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1.
Int Immunopharmacol ; 75: 105785, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31404891

RESUMO

Endogenous opioids are neuro-peptides with multifunctional properties. Historically, opioids are used to mediate pain; however, excess opiate consumption can lead to addiction. One endogenous opioid, methionine enkephalin (MENK), was reported to modulate cell growth, MENK was identified as an opioid growth factor (OGF) that interacts with the OGF receptor (OGFr) and regulates cell proliferation. Further, opioid antagonists, including naltrexone and naloxone are widely used to reverse drug and alcohol overdoses. Naltrexone (NTX) acts on all opioid receptors, blocking the interaction between OGF and OGFr, and thus influencing cell growth. During the last decades, insights have been made concerning the interaction between OGF and OGFr, confirming that both opioids and opioid antagonists have an important role in balancing host homeostasis, host immunity and mediating cancer therapy. This review provides insight into the interactions between OGF and OGFr in the treatment of cancers.


Assuntos
Encefalina Metionina/uso terapêutico , Naltrexona/uso terapêutico , Antagonistas de Entorpecentes/uso terapêutico , Neoplasias/tratamento farmacológico , Animais , Encefalina Metionina/farmacologia , Humanos , Naltrexona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Neoplasias/imunologia , Neoplasias/metabolismo
2.
Mol Pharmacol ; 96(4): 505-514, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31383769

RESUMO

Phosphorylation of sites on the C terminus of the µ-opioid receptor (MOR) results in the induction of acute desensitization that is thought to be a precursor for the development of long-term tolerance. Alanine mutations of all 11 phosphorylation sites on the C terminus of MORs almost completely abolished desensitization and one measure of tolerance in locus coeruleus neurons when these phosphorylation-deficient MORs were virally expressed in MOR knockout rats. In the present work, we identified specific residues that underlie acute desensitization, receptor internalization, and tolerance and examined four MOR variants with different alanine or glutamate mutations in the C terminus. Alanine mutations in the sequence between amino acids 375 and 379 (STANT-3A) and the sequence between amino acids 363 and 394 having four additional alanine substitutions (STANT + 7A) reduced desensitization and two measures of long-term tolerance. After chronic morphine treatment, alanine mutations in the sequence between 354 and 357 (TSST-4A) blocked one measure of long-term tolerance (increased acute desensitization and slowed recovery from desensitization) but did not change a second (decreased sensitivity to morphine). With the expression of receptors having glutamate substitutions in the TSST sequence (TSST-4E), an increase in acute desensitization was present after chronic morphine treatment, but the sensitivity to morphine was not changed. The results show that all 11 phosphorylation sites contribute, in varying degrees, to acute desensitization and long-term tolerance. That acute desensitization and tolerance are not necessarily linked illustrates the complexity of events that are triggered by chronic treatment with morphine. SIGNIFICANCE STATEMENT: In this work, we showed that the degree of phosphorylation on the C terminus of the µ-opioid receptor alters acute desensitization and internalization, and in measures of long-term tolerance to morphine. The primary conclusion is that the degree of phosphorylation on the 11 possible sites of the C terminus has different roles for expression of the multiple adaptive mechanisms that follow acute and long-term agonist activation. Although the idea that acute desensitization and tolerance are intimately linked is generally supported, these results indicate that disruption of one phosphorylation cassette of the C terminus TSST (354-357) distinguishes the two processes.


Assuntos
Encefalina Metionina/farmacologia , Mutação , Receptores Opioides mu/química , Receptores Opioides mu/metabolismo , Potenciais de Ação/efeitos dos fármacos , Alanina/metabolismo , Animais , Tolerância a Medicamentos , Feminino , Técnicas de Inativação de Genes , Ácido Glutâmico/metabolismo , Masculino , Fosforilação/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptores Opioides mu/genética
3.
Int Immunopharmacol ; 75: 105723, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31408839

RESUMO

The standard treatments for neoplasia include surgery, chemotherapy, hormone antagonists and radiotherapy, which can prolong survival, but rarely cure the tumors of gynecological cancer patients. OGF - OGFr expression, in various gynecologic cells and tissues, is an intersection point between cell development, neuroendocrine function and immune modulation. It has been identified that OGF and OGFr expression differs between gynecological tumor and normal cells. Further, exogenous or endogenous OGF and OGFr antagonists have been known to have a role in regulating cell viability and apoptosis. Moreover, the expression of proteins in the OGF - OGFr axis modulate differentiation and membrane expression of immune cells, which can enhance the immune response. In vivo and in vitro assays have shown that OGF and OGFr antagonists inhibit mitosis as well as induce apoptosis in gynecologic cancer cells. Although immune augmentation combination therapies can intensify cytotoxic activity, OGF or OGFr antagonists do not increase toxicities associated with dual-immune regulation. In conclusion, the OGF - OGFr axis provides significant strategies for antitumor efficiency in gynecological cancer.


Assuntos
Encefalina Metionina/metabolismo , Neoplasias dos Genitais Femininos/metabolismo , Receptores Opioides/metabolismo , Animais , Feminino , Humanos
4.
Amino Acids ; 51(8): 1201-1207, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31302778

RESUMO

Rat sialorphin (Gln-His-Asn-Pro-Arg) is a natural blocker of neprilysin (NEP) that belongs to the family of endogenous opioid peptide-degrading enzymes. Studies have confirmed the efficiency of sialorphin in blocking the activity of NEP, both in vitro and in vivo. It has been demonstrated that this inhibitor has a strong analgesic, anti-inflammatory, immunological and metabolic effect either directly or indirectly by affecting the level of Met/Leu-enkephalins. In this work, sialorphin and their 12 analogues were synthesised using the solid-phase method. The effect of the peptides on the degradation of Met-enkephalin by NEP and metabolic degradation in human plasma was investigated in vitro. We show that the change in the N-terminal amino acid configuration from L to D in almost all peptides, except D-Arg-His-Asn-Pro-Arg (peptide XI), led to the abolition of their inhibitory activity. With molecular modelling technique we explained the structural properties of the L and D-arginine located on the N-terminal part of the peptide. The detailed analysis of the protein binding pocket allowed us to explain why D-arginine is so unique among all D residues. Peptide XI showed the highest stability among the tested peptides in human plasma. For instance sialorphin after a 2-hour incubation in human plasma was almost completely decomposed, while the level of peptide XI dropped to 45% after 48 h under these conditions.


Assuntos
Encefalina Metionina/metabolismo , Modelos Moleculares , Neprilisina/farmacologia , Peptídeos/química , Peptídeos/farmacologia , Humanos , Técnicas In Vitro
5.
Int J Mol Sci ; 20(10)2019 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-31109149

RESUMO

Ghrelin is an endogenous ligand for orphan growth hormone secretagogue receptors. Ghrelin receptors have been found in central nervous system (CNS) areas responsible for pain modulation and transmission. This study investigated the effects of intracerebroventricular (ICV) and intra-arcuate nucleus (ARC) injection of ghrelin on pain behavioral responses and levels of ß-endorphin (ß-EP) and met-enkephalin (MENK) in the periaqueductal gray area (PAG) during the formalin test in rats. Thirty-five male rats were studied in five groups. Ghrelin was injected into the left lateral ventricle (ICV, 5 µL) or into the ARC (1 µL). After 15 min, formalin (2.5%) was subcutaneously injected into the left hind paw. Behavioral nociceptive scores were recorded for 60 min. MENK and ß-EP were collected by microdialysis in the PAG and determined by high-performance liquid chromatography (HPLC). ICV and ARC injection of ghrelin significantly reduced pain in all phases of the formalin test (p < 0.001). Dialysate concentrations of MENK and ß-EP in the PAG increased in all the phases (p < 0.01). In conclusion, the present study shows that the ARC nucleus and the endogenous opioid system are involved in ghrelin-induced pain modulation.


Assuntos
Núcleo Arqueado do Hipotálamo/efeitos dos fármacos , Encefalina Metionina/metabolismo , Grelina/uso terapêutico , Dor/tratamento farmacológico , Substância Cinzenta Periaquedutal/efeitos dos fármacos , beta-Endorfina/metabolismo , Animais , Núcleo Arqueado do Hipotálamo/metabolismo , Grelina/administração & dosagem , Injeções , Masculino , Dor/metabolismo , Medição da Dor , Substância Cinzenta Periaquedutal/metabolismo , Ratos
6.
Org Biomol Chem ; 17(21): 5305-5315, 2019 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-31094391

RESUMO

Numerous studies demonstrate the promise of opioid peptides as analgesics, but poor oral bioavailability has limited their therapeutic development. This study sought to increase the oral bioavailability of opioid peptides by cyclization, using Hantzsch-based macrocyclization strategies to produce two new series of cyclized DAMGO and Leu/Met-enkephalin analogs. Opioid receptor affinity and selectivity for compounds in each series were assessed in vitro with radioligand competition binding assays. Compounds demonstrated modest affinity but high selectivity for the mu, delta, and kappa opioid receptors (MOR, DOR and KOR), while selectivity for mu opioid receptors varied by structure. Antinociceptive activity of each compound was initially screened in vivo following intracerebroventricular (i.c.v.) administration and testing in the mouse 55 °C warm-water tail-withdrawal test. The four most active compounds were then evaluated for dose- and time-dependent antinociception, and opioid receptor selectivity in vivo. Cyclic compounds 1924-10, 1936-1, 1936-7, and 1936-9 produced robust and long- lasting antinociception with ED50 values ranging from 0.32-0.75 nmol following i.c.v. administration mediated primarily by mu- and delta-opioid receptor agonism. Compounds 1924-10, 1936-1 and 1936-9 further displayed significant time-dependent antinociception after oral (10 mg kg-1, p.o.) administration. A higher oral dose (30 mg kg-1. p.o.) of all four cyclic peptides also reduced centrally-mediated respiration, suggesting successful penitration into the CNS. Overall, these data suggest cyclized opioid peptides synthesized by a Hantzsch-based macrocyclization strategy can retain opioid agonist activity to produce potent antinociception in vivo while conveying improved bioavailability following oral administration.


Assuntos
Analgésicos Opioides/farmacologia , Ala(2)-MePhe(4)-Gly(5)-Encefalina/farmacologia , Encefalina Metionina/farmacologia , Receptores Opioides/agonistas , Tiazóis/farmacologia , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/química , Animais , Ciclização , Relação Dose-Resposta a Droga , Ala(2)-MePhe(4)-Gly(5)-Encefalina/administração & dosagem , Ala(2)-MePhe(4)-Gly(5)-Encefalina/química , Encefalina Metionina/administração & dosagem , Encefalina Metionina/química , Injeções Intraventriculares , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Conformação Molecular , Taxa Respiratória , Tiazóis/administração & dosagem , Tiazóis/química
7.
Int Immunopharmacol ; 73: 23-40, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31078923

RESUMO

The incidence and mortality of type 2 diabetes mellitus (T2DM) rank among the top ten worldwide. Emerging studies indicate pathological roles for the immune system in inflammation, insulin resistance and islet ß-cell damage in subjects with T2DM. Methionine enkephalin (MENK) is present in endocrine cells of the pancreas and has been suggested to be an important mediator between the immune and neuroendocrine systems. Therefore, it may play a role in modulating insulin secretion from islet cells. Since little is known about the effect of MENK on T2DM, therefore it was the aim of this study to characterize the role and possible mechanism of action of MENK on plasma glucose and serum insulin levels in T2DM rats and INS-1 cells in vivo and in vitro. MENK significantly decreased the plasma glucose level and increased the serum insulin concentration in T2DM rats. It also increased the serum levels of the cytokines IL-5 and IL-10, while decreased TNF-α and IL-2 levels. We further confirmed that MENK regulated glucose metabolism by upregulating opioid receptor expression and modulating the IL-33/ST2 and MyD88-TRAF6-NF-κB p65 signaling pathways. Based on these results, an intraperitoneal injection of MENK represents a potentially new approach for T2DM.


Assuntos
Citocinas/imunologia , Diabetes Mellitus Tipo 2/imunologia , Encefalina Metionina/farmacologia , Receptores de Interleucina-1/imunologia , Animais , Glicemia/análise , Linhagem Celular Tumoral , Citocinas/sangue , Diabetes Mellitus Tipo 2/metabolismo , Insulina/metabolismo , Masculino , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Pâncreas/efeitos dos fármacos , Pâncreas/imunologia , Pâncreas/metabolismo , Ratos Sprague-Dawley , Receptores Opioides/genética , Receptores Opioides/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator 6 Associado a Receptor de TNF/genética , Fator 6 Associado a Receptor de TNF/metabolismo
8.
Life Sci ; 224: 232-240, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30930116

RESUMO

AIMS: Opioid receptor blockers such as naloxone and naltrexone have been suggested to have a bone mass-increasing effect. However, the mechanisms at play have not been clarified. We examined the effects of naltrexone on osteoblasts and determined the expression of opioid growth factor receptor (OGFR) in osteoblasts. Naltrexone blocks the OGFR and other canonical opioid receptors. Thus, we designed experiments to clarify the effects of naltrexone on bone tissue by examining the physiological role of OGFR signaling in osteoblasts and the changes in bone structure after naltrexone systemic administration in mice. MAIN METHODS: We used mouse osteoblast-like cell line MC3T3-E1 for in vitro experiments. We cultured MC3T3-E1 cells in the presence of the OGFR agonist met-enkephalin (met-enk). Then, we measured cell proliferation activity and analyzed the expression levels of cell proliferation-related genes. For our in vivo experiments, we administered naltrexone intraperitoneally to mice daily for 28 days and administered the animals in the control group equivalent volumes of saline. After sacrificing the mice, we performed micro-computed tomography and bone morphology analyses. KEY FINDINGS: Met-enk suppressed cell proliferation in MC3T3-E1 cells. Moreover, Low dose naltrexone administration significantly increased their femoral bone mass, bone formation ratio, and osteoblast number/bone surface values when comparing the values for the same variables in the control group. SIGNIFICANCE: Our results suggest that naltrexone increases bone mass due to osteoblast number increments caused by the OGFR signaling block. Opioid receptor blockers have potential as therapeutic agents for osteoporosis as well as opioid antagonists.


Assuntos
Densidade Óssea/efeitos dos fármacos , Naltrexona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Osteoblastos/citologia , Receptores Opioides/química , Animais , Proliferação de Células , Células Cultivadas , Encefalina Metionina/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Naltrexona/administração & dosagem , Antagonistas de Entorpecentes/administração & dosagem , Neurotransmissores/farmacologia , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Receptores Opioides/genética , Receptores Opioides/metabolismo
9.
J Chem Phys ; 150(12): 124105, 2019 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-30927873

RESUMO

Locating the minimum free energy paths (MFEPs) between two conformational states is among the most important tasks of biomolecular simulations. For example, knowledge of the MFEP is critical for focusing the effort of unbiased simulations that are used for the construction of Markov state models to the biologically relevant regions of the system. Typically, existing path searching methods perform local sampling around the path nodes in a pre-selected collective variable (CV) space to allow a gradual downhill evolution of the path toward the MFEP. Despite the wide application of such a strategy, the gradual path evolution and the non-trivial a priori choice of CVs are also limiting its overall efficiency and automation. Here we demonstrate that non-local perpendicular sampling can be pursued to accelerate the search, provided that all nodes are reordered thereafter via a traveling-salesman scheme. Moreover, path-CVs can be computed on-the-fly and used as a coordinate system, minimizing the necessary prior knowledge about the system. Our traveling-salesman based automated path searching method achieves a 5-8 times speedup over the string method with swarms-of-trajectories for two peptide systems in vacuum and solution, making it a promising method for obtaining initial pathways when investigating functional conformational changes between a pair of structures.


Assuntos
Dipeptídeos/química , Encefalina Metionina/química , Modelos Químicos , Termodinâmica , Cadeias de Markov , Conformação Proteica
10.
Fish Shellfish Immunol ; 88: 432-440, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30862518

RESUMO

Opioid neuropeptides are developed early in the course of a long evolutionary process. As the endogenous messengers of immune system, opioid neuropeptides participate in regulating immune response. In this study, the mechanism that Met-enkephalin (M-ENK) inhibits ROS production through Wnt/ß-catenin signaling was investigated in the ZF4 cells of zebrafish. ZF4 cells were exposed to 0, 10, 20, 40, 80, and 160 µM Met-enkephalin (M-ENK) for 24 h, and the cell viability was detected with 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) assay. The cell viability was significantly increased by 10, 20, 40, 80, and 160 µM M-ENK. After ZF4 cells were exposed to 0, 20, 40, and 80 µM M-ENK for 24 h, the mRNA expression of Wnt10b, ß-catenin, and CCAAT/enhancer binding protein α (C/EBPα) was significantly increased by 40 and 80 µM M-ENK. However, the mRNA and protein expression of GSK-3ß was significantly decreased by 40 and 80 µM M-ENK. The protein expression of ß-catenin was significantly induced by 40 and 80 µM M-ENK, while the protein expression of p-ß-catenin was significantly decreased by 20, 40, and 80 µM M-ENK. In addition, the mRNA expression of CAT, SOD, and GSH-PX was significantly increased by 40 and 80 µM M-ENK. The levels of H2O2, ·OH, and O2·- were significantly decreased, but the activity of CAT, SOD, and GSH-PX was significantly increased by 40 and 80 µM M-ENK. The fluorescence intensity of reactive oxygen species (ROS) was decreased, and that of mitochondrial membrane potential (MMP) was increased with the increase of M-ENK concentration in ZF4 cells. The results showed that M-ENK could induce Wnt/ß-catenin signaling, which further inhibited ROS production through the induction of C/EBPα, MMP, and the activities of antioxidant enzymes.


Assuntos
Encefalina Metionina/farmacologia , Neurotransmissores/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Via de Sinalização Wnt , Peixe-Zebra , Animais , Proteína alfa Estimuladora de Ligação a CCAAT/metabolismo , Catalase/metabolismo , Sobrevivência Celular , Células Cultivadas , Glutationa Peroxidase/metabolismo , Peróxido de Hidrogênio/metabolismo , Potencial da Membrana Mitocondrial , Superóxido Dismutase/metabolismo , beta Catenina/metabolismo
11.
Int Immunopharmacol ; 68: 193-203, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30654309

RESUMO

The purpose of this study was to identify the modulatory effect of MENK on MDSCs and to investigate the relationship between this modulation and the expression of opioid receptors. Our results showed that MENK could inhibit the proliferation of MDSCs from both marine bone marrow and spleen. MENK also could promote the expression of opioid receptors MOR and DOR. MENK suppressed the PMN-MDSCs generated from splenocyte while up-regulated M-MDSCs. The stimulation of MENK increased the production of IL-4 secreted by MDSCs from slpenocytes. Our currently data indicated that MENK could suppress the accumulation of MDSCs in tumor-bearing mice via binding to and up-regulating expressions of subunits of opioid receptors. Therefore, it is concluded that MENK, through triggering opioid receptors could exert inhibiting modulation on MDSCs.


Assuntos
Encefalina Metionina/farmacologia , Células Supressoras Mieloides/efeitos dos fármacos , Receptores Opioides/metabolismo , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Citocinas/metabolismo , Feminino , Camundongos Endogâmicos C57BL , Células Supressoras Mieloides/metabolismo , Neoplasias/metabolismo , Baço/citologia
12.
Stress ; 22(2): 256-264, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30636454

RESUMO

It was hypothesized that there is cross-talk between the classical constituents of the hypothalamo-pituitary-adrenocortical axis (HPA) and Met-enkephalin in the HPA axis. The study examined effects of isolation stress, sex, and age on concentrations of native Met-enkephalin and pro-enkephalin (PENK) gene expression in tissues of the HPA (hypothalamus, pituitary gland and adrenal cortex) in 3-, 6- and 9-month old female and male lambs. In addition, the effects of isolation stress on in vitro release Met-enkephalin from fragments of the hypothalamus or adrenal cortex were examined. Isolation stress was followed by decreases in the concentration of Met-enkephalin in both the pituitary gland and adrenal cortex. There were also increases in the hypothalamic concentration of Met-enkephalin together with increases in PENK gene expression in the HPA in 6- and 9-months old females and males. There were reductions in release of Met-enkephalin from hypothalamic and adrenocortical tissue in vitro after isolation stress. In the presence of naltrexone, there were increases in basal release in vitro of Met-enkephalin from hypothalamic tissue from control and stressed female lambs but a decrease in tissue from stressed male lambs. In a somewhat similar manner, the presence of naltrexone was associated with increases in the basal release of Met-enkephalin from adrenocortical tissue from control female lambs but a decrease with tissue from stressed female and both stressed and control male lambs. Lay summary The present studies examine the impact of isolation stress on Met-enkephalin in growing female and male lambs. The results clearly showed the involvement of Met-enkephalin modulation of the psychological stress response in growing female and male lambs.


Assuntos
Encefalina Metionina/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Isolamento Social , Estresse Psicológico/metabolismo , Analgésicos Opioides , Animais , Corticosterona/metabolismo , Feminino , Hipotálamo/metabolismo , Masculino , Hipófise/metabolismo , Polônia , Ovinos
13.
Mol Neurobiol ; 56(3): 1578-1595, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29907903

RESUMO

In the present study, we characterize the antinociceptive effects produced by the chemokine CCL4 in mice. The intraplantar administration of very low doses of CCL4 (0.1-3 pg) produced bilateral antinociception assessed by the unilateral hot-plate test (UHP) without evoking chemotactic responses at the injection site. Moreover, the subcutaneous administration of CCL4 (3-100 pg/kg) also yielded bilateral antinociception in the UHP and the paw pressure test and reduced the number of spinal neurons that express Fos protein in response to noxious stimulation. The implication of peripheral CCR5 but not CCR1 in CCL4-evoked antinociception was deduced from the inhibition produced by systemic but not intrathecal, administration of the CCR5 antagonist DAPTA, and the inefficacy of the CCR1 antagonist J113863. Besides, the inhibition observed after subcutaneous but not intrathecal administration of naloxone demonstrated the involvement of peripheral opioids and the efficacy of naltrindole but not cyprodime or nor-binaltorphimine supported the participation of δ-opioid receptors. In accordance, plasma levels of met-enkephalin, but not ß-endorphin, were augmented in response to CCL4. Likewise, CCL4-evoked antinociception was blocked by the administration of an anti-met-enk antibody. Leukocyte depletion experiments performed with cyclophosphamide, anti-Ly6G, or anti-CD3 antibodies indicated that the antinociceptive effect evoked by CCL4 depends on circulating T lymphocytes. Double immunofluorescence experiments showed a four times more frequent expression of met-enk in CD4+ than in CD8+ T lymphocytes. CCL4-induced antinociception almost disappeared upon CD4+, but not CD8+, lymphocyte depletion with selective antibodies, thus supporting that the release of met-enk from CD4+ lymphocytes underlies the opioid antinociceptive response evoked by CCL4.


Assuntos
Analgésicos/uso terapêutico , Linfócitos T CD4-Positivos/efeitos dos fármacos , Quimiocina CCL4/uso terapêutico , Encefalina Metionina/metabolismo , Nociceptividade/efeitos dos fármacos , Dor/tratamento farmacológico , Analgésicos/farmacologia , Animais , Linfócitos T CD4-Positivos/metabolismo , Quimiocina CCL4/farmacologia , Camundongos , Naloxona/farmacologia , Naltrexona/análogos & derivados , Naltrexona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Dor/metabolismo , Medição da Dor
14.
Pharmacol Rep ; 71(1): 42-47, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30391790

RESUMO

BACKGROUND: Inflammatory bowel diseases (IBD) are a group of chronic and recurrent gastrointestinal disorders that are difficult to control. Recently, a new IBD therapy based on the targeting of the endogenous opioid system has been proposed. Consequently, due to the fact that endogenous enkephalins have an anti-inflammatory effect, we aimed at investigating the degradation of serum enkephalin (Met- and Leu-enkephalin) in patients with IBD. METHODS: Enkephalin degradation in serum of patients with IBD was characterized using mass spectrometry methods. Calculated half-life (T1/2) of enkephalins were compared and correlated with the disease type and gender of the patients. Additionally, statistical analysis was used to examine the dynamics of changes in terms of inhibition of enkephalins degradation within research groups. RESULTS: Our research indicates that the degree of enkephalins degradation depends on the gender of the patients. The difference is most evident for the rate of Met-enkephalin degradation between men (mean T1/2 = 13.61 min) and women (mean T1/2 = 21.84 min) with Crohn's disease (CD). CONCLUSIONS: The most significant alternation of enkephalins degradation in serum samples of IBD patients, compared to control group, were observed in both Crohn's disease and ulcerative colitis (UC) female patients. We suggest that the differences observed between the genders in IBD patients may be explained by regulation of enkephalinases activity by estradiol.


Assuntos
Colite Ulcerativa/sangue , Doença de Crohn/sangue , Encefalina Leucina/sangue , Encefalina Metionina/sangue , Adulto , Biomarcadores/sangue , Estudos de Casos e Controles , Cromatografia Líquida de Alta Pressão , Colite Ulcerativa/diagnóstico , Doença de Crohn/diagnóstico , Feminino , Meia-Vida , Humanos , Masculino , Estudos Prospectivos , Proteólise , Fatores Sexuais , Espectrometria de Massas por Ionização por Electrospray
15.
Amino Acids ; 51(2): 319-329, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30392096

RESUMO

Quercetin and resveratrol are polyphenolic compounds, members of the flavonoid and the stilbene family, respectively, both medicinally important as dietary anticancer and antioxidant agents. They are present in a variety of foods-including fruits, vegetables, tea, wine, as well as other dietary supplements-and are responsible for various health benefits. Different quercetin and resveratrol esters of Leu/Met-enkephalin and tetrapeptide Leu-Ser-Lys-Leu (LSKL) were synthesized as model systems for monitoring the influence of the peptides on biological activity of resveratrol and quercetin. General formula of the main peptidyl-quercetin derivatives is 2-[3-(aa)n-4-hydroxyphenyl]-3,5,7-tri-hydroxy-4H-1-benzopyran-4-on, and the general formula of the main peptidyl-resveratrol derivatives is (E)-5-[4-(aa)n)styryl]benzene-1,3-diol. The antioxidant and anticancer activities of prepared compounds were investigated. Significant anticancer activity was obtained for the LSKL-based both quercetin and resveratrol derivatives. All prepared compounds exhibit antioxidant activity, in particular quercetin derivative containing Met-enkephalin.


Assuntos
Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Neoplasias/dietoterapia , Quercetina/análogos & derivados , Quercetina/farmacologia , Resveratrol/análogos & derivados , Resveratrol/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/uso terapêutico , Antioxidantes/síntese química , Antioxidantes/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Suplementos Nutricionais , Encefalina Leucina/química , Encefalina Metionina/química , Ésteres/síntese química , Células HCT116 , Humanos , Células MCF-7 , Peptídeos/química , Compostos Fitoquímicos/síntese química , Quercetina/síntese química , Quercetina/uso terapêutico , Resveratrol/síntese química , Resveratrol/uso terapêutico , Solubilidade , Fator de Crescimento Transformador beta/metabolismo
16.
ACS Chem Neurosci ; 10(4): 2022-2032, 2019 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-30571911

RESUMO

Opioid peptides are critically involved in a variety of physiological functions necessary for adaptation and survival, and as such, understanding the precise actions of endogenous opioid peptides will aid in identification of potential therapeutic strategies to treat a variety of disorders. However, few analytical tools are currently available that offer both the sensitivity and spatial resolution required to monitor peptidergic concentration fluctuations in situ on a time scale commensurate with that of neuronal communication. Our group has developed a multiple-scan-rate waveform to enable real-time voltammetric detection of tyrosine containing neuropeptides. Herein, we have evaluated the waveform parameters to increase sensitivity to methionine-enkephalin (M-ENK), an endogenous opioid neuropeptide implicated in pain, stress, and reward circuits. M-ENK dynamics were monitored in adrenal gland tissue, as well as in the dorsal striatum of anesthetized and freely behaving animals. The data reveal cofluctuations of catecholamine and M-ENK in both locations and provide measurements of M-ENK dynamics in the brain with subsecond temporal resolution. Importantly, this work also demonstrates how voltammetric waveforms can be customized to enhance detection of specific target analytes, broadly speaking.


Assuntos
Glândulas Suprarrenais/metabolismo , Técnicas Eletroquímicas/métodos , Encefalina Metionina/metabolismo , Substância Negra/metabolismo , Glândulas Suprarrenais/química , Animais , Encefalina Metionina/análise , Masculino , Microinjeções/métodos , Técnicas de Cultura de Órgãos , Ratos , Ratos Sprague-Dawley , Substância Negra/química
17.
Int Immunopharmacol ; 65: 76-83, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30290369

RESUMO

The goal of this work was to investigate how MENK could regulate the functions of CD8+T cells and to explore the relationship between this regulation and opioid receptor expression. Our results showed that the opioid receptors presented on the cell menbrane of CD8+T cells were MOR and DOR. MENK promoted the expression of opioid receptors as well as the elevation of the surface molecules such as CD28, PD-1, CTLA-4 and FasL and intracellular granzyme B. Selectively blocking the MOR by CTAP or DOR by NTI could result in inhibition of the corresponding CD8+T cells proliferation and the expressions of surface molecules. In addition, non-selectively blocking both MOR and DOR by NTX could further impair the functions and proliferation of CD8+T cells. Our currently data indicated that MENK could play a vital role in immune functions via precise regulation to subunits of opioid receptors.


Assuntos
Linfócitos T CD8-Positivos/efeitos dos fármacos , Encefalina Metionina/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Ativação Linfocitária/efeitos dos fármacos , Neurotransmissores/farmacologia , Receptores Opioides/metabolismo , Animais , Linfócitos T CD8-Positivos/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Subunidades Proteicas , Receptores Opioides/genética
18.
PLoS One ; 13(10): e0204830, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30286124

RESUMO

The objective of this study was to evaluate the effect of low-dose naltrexone (LDN) as a carboplatin chemotherapy-associated drug in female dogs with mammary carcinoma in benign mixed tumors (MC-BMT) after mastectomy and to assess its association with quality of life and survival rates. Sixty female dogs were included in this study, all of which had histopathological diagnosis of MC-BMT and were divided into three groups: G1 (control), consisting of animals submitted only to mastectomy with or without regional metastasis; G2, composed of treated animals that did not present with metastasis; and G3, treated dogs that presented with metastasis. G2 and G3 were also subdivided according to the treatment administered: chemotherapy alone (MC-BMT(-) C/MC-BMT(+) C) or LDN and chemotherapy (MC-BMT(-) C+LDN/MC-BMT(+) C+LDN). All animals were subjected to clinical evaluation, mastectomy, peripheral blood lymphocyte immunophenotyping, beta-endorphin and met-enkephalin quantification, and evaluation of survival rates and quality of life scores. The results showed higher serum concentrations of beta-endorphin and met-enkephalin, fewer chemotherapy-related side effects, and better quality of life and survival rates in the LDN-treated groups than in LDN-untreated groups (P < 0.05). Evaluation of clinical and pathological parameters indicated a significant association between the use of LDN and both prolonged survival and enhanced quality of life. These results indicate that LDN is a viable chemotherapy-associated treatment in female dogs with MC-BMT, maintaining their quality of life and prolonging survival rates.


Assuntos
Carboplatina/administração & dosagem , Carboplatina/farmacologia , Linfócitos/metabolismo , Neoplasias Mamárias Animais/tratamento farmacológico , Naltrexona/administração & dosagem , Animais , Cães , Sinergismo Farmacológico , Encefalina Metionina/metabolismo , Feminino , Imunofenotipagem , Neoplasias Mamárias Animais/imunologia , Neoplasias Mamárias Animais/cirurgia , Mastectomia/veterinária , Naltrexona/farmacologia , Metástase Neoplásica , Qualidade de Vida , Análise de Sobrevida , Resultado do Tratamento , beta-Endorfina/metabolismo
19.
Int Immunopharmacol ; 65: 312-322, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30343258

RESUMO

This study was to explore the effect and mechanisms of anti- human gastric cancer by MENK in vitro and in vivo. The results showed in MENK-treated xenograft tissue, the percentage of M2-type macrophages decreased while M1-type macrophages increased. MENK increased the expression of M1-related cytokine TNF-α and attenuated the expression of M2-related cytokine IL-10 expression. MENK upregulated the expression of opioid receptor (OGFr), while it inhibited HGC27 and SGC7901 cells through blocking PI3K/AKT/mTOR signal pathway in vitro and in vivo. These effects of MENK could be cancelled when OGFr was knockdown. This indicates that binding to OGFr by MENK appears to be essential for the anti- GC cells. Therefore, it is concluded that MENK might skew macrophage toward M2 phenotype from M1 phenotype within tumor and induce cells apoptosis though blocking OGFr/PI3K/AKT/mTOR signaling pathway.


Assuntos
Antineoplásicos/uso terapêutico , Encefalina Metionina/uso terapêutico , Macrófagos/fisiologia , Neoplasias Gástricas/tratamento farmacológico , Animais , Apoptose , Diferenciação Celular , Citocinas/metabolismo , Feminino , Xenoenxertos , Humanos , Macrófagos/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Camundongos Nus , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores Opioides/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Células Th2/imunologia , Evasão Tumoral
20.
Toxicol Appl Pharmacol ; 359: 12-23, 2018 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-30222981

RESUMO

Obesity and its related metabolic disorders including insulin resistance and fatty liver become major public health concerns in both developed and developing countries. Brown adipose tissue (BAT), a critical organ of energy expenditure due to thermogenesis, has been considered as an attractive target for prevention or treatment of obesity and obesity related diseases. Previous studies indicate Met-enkephalin (MetEnk) has the potential on adipocyte browning, however, whether MetEnk displays the impact on adipocyte browning in vivo to improve obesity associated morbidities is still unclear. In the present study, we showed that MetEnk effectively prevented high fat diet (HFD) induced C57BL/6J mice weight gain, clearly enhanced glucose tolerance and insulin sensitivity, and dramatically reduced hepatic steatosis in HFD fed mice. Mechanically, MetEnk restored protein kinase A (PKA) signaling pathway in HFD challenged mice and promoted subcutaneous white adipose tissue (WAT) browning. Our study suggests that MetEnk can be considered as a potential therapeutic peptide for diet-induced obesity and metabolic disorders.


Assuntos
Tecido Adiposo Marrom/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Encefalina Metionina/uso terapêutico , Síndrome Metabólica/tratamento farmacológico , Adipócitos Marrons/efeitos dos fármacos , Tecido Adiposo Marrom/crescimento & desenvolvimento , Tecido Adiposo Marrom/patologia , Animais , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Citocinas/metabolismo , Intolerância à Glucose/tratamento farmacológico , Resistência à Insulina , Masculino , Síndrome Metabólica/patologia , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Receptores Opioides delta/efeitos dos fármacos
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