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Science (New York, N.Y.) Mar 2022Angiotensin-converting enzyme (ACE) regulates blood pressure by cleaving angiotensin I to produce angiotensin II. In the brain, ACE is especially abundant in striatal...
Angiotensin-converting enzyme (ACE) regulates blood pressure by cleaving angiotensin I to produce angiotensin II. In the brain, ACE is especially abundant in striatal tissue, but the function of ACE in striatal circuits remains poorly understood. We found that ACE degrades an unconventional enkephalin heptapeptide, Met-enkephalin-Arg-Phe, in the nucleus accumbens of mice. ACE inhibition enhanced µ-opioid receptor activation by Met-enkephalin-Arg-Phe, causing a cell type-specific long-term depression of glutamate release onto medium spiny projection neurons expressing the Drd1 dopamine receptor. Systemic ACE inhibition was not intrinsically rewarding, but it led to a decrease in conditioned place preference caused by fentanyl administration and an enhancement of reciprocal social interaction. Our results raise the enticing prospect that central ACE inhibition can boost endogenous opioid signaling for clinical benefit while mitigating the risk of addiction.
Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Behavior, Animal; Captopril; Enkephalin, Methionine; Female; Fentanyl; Male; Mice; Miniature Postsynaptic Potentials; Neuronal Plasticity; Nucleus Accumbens; Opioid Peptides; Patch-Clamp Techniques; Peptidyl-Dipeptidase A
PubMed: 35201898
DOI: 10.1126/science.abl5130 -
General and Comparative Endocrinology Oct 2023Although methionine-enkephalin (M-ENK) is implicated in the regulation of reproductive functions in vertebrates, its function in reptiles is little understood. This...
Although methionine-enkephalin (M-ENK) is implicated in the regulation of reproductive functions in vertebrates, its function in reptiles is little understood. This study aims to elucidate the role of M-ENK on seasonal and follicle stimulating hormone (FSH)-induced ovarian recrudescence in the gecko Hemidactylus frenatus. In the first experiment, administration of 5 µg M-ENK did not affect germinal bed activity or follicular developmental stages I, II, and III (previtellogenic) and IV (vitellogenic), but there were no stage V (vitellogenic) follicles in the ovary. However, there was a significant decrease in the mean numbers of oogonia and primary oocytes in the germinal bed associated with the complete absence of stage IV and V follicles in 25 µg M-ENK-treated lizards in contrast to experimental controls. Furthermore, there was a significant decrease in gonadotropin-releasing hormone - immunoreactive (GnRH-ir) content in the median eminence (ME) and pars distalis (PD) of the pituitary gland and sparse labelling of hypothalamic GnRH-ir neurons in 25 µg M-ENK-treated lizards. In the second experiment, treatment with FSH during the regression phase of the ovarian cycle resulted in the appearance of stage IV and V follicles, in contrast to their absence in the initial controls and treatment controls. However, treatment with 25 µg M-ENK + FSH did not result in the appearance of these follicles, indicating the inhibitory effect of M-ENK on FSH-induced ovarian recrudescence. These findings suggest that M-ENK inhibits the germinal bed and vitellogenic follicular growth in a dose-dependent manner, possibly mediated through the suppression of GnRH release in the ME and PD. In addition, M-ENK may also act at the level of the ovary in the gecko.
Topics: Female; Animals; Ovary; Follicle Stimulating Hormone; Analgesics, Opioid; Ovarian Follicle; Enkephalin, Methionine; Seasons; Gonadotropin-Releasing Hormone; Lizards; Methionine
PubMed: 37536461
DOI: 10.1016/j.ygcen.2023.114353 -
International Immunopharmacology Aug 2016Methionine enkephalin (MENK), an endogenous neuropeptide has a crucial role in both neuroendocrine and immune systems. MENK is believed to have an immunoregulatory...
Methionine enkephalin (MENK), an endogenous neuropeptide has a crucial role in both neuroendocrine and immune systems. MENK is believed to have an immunoregulatory activity to have cancer biotherapy activity by binding to the opioid receptors on immune and cancer cells. Clinical trial studies in cancer patients have shown that MENK activates immune cells directly and by inhibiting regulatory T-cells (Tregs). MENK may also change the tumor microenvironment by binding to opioid receptor on or in cancer cells. All of these mechanisms of action have biologic significance and potential for use in cancer immunotherapy. Furthermore, they reveal a relationship between the endocrine and immune systems. Due to the apparent role of MENK in cancer therapy we reviewed herein, the research undertaken with MENK in recent years; which has advanced our understanding of the role MENK has in cancer progression and its relationship to immunity, supporting MENK as a new strategy for cancer immunotherapy.
Topics: Antineoplastic Agents; Cell Proliferation; Clinical Trials as Topic; Dendritic Cells; Enkephalin, Methionine; Humans; Immune System; Immunotherapy; Killer Cells, Natural; Macrophages; Neoplasms; Neurosecretory Systems; Receptors, Opioid; T-Lymphocytes, Regulatory
PubMed: 26927200
DOI: 10.1016/j.intimp.2016.02.015 -
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 -
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 -
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 -
Vitamins and Hormones 2019The pentapeptides methionine-enkephalin and leucine-enkephalin belong to the opioid family of peptides, and the non-opiate peptide adrenocorticotropin hormone (ACTH) to...
The pentapeptides methionine-enkephalin and leucine-enkephalin belong to the opioid family of peptides, and the non-opiate peptide adrenocorticotropin hormone (ACTH) to the melanocortin peptide family. Enkephalins/ACTH are derived from pro-enkephalin, pro-dynorphin or pro-opiomelanocortin precursors and, via opioid and melanocortin receptors, are responsible for many biological activities. Enkephalins exhibit the highest affinity for the δ receptor, followed by the μ and κ receptors, whereas ACTH binds to the five subtypes of melanocortin receptor, and is the only member of the melanocortin family of peptides that binds to the melanocortin-receptor 2 (ACTH receptor). Enkephalins/ACTH and their receptors exhibit a widespread anatomical distribution. Enkephalins are involved in analgesia, angiogenesis, blood pressure, embryonic development, emotional behavior, feeding, hypoxia, limbic system modulation, neuroprotection, peristalsis, and wound repair; as well as in hepatoprotective, motor, neuroendocrine and respiratory mechanisms. ACTH plays a role in acetylcholine release, aggressive behavior, blood pressure, bone maintenance, hyperalgesia, feeding, fever, grooming, learning, lipolysis, memory, nerve injury repair, neuroprotection, sexual behavior, sleep, social behavior, tissue growth and stimulates the synthesis and secretion of glucocorticoids. Enkephalins/ACTH are also involved in many pathologies. Enkephalins are implicated in alcoholism, cancer, colitis, depression, heart failure, Huntington's disease, influenza A virus infection, ischemia, multiple sclerosis, and stress. ACTH plays a role in Addison's disease, alcoholism, cancer, Cushing's disease, dermatitis, encephalitis, epilepsy, Graves' disease, Guillain-Barré syndrome, multiple sclerosis, podocytopathies, and stress. In this review, we provide an updated description of the enkephalinergic and ACTH systems.
Topics: Adrenocorticotropic Hormone; Amino Acid Sequence; Animals; Enkephalins; Humans; Nervous System; Nervous System Physiological Phenomena; Protein Precursors; Receptors, Corticotropin; Receptors, Opioid; Signal Transduction; Tissue Distribution
PubMed: 31421699
DOI: 10.1016/bs.vh.2019.05.001 -
Biochemical Pharmacology Oct 2021Diabetes is a multi-faceted disorder with increasing prevalence and rising healthcare costs. The burden of diabetes is increased because of associated complications... (Review)
Review
Diabetes is a multi-faceted disorder with increasing prevalence and rising healthcare costs. The burden of diabetes is increased because of associated complications affecting nearly all organs including the eye. The underlying pathophysiology for the onset of these ocular surface disorders is not well known. Enkephalins are endogenous opioids that originate in the brain and have numerous actions in the human body. Opioid growth factor (OGF), chemically termed [Met]-enkephalin, binds to a novel, nuclear-associated receptor and mediates cellular homeostasis. Serum OGF levels are elevated in diabetic individuals and rodent models of diabetes. Sustained blockade of the OGF receptor (OGFr) with opioid receptor antagonists, such as naltrexone (NTX), reverses many complications of diabetes in the animal model, including delayed cutaneous wound healing, dry eye, altered corneal surface sensitivity, and keratopathy. The increased enkephalin levels observed in diabetes suggest a relationship between endogenous opioid peptides and the pathophysiology of diabetes. It is common for diabetic patients to undergo insulin therapy to restore normal blood glucose levels. However, this restoration does not alter OGF serum levels nor ameliorate ocular surface complications in the animal model of diabetes. Moreover, sex differences in the prevalence of diabetes, response to insulin therapy, and abnormalities in the OGF-OGFr axis have been reported. This review highlights current knowledge on the dysregulation of the OGF-OGFr pathway and possible relationships of insulin and enkephalins to the development of ocular surface defects in diabetes. It proposes that this dysregulation is a fundamental mechanism for the pathobiology of diabetic complications.
Topics: Animals; Corneal Diseases; Diabetes Complications; Diabetes Mellitus; Dry Eye Syndromes; Enkephalins; Humans; Insulin; Naltrexone; Narcotic Antagonists; Receptors, Opioid
PubMed: 34324868
DOI: 10.1016/j.bcp.2021.114712 -
Life Sciences Jan 2023Obesity and its related metabolic disorders, including insulin resistance and fatty liver, have become a serious global public health problem. Previous studies have...
AIMS
Obesity and its related metabolic disorders, including insulin resistance and fatty liver, have become a serious global public health problem. Previous studies have shown Methionine Enkephalin (MetEnk) has the potential on adipocyte browning, however, its effects on the potential mechanisms of its regulation in browning as well as its improvement in energy metabolic homeostasis remain to be deciphered.
MAIN METHODS
C57BL/6J male mice were fed with high-fat diet (HFD) to induce obesity model, and MetEnk was injected subcutaneously to detect changes in the metabolic status of mice, adipocytes and HepG2 cells were also treated with MetEnk, and transcriptomic, metabolomic were used to detect the changes of lipid metabolism, mitochondrial function, inflammation and other related factors.
KEY FINDINGS
We found that MetEnk effectively protected against obesity weight gain in HFD-induced C57BL/6J mice, significantly improved glucose tolerance and insulin sensitivity, reduced the expression levels of interleukin 6 (IL-6), promoted white fat browning, moreover, using a combination of transcriptomic, metabolomic and inhibitors, it was found that MetEnk improved mitochondrial function, promoted thermogenesis and lipolysis by activating cAMP/PKA pathway in adipocytes, further analysis found that MetEnk also promoted lipolysis and alleviated inflammation through AMP-activated protein kinase (AMPK) pathway in mice liver and HepG2 cells.
SIGNIFICANCE
Our study provides profound evidence for the role of MetEnk in improving lipid metabolism disorders. This study provides a mechanical foundation for investigating the potential of MetEnk to improve obesity and its associated metabolic disorders.
Topics: Male; Mice; Animals; Enkephalin, Methionine; Mice, Inbred C57BL; Adipose Tissue, White; Thermogenesis; Diet, High-Fat; Insulin Resistance; Obesity; Inflammation; Adipose Tissue, Brown
PubMed: 36396109
DOI: 10.1016/j.lfs.2022.121189 -
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