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Spinal cord stimulation (SCS)-induced analgesia was characterized, and its underlying mechanisms were examined in a spared nerve injury model of neuropathic pain in rats. The analgesic effect of SCS with moderate mechanical hypersensitivity was increased with increasing stimulation intensity between the 20% and 80% motor thresholds. Various frequencies (2, 15, 50, 100, 10000 Hz, and 2/100 Hz dense-dispersed) of SCS were similarly effective. SCS-induced analgesia was maintained without tolerance within 24 h of continuous stimulation. SCS at 2 Hz significantly increased methionine enkephalin content in the cerebrospinal fluid. The analgesic effect of 2 Hz was abolished by μ or κ opioid receptor antagonist. The effect of 100 Hz was prevented by a κ antagonist, and that of 10 kHz was blocked by any of the μ, δ, or κ receptor antagonists, suggesting that the analgesic effect of SCS at different frequencies is mediated by different endorphins and opioid receptors.
Subject(s)
Animals , Rats , Analgesics , Narcotic Antagonists/pharmacology , Neuralgia/therapy , Opioid Peptides , Receptors, Opioid/physiology , Receptors, Opioid, kappa , Spinal Cord , Spinal Cord StimulationABSTRACT
OBJECTIVE To investigate enhanced immune function of methionine encephalin (MENK) and its anti-tumor mechanism in CT26 colon cancer mouse model. METHODS 3×106 CT26 cells were implanted subcutaneously in BALB/c mice. Four days after, MENK was peritoneally administrated at the concentration of 20 mg·kg-1 for 14 d. The percentage of MDSCs in bone marrow, spleen, blood, tumor and liver were detected by flow cytometry. Non- esterified fatty acid (NEFA), triglycerides (TG) and total cholesterol (T-CHO) in liver homogenate were tested by a NEFA test kit, a TG test kit and a T- CHO test kit respectively. qRT- PCR and Western blot were used to measure mRNA and protein levels of inflammation-, glycometabolsim- and lipometabolsim-associated indexes in liver. RESULTS MENK decreased percentages of MDSCs in bone marrow, spleen, blood and tumor in colon cancer mice. MENK-treated mice displayed elevated ratio of CD4+T and CD8+T cells in spleen as well as increased T and B lymphocytes proliferation. Meanwhile, MENK also ameliorated liver damage reflected by lower levels of GPT and GOT in serum and reduced risks of cancer- associated index including inflammation, high lipid and high glucose. Furthermore, MENK lowered down the levels of NEFA, TG and T- CHO in liver homogenate. MENK treatment decreased expression of p- STAT3, increased expression of p-AKT, IRS1 and Glut4 at protein level as well as reduced lipogenesis-associated genes and elevated glycolysis-associated genes in liver of tumor bearing mice. Also, abated expression of genes associated with MDSCs generation (M-CSF, GM-CSF, IL-6, IL-1β) and migration (S100A9, KC) was observed within shrunken subcutaneous tumor by MENK intervention. CONCLUSION MENK has the ability to strength immune function against colon cancer by reducing MDSCs and improving liver metabolism.
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OBJECTIVE: To investigate the signal transduction mechanism of macrophages polarization induced by methionine enkephalin (MENK), which can promote tumoricidal responses in vitro. METHODS: The phenotype of macrophages were assessed by the quantitative analysis of key surface molecules on macrophages with flow cytometry (CD64, CD206). The expressions of NF-kB/STAT6 signal transduction were analyzed with Western-blotting. RESULTS: MENK(10-12 mol · L-1) could significantly decrease the expression of CD206 (P < 0.01), and at the same time, it could increase the expression of CD64 significantly (P < 0.01). MENK could increase the expression of NF-κB compared with MENK-untreated group. Furthermore MENK could inhibit the activation of STAT6 which is mediated by IL4 (P < 0.05). CONCLUSION: MENK could inhibit the activation of STAT6 signaling pathway mediated by IL4. Meanwhile, MENK could increase the expression of NF-κB and be conducive to the combination of NF-kB sites with M1-type cytokines, consequently MENK could induced the conversion of macrophages from M2 to M1 phenotype effectively.
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OBJECTIVES: To predict the structure of protein, which dictates the function it performs, a newly designed algorithm is developed which blends the concept of self-organization and the genetic algorithm. METHODS: Among many other approaches, genetic algorithm is found to be a promising cooperative computational method to solve protein structure prediction in a reasonable time. To automate the right choice of parameter values the influence of self-organization is adopted to design a new genetic operator to optimize the process of prediction. Torsion angles, the local structural parameters which define the backbone of protein are considered to encode the chromosome that enhances the quality of the confirmation. Newly designed self-configured genetic operators are used to develop self-organizing genetic algorithm to facilitate the accurate structure prediction. RESULTS: Peptides are used to gauge the validity of the proposed algorithm. As a result, the structure predicted shows clear improvements in the root mean square deviation on overlapping the native indicates the overall performance of the algorithm. In addition, the Ramachandran plot results implies that the conformations of phi-psi angles in the predicted structure are better as compared to native and also free from steric hindrances. CONCLUSIONS: The proposed algorithm is promising which contributes to the prediction of a native-like structure by eliminating the time constraint and effort demand. In addition, the energy of the predicted structure is minimized to a greater extent, which proves the stability of protein.
Subject(s)
Enkephalin, Methionine , Islet Amyloid Polypeptide , Operator Regions, Genetic , PeptidesABSTRACT
Objective:To explore the mechanism of immunomodulatory effects of methionine-enkephalin(MENK)on dendritic cells(DC).Methods:We used scanning electronic microscope for DC morpholopy,assay for acid phosphatas activity,flow cytometry(FCM) and ELISA to study the effects of DC by MENK.Results:MENK(10-12mol/L) could increase the expression of MHC classⅡ,CD86 and CD40 molecules on DC surface(P
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Objective To observe the effects of methionine enkephalin (M-Enk) on migration of macrophages from mice with impaired liver and its immunomodulatory mechanisms. MethodsLiver of mice was impaired by feeding CCl4 and macrophage migration inhibitory factor (MMIF) was produced by Con A-stimulated spleen lympho- cytes. Inhibition of macrophage migration was measured in reaction system by adding M-Enk. Results Migration of macrophages in both liver-impaired and control group were suppressed by MMIF, but the suppression might be re- versed by adding 1 μmol/L M-Enk (P＜0. 05). M-Enk could significantly inhibit in vitro both of the combination of MMIF with macrophages and production of MMIF from lymphocytes (P＜0. 01). Macrophages from liver-imparied group showed a higher sensitivity compared to the control group (P＜0. 05). ConclusionThe study suggests that opi- oid peptieds play an important role in the modulation of the immune response under stress as liver impairment.
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AIM\ To observe the effect of methionine enkephalin(Met Enk) on proliferation and mechanism involved by opiate receptor of peripheral blood lymphocyte(PBL) from patients with systemic lupus erythematosus(SLE). METHODS\ Lymphocyte proliferation assay. RESULTS\ Naloxone (Nal,1?10 -6 mol?L -1 )could block the increasing effect of Met Enk(1?10 -8 ～1?10 -6 mol?L -1 )on the PBL proliferation of normal humans,but there was no direct effect on that. However,Nal could not only block the promotive action of Met Enk on PBL proliferation of SLE patients,but there was a direct decreasing effect on it. CONCLUSION\ Endogenous Met Enk may participate in the abnormal regulation with SLE PBL via opiate receptor.
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Rat with amputation operation stress possessed a decline of NK activity and splenocyte pro-liferation to mitogen ConA.Amygdaloid nuclei lesion could antagonize the decrease of those ofcell-mediated immunity.Further results showed that serum corticosterone and methionine-enkephahn was high in stress' rats.Amugdaloid Nuclei lesion could antagonize the increase ofserum corticosterone level,but seem no dffeet on serum methionine-enkephalin level,thereforesuggesting that it is related to ratio of corticosterone to enkephalin changed by decrease of corti-costerone that amygdaloid neuclei lesion antagonized the decline of immunogical function inducedby stress.
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The effects of methionine-enkephalin (M-EnK) on mitogenic and mixed lymphocyte culture (MLC) proliferation of splenocytes from Zn-deficient, restricted and control mice were evaluated. The data from this experiment showed that M-Enk could suppress the responses of splenocyte from th 3 groups to eoncanavalin A(Con A), but less inhibition was observed in the Zn-deficient group. M-Enk could also enhance the responses to Pokeweed Mitogen (PWM) and decrease the response to Lipopolysaceharide (LPS) in all groups. Alteration of proliferative responses to LPS,Con A and FWM was reversible in the presence of 10 ?mol/L naloxone, indicating that the effect of M-Enk on cellular proliferation was mediated by the opioid receptor. In the proliferation of MLC, the response of lymphocytes from Zndeficient mice was increased in the absence of M-Enk and M-Enk could suppress this increased response. It is therefore concluded that Met-Enk can modify the pattern of mitogenic responses and the alteration in Con A and MLC responses can be influenced by zinc deficiency.