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Advances in Neurobiology 2024It has become apparent that endogenous opioids act not only as neurotransmitters and neuromodulators, but have multiple functions in the body. Activation of the opioid...
It has become apparent that endogenous opioids act not only as neurotransmitters and neuromodulators, but have multiple functions in the body. Activation of the opioid system by opiate drugs is associated with a risk of cancer development through direct stimulation of tumor cell proliferation and through immunosuppression. In contrast, the endogenous peptide opioid [Met]-enkephalin, now commonly referred to as Opioid Growth Factor (OGF), negatively regulates cell proliferation in a wide number of cells during development, homeostasis, and neoplasia. This action is mediated through the opioid growth factor receptor, originally designated the zeta (ζ) opioid receptor. Further, contrary to the traditional notion of opiates as immunosuppressive, endogenous OGF has been shown to possess a number of positive immunomodulatory properties and may provide a beneficial effect in cancer by augmenting the activity of cells involved in both innate and acquired immunity. Taken together, the evidence supports consideration of opioid peptides such as OGF as new strategies for cancer therapy.
Topics: Animals; Humans; Cell Proliferation; Enkephalin, Methionine; Neoplasms; Opioid Peptides; Receptors, Opioid
PubMed: 38874718
DOI: 10.1007/978-3-031-45493-6_4 -
ACS Applied Materials & Interfaces Jun 2024Methionine-enkephalin (Met-Enk) is an endogenous opioid peptide that is involved in various physiological processes including memory. A technological gap in the...
Methionine-enkephalin (Met-Enk) is an endogenous opioid peptide that is involved in various physiological processes including memory. A technological gap in the understanding of Met-Enk's role in memory is the lack of rapid measurement tools to selectively quantify Met-Enk concentrations . Here, we integrate molecularly imprinted polymers (MIPs) with carbon fiber microelectrodes (CFMs) to selectively detect Met-Enk by using fast-scan cyclic voltammetry (FSCV). We report two MIP conditions that yield 2-fold and 5-fold higher selectivity toward Met-Enk than the tyrosine-containing hexapeptide fragment angiotensin II (3-8). We demonstrate that MIP technology can be combined with FSCV at CFMs to create rapid and selective sensors for Met-Enk. This technology is a promising platform for creating selective sensors for other peptides and biomarkers.
Topics: Carbon Fiber; Enkephalin, Methionine; Microelectrodes; Electrochemical Techniques; Molecular Imprinting; Molecularly Imprinted Polymers; Carbon
PubMed: 38804619
DOI: 10.1021/acsami.4c03093 -
Fish & Shellfish Immunology Jul 2024In this study, the expressions and distributions of methionine-enkephalin (Met-enk) and δ opioid receptor in the nervous system of Octopus ocellatus, and the immune...
In this study, the expressions and distributions of methionine-enkephalin (Met-enk) and δ opioid receptor in the nervous system of Octopus ocellatus, and the immune regulatory mechanisms of Met-enk on O. ocellatus were explored. The distributions and expressions of Met-enk and δ opioid receptor were assessed by immunohistochemistry and enzyme-linked immunosorbent assay. UV-spectrophotometer, microplate reader, and flow cytometer were used to examine the effects of different concentrations of Met-enk on phagocytosis, antioxidant effects, and body surface mucus immunity of O. ocellatus hemocytes. The data were used to study the mechanisms of Met-enk immunity regulation in O. ocellatus. According to the results, the expression levels of Met-enk and δ opioid receptor in O. ocellatus lymphocytes were higher than those in hemocytes. The expression levels of Met-enk in the ganglia of O. ocellatus decreased in the following order: pedal ganglia > cerebral ganglia > visceral ganglia > optic ganglia > stellate ganglia. Moreover, the phagocytic activity of O. ocellatus hemocytes was enhanced with increasing Met-enk concentration. With increasing Met-enk concentration, the expressions of nitric oxide, total nitric oxide synthase, inducible nitric oxide synthase, catalase, hydrogen peroxide, myeloperoxidase, reduced glutathione, α-naphthy acetate esterase, and methionine aminopeptidases decreased in serums of O. ocellatus in the experimental group compared to the blank group. Similarly, the content of reduced glutathione in the hemocytes of O. ocellatus was also lower in the experimental group than in the blank group; however, the expressions of other substances were higher compared to the blank group. Furthermore, α-naphthy acetate esterase, myeloperoxidase, and hydrogen peroxide expressions in mucus immunity trials of the body surface were lower in the experimental group compared to the blank group. These results indicate that the distributions and expressions of Met-enk and δ opioid receptor in the nervous system of O. ocellatus were related to axoplasmic transport and immune regulation mechanisms. Met-enk participates in cellular immunity, humoral immunity, and mucus immunity in the form of neurotransmitters, thereby regulating the immune response of O. ocellatus.
Topics: Animals; Enkephalin, Methionine; Receptors, Opioid, delta; Octopodiformes; Immunity, Innate; Hemocytes; Gene Expression Regulation
PubMed: 38754647
DOI: 10.1016/j.fsi.2024.109637 -
Brain Structure & Function Jul 2024Enkephalins are endogenous opioid pentapeptides that play a role in neurotransmission and pain modulation in vertebrates. However, the distribution pattern of...
Enkephalins are endogenous opioid pentapeptides that play a role in neurotransmission and pain modulation in vertebrates. However, the distribution pattern of enkephalinergic neurons in the brains of reptiles has been understudied. This study reports the organization of the methionine-enkephalin (M-ENK) and leucine-enkephalin (L-ENK) neuronal systems in the central nervous system of the gecko Hemidactylus frenatus using an immunofluorescence labeling method. Although M-ENK and L-ENK-immunoreactive (ir) fibers extended throughout the pallial and subpallial subdivisions, including the olfactory bulbs, M-ENK and L-ENK-ir cells were found only in the dorsal septal nucleus. Enkephalinergic perikarya and fibers were highly concentrated in the periventricular and lateral preoptic areas, as well as in the anterior and lateral subdivisions of the hypothalamus, while enkephalinergic innervation was observed in the hypothalamic periventricular nucleus, infundibular recess nucleus and median eminence. The dense accumulation of enkephalinergic content was noticed in the pars distalis of the hypophysis. In the thalamus, the nucleus rotundus and the dorsolateral, medial, and medial posterior thalamic nuclei contained M-ENK and L-ENK-ir fibers, whereas clusters of M-ENK and L-ENK-ir neurons were observed in the pretectum, mesencephalon, and rhombencephalon. The enkephalinergic fibers were also seen in the area X around the central canal, as well as the dorsal and ventral horns. The widespread distribution of enkephalin-containing neurons within the central nervous system implies that enkephalins regulate a variety of functions in the gecko, including sensory, behavioral, hypophysiotropic, and neuroendocrine functions.
Topics: Animals; Lizards; Neurons; Enkephalin, Leucine; Enkephalin, Methionine; Brain; Central Nervous System; Enkephalins; Male; Female
PubMed: 38713249
DOI: 10.1007/s00429-024-02805-4 -
Poultry Science Jun 2024The effects of the administration of the opioid agonist, morphine, on plasma and tissue concentrations of Met-enkephalin were determined in 14 wk old female chickens. In...
Research Note: Morphine influences circulating and tissue concentrations of met-enkephalin and proenkephalin (PENK) expression and plasma concentrations of corticosterone in chickens.
The effects of the administration of the opioid agonist, morphine, on plasma and tissue concentrations of Met-enkephalin were determined in 14 wk old female chickens. In addition, effects of morphine on proenkephalin (PENK) expression were examined. Plasma concentrations of Met-enkephalin were reduced 10 minutes after morphine administration. Plasma concentrations of peptides that contain Met-enkephalin motifs were decreased 30 minutes after morphine administration. Tissue concentrations of Met-enkephalin tended to be depressed following morphine administration. Adrenal concentrations of PENK peptides containing Met-enkephalin motifs were decreased in chickens challenged with morphine. Expression of PENK in the anterior pituitary gland and adrenal glands were decreased in morphine treated compared to control pullets. In contrast, plasma concentrations of corticosterone were elevated 10 min after morphine treatment. Morphine also induced changes in mu (µ) opioid receptors and delta (δ) opioid receptors in both anterior pituitary tissue and adrenal tissues.
Topics: Animals; Morphine; Chickens; Enkephalin, Methionine; Female; Corticosterone; Protein Precursors; Enkephalins; Analgesics, Opioid; Adrenal Glands; Avian Proteins
PubMed: 38603935
DOI: 10.1016/j.psj.2024.103712 -
Cells Jan 2024The recent emphasis on circadian rhythmicity in critical skin cell functions related to homeostasis, regeneration and aging has shed light on the importance of the...
The recent emphasis on circadian rhythmicity in critical skin cell functions related to homeostasis, regeneration and aging has shed light on the importance of the circadian clock gene as a vital antitumor gene. Furthermore, delta-opioid receptors (DOPrs) have been identified as playing a crucial role in skin differentiation, proliferation and migration, which are not only essential for wound healing but also contribute to cancer development. In this study, we propose a significant association between cutaneous opioid receptor (OPr) activity and circadian rhythmicity. To investigate this link, we conducted a 48 h circadian rhythm experiment, during which RNA samples were collected every 5 h. We discovered that the activation of DOPr by its endogenous agonist Met-Enkephalin in N/TERT-1 keratinocytes, synchronized by dexamethasone, resulted in a statistically significant 5.6 h delay in the expression of the core clock gene . Confocal microscopy further confirmed the simultaneous nuclear localization of the DOPr-β-arrestin-1 complex. Additionally, DOPr activation not only enhanced but also induced a phase shift in the rhythmic binding of β-arrestin-1 to the promoter. Furthermore, we observed that β-arrestin-1 regulates the transcription of its target genes, including , by facilitating histone-4 acetylation. Through the ChIP assay, we determined that Met-Enkephalin enhances β-arrestin-1 binding to acetylated H4 in the promoter. In summary, our findings suggest that DOPr activation leads to a phase shift in expression via β-arrestin-1-facilitated chromatin remodeling. Consequently, these results indicate that DOPr, much like its role in wound healing, may also play a part in cancer development by influencing .
Topics: Humans; beta-Arrestins; Receptors, Opioid; Keratinocytes; Circadian Rhythm; beta-Arrestin 1; Enkephalin, Methionine; Neoplasms
PubMed: 38334624
DOI: 10.3390/cells13030232 -
Proteome Science Jan 2024The aim of this work was to investigate the immunological effect of MENK by analyzing the protein spectrum and bioinformatics of macrophage RAW264.7, and to explore the...
OBJECTIVE
The aim of this work was to investigate the immunological effect of MENK by analyzing the protein spectrum and bioinformatics of macrophage RAW264.7, and to explore the relationship between macrophage and ferroptosis.
RESULT
We employed proteomic analysis to identify differentially expressed proteins (DEPs) between macrophages and macrophages intervened by MENK. A total of 208 DEPs were identified. Among these, 96 proteins had upregulated expression and 112 proteins had downregulated expression. Proteomic analysis revealed a significant enrichment of DEPs associated with iron metabolism. The identification of hub genes was conducted using KEGG pathway diagrams and protein-protein interaction (PPI) analysis. The hub genes identified in this study include HMOX1 and Ferritin (FTH and FTL). A correlation was established between HMOX1, FTH, and FTL in the GO and KEGG databases. The results of PCR, WB and immunofluorescence showed that MENK downregulated the level of HMOX1 and FTH.
CONCLUSION
MENK had the potential to become an adjuvant chemotherapy drug by regulating iron metabolism in macrophages, reducing levels of HMOX1 and ferritin. We proposed an innovative research direction on the therapeutic potential of MENK, focusing on the relationship between ferroptosis and macrophage activity.
PubMed: 38245706
DOI: 10.1186/s12953-024-00228-x -
International Immunopharmacology Dec 2023This study aimed to investigate the underlying regulatory effects of methionine enkephalin (MENK) on osteosarcoma.
OBJECTIVE
This study aimed to investigate the underlying regulatory effects of methionine enkephalin (MENK) on osteosarcoma.
METHODS
The Cell Counting Kit-8 assay, clone formation, wound healing, transwell assay, and flow cytometry were performed to measure the effects of MENK on the proliferation, migration, invasion, and apoptosis of MG-63 and Saos-2 cells. Opiate growth factor receptor expression (OGFr) in cells was stably knocked down using siRNA. A tumor model was established by inoculating MG-63 cells into mice. Flow cytometry was performed to identify alterations in mice bone marrow, spleen, and tumor tissue immune cells. The phenotype of tumor-associated macrophages was determined using immunohistochemistry. After OGFr knockdown or/and treatment with MENK, Bax, Bcl-2, caspase 3, caspase 9, and PARP expression levels were characterized using qRT-PCR, western blot, and WES, respectively.
RESULTS
MENK could significantly inhibit the proliferation, invasion, and migration of MG-63 and Saos-2, arrest the cell cycle in the G0/G1 phase, upregulate Bax, caspase 3, caspase 9, and PARP expression, and downregulate Bcl-2 expression. Tumor size and weight were lower in the MENK group than those in the control group. MENK-treated mice exhibited a reduced ratio of CD11b + Gr-1 + myeloid-derived suppressor cells. MENK increased the ratio of M1-type macrophages and decreased the proportion of M2-type macrophages in tumor tissue. Furthermore, the level of TNF-α significantly increased while that of IL-10 decreased in MENK-treated mice. The effect of MENK could be partly reversed by OGFr knockdown.
CONCLUSION
MENK reduces the abundance of myeloid-derived suppressor cells, induces M1 polarization of macrophages, and exhibits an inhibitory effect on osteosarcoma.
Topics: Animals; Mice; Caspase 3; Caspase 9; Poly(ADP-ribose) Polymerase Inhibitors; bcl-2-Associated X Protein; Osteosarcoma; Enkephalin, Methionine; Bone Neoplasms
PubMed: 37976597
DOI: 10.1016/j.intimp.2023.111226 -
BMC Immunology Oct 2023Novel prophylactic drugs and vaccination strategies for protection against influenza virus should induce specific effector T-cell immune responses in pulmonary airways...
Novel prophylactic drugs and vaccination strategies for protection against influenza virus should induce specific effector T-cell immune responses in pulmonary airways and peripheral lymphoid organs. Designing approaches that promote T-cell-mediated responses and memory T-cell differentiation would strengthen host resistance to respiratory infectious diseases. The results of this study showed that pulmonary delivery of MENK via intranasal administration reduced viral titres, upregulated opioid receptor MOR and DOR, increased the proportions of T-cell subsets including CD8 T cells, CD8 T cells, NP/PA-effector CD8 T cells in bronchoalveolar lavage fluid and lungs, and CD4/CD8 T cells in lymph nodes to protect mice against influenza viral challenge. Furthermore, we demonstrated that, on the 10th day of infection, the proportions of CD4 T and CD8 T cells were significantly increased, which meant that a stable T and T lineage was established in the early stage of influenza infection. Collectively, our data suggested that MENK administered intranasally, similar to the route of natural infection by influenza A virus, could exert antiviral activity through upregulating T-cell-mediated adaptive immune responses against influenza virus.
Topics: Mice; Animals; Humans; Influenza, Human; CD8-Positive T-Lymphocytes; Enkephalin, Methionine; Memory T Cells; Influenza A virus; Immunologic Memory; Mice, Inbred C57BL
PubMed: 37828468
DOI: 10.1186/s12865-023-00573-0 -
International Immunopharmacology Nov 2023This study was to study the role of methionine enkephalin (menk) in cell invasion and migration as well as NK cells activation of tumor microenvironment in cervical...
This study was to study the role of methionine enkephalin (menk) in cell invasion and migration as well as NK cells activation of tumor microenvironment in cervical cancer. The results showed that menk inhibited cervical cancer migration and invasion. In addition, we found menk affected epithelial to mesenchymal transition (EMT) related indicators, with increasing E-cadherin level, decreasing N-cadherin and vimentin level. Through in vivo mouse model, we found that menk IFNγ and NKP46 expression was upregulated in tumor tissues by menk compared with controls, while LAG3 expression was inhibited by menk, besides, there was an upregulation of CD11b NCR1 NKs of tumor microenvironment in cervical cancer. Therefore, we concluded that menk inhibited cancer migration and invasion via affecting EMT related indicators and activated CD11b NCR1 NKs of tumor microenvironment in cervical cancer, laying a theoretical foundation for the further clinical treatment of menk.
Topics: Humans; Female; Mice; Animals; Uterine Cervical Neoplasms; Enkephalin, Methionine; Epithelial-Mesenchymal Transition; Tumor Microenvironment; Natural Cytotoxicity Triggering Receptor 1; Cell Line, Tumor; Cell Movement
PubMed: 37741126
DOI: 10.1016/j.intimp.2023.110967