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European Journal of Pharmacology Sep 2020Methionine enkephalin (MENK) is an opioid peptide composed of five amino acids with multiple biological activities. Since its discovery, MENK has become prominent in... (Review)
Review
Methionine enkephalin (MENK) is an opioid peptide composed of five amino acids with multiple biological activities. Since its discovery, MENK has become prominent in neuroregulation and immunoregulation. Tumors have increasingly been a spotlight because of their terrible trends and refractory characteristic. The therapeutic potential of MENK was investigated on a large scale, and there are numerous evidences that MENK exerts anti-tumor effects via two mechanisms. The first mechanism explains the enhanced anti-tumor immune effects of MENK. The second mechanism shows that MENK directly inhibits tumor cell proliferation. However, numerous reports have clarified the pro-tumor role of MENK by inhibiting T and B cell proliferation, promoting tumor cell growth by binding to opioid receptors, leading to desensitization of lymphocytes, and inducing tolerance. It is particularly intriguing that dual reactions are triggered when MENK combines with its opioid receptors; thus, anti-tumor response of the whole body is influenced. This review will expound the dual roles of MENK in tumor responses based on immune cells, cytokines, and tumor cells to provide better suggestions for its application in tumor treatment.
Topics: Animals; Antineoplastic Agents; Enkephalin, Methionine; Humans; Neoplasms
PubMed: 32535097
DOI: 10.1016/j.ejphar.2020.173253 -
International Immunopharmacology Oct 2022There is evidence that methionine enkephalin (MENK), an opioid peptide, promotes anti-tumor immune responses. In this study, the effect of MENK on colorectal cancer...
There is evidence that methionine enkephalin (MENK), an opioid peptide, promotes anti-tumor immune responses. In this study, the effect of MENK on colorectal cancer (CRC) and its mechanisms of action were examined in vivo. The intraperitoneal administration of 20 mg/kg MENK effectively inhibited MC38 subcutaneous colorectal tumor growth in mice. MENK inhibited tumor progression by increasing the immunogenicity and recognition of MC38 cells. MENK down-regulated the oncogene Kras and anti-apoptotic Bclxl and Bcl2, suppressed Il1b, Il6, iNOS, and Arg1 (encoding inflammatory cytokines), and increased Il17a and Il10 levels. MENK promoted a tumor suppressive state by decreasing the immune checkpoints Pd-1, Pd-l1, Lag3, Flgl1, and 2b4 in CRC. MENK also altered the immune status of the tumor immune microenvironment (TIME). It increased the infiltration of M1-type macrophages, CD8T cells, and CD4T cells and decreased the proportions of G-MDSCs, M-MDSCs, and M2-type macrophages. MENK accelerated CD4T and CD8T cell activation in the TIME and up-regulated IFN-γ, TNF-α, and IL-17A in CD4T cells and Granzyme B in CD8T cells. In addition, analyses of PD-1 and PD-L1 expression indicated that MENK promoted the anti-tumor immune response mediated by effector T cells. Finally, OGFr was up-regulated at the protein and mRNA levels by MENK, and the inhibitory effects of MENK on tumor growth were blocked by NTX, a specific blocker of OGFr. These finding indicate that MENK remodels the TIME in CRC to inhibit tumor progression by binding to OGFr. MENK is a potential therapeutic agent for CRC, especially for improving the efficacy of immunotherapy.
Topics: Animals; B7-H1 Antigen; Colorectal Neoplasms; Enkephalin, Methionine; Immunologic Factors; Mice; Programmed Cell Death 1 Receptor; Tumor Microenvironment
PubMed: 35988519
DOI: 10.1016/j.intimp.2022.109125 -
International Immunopharmacology Sep 2022Immunotherapy for cervical carcinoma is becoming increasingly important recently. In these studies methionine enkephalin (menk) is shown to inhibit cervical tumor cell...
Immunotherapy for cervical carcinoma is becoming increasingly important recently. In these studies methionine enkephalin (menk) is shown to inhibit cervical tumor cell proliferation in vitro in association with an increase in the expression of apoptosis markers and mediators, including an increase in fas, caspase 8, and caspase 3 expression and intrinsic expression of the signaling pathway mediator bax. In vivo, tumor growth was restrained in mice xenotransplant model with typical pathological features of apoptosis. Furthermore, myeloid derived suppressor cells (MDSCs) had a significant decrease in circulation and in tumor site. In brief, these findings showed menk could inhibit tumor growth in vitro and in vivo, providing direction of further research and clinical application prospect.
Topics: Animals; Apoptosis; Carcinoma; Cell Line, Tumor; Enkephalin, Methionine; Female; Humans; Immunologic Factors; Mice; Myeloid-Derived Suppressor Cells; Uterine Cervical Neoplasms
PubMed: 35738090
DOI: 10.1016/j.intimp.2022.108933 -
International Immunopharmacology May 2023Metastasis is one of the most difficult challenges for clinical lung cancer treatment. Epithelial-mesenchymal transition (EMT) is the crucial step of tumor metastasis....
Methionine enkephalin suppresses lung cancer metastasis by regulating the polarization of tumor-associated macrophages and the distribution of myeloid-derived suppressor cells in the tumor microenvironment and inhibiting epithelial-mesenchymal transition.
Metastasis is one of the most difficult challenges for clinical lung cancer treatment. Epithelial-mesenchymal transition (EMT) is the crucial step of tumor metastasis. Immune cells in the tumor microenvironment (TME), such as tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs), promote cancer cell EMT. In this study, we explored the effect of methionine enkephalin (MENK) on the EMT process in vitro and in vivo, and its influence on TAMs, MDSCs, and associated cytokines in vivo. The results showed that MENK suppressed growth, migration, and invasion of lung cancer cells and inhibited the EMT process by interacting with opioid growth factor receptor. MENK reduced the number of M2 macrophages and MDSC infiltration, and downregulated the expression of interleukin-10 and transforming growth factor-β1 in both primary and metastatic tumors of nude mice. The present findings suggest that MENK is a potential target for suppressing metastasis in lung cancer treatment.
Topics: Animals; Mice; Myeloid-Derived Suppressor Cells; Epithelial-Mesenchymal Transition; Tumor-Associated Macrophages; Enkephalin, Methionine; Tumor Microenvironment; Mice, Nude; Cell Line, Tumor; Lung Neoplasms; Cell Movement
PubMed: 36989897
DOI: 10.1016/j.intimp.2023.110064 -
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 -
Cellular and Molecular Neurobiology 20061. In addition to his many fine contributions in furthering our understanding of the neurochemical action of ecosanoids, catchelomines, steroids, anandamines,... (Review)
Review
1. In addition to his many fine contributions in furthering our understanding of the neurochemical action of ecosanoids, catchelomines, steroids, anandamines, cannabinoids, endorphins, and the many modifications made to these neural factors, twenty years ago Julius Axelrod published a noteworthy paper concerning the nature of neuropeptides and their potential for multiple neurophysiological effects (Redgate et al., 1986). 2. In that report, Axelrod and coworkers described the neurological actions of the then recently discovered leucine- and methionine-enkephalins, and their biological functions which were novel, atypical, and in possession of neurological effects that were significantly "much more than additive." 3. In this short communication I would like to expand on this observation concerning the "additive effects" contained within the amino acid sequence of the atypical neurotransmitter peptides leucine- and methonine-enkephalin.
Topics: Animals; Dopamine; Enkephalin, Leucine; Enkephalin, Methionine; Glycine; Humans; Neuropeptides; Signal Transduction; Tissue Distribution
PubMed: 16802191
DOI: 10.1007/s10571-006-9100-6 -
British Journal of Pharmacology Feb 19971. A method is described for the rapid extraction of opioid peptides from the brain and other tissues. The method is based on acid extraction of tissues followed by...
1. A method is described for the rapid extraction of opioid peptides from the brain and other tissues. The method is based on acid extraction of tissues followed by adsorption of the extract onto Amberlite XAD-2 resin. Elution with methanol separates the enkephalins and α-endorphin from β-endorphin. 2. Over 90% of the opioid peptide activity isolated from brain and gut of several species by our method was due to methionine- and leucine-enkephalin. In contrast, the major opioid peptide activity recovered from the pituitary was due to peptides of much greater mol. wt. than the enkephalins. 3. An opioid peptide with properties unlike those of the known endorphins or enkephalins was present in brain extracts. This peptide, termed ∈-endorphin, has an apparent mol. wt. of 700 to 1200; it constituted between 5 to 10% of the total opioid activity in our extracts. 4. A differential assay of methionine- and leucine-enkephalin was made either by destroying methionine-enkephalin activity with cyanogen bromide or by separating the peptides by thin layer chromatography. 5. The ratio of methionine-enkephalin to leucine-enkephalin varied greatly in different brain regions. The highest proportions of leucine-enkephalin were found in the cerebral cortex and hippocampus. 6. Formaldehyde perfusion and fixation of the brain had no significant effect on the brain content of enkephalin, indicating that proteolytic breakdown is not a major problem in the extraction of these peptides. 7. It is suggested that the enkephalins may have a neurotransmitter role in both brain and peripheral tissues and that methionine- and leucine-enkephalin may subserve separate neuronal functions.
Topics: Animals; Biological Assay; Brain; Enkephalin, Leucine; Enkephalin, Methionine; Guinea Pigs; History, 20th Century; Ileum; Mice; Pituitary Gland; Rabbits; Rats; Tissue Distribution
PubMed: 9142421
DOI: 10.1111/j.1476-5381.1997.tb06829.x -
Neuroscience Oct 2016Using an immunohistochemical technique, we mapped the immunoreactive structures containing methionine-enkephalin-Arg-Gly-Leu (Met-8) (a marker for the pro-enkephalin...
Using an immunohistochemical technique, we mapped the immunoreactive structures containing methionine-enkephalin-Arg-Gly-Leu (Met-8) (a marker for the pro-enkephalin system) in the human diencephalon. Compared with previous studies, we observed a more widespread distribution of Met-8 in the human diencephalon. Met-8-immunoreactive cell bodies and fibers exhibited a more widespread distribution in the hypothalamus than in the thalamus. We observed six populations of Met-8-immunoreactive cell bodies. These perikarya were observed in the paratenial thalamic nucleus, ventromedial and dorsomedial hypothalamic nuclei, lateral hypothalamic area, pallidohypothalamic nucleus and in the paraventricular hypothalamic nucleus (posterior part). In the thalamus, Met-8-immunoreactive fibers were primarily observed in the midline region, whereas in the hypothalamus, these fibers were widely distributed. In general, a moderate/low density of Met-8-immunoreactive fibers was observed in the diencephalic nuclei. A moderate density was observed in the paraventricular thalamic nucleus, reuniens thalamic nucleus, lateral and medial geniculate nuclei, dorsomedial hypothalamic nucleus, paraventricular hypothalamic nucleus (posterior part) and ventromedial hypothalamic nucleus. The present study is the first to demonstrate the presence of clusters of Met-8-immunoreactive cell bodies in the human thalamus and hypothalamus, the distribution of fibers containing neuropeptides in the hypothalamus and the presence of these fibers in several thalamic nuclei. This neuroanatomical study will serve to elucidate the physiological roles of Met-8 in future studies of the human diencephalon.
Topics: Aged, 80 and over; Diencephalon; Enkephalin, Methionine; Enkephalins; Female; Humans; Immunohistochemistry; Male; Protein Precursors
PubMed: 27531857
DOI: 10.1016/j.neuroscience.2016.08.010 -
Analytical Biochemistry Oct 2018The aim of this work was to assess the influence of preanalytical variables on the stability of two endogenous opioid peptides (Methionine-Enkephalin and...
The aim of this work was to assess the influence of preanalytical variables on the stability of two endogenous opioid peptides (Methionine-Enkephalin and Leucine-Enkephalin) in human plasma. For this purpose, first a sensitive LC-MS/MS analytical method was developed and validated for the simultaneous quantitative analysis of these two peptides. The methodology consisted of a simple protein precipitation step followed by UPLC separation and MRM quantitative analysis using a stable isotope labelled Methionine-Enkephalin as internal standard. The method with a limit of quantitation of 10 pg/mL showed good reproducibility with excellent accuracy and precision, and was linear up to 2000 pg/mL. An extensive evaluation of the pre-analytical stability of these peptides in human blood was carried out to ensure an adequate sample collection procedure to obtain reliable results in the analysis of clinical samples.
Topics: Chromatography, High Pressure Liquid; Enkephalin, Leucine; Enkephalin, Methionine; Humans; Mass Spectrometry; Molecular Structure
PubMed: 29981318
DOI: 10.1016/j.ab.2018.07.001 -
Journal of Chemical Neuroanatomy May 2013We have studied the distribution of immunoreactive cell bodies and axons are containing methionine-enkephalin in the minipig brainstem. Immunoreactive axons were widely...
We have studied the distribution of immunoreactive cell bodies and axons are containing methionine-enkephalin in the minipig brainstem. Immunoreactive axons were widely distributed, whereas the distribution of perikarya was less widespread. A high or moderate density of axons containing methionine-enkephalin were found from rostral to caudal levels in the substantia nigra, nucleus interpeduncularis, nucleus reticularis tegmenti pontis, nucleus dorsalis raphae, nucleus centralis raphae, nuclei dorsalis and ventralis tegmenti of Gudden, locus ceruleus, nucleus sensorius principalis nervi trigemini, nucleus cuneatus externalis, nucleus tractus solitarius, nuclei vestibularis inferior and medialis, nucleus ambiguus, nucleus olivaris inferior and in the nucleus tractus spinalis nervi trigemini. Immunoreactive perikarya were observed in the nuclei centralis and dorsalis raphae, nucleus motorius nervi trigemini, nucleus centralis superior, nucleus nervi facialis, nuclei parabrachialis medialis and lateralis, nucleus ventralis raphae, nucleus reticularis lateralis and in the formatio reticularis. We have also described the presence of perikarya containing methionine-enkephalin in the nuclei nervi abducens, ruber, nervi oculomotorius and nervi trochlearis. These results suggest that in the minipig the pentapeptide may be involved in many physiological functions (for example, proprioceptive and nociceptive information; motor, respiratory and cardiovascular mechanisms).
Topics: Animals; Brain Chemistry; Brain Stem; Enkephalin, Methionine; Female; Immunohistochemistry; Male; Neurons; Swine; Swine, Miniature
PubMed: 23538385
DOI: 10.1016/j.jchemneu.2013.03.002