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1.
Cells ; 13(3)2024 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-38334624

RESUMO

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 PER2 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 PER2. Confocal microscopy further confirmed the simultaneous nuclear localization of the DOPr-ß-arrestin-1 complex. Additionally, DOPr activation not only enhanced but also induced a phase shift in the rhythmic binding of ß-arrestin-1 to the PER2 promoter. Furthermore, we observed that ß-arrestin-1 regulates the transcription of its target genes, including PER2, by facilitating histone-4 acetylation. Through the ChIP assay, we determined that Met-Enkephalin enhances ß-arrestin-1 binding to acetylated H4 in the PER2 promoter. In summary, our findings suggest that DOPr activation leads to a phase shift in PER2 expression via ß-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 PER2.


Assuntos
Neoplasias , Receptores Opioides , Humanos , beta-Arrestinas , Receptores Opioides/genética , Queratinócitos , Ritmo Circadiano/fisiologia , beta-Arrestina 1 , Encefalina Metionina
2.
Int Immunopharmacol ; 125(Pt B): 111226, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37976597

RESUMO

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.


Assuntos
Neoplasias Ósseas , Osteossarcoma , Animais , Camundongos , Caspase 3 , Caspase 9 , Inibidores de Poli(ADP-Ribose) Polimerases , Proteína X Associada a bcl-2 , Osteossarcoma/tratamento farmacológico , Encefalina Metionina/farmacologia , Encefalina Metionina/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico
3.
BMC Immunol ; 24(1): 38, 2023 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-37828468

RESUMO

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+ TEM cells, NP/PA-effector CD8+ TEM cells in bronchoalveolar lavage fluid and lungs, and CD4+/CD8+ TCM 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+ TM and CD8+ TM cells were significantly increased, which meant that a stable TCM and TEM 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.


Assuntos
Vírus da Influenza A , Influenza Humana , Camundongos , Animais , Humanos , Linfócitos T CD8-Positivos , Encefalina Metionina/farmacologia , Células T de Memória , Memória Imunológica , Camundongos Endogâmicos C57BL
4.
Int Immunopharmacol ; 124(Pt B): 110967, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37741126

RESUMO

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.


Assuntos
Neoplasias do Colo do Útero , Humanos , Feminino , Camundongos , Animais , Neoplasias do Colo do Útero/tratamento farmacológico , Encefalina Metionina/farmacologia , Transição Epitelial-Mesenquimal , Microambiente Tumoral , Receptor 1 Desencadeador da Citotoxicidade Natural , Linhagem Celular Tumoral , Movimento Celular
5.
Gen Comp Endocrinol ; 342: 114353, 2023 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-37536461

RESUMO

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.


Assuntos
Lagartos , Ovário , Feminino , Animais , Hormônio Foliculoestimulante/farmacologia , Analgésicos Opioides/farmacologia , Folículo Ovariano , Encefalina Metionina/farmacologia , Estações do Ano , Hormônio Liberador de Gonadotropina/farmacologia , Lagartos/fisiologia , Metionina/farmacologia
6.
Acta Neurobiol Exp (Wars) ; 83(1): 84-96, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37078817

RESUMO

In the central nervous system, long­term effects of a vagotomy include disturbance of monoaminergic activity of the limbic system. Since low vagal activity is observed in major depression and autism spectrum disorder, the study aimed to determine whether animals fully recovered after subdiaphragmatic vagotomy demonstrates neurochemical indicators of altered well­being and social component of sickness behavior. Bilateral vagotomy or sham surgery was performed in adult rats. After one month of recovery, rats were challenged with lipopolysaccharide or vehicle to determine the role of central signaling upon sickness. Striatal monoamines and met­enkephalin concentrations were evaluated using HPLC and RIA methods. We also defined a concentration of immune­derived plasma met­enkephalin to establish a long­term effect of vagotomy on peripheral analgesic mechanisms. The data indicate that 30 days after vagotomy procedure, striatal dopaminergic, serotoninergic, and enkephalinergic neurochemistry was altered, both under physiological and inflammatory conditions. Vagotomy prevented inflammation­induced increases of plasma met­enkephalin - an opioid analgesic. Our data suggest that in a long perspective, vagotomized rats may be more sensitive to pain and social stimuli during peripheral inflammation.


Assuntos
Transtorno do Espectro Autista , Encefalina Metionina , Ratos , Animais , Encefalina Metionina/farmacologia , Vagotomia , Nervo Vago/fisiologia , Inflamação , Aminas
7.
Int Immunopharmacol ; 118: 110064, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-36989897

RESUMO

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-ß1 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.


Assuntos
Neoplasias Pulmonares , Células Supressoras Mieloides , Animais , Camundongos , Transição Epitelial-Mesenquimal , Macrófagos Associados a Tumor/metabolismo , Encefalina Metionina/farmacologia , Encefalina Metionina/uso terapêutico , Encefalina Metionina/metabolismo , Microambiente Tumoral , Camundongos Nus , Linhagem Celular Tumoral , Movimento Celular
8.
J Pain ; 24(5): 840-859, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36586660

RESUMO

Venom-derived NaV1.7 channel blockers have promising prospects in pain management. The 34-residue tarantula peptide GpTx-1 is a potent NaV1.7 channel blocker. Its powerful analog [Ala5, Phe6, Leu26, Arg28]GpTx-1 (GpTx-1-71) displayed excellent NaV1.7 selectivity and analgesic properties in mice. The current study aimed to elucidate the anti-hyperalgesic activities of GpTx-1-71 in inflammatory pain and reveal the underlying mechanisms. Our results demonstrated that intrathecal and intraplantar injections of GpTx-1-71 dose-dependently attenuated CFA-induced inflammatory hypersensitivity in rats. Moreover, GpTx-1-71-induced anti-hyperalgesia was significantly reduced by opioid receptor antagonists and the enkephalin antibody and diminished in proenkephalin (Penk) gene knockout animals. Consistently, GpTx-1-71 treatment increased the enkephalin level in the spinal dorsal horn and promoted the Penk transcription and enkephalin release in primary dorsal root ganglion (DRG) neurons, wherein sodium played a crucial role in these processes. Mass spectrometry analysis revealed that GpTx-1-71 mainly promoted the secretion of Met-enkephalin but not Leu-enkephalin from DRG neurons. In addition, the combination of subtherapeutic Met-enkephalin and GpTx-1-71 produced synergistic anti-hyperalgesia in CFA-induced inflammatory hypersensitivity. These findings suggest that the endogenous enkephalin pathway is essential for GpTx-1-71-induced spinal and peripheral analgesia in inflammatory pain. PERSPECTIVE: This article presents a possible pharmacological mechanism underlying NaV1.7 blocker-induced analgesia in inflammatory pain, which helps us to better understand and develop venom-based painkillers for incurable pain.


Assuntos
Hiperalgesia , Dor , Ratos , Camundongos , Animais , Dor/tratamento farmacológico , Hiperalgesia/tratamento farmacológico , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Encefalinas/metabolismo , Encefalina Metionina/metabolismo , Encefalina Metionina/farmacologia , Encefalina Metionina/uso terapêutico , Gânglios Espinais/metabolismo , Canal de Sódio Disparado por Voltagem NAV1.7/metabolismo
9.
Life Sci ; 312: 121189, 2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36396109

RESUMO

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.


Assuntos
Encefalina Metionina , Resistência à Insulina , Masculino , Camundongos , Animais , Encefalina Metionina/farmacologia , Camundongos Endogâmicos C57BL , Tecido Adiposo Branco/metabolismo , Termogênese , Dieta Hiperlipídica/efeitos adversos , Obesidade/metabolismo , Inflamação/metabolismo , Tecido Adiposo Marrom/metabolismo
10.
Int J Mol Sci ; 23(19)2022 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-36232883

RESUMO

Pain is a worldwide public health problem and its treatment is still a challenge since clinically available drugs do not completely reverse chronic painful states or induce undesirable effects. Crotalphine is a 14 amino acids synthetic peptide that induces a potent and long-lasting analgesic effect on acute and chronic pain models, peripherally mediated by the endogenous release of dynorphin A and the desensitization of the transient receptor potential ankyrin 1 (TRPA1) receptor. However, the effects of crotalphine on the central nervous system (CNS) and the signaling pathway have not been investigated. Thus, the central effect of crotalphine was evaluated on the partial sciatic nerve ligation (PSNL)-induced chronic neuropathic pain model. Crotalphine (100 µg/kg, p.o.)-induced analgesia on the 14th day after surgery lasting up to 24 h after administration. This effect was prevented by intrathecal administration of CB1 (AM251) or CB2 (AM630) cannabinoid receptor antagonists. Besides that, crotalphine-induced analgesia was reversed by CTOP, nor-BNI, and naltrindole, antagonists of mu, kappa, and delta-opioid receptors, respectively, and also by the specific antibodies for ß-endorphin, dynorphin-A, and met-enkephalin. Likewise, the analgesic effect of crotalphine was blocked by the intrathecal administration of minocycline, an inhibitor of microglial activation and proliferation. Additionally, crotalphine decreased the PSNL-induced IL-6 release in the spinal cord. Importantly, in vitro, crotalphine inhibited LPS-induced CD86 expression and upregulated CD206 expression in BV-2 cells, demonstrating a polarization of microglial cells towards the M2 phenotype. These results demonstrated that crotalphine, besides activating opioid and cannabinoid analgesic systems, impairs central neuroinflammation, confirming the neuromodulatory mechanism involved in the crotalphine analgesic effect.


Assuntos
Analgesia , Canabinoides , Neuralgia , Aminoácidos/metabolismo , Analgésicos/metabolismo , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Analgésicos Opioides/metabolismo , Anquirinas/metabolismo , Antagonistas de Receptores de Canabinoides/uso terapêutico , Canabinoides/uso terapêutico , Dinorfinas/metabolismo , Encefalina Metionina/metabolismo , Humanos , Interleucina-6/metabolismo , Lipopolissacarídeos/metabolismo , Microglia/metabolismo , Minociclina/uso terapêutico , Neuralgia/metabolismo , Peptídeos , Fenótipo , Receptores Opioides/metabolismo , Medula Espinal , beta-Endorfina/metabolismo
11.
J Chem Inf Model ; 62(19): 4783-4798, 2022 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-36122323

RESUMO

Computer simulations of biomolecules such as molecular dynamics often suffer from insufficient sampling. Due to limited computational resources, insufficient sampling prevents obtaining proper equilibrium distributions of observed properties. To deal with this problem, we proposed a simulation protocol for efficient resampling of collected off-equilibrium trajectories. These trajectories are utilized for the initial mapping of the conformational space, which is later properly resampled by the introduced Iterative Landmark-Based Umbrella Sampling (ILBUS) method. Reconstruction of static equilibrium properties is achieved by the multistate Bennett acceptance ratio (MBAR) method, which enables efficient use of simulated data. The ILBUS protocol is geometry-based and does not demand any additional collective variable or a dimensional-reduction technique. The only requirement is a set of suitably spaced reference conformations, which serve as landmarks in the mapped conformational space. Additionally, the ILBUS protocol encompasses an iterative process that optimizes the force constant used in the umbrella sampling simulation. Such tuning is an inherent feature of the protocol and does not need to be performed by the user in advance. Furthermore, even the simulations with suboptimal force constants can be used in estimates by MBAR. We demonstrate the feasibility and the performance of this approach in the study of the conformational landscape of the alanine dipeptide, met-enkephalin, and adenylate kinase.


Assuntos
Adenilato Quinase , Simulação de Dinâmica Molecular , Alanina , Dipeptídeos/química , Encefalina Metionina
12.
Cell Rep ; 40(13): 111440, 2022 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-36170833

RESUMO

Low dopamine D2 receptor (D2R) availability in the striatum can predispose for cocaine abuse; though how low striatal D2Rs facilitate cocaine reward is unclear. Overexpression of D2Rs in striatal neurons or activation of D2Rs by acute cocaine suppresses striatal Penk mRNA. Conversely, low D2Rs in D2-striatal neurons increases striatal Penk mRNA and enkephalin peptide tone, an endogenous mu-opioid agonist. In brain slices, met-enkephalin and inhibition of enkephalin catabolism suppresses intra-striatal GABA transmission. Pairing cocaine with intra-accumbens met-enkephalin during place conditioning facilitates acquisition of preference, while mu-opioid receptor antagonist blocks preference in wild-type mice. We propose that heightened striatal enkephalin potentiates cocaine reward by suppressing intra-striatal GABA to enhance striatal output. Surprisingly, a mu-opioid receptor antagonist does not block cocaine preference in mice with low striatal D2Rs, implicating other opioid receptors. The bidirectional regulation of enkephalin by D2R activity and cocaine offers insights into mechanisms underlying the vulnerability for cocaine abuse.


Assuntos
Transtornos Relacionados ao Uso de Cocaína , Cocaína , Analgésicos Opioides/farmacologia , Animais , Cocaína/farmacologia , Transtornos Relacionados ao Uso de Cocaína/metabolismo , Corpo Estriado/metabolismo , Encefalina Metionina/metabolismo , Encefalina Metionina/farmacologia , Encefalinas/metabolismo , Encefalinas/farmacologia , Camundongos , Antagonistas de Entorpecentes/metabolismo , Antagonistas de Entorpecentes/farmacologia , RNA Mensageiro/metabolismo , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Recompensa , Ácido gama-Aminobutírico/metabolismo
13.
J Neurosci ; 42(42): 7862-7874, 2022 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-36096670

RESUMO

Peripheral neuropathic pain induced by the chemotherapeutic cisplatin can persist for months to years after treatment. Histone deacetylase 6 (HDAC6) inhibitors have therapeutic potential for cisplatin-induced neuropathic pain since they persistently reverse mechanical hypersensitivity and spontaneous pain in rodent models. Here, we investigated the mechanisms underlying reversal of mechanical hypersensitivity in male and female mice by a 2 week treatment with an HDAC6 inhibitor, administered 3 d after the last dose of cisplatin. Mechanical hypersensitivity in animals of both sexes treated with the HDAC6 inhibitor was temporarily reinstated by a single injection of the neutral opioid receptor antagonist 6ß-naltrexol or the peripherally restricted opioid receptor antagonist naloxone methiodide. These results suggest that tonic peripheral opioid ligand-receptor signaling mediates reversal of cisplatin-induced mechanical hypersensitivity after treatment with an HDAC6 inhibitor. Pointing to a specific role for δ opioid receptors (DORs), Oprd1 expression was decreased in DRG neurons following cisplatin administration, but normalized after treatment with an HDAC6 inhibitor. Mechanical hypersensitivity was temporarily reinstated in both sexes by a single injection of the DOR antagonist naltrindole. Consistently, HDAC6 inhibition failed to reverse cisplatin-induced hypersensitivity when DORs were genetically deleted from advillin+ neurons. Mechanical hypersensitivity was also temporarily reinstated in both sexes by a single injection of a neutralizing antibody against the DOR ligand met-enkephalin. In conclusion, we reveal that treatment with an HDAC6 inhibitor induces tonic enkephalin-DOR signaling in peripheral sensory neurons to suppress mechanical hypersensitivity.SIGNIFICANCE STATEMENT Over one-fourth of cancer survivors suffer from intractable painful chemotherapy-induced peripheral neuropathy (CIPN), which can last for months to years after treatment ends. HDAC6 inhibition is a novel strategy to reverse CIPN without negatively interfering with tumor growth, but the mechanisms responsible for persistent reversal are not well understood. We built on evidence that the endogenous opioid system contributes to the spontaneous, apparent resolution of pain caused by nerve damage or inflammation, referred to as latent sensitization. We show that blocking the δ opioid receptor or its ligand enkephalin unmasks CIPN in mice treated with an HDAC6 inhibitor (latent sensitization). Our work provides insight into the mechanisms by which treatment with an HDAC6 inhibitor apparently reverses CIPN.


Assuntos
Antineoplásicos , Neuralgia , Camundongos , Masculino , Feminino , Animais , Desacetilase 6 de Histona/metabolismo , Cisplatino/toxicidade , Receptores Opioides delta , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Hiperalgesia/metabolismo , Antagonistas de Entorpecentes/farmacologia , Ligantes , Analgésicos Opioides/efeitos adversos , Camundongos Endogâmicos C57BL , Neuralgia/induzido quimicamente , Neuralgia/tratamento farmacológico , Neuralgia/metabolismo , Inibidores de Histona Desacetilases , Niacinamida , Antineoplásicos/toxicidade , Encefalina Metionina , Encefalinas , Anticorpos Neutralizantes
14.
Int Immunopharmacol ; 111: 109125, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35988519

RESUMO

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, CD8+T cells, and CD4+T cells and decreased the proportions of G-MDSCs, M-MDSCs, and M2-type macrophages. MENK accelerated CD4+TEM and CD8+TEM cell activation in the TIME and up-regulated IFN-γ, TNF-α, and IL-17A in CD4+T cells and Granzyme B in CD8+T 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.


Assuntos
Neoplasias Colorretais , Encefalina Metionina , Animais , Antígeno B7-H1 , Neoplasias Colorretais/tratamento farmacológico , Encefalina Metionina/farmacologia , Encefalina Metionina/uso terapêutico , Fatores Imunológicos , Camundongos , Receptor de Morte Celular Programada 1 , Microambiente Tumoral
15.
Sci Rep ; 12(1): 12584, 2022 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-35869117

RESUMO

With different countries facing multiple waves, with some SARS-CoV-2 variants more deadly and virulent, the COVID-19 pandemic is becoming more dangerous by the day and the world is facing an even more dreadful extended pandemic with exponential positive cases and increasing death rates. There is an urgent need for more efficient and faster methods of vaccine development against SARS-CoV-2. Compared to experimental protocols, the opportunities to innovate are very high in immunoinformatics/in silico approaches, especially with the recent adoption of structural bioinformatics in peptide vaccine design. In recent times, multi-epitope-based peptide vaccine candidates (MEBPVCs) have shown extraordinarily high humoral and cellular responses to immunization. Most of the publications claim that respective reported MEBPVC(s) assembled using a set of in silico predicted epitopes, to be the computationally validated potent vaccine candidate(s) ready for experimental validation. However, in this article, for a given set of predicted epitopes, it is shown that the published MEBPVC is one among the many possible variants and there is high likelihood of finding more potent MEBPVCs than the published candidates. To test the same, a methodology is developed where novel MEBP variants are derived by changing the epitope order of the published MEBPVC. Further, to overcome the limitations of current qualitative methods of assessment of MEBPVC, to enable quantitative comparison and ranking for the discovery of more potent MEBPVCs, novel predictors, Percent Epitope Accessibility (PEA), Receptor specific MEBP vaccine potency (RMVP), MEBP vaccine potency (MVP) are introduced. The MEBP variants indeed showed varied MVP scores indicating varied immunogenicity. Further, the MEBP variants with IDs, SPVC_446 and SPVC_537, had the highest MVP scores indicating these variants to be more potent MEBPVCs than the published MEBPVC and hence should be preferred candidates for immediate experimental testing and validation. The method enables quicker selection and high throughput experimental validation of vaccine candidates. This study also opens the opportunity to develop new software tools for designing more potent MEBPVCs in less time.


Assuntos
COVID-19 , SARS-CoV-2 , COVID-19/prevenção & controle , Encefalina Metionina/análogos & derivados , Epitopos , Epitopos de Linfócito B , Epitopos de Linfócito T , Humanos , Simulação de Acoplamento Molecular , Pandemias/prevenção & controle , Peptídeos , Vacinas de Subunidades
16.
Int Immunopharmacol ; 110: 108933, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35738090

RESUMO

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.


Assuntos
Carcinoma , Células Supressoras Mieloides , Neoplasias do Colo do Útero , Animais , Apoptose , Linhagem Celular Tumoral , Encefalina Metionina/metabolismo , Encefalina Metionina/farmacologia , Encefalina Metionina/uso terapêutico , Feminino , Humanos , Fatores Imunológicos/metabolismo , Camundongos , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/metabolismo
17.
Int J Biol Sci ; 18(7): 2882-2897, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35541895

RESUMO

Cold-inducible RNA-binding protein (CIRBP) is documented to be required for maintaining cardiac function, however, its role in chemotherapy-induced cardiotoxicity remains obscured. Herein, we report that CIRBP decreases cardiomyocyte apoptosis and attenuates cardiotoxicity through disrupting OGF-OGFR signal. CIRBP deficiency is involved in diverse chemotherapeutic agents induced cardiomyocyte apoptosis. Delivery of exogenous CIRBP to the mouse myocardium significantly mitigated doxorubicin-induced cardiac apoptosis and dysfunction. Specifically, OGFR was identified as a downstream core effector responsible for chemotherapy-induced cardiomyocyte apoptosis. CIRBP was shown to interact with OGFR mRNA and to repress OGFR expression by reducing mRNA stability. CIRBP-mediated cytoprotection against doxorubicin-induced cardiac apoptosis was demonstrated to largely involve OGFR repression by CIRBP. NTX as a potent antagonist of OGFR successfully rescued CIRBP ablation-rendered susceptibility to cardiac dyshomeostasis upon exposure to doxorubicin, whereas another antagonist ALV acting only on opioid receptors did not. Taken together, our results demonstrate that CIRBP confers myocardium resistance to chemotherapy-induced cardiac apoptosis and dysfunction by dampening OGF/OGFR axis, shedding new light on the mechanisms of chemo-induced cardiotoxicity and providing insights into the development of an efficacious cardioprotective strategy for cancer patients.


Assuntos
Cardiotoxicidade , Doxorrubicina , Encefalina Metionina , Animais , Apoptose/efeitos dos fármacos , Cardiotoxicidade/etiologia , Cardiotoxicidade/metabolismo , Cardiotoxicidade/patologia , Proliferação de Células , Doxorrubicina/toxicidade , Encefalina Metionina/metabolismo , Encefalina Metionina/farmacologia , Humanos , Camundongos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Proteínas de Ligação a RNA/genética
18.
Science ; 375(6585): 1177-1182, 2022 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-35201898

RESUMO

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.


Assuntos
Encefalina Metionina/análogos & derivados , Plasticidade Neuronal , Núcleo Accumbens/metabolismo , Peptidil Dipeptidase A/metabolismo , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Captopril/farmacologia , Encefalina Metionina/metabolismo , Feminino , Fentanila/farmacologia , Masculino , Camundongos , Potenciais Pós-Sinápticos em Miniatura , Peptídeos Opioides/metabolismo , Técnicas de Patch-Clamp
19.
Matern Child Nutr ; 18(2): e13307, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-34939318

RESUMO

The Diabetes and Antenatal Milk Expressing (DAME) randomised controlled trial (RCT) was conducted in 2011-2015, at six sites in Melbourne, Australia to explore the effect of advising women with diabetes in pregnancy to express breast milk from 36 weeks gestation. Infants whose mothers were randomised to express in pregnancy were more likely to be exclusively breast milk fed during their hospital stay, and there was no evidence of harm. This paper explores women's views and experiences of antenatal expressing. In this two-arm RCT, 635 women with diabetes in pregnancy who were otherwise of low medical risk were randomised at 36-37 weeks gestation to usual care (not expressing, n = 316), or the intervention, where women were advised to hand express for 10 min twice daily until birth (n = 319). Semistructured face-to-face interviews were conducted with 10 women who expressed antenatally. They were asked about their experiences of antenatal expressing, including how they felt about the overall experience, the amount of breast milk they expressed, making time to express, and their experience of breastfeeding. Thematic analysis of the in-depth interviews identified six themes: (1) learning and adapting expressing, (2) feelings and sensations associated with expressing, (3) support, (4) dis/empowerment, (5) health, and (6) the value of breast milk. Women had both positive and negative experiences of antenatal expressing. If health professionals are advising antenatal expressing to women, it is important they understand the range of outcomes and experiences.


Assuntos
Diabetes Mellitus , Cuidado Pré-Natal , Aleitamento Materno , Encefalina Metionina/análogos & derivados , Feminino , Humanos , Lactente , Leite Humano , Gravidez , Pesquisa Qualitativa
20.
J Neurosci Res ; 100(2): 551-563, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34821408

RESUMO

Multiple sclerosis (MS) is a progressive disease of the central nervous system (CNS) that primarily affects women during the second or third decade of life. The mechanism is hypothesized to involve unregulated peripheral inflammation resulting in blood-brain barrier damage, and eventual axonal damage and demyelination. Based on this understanding, the animal model of MS, experimental autoimmune encephalomyelitis (EAE), often is utilized to study lymphocyte activation. Therapeutic paradigms of exogenous opioid growth factor (OGF) or low-dose naltrexone (LDN) treatment can modulate EAE, but little is reported regarding OGF or LDN effects on peripheral inflammation, microglia activation, and/or macrophage proliferation. Moreover, little is known about differential responses to LDN or OGF relative to the duration and timing of treatment. Utilizing a female mouse model of EAE, two treatment regimens were established to investigate differences between prophylactic treatment and traditional therapy initiated at the time of disease presentation. Prophylactic OGF or LDN treatment delayed the onset of behavior, suppressed neutrophil replication, and curtailed lymphocyte proliferation which ultimately improved behavioral outcome. Traditional therapy with OGF or LDN reversed behavioral deficits, restored OGF and IL-17 serum levels, and inhibited microglial activation within 8 days. Reduced serum OGF levels in untreated EAE mice correlated with increased microglia activation within lumbar spinal cords. Both treatment regimens of OGF or LDN reduced activated microglia, whereas only prophylactic treatment prevented CNS macrophage aggregation. These data demonstrate that the timing of LDN or OGF treatment initiation alters outcomes and can prevent or reverse behavioral deficits, cytokine activation, and spinal cord pathology.


Assuntos
Analgésicos Opioides , Encefalomielite Autoimune Experimental , Analgésicos Opioides/farmacologia , Animais , Encefalomielite Autoimune Experimental/patologia , Encefalina Metionina/farmacologia , Feminino , Humanos , Imunidade , Camundongos , Camundongos Endogâmicos C57BL , Microglia/patologia , Medula Espinal/patologia
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