): 8622-8629, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31351730

RESUMO

This work aimed to study the opioid peptide ß-casomorphin-7 (BCM7) degradation or stability during digestion using human gastrointestinal (GI) juices and porcine jejunal brush border membrane (BBM) peptidases. Synthetic BCM7 was subjected to in vitro digestion by GI fluids obtained from human volunteers for 180 min, and to downstream degradation with porcine BBM vesicles. The BCM7 was sampled at 4 time points over 24 h after BBM addition. The digests were profiled by HPLC-electrospray ionization mass spectrometry (ESI/MS) to monitor BCM7 during GI digestion, and intact BCM7 through BBM digestion was quantified by reverse-phase (RP)-HPLC. We found that BCM7 was partly digested with human GI enzymes, as 3 proteolytic fragments in addition to f(60-66) YPFPGPI were detected: f(62-66) FPGPI, f(60-65) YPFPGP and f(61-66) PFPGPI. The RP-HPLC analysis revealed that 42% of the initial peptide was degraded after only 2 h of BBM digestion, and as much as 79% was degraded after 4-h digestion with supplementation of BBM. In conclusion, this study showed that most of BCM7 was degraded during GI and BBM digestion, although a small amount (5%) was still detected after 24-h digestion. It remains to be studied whether the small amount of intact BCM7 detected after in vitro digestion is transported via active transceptors in the human intestinal epithelial cells and enters blood circulation.


Assuntos
Endorfinas/metabolismo , Trato Gastrointestinal/metabolismo , Jejuno/metabolismo , Microvilosidades/metabolismo , Fragmentos de Peptídeos/metabolismo , Animais , Cromatografia Líquida de Alta Pressão , Digestão , Humanos , Microvilosidades/enzimologia , Peptídeo Hidrolases/metabolismo , Suínos
7.
J Neuroimmunol ; 332: 99-111, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-30999218

RESUMO

Neurotransmitters and neurochemicals can act on lymphocytes by binding to receptors expressed by lymphocytes. This review describes lymphocyte expression of receptors for a selection of neurotransmitters and neurochemicals, the anatomical locations where lymphocytes can interact with neurotransmitters, and the effects of the neurotransmitters on lymphocyte function. Implications for health and disease are also discussed.


Assuntos
Adenosina/metabolismo , Endocanabinoides/metabolismo , Endorfinas/metabolismo , Linfócitos/metabolismo , Neuroimunomodulação/fisiologia , Neurotransmissores/metabolismo , Animais , Medula Óssea/inervação , Encéfalo/fisiologia , Humanos , Tecido Linfoide/inervação , Neurônios/metabolismo , Nociceptividade/fisiologia , Receptores de Neurotransmissores/imunologia , Receptores de Neurotransmissores/metabolismo , Recompensa , Timo/inervação
8.
Nutr Rev ; 77(5): 278-306, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30722004

RESUMO

CONTEXT: Various epidemiological studies suggest a positive association between exposure to cow's milk A1 ß-casein protein and risk for noncommunicable chronic diseases. The consumption of A2 cow's milk is increasing, likely because A2 milk is postulated to have positive effects on digestive health. OBJECTIVE: A systematic review was conducted to investigate associations between A1 ß-casein and health-related outcomes in humans. DATA SOURCES: Five electronic databases, 3 clinical trial registries, and the internet were searched systematically. STUDY SELECTION: Using predefined inclusion criteria, 2 authors independently selected studies investigating the effect of A1 ß-casein or ß-casomorphin-7 intake/exposure on any health-related outcome in humans. Discrepancies were resolved by consensus. DATA EXTRACTION: Two authors independently extracted data and assessed risk of bias. The certainty of evidence per outcome was evaluated using the GRADE approach. Discrepancies were resolved by consensus. RESULTS: Fifteen randomized controlled trials, 2 case-control studies, and 8 ecological studies were included. Most randomized controlled studies and case-control studies investigating a potential effect on various outcomes were based on intermediate markers and found no significant difference between the 2 milk types. In contrast, most ecological studies reported that population-level A1 ß-casein exposure is associated with adverse health outcomes. The certainty of the evidence for the included outcomes, as assessed by the GRADE approach, was rated as moderate for digestive symptoms and as low to very low for all other outcomes. CONCLUSIONS: Human-based evidence from clinical trials and epidemiological studies published prior to October 2017 provides moderate certainty for adverse digestive health effects of A1 ß-casein compared with A2 ß-casein but low or very low certainty for other health effects. These conclusions may change in the future, given the emergent nature of this topic and the ongoing research in this area. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration number CRD42016043795.


Assuntos
Caseínas/análise , Digestão/efeitos dos fármacos , Leite/química , Animais , Biomarcadores/análise , Estudos de Casos e Controles , Bovinos , Endorfinas/análise , Feminino , Humanos , Fragmentos de Peptídeos/análise , Ensaios Clínicos Controlados Aleatórios como Assunto
9.
Neuropeptides ; 74: 82-87, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30738575

RESUMO

BACKGROUND: Chimeric opioid MCRT was a novel multi-target ligand based on morphiceptin and PFRTic-NH2, and produced potent analgesia (ED50 = 0.03 nmol/mouse) with less upper gastrointestinal dysmotility. In this study, we sought to perform the tests to evaluate the pharmacological effects of MCRT on distal colon motility and defecation function. Moreover, opioid receptor antagonists and neuropeptide FF (NPFF) receptor antagonists were utilized to explore the mechanisms. METHODS: Isolated mouse colon bioassay and colonic bead expulsion were to characterize MCRT-induced inhibition of colonic motility in vitro and in vivo, respectively. Fecal pellet output was to evaluate the defecation function. RESULTS: (1) In vitro, MCRT increased colonic contraction via µ- and δ- opioid receptors (MOR and DOR). (2) In vivo, MCRT delayed colonic bead expulsion (ED50 = 1.1 nmol/mouse) independent of opioid and NPFF receptors. (3) In vivo, MCRT inhibited fecal number (ED50 = 1.43 nmol/mouse) and dry weight (ED50 = 1.63 nmol/mouse), which was mediated by DOR partially but not MOR. CONCLUSIONS: (1) Data indicated that MCRT was less prone to induce gastrointestinal dysmotility at analgesic doses, and provided a possibility for safer opioid analgesic. (2) Based on the mechanism explorations, we speculated on the existence of such an opioid receptor subtype or MOR/DOR heterodimer, which was involved in the central analgesia and the in vitro colonic contractions but not the central colonic dysmotility.


Assuntos
Analgésicos Opioides/administração & dosagem , Colo/fisiologia , Endorfinas/administração & dosagem , Motilidade Gastrointestinal , Receptores Opioides delta/fisiologia , Receptores Opioides mu/fisiologia , Animais , Colo/efeitos dos fármacos , Constipação Intestinal/induzido quimicamente , Endorfinas/fisiologia , Motilidade Gastrointestinal/efeitos dos fármacos , Masculino , Camundongos , Receptores de Neuropeptídeos/fisiologia
10.
Med Sci Monit ; 25: 121-127, 2019 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-30610183

RESUMO

BACKGROUND The aim of this study was to investigate the protective effect of ß-casomorphin-7 (ß-CM-7) and its possible mechanisms on acute kidney injury (AKI). MATERIAL AND METHODS Rats were randomly divided into a sham group, a cecal ligation and puncture (CLP) group, and a CLP+ß-CM-7 group. Kidney index, kidney function, and histopathology changes were assessed. The expression of neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (Kim-1), nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha (IκBα), and p-IκBα in kidney tissues were detected by Western blotting. Inflammatory and oxidative stress factors were detected by ELISA kits. RESULTS The results showed that treatment with ß-CM-7 reduced the levels of creatinine (Cre), blood urea nitrogen (BUN), NGAL, and Kim-1 induced by CLP, weakening the pathological damage. In the CLP + ß-CM-7 group, the tumor necrosis factor-α (TNF-α) level and the DNA-binding activity of NF-κB p65 were significantly reduced and the interleukin-10 (IL-10) level was significantly increased compared with the CLP group. ß-CM-7 decreased the expression of p-IκBα/IκBα. In addition, ß-CM-7 increased the activity of superoxide dismutase (SOD) and decreased the level of malondialdehyde (MDA) in kidney tissue. CONCLUSIONS ß-CM-7 attenuated sepsis-induced AKI through reducing inflammation and oxidative stress and by inhibition of nuclear factor (NF)­κB activities. This study provides a new therapeutic agent for attenuating sepsis-induced kidney injury.


Assuntos
Lesão Renal Aguda/fisiopatologia , Endorfinas/farmacologia , NF-kappa B/metabolismo , Fragmentos de Peptídeos/farmacologia , Lesão Renal Aguda/tratamento farmacológico , Animais , Nitrogênio da Ureia Sanguínea , Ceco/patologia , Moléculas de Adesão Celular , Creatinina/metabolismo , Endorfinas/metabolismo , Inflamação/patologia , Rim/lesões , Rim/patologia , Ligadura , Lipocalina-2 , Masculino , Malondialdeído/metabolismo , Inibidor de NF-kappaB alfa , NF-kappa B/efeitos dos fármacos , Estresse Oxidativo , Fragmentos de Peptídeos/metabolismo , Ratos , Ratos Sprague-Dawley , Sepse/complicações , Sepse/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos
11.
Nutrients ; 11(1)2019 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-30621149

RESUMO

Opioid peptides released during digestion of dietary proteins such as casein, were suggested to contribute to autism development, leading to the announcement of opioid excess hypothesis of autism. This paper examines role of enzyme proline dipeptidyl peptidase-4 (DPPIV; EC 3.4.14.5) and it is exogenous substrate, ß-casomorphin-7 (BCM7) in autism etiology. Our study included measurements of DPPIV and BCM7 concentrations in serum and urine, which were analyzed with ELISA assays and activity of DPPIV was measured by colorimetric test. The effect of opioid peptides from hydrolysed bovine milk on DPPIV gene expression in peripheral blood mononuclear cells (PBMC) in autistic and healthy children was determined using the Real-Time PCR (Polymerase Chain Reaction) method. Our research included 51 healthy children and 86 children diagnosed with autism spectrum disorder (ASD, ICDF84). We determined that the concentration of BCM7 in serum was significantly, 1.6-fold, higher in the ASD group than in controls (p < 0.0001). Concentration of DPPIV was found to also be significantly higher in serum from ASD children compared to the control group (p < 0.01), while we did not notice significant difference in enzymatic activity of serum DPPIV between the two study groups. We confirmed correlation according to the gender between analyzed parameters. The inspiration for this study emanated from clinical experience of the daily diet role in relieving the symptoms of autism. Despite this, we have concluded that milk-derived opioid peptides and DPPIV are potentially factors in determining the pathogenesis of autism; conducted studies are still limited and require further research.


Assuntos
Transtorno do Espectro Autista/enzimologia , Dipeptidil Peptidase 4/fisiologia , Leite/química , Peptídeos Opioides/fisiologia , Animais , Transtorno do Espectro Autista/sangue , Transtorno do Espectro Autista/etiologia , Criança , Pré-Escolar , Dipeptidil Peptidase 4/sangue , Dipeptidil Peptidase 4/genética , Endorfinas/sangue , Endorfinas/farmacologia , Endorfinas/fisiologia , Feminino , Expressão Gênica/efeitos dos fármacos , Humanos , Leucócitos Mononucleares/enzimologia , Masculino , Peptídeos Opioides/sangue , Peptídeos Opioides/urina , Fragmentos de Peptídeos/sangue , Fragmentos de Peptídeos/farmacologia , Fragmentos de Peptídeos/fisiologia , Prolina , Fatores Sexuais
12.
Nutrition ; 57: 259-267, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30199719

RESUMO

Objective Beta-casein is a major protein in breast milk and an important source for several bioactive peptides that are encrypted within the sequence. Beta-casomorphins (BCMs) are short-chain proteolytic peptides that are derived from the beta-casein protein and have opioid effects in newborns. Human milk is known to contain naturally occurring milk-protein-derived bioactive peptides but the identification of naturally occurring beta-casein-derived BCMs in human breast milk has been limited due to difficulties in the detection of BCM peptides, which are small and circulate in low concentrations. Methods The present study aimed to identify the naturally occurring BCM peptides from beta-casein in human breast milk using liquid chromatography-tandem mass spectrometry. The BCM peptides identified in the breast milk were analysed to predict the milk proteases responsible for the cleavage patterns using a computational tool EnzymePredictor. Results In-depth peptidomics analysis of breast milk samples that were collected at different lactation stages during human lactation revealed the presence of BCMs including BCM-8, -9, -10, and -11 as well as precursors and truncated forms of the original peptide, which suggests that milk protease activity in the mammary gland generates biologically relevant BCMs. Conclusions To our knowledge, this is the first report to describe the presence of naturally occurring human BCM-10 and -11 in breast milk. Our study provides evidence of beta-casein-derived BCM peptides in human milk before infant digestion. Proteases that are present in milk are likely specific in their proteolysis of beta-casein. The identified bioactive BCM-8, -9, -10, and -11 as well as the precursor peptides meet the structural requirements to elicit opioid, immunomodulatory, antioxidative, and satiety functions in newborns.


Assuntos
Aleitamento Materno , Endorfinas/metabolismo , Lactação/metabolismo , Proteínas do Leite/metabolismo , Leite Humano/metabolismo , Peptídeo Hidrolases/metabolismo , Peptídeos/metabolismo , Adulto , Caseínas/metabolismo , Cromatografia Líquida/métodos , Dieta , Digestão , Endorfinas/farmacologia , Feminino , Humanos , Lactente , Fenômenos Fisiológicos da Nutrição do Lactente , Recém-Nascido , Proteólise , Espectrometria de Massas em Tandem/métodos
13.
Med Sci Sports Exerc ; 51(5): 970-978, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30557194

RESUMO

INTRODUCTION: Endorphins, endocannabinoids, monoamines, and neurotrophins have all been implicated in the euphoric response to endurance running, known as a runner's high (RH). The epitranscriptional mechanisms regulating this effect have not been defined. Here, we investigate peripheral micro-ribonucleic acid (miRNA) changes unique to athletes experiencing postrun euphoria, yielding insights into gene networks that control an RH. METHODS: A cohort study involving 25 collegiate runners (48% females, age = 20 ± 1 yr) examined salivary RNA levels before and after a long-distance run. Participants were divided into RH and nonrunner's high (NRH) groups based on surveys of four criteria (mood, lost sense of time, run quality, and euphoria). Physiological measures were also recorded (temperature, heart rate, blood pressure, pupillary dilatation, and salivary serotonin). Levels of miRNAs and their messenger RNA targets were compared across pre- and postrun samples from RH and NRH groups with two-way ANOVA. Representation of opioid, gamma-aminobutyic acid (GABA), endocannabinoid, neurotrophin, serotonergic, and dopaminergic pathways was assessed in DIANA miRPath. Pearson's correlation analyses examined relationships between miRNAs and RH indices. RESULTS: RH participants (n = 13) demonstrated postrun mydriasis (P = 0.046) and hypothermia (P = 0.043) relative to NRH participants (n = 12) but had no difference in serotonin dynamics (P = 0.88). Six miRNAs (miR-194-5p, miR-4676-3p, miR-4254, miR-4425, miR-1273-3p, miR-6743-5p) exhibited significant effects (false discovery rate P value < 0.05) across pre- or postrun and RH/NRH groups. These miRNAs displayed target enrichment for opioid (P = 2.74E-06) and GABA (P = 0.00016) pathways. miR-1237-3p levels were related with lost sense of time (R = 0.40). Mitogen-activated protein kinase (MAPK11), an endocannabinoid target of miR-1273-3p, was nominally elevated in RH participants (false discovery rate P value = 0.11). CONCLUSIONS: Unique dynamics in miRNA concentration occur in athletes with subjective/objective evidence of RH, targeting genes implicated endorphin, endocannabinoid, and GABAergic signaling.


Assuntos
Euforia/fisiologia , MicroRNAs/análise , Corrida/fisiologia , Transcriptoma , Estudos de Coortes , Endocanabinoides , Endorfinas , Feminino , Humanos , Masculino , Saliva , Serotonina , Adulto Jovem , Ácido gama-Aminobutírico
14.
Animal ; 13(4): 777-783, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30139413

RESUMO

ß-Casomorphin is an opioid-like bioactive peptide derived from ß-casein of milk that plays a crucial role in modulating animal's feed intake, growth, nutrient utilization and immunity. However, the effect of ß-casomorphin on lipid metabolism in chickens and its mechanism remain unclear. The aim of this study was to investigate the effects of ß-casomorphin on fat deposition in broiler chickens and explore its mechanism of action. A total of 120 21-day-old Arbor Acres male broilers (747.94±8.85 g) was chosen and randomly divided into four groups with six replicates of five birds per replicate. Three groups of broilers were injected with 0.1, 0.5 or 1.0 mg/kg BW of ß-casomorphin in 1 ml saline for 7 days, whereas the control group received 1 ml saline only. The results showed that subcutaneous administration of ß-casomorphin to broiler chickens increased average daily gain, average daily feed intake and fat deposition, and decreased feed : gain ratio (P<0.05). The activity of malate dehydrogenase in the pectoral muscle, liver and abdominal adipose tissue was also increased along with the concentrations of insulin, very-low-density lipoprotein and triglyceride in the plasma (P<0.05). The activity of hormone-sensitive lipase in the liver and abdominal adipose tissue and the concentration of glucagon in the plasma were decreased by injection with ß-casomorphin (P<0.05). Affymetrix gene chip analysis revealed that administering 1.0 mg/kg BW ß-casomorphin caused differential expression of 168 genes in the liver with a minimum of fourfold difference. Of those, 37 genes are directly involved in lipid metabolism with 18 up-regulated genes such as very low density lipoprotein receptor gene and fatty acid synthase gene, and 19 down-regulated genes such as lipoprotein lipase gene and low density lipoprotein receptor gene. In conclusion, ß-casomorphin increased growth performance and fat deposition of broilers. Regulation of fat deposition by ß-casomorphin appears to take place through changes in hormone secretion and enzyme activities by controlling the gene expression of lipid metabolism and feed intake, increasing fat synthesis and deposition.


Assuntos
Gordura Abdominal/fisiologia , Galinhas , Endorfinas/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Gordura Abdominal/efeitos dos fármacos , Ração Animal , Animais , Endorfinas/administração & dosagem , Regulação da Expressão Gênica/efeitos dos fármacos , Insulina/metabolismo , Fígado/enzimologia , Malato Desidrogenase/metabolismo , Masculino , Distribuição Aleatória , Triglicerídeos/metabolismo
15.
J Dairy Sci ; 102(1): 113-123, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30391182

RESUMO

This study addresses the hypothesis that the extracellular cell-associated X-prolyl dipeptidyl-peptidase activity initially described in Streptococcus thermophilus could be attributable to the intracellular X-prolyl dipeptidyl-peptidase PepX. For this purpose, a PepX-negative mutant of S. thermophilus LMD-9 was constructed by interrupting the pepX gene and named LMD-9-ΔpepX. When cultivated, the S. thermophilus LMD-9 wild type strain grew more rapidly than its ΔpepX mutant counterpart. Thus, the growth rate of the LMD-9-ΔpepX strain was reduced by a factor of 1.5 and 1.6 in milk and LM17 medium (M17 medium supplemented with 2% lactose), respectively. The negative effect of the PepX inactivation on the hydrolysis of ß-casomorphin-7 was also observed. Indeed, when incubated with this peptide, the LMD-9-ΔpepX mutant cells were unable to hydrolyze it, whereas this peptide was completely degraded by the S. thermophilus LMD-9 wild type cells. This hydrolysis was not due to leakage of intracellular PepX, as no peptide hydrolysis was highlighted in cell-free filtrate of wild type strain. Therefore, based on these results, it can be presumed that though lacking an export signal, the intracellular PepX might have accessed the ß-casomorphin-7 externally, perhaps via its galactose-binding domain-like fold, this domain being known to help enzymes bind to several proteins and substrates. Therefore, the identification of novel distinctive features of the proteolytic system of S. thermophilus will further enhance its credibility as a starter in milk fermentation.


Assuntos
Dipeptidil Peptidases e Tripeptidil Peptidases/metabolismo , Peptídeo Hidrolases/metabolismo , Streptococcus thermophilus/enzimologia , Animais , Cromatografia Líquida de Alta Pressão , Cromatografia de Fase Reversa , Dipeptidil Peptidases e Tripeptidil Peptidases/química , Dipeptidil Peptidases e Tripeptidil Peptidases/genética , Endorfinas/metabolismo , Hidrólise , Leite/química , Leite/microbiologia , Fragmentos de Peptídeos/metabolismo , Peptídeos/análise , Peptídeos/metabolismo , Proteólise , Streptococcus thermophilus/genética , Streptococcus thermophilus/crescimento & desenvolvimento
17.
Anat Histol Embryol ; 47(5): 481-492, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30027642

RESUMO

Using an immunocytochemical technique, we have studied in the alpaca brainstem the distribution of immunoreactive structures containing prodynorphin (alpha-neoendorphin)- and pro-opiomelanocortin (adrenocorticotrophin hormone (18-39) (ACTH), beta-endorphin (1-27))-derived peptides. No peptidergic-immunoreactive cell body was observed. Immunoreactive fibres were widely distributed, although in most of the brainstem nuclei the density of the peptidergic fibres was low or very low. In general, the distribution of the immunoreactive fibres containing the peptides studied was very similar. A close anatomical relationship occurred among the fibres containing alpha-neoendorphin, ACTH or beta-endorphin (1-27), suggesting a functional interaction among the three peptides in many of the brainstem nuclei. The number of fibres belonging to the prodynorphin system was higher than that of the pro-opiomelanocortin system. A moderate/low density of immunoreactive fibres was observed in 65.11% (for alpha-neoendorphin (1-27)), 18.18% (for ACTH) and 13.95% (for beta-endorphin) of the brainstem nuclei/tracts. In the alpaca brainstem, a high density of immunoreactive fibres was not observed. The neuroanatomical distribution of the immunoreactive fibres suggests that the peptides studied are involved in auditory, motor, gastric, feeding, vigilance, stress, respiratory and cardiovascular mechanisms, taste response, sleep-waking cycle and the control of pain transmission.


Assuntos
Hormônio Adrenocorticotrópico/metabolismo , Tronco Encefálico/metabolismo , Endorfinas/metabolismo , Fragmentos de Peptídeos/metabolismo , Pró-Opiomelanocortina/metabolismo , Precursores de Proteínas/metabolismo , beta-Endorfina/metabolismo , Animais , Camelídeos Americanos , Imuno-Histoquímica , Masculino , Neurônios/metabolismo , Coloração e Rotulagem
18.
Food Res Int ; 111: 574-581, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30007720

RESUMO

Food-derived opioid peptides that are released from proteins by digestion, fermentation, or food production processes lead to several health problems. The opioids are generally resistant to hydrolyze by proteases, except the dipeptidyl peptidase IV (DPPIV, EC 3.4.14.5) enzyme, because of proline amino acid. ß-casomorphin (BCM) from milk casein, gluteomorphin (GM) from wheat gluten, and soymorphin (SM) from the soybean ß-conglycinin ß-subunit are natural substrates of DPPIV because of their amino acid sequences and proline location. In the present study, DPPIV from Lactococcus lactis spp. lactis was purified and characterized by mass spectrometry. Purified DPPIV was added to standard BCM, GM, and SM, and hydrolysis percentages of morphins were measured by HPLC analysis. The results indicated that DPPIV enzyme hydrolyzed food-derived opioids (from 0.1 mM to 2 mM), BCM (33.42% for 2 mM), SM (83.81% for 2 mM), and GM (45.73% for 2 mM) in vitro. Hydrolysis percentages of SM were considerably higher than the same concentrations with BCM and GM. For dietary supplements to be promising for reducing the adverse effects of food derived opioids, this must be supported by in vivo studies of DPPIV use in the human body.


Assuntos
Analgésicos Opioides/química , Dipeptidil Peptidase 4/metabolismo , Lactococcus lactis/enzimologia , Animais , Antígenos de Plantas/química , Caseínas/química , Endorfinas/química , Globulinas/química , Glutens/química , Hidrólise , Peso Molecular , Derivados da Morfina/química , Fragmentos de Peptídeos/química , Proteínas de Armazenamento de Sementes/química , Proteínas de Soja/química
19.
Med Hypotheses ; 116: 119-121, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29857894

RESUMO

Obstructive jaundice disease is often accompanied by an increase in plasma endogenous opioids levels. Theses elevated endogenous opioids bring complications like pruritus, cardiac and vascular abnormalities in patients with cholestasis. However, little is known about the mechanism of increased endogenous opioids synthesis in cholestatic liver diseases. Different from the tradition view that the liver is the source of endogenous opioids peptides, recent researches give clues that skin may be another important organ in which endogenous opioid peptides were synthesized during cholestasis. Skin cells like keratinocytes, fibroblasts, macrophages and other inflammation cells had been reported to produce endogenous opioid peptides under certain physical and pathological conditions. In the course of obstructive jaundice, all these cells had the potential to be activated by different molecular mechanisms. And some cells like keratinocyte and inflammation cells had been proved to correlate with elevated plasma levels of enkephalin and beta-endorphin in patients with obstructive jaundice. Hence, we hypothesize that skin may be the site in which abundant endogenous opioid peptides been produced during the course of obstructive jaundice. These skin-cell related mechanisms should be further studied to resolve the puzzle of elevated peripheral opiate tone during obstructive jaundice.


Assuntos
Icterícia Obstrutiva/patologia , Peptídeos Opioides/metabolismo , Pele/patologia , Animais , Colestase/complicações , Derme/metabolismo , Endorfinas/sangue , Encefalinas/sangue , Fibroblastos/citologia , Cardiopatias/complicações , Humanos , Inflamação , Queratinócitos/citologia , Melanócitos/citologia , Células de Merkel/citologia , Modelos Teóricos , Peptídeos/química , Prurido/complicações , Doenças Vasculares/complicações
20.
Drug Saf ; 41(11): 1023-1033, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29796831

RESUMO

Prescription opioid use has increased rapidly in developed countries, as have fatalities and other related adverse events. This review examines the intrinsic characteristics of opioids, including their mechanisms of action and pharmacokinetic and pharmacodynamic properties, to determine how the use of a regonised pharmacological remedy for a medically confirmed ailment could result in an accidental fatality. Opioids trigger biological processes that inhibit their own therapeutic effect. Prolonged use of opioids can result in activation of pronociceptive systems, leading to opioid-induced hyperalgesia and tolerance, while opioid metabolites can antagonise the antinociceptive action of the parent drug, also leading to opioid-induced hyperalgesia and tolerance. Pain stimulates respiration and counteracts the respiratory depression effect of opioids. Analgesia from opioids leads to loss of this protective mechanism, leading to increased risk of death due to respiratory failure. Increased patient counseling during opioid prescribing and dispensing, and limiting prescription to short-term use in non-malignant pain, may decrease the adverse effects of opioids. The vast majority of patients who unintentionally experience serious adverse events from pharmaceutical opioids do not start out as drug seekers. Even opioid use within prescribing guidelines can place some patients at risk of death and may prevent patients from seeking help for prescription opioid dependence.


Assuntos
Analgésicos Opioides/farmacologia , Dor/tratamento farmacológico , Analgésicos Opioides/farmacocinética , Analgésicos Opioides/uso terapêutico , Família 2 do Citocromo P450/metabolismo , Família 3 do Citocromo P450/metabolismo , Esquema de Medicação , Tolerância a Medicamentos/fisiologia , Endorfinas/metabolismo , Humanos , Hiperalgesia/induzido quimicamente , Nociceptividade/efeitos dos fármacos , Educação de Pacientes como Assunto , Receptores Acoplados a Proteínas-G/metabolismo , Receptores Opioides/metabolismo , Respiração/efeitos dos fármacos , Fatores de Tempo
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