CN112730849A - Application of endogenous orphan enkephalin as serum biomarker for diabetes mellitus combined with asymptomatic myocardial ischemia - Google Patents
Application of endogenous orphan enkephalin as serum biomarker for diabetes mellitus combined with asymptomatic myocardial ischemia Download PDFInfo
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Abstract
The invention belongs to the technical field of medicines, and provides application of endogenous orphan enkephalin (N/OFQ) serving as a serum biomarker for diabetes combined with asymptomatic myocardial ischemia in order to solve the problem that no effective index which can be directly detected from blood exists in diagnosis of asymptomatic myocardial ischemia (SMI). The application of endogenous orphan enkephalin in preparing a diagnostic reagent or a kit for detecting diabetes combined with asymptomatic myocardial ischemia. The serum N/OFQ in the body of the patient with the diabetes combined SMI is obviously increased and is positively correlated with the severity of coronary artery lesion, so that the N/OFQ is determined to be a potential index for predicting the SMI. Since N/OFQ can play a role in acute myocardial ischemia, N/OFQ becomes possible to be used as a new index for predicting the combination of SMI of diabetic patients.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to application of endogenous orphan enkephalin serving as a serum biomarker for diabetes combined with asymptomatic myocardial ischemia.
Background
Coronary heart disease is a myocardial ischemia-hypoxic disease caused by coronary atherosclerosis, the occurrence of the myocardial ischemia-hypoxic disease is related to lipid plaque deposition and the activity of neutrophils and macrophages, and asymptomatic myocardial ischemia (SMI) is one of the coronary heart diseases, also called latent coronary heart disease, and is not easy to be discovered due to lack of clinical symptoms, but often causes more serious consequences. Diabetes is a recognized risk factor of cardiovascular diseases, and domestic and foreign studies show that the prevalence rate of SMI of diabetics is 12-34% [1-2 ].
Endogenous nociceptin/orphanin fq (N/OFQ) is a novel opioid peptide consisting of 17 amino acids, widely exists in the central and peripheral nervous systems and peripheral organs of humans, has the effects of active peptides and neurotransmitters, has been proved to be related to pain, mood disorders and the like, is involved in the regulation of multiple systems such as exercise, cardiovascular and urinary and pain sensation, and plays an important role in the physiological regulation process of human bodies [3 ]. The relationship between N/OFQ and myocardial ischemia is shown in that N/OFQ can increase the incidence rate of arrhythmia after acute myocardial ischemia through a PKC (PKC) pathway, and can regulate beta receptor externalization to cause the occurrence of ischemic arrhythmia in the early stage of acute myocardial infarction [4-5 ]. In addition, clinical studies by Fontana et al have shown elevated plasma N/OFQ levels in patients with acute unstable angina, and animal studies by Guo et al have shown that acute coronary artery disease can affect N/OFQ levels [4-6 ].
Four clinical tests of heart and lung, including troponin, myoglobin, creatine kinase isoenzyme and B-type natriuretic peptide, can be raised within hours after acute myocardial infarction and recovered to normal level after several days. Currently, there is no effective index for diagnosing SMI in asymptomatic myocardial ischemia that can be detected directly from blood.
Reference documents:
【1】 Ferrini M, Johansson I, Aboyans V. Heart failure and its complications in patients with diabetes: Mounting evidence for a growing burden[J]. Eur J Prev Cardiol, 2019, 26(2_suppl):106-113.
【2】Wander GS, Bansal M, Kasliwal RR. Prediction and early detection of cardiovascular disease in South Asians with diabetes mellitus[J]. Diabetes Metab Syndr, 2020, 14(4):385-393.
【3】Park JY, Chae S, Kim CS, et al. Role of nociceptin/orphanin FQ and nociceptin opioid peptide receptor in depression and antidepressant effects of nociceptin opioid peptide receptor antagonists[J]. Korean J Physiol Pharmacol, 2019,23(6):427-448.
【4】Han Y, Guo Z, Wang LL, et al. Antagonism of endogenous nociceptin/orphanin FQ inhibits infarction-associated ventricular arrhythmias via PKC-dependent mechanism in rats[J]. Br J Pharmacol, 2013, 170(3):614-623.
【5】 Chang bear, Han Yi, Guo Zheng endogenous orphan enkephalin influences the rat ischemic arrhythmia by regulating beta 1 adrenergic receptors [ J ] Tianjin medicine, 2019,47(03): 245-.
【6】Krepuska M, Sótonyi P, Csobay-Novák C, et al. Plasma nociceptin/orphanin FQ levels are lower in patients with chronic ischemic cardiovascular diseases--A pilot study[J]. Regul Pept, 2011, 169(1-3):1-5.）。
Disclosure of Invention
The invention provides application of endogenous orphan enkephalin serving as a serum biomarker for diabetes combined with asymptomatic myocardial ischemia, aiming at solving the problem that no effective index which can be directly detected from blood exists in the current diagnosis of asymptomatic myocardial ischemia SMI.
The invention is realized by the following technical scheme: use of an endogenous orphan enkephalin N/OFQ, wherein the amino acid sequence of the endogenous orphan enkephalin N/OFQ is as follows: Phe-Gly-Gly-Phe-Thr-Gly-Ala-Arg-Lys-Ser-Ala-Arg-Lys-Leu-Ala-Asn-Gln; the endogenous orphan enkephalin is used for preparing a diagnostic reagent or a kit for detecting diabetes combined with asymptomatic myocardial ischemia.
The detection refers to endogenous orphan enkephalin N/OFQ in serum of a tested individual.
A diagnostic kit for detecting diabetes mellitus combined with asymptomatic myocardial ischemia comprises a reagent for detecting the expression of endogenous orphan enkephalin.
Further, a diagnostic kit for detecting diabetes mellitus combined with asymptomatic myocardial ischemia comprises a reagent for detecting the expression of endogenous orphan enkephalin N/OFQ.
The expression level of the endogenous orphan enkephalin is increased under the state of diabetes combined with asymptomatic myocardial ischemia, and the endogenous orphan enkephalin can be used as a serum biomarker of the diabetes combined with asymptomatic myocardial ischemia for early diagnosis of the diabetes combined with asymptomatic myocardial ischemia.
The serum N/OFQ in the body of the patient with the diabetes combined SMI is obviously increased and is positively correlated with the severity of coronary artery lesion, so that the N/OFQ is determined to be a potential index for predicting the SMI. Since N/OFQ can play a role in acute myocardial ischemia, N/OFQ becomes possible to be used as a new index for predicting the combination of SMI of diabetic patients.
The invention has the beneficial effects that: provides a novel target for predicting and diagnosing the diabetes combined with asymptomatic myocardial ischemia by taking N/OFQ as a marker, and the serum N/OFQ level of a diabetes combined SMI patient is increased. N/OFQ is positively correlated with the course of diabetes, fasting blood glucose level, HbA1C, LDL-C level; the participation of LDL-C in the generation of SMI positively correlates with the severity of coronary artery disease in diabetic patients. The N/OFQ is used as an index for testing, and the serum N/OFQ has better diagnostic significance on SMI.
Drawings
FIG. 1 shows the increase in serum N/OFQ levels in group D compared to group D,P<0.01
FIG. 2 shows DN sets of coronary lesion counts;
FIG. 3 is a ROC curve for N/OFQ prediction of diabetic patients with combined SMI occurrence.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are some embodiments of the present invention, but not all embodiments; all other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The invention mainly relates to a diagnostic reagent or a kit for preparing and detecting diabetes combined with asymptomatic myocardial ischemia by using endogenous orphan enkephalin.
The amino acid sequence of the endogenous orphan enkephalin N/OFQ is as follows: Phe-Gly-Gly-Phe-Thr-Gly-Ala-Arg-Lys-Ser-Ala-Arg-Lys-Leu-Ala-Asn-Gln.
Furthermore, the endogenous orphan enkephalin is used for preparing a diagnostic reagent or a kit for detecting diabetes combined with asymptomatic myocardial ischemia.
The detection refers to endogenous orphan enkephalin N/OFQ in serum of a tested individual.
A diagnostic reagent for detecting diabetes mellitus associated with silent myocardial ischemia, said reagent comprising a reagent that detects the expression of endogenous nociceptin.
Further, a diagnostic kit for detecting diabetes mellitus combined with asymptomatic myocardial ischemia comprises a reagent for detecting the expression of endogenous orphan enkephalin, namely N/OFQ.
The expression level of the endogenous orphan enkephalin is increased under the state of diabetes combined with asymptomatic myocardial ischemia, and the endogenous orphan enkephalin can be used as a serum biomarker of the diabetes combined with asymptomatic myocardial ischemia for early diagnosis of the diabetes combined with asymptomatic myocardial ischemia.
Experimental example 1:
1. general data: approved by ethical committee of the second hospital of Shanxi medical university, 120 patients who underwent selective coronary angiography from 5 months to 12 months in 2019 were enrolled, wherein 60 patients were in the diabetes mellitus group alone (group D), 60 patients were in the diabetes mellitus combination SMI group (group DN), and informed consent was issued with the patients and their family members.
Inclusion criteria were: (1) age 55-70 years old; (2) the diagnosis of the type 2 diabetes mellitus is carried out by a professional physician in the endocrinology department, and the diagnosis standard is based on the diabetes diagnosis standard established by WHO in 1999; (3) hypertensive patients have good blood pressure control for more than 5 years, hyperlipidemic patients have good blood lipid control, where hypertension is defined as a systolic pressure exceeding 140mmHg and/or a diastolic pressure exceeding 90mmHg and/or the use of antihypertensive drugs. Hyperlipidemia is defined as total cholesterol levels above 240mg/dL and/or treatment for hyperlipidemia.
Exclusion criteria: (1) organic heart disease: such as dilated cardiomyopathy, valvular heart disease; (2) a past history of open chest surgery (cardiac surgery) or percutaneous coronary intervention; (3) electrocardiographic abnormalities, including pathological Q-wave, ST-segment or T-wave ischemic changes, and left bundle branch block; (4) patients with severe liver, brain, renal dysfunction (e.g., liver cirrhosis, ischemic or hemorrhagic cerebrovascular disease, nephrotic syndrome, etc.), coagulation dysfunction, immune system disease, acute and chronic infection (e.g., severe sepsis), and mood disorder; (5) patients with local anesthetic allergy, special medication history and drug abuse are combined.
2. Coronary angiography examination method: after local anesthesia with lidocaine, percutaneous radial artery puncture is performed, insertion is performed by searching for the left or right coronary artery mouth, and contrast medium is injected to visualize the coronary artery. The main trunk of the whole left or right coronary artery and the vessel cavities of the branches thereof are displayed to know whether the vessel has a stenotic focus, and two special cardiovascular physicians make definite diagnosis on the pathological change position, range, severity, vessel wall condition and the like.
3. Gensini rating: coronary heart disease is defined when the stenosis of one or more vessel lumens is 50% or more. Degree of stenosis: 1-25% of 1 point; 26% -50% of 2 min; 51% -75% of 4 minutes; 76% -90% of 8 minutes; 91% -99% for 16 min; and 32 points are calculated according to 100 percent. And (3) lesion parts: left stem (LM) × 5 min; left Anterior Descending (LAD): near section is multiplied by 2.5 minutes, middle section is multiplied by 1.5 minutes; diagonal branch D1X 1 point, D2X 0.5 point; left Circumflex (LCX) near segment is multiplied by 2.5 minutes, far segment is multiplied by 1 minute; the posterior descending branch is multiplied by 1; posterior branch is multiplied by 0.5 min; the proximal, middle, distal and posterior descending branches of the Right Coronary Artery (RCA) were divided by 1. The Gensini score of each vessel segment is the product of the arterial stenosis score and the coefficient, and the Gensini product of the whole coronary artery system is the sum of the Gensini scores of the segments. The highest score is the integral when the left stem is completely occluded, i.e., 160 points.
4. Observation indexes are as follows: in the early morning of surgery, 4ml of non-infusion side elbow venous blood of a patient is collected and serum is separated from a venous vacuum blood collection tube containing a STTIII separation gel coagulant and stored in a refrigerator at the temperature of-70 ℃ for testing. The basic vital signs such as heart rate, pulse rate, systolic pressure, diastolic pressure, mean arterial pressure, pulse oxygen saturation and the like are monitored and recorded during the operation. Blood glucose measurement by glucose oxidase method and serum N/OFQ measurement by ELISA method (MM-12706H1-96T). Blood lipid levels (triglycerides, low density lipoprotein cholesterol, high density lipoprotein cholesterol) were recorded.
5. Statistical analysis: statistical analysis was performed using SPSS25.0 software. The measured data conform to the normal distribution by mean + -standard deviation: (
) Representing, using independent samplestThe test was compared between groups. The counting data are expressed in percentage, and the comparison of the rate is carried outc 2 And (6) checking. Correlation analysis between the metrology data was performed using Pearson correlation. And analyzing the influence factors of combining SMI of the diabetic by applying Logistic regression, drawing an ROC curve, and describing the prediction value of the N/OFQ to the SMI. Proof level α =0.05, P<A difference of 0.05 is statistically significant.
6. Results
A. General data comparison for two groups of patients: the age, sex, height, weight, Body Mass Index (BMI), combined hypertension, glycated hemoglobin (HbA 1 c), aspartate Aminotransferase (AST), and alanine Aminotransferase (ALT) of the two groups of patients had no statistical difference (P>0.05, see table 1). DN group fasting blood glucose level, diabetic course, Triglyceride (TG), low density lipoprotein cholesterol (LDL-C) level higher than D group, and high density lipoproteinWhite cholesterol (HDL-C) levels were lower than those in group D, and the differences were statistically significant (P<0.01, see table 1).
TABLE 1 general data comparison of two groups of patients (n = 60，
）
In comparison with the group D,* P<0.05，** P<0.01。
B. comparison of serum N/OFQ concentrations in two groups of patients: DN group serum N/OFQ level is higher than that of group D, and the difference is statistically significant (P<0.01, see table 2). The results of comparison of serum N/OFQ concentrations of two groups of patients are shown in FIG. 1, and it can be seen from FIG. 1 that the serum N/OFQ concentration of DN group is higher than that of D group, (6.779 + -1.174) ng/Lvs(4.077. + -. 0.927) ng/L, the difference being of statistical significance (P<0.01）。
TABLE 2 comparison of serum N/OFQ concentrations in two groups of patients: (n = 60，
）
In comparison with the group D,* P<0.05，** P<0.01。
C. DN group coronary angiography results, Gensini integration: the number of coronary artery lesion branches in DN group is shown in FIG. 2 and Table 3, and can be known from FIG. 2 and Table 3: DN coronary angiography results showed that 30 cases (50%) were single-branch lesions (1 group), 12 cases (20%) were double-branch lesions (2 group), and 18 cases (30%) were multiple-branch lesions (. gtoreq.3 group).
TABLE 3 DN sets of coronary angiography results, Gensini integration
D. Multi-factor stepwise Logistic regression analysis: LDL-C, elevated serum N/OFQ levels are risk factors for diabetic patients with combined SMI (SMI)P<0.05, see table 4).
TABLE 4 Multi-factor Logistic analysis of diabetes mellitus incorporating SMI influencing factors
E. Correlation analysis of DN group serum N/OFQ level with each clinical index: DN group diabetes course, fasting blood glucose level, HbA1c, LDL-C, Gensini score and serum N/OFQ level are positively correlated (II) ((III))P<0.05, see table 5). Age, height, weight, BMI, AST, ALT, TG, HDL-C were not significantly correlated with serum N/OFQ levels ((R))P>0.05, see table 5).
TABLE 5 correlation analysis of DN group serum N/OFQ, Lp-PLA2 levels with clinical indices
F. ROC curve analysis of N/OFQ predictive diabetic patients combined with SMI: the analysis results are shown in FIG. 3, and the area under the curve where N/OFQ predicts SMI occurrence is 0.949 (95％CI：0.911～0.986，P<0.001), a predicted cutoff value of 5.184ng/L, a sensitivity of 91.7%, and a specificity of 88.3%, when the john index reaches a maximum of 0.8. From the ROC results, N/OFQ has better diagnostic significance for SMI.
The critical point of the N/OFQ diagnosis is determined to be 5.184ng/L through an ROC curve, and the N/OFQ diagnosis has higher sensitivity and specificity and the range of suspicious values is (4.437, 5.863) ng/L.
Selecting the point which is most right above the ROC curve, calculating the Yotans index according to the sensitivity and specificity of each possible tangent point in the statistical result, selecting the maximum tangent point as a critical point, wherein the rising part of the critical point is not completely vertical to the X axis along with the reduction of the tangent point value, the specificity is slowly reduced while the sensitivity is continuously increased, after a first obvious break point appears about the sensitivity of 0.8 and the 1-specificity of 0.067, the sensitivity rising speed is slowed down, the specificity decreasing speed is increased, the overlapping degree is increased until the sensitivity is about 0.93, a second break point appears about the 1-specificity of 0.3, and the straight line basically horizontally reaches the upper right corner. The range of suspect values is suitably chosen to have a sensitivity between 0.8 and 0.93, with more heavy regions included in between. According to the statistical result, the original values of the two points are respectively determined to be 4.437 and 5.863 ng/L.
Li Sufeng [7 ]]The studies by others show that: the serum N/OFQ and CRP levels of the paroxysmal atrial fibrillation group (PAAF group) and the persistent atrial fibrillation group (PEAF group) are higher than those of the control group, and the N/OFQ and CRP levels of the PEAF group are higher than those of the PAAF group, and the difference has statistical significance (theP<0.05). Group II of PAAF and PEAF: (>75 years old) and group I (75 years old) showed statistically significant differences in the levels of serum N/OFQ (P<0.05). Multi-factor stepwise Logistic regression analysis N/OFQ, CRP level increase and LAD increase are risk factors for atrial fibrillation. The age of patients with atrial fibrillation was positively correlated with serum N/OFQ levels. LVEF of patients with atrial fibrillation is negatively correlated with serum N/OFQ levels, but not significantly correlated with serum CRP levels. The N/OFQ and the CRP have better diagnostic significance on atrial fibrillation, the diagnostic value of the joint prediction of the N/OFQ and the CRP is the highest, and the diagnostic value of the N/OFQ is higher than that of the CRP. And (4) conclusion: N/OFQ and CRP are related to atrial fibrosis caused by inflammatory reaction and occurrence and development of preoperative atrial fibrillation of artificial total knee joint, and reduction of the degree of inflammatory reaction of patients with atrial fibrillation and levels of N/OFQ and CRP can help to reduce incidence rate of preoperative atrial fibrillation.
Liu [8] et al found elevated N/OFQ concentrations in brain, spinal cord and serum of rats in the group of chronic stress injury and diabetic neuropathy. Zingale [9] et al found that N/OFQ fragment could inhibit the degradation of insulin by insulin-degrading enzyme, suggesting that there may be a regulatory mechanism in central nervous system. Sliepen [10] et al found that N/OFQ could selectively and dose-dependently reverse cancer-induced rat bone pain behavior. The NOP receptor system may be a potential target for the treatment of bone pain caused by cancer.
Micioni [11] et al found that N/OFQ activation of N/OFQ peptide receptors (NOPs) resulted in increased food intake in experimental animals and that this effect could be blocked by NOP antagonists, and NOP agonists and antagonists have now been synthesized and tested for their potential modulating effects on feeding behaviour in vitro and in vivo. The results appear to indicate that the N/OFQ system may be a potential therapeutic target for the neuro-control of feeding behavior and related conditions, especially binge eating behavior.
Han [12] et al found that N/OFQ would impair the recognition of new objects during information acquisition, but not the retrieval phase. The N/OFQ will also suppress contextual fear memory during the information acquisition phase, as indicated by pre-training rather than post-training the N/FQ, which can impair memory in the contextual fear adjustment task.
It is found by Xiong [13] et al that the up-regulation of beta 1 receptor in myocardial cell membrane in early stage of acute myocardial ischemia (15 min) is a key factor for ischemic arrhythmia, and endogenous N/OFQ is one of the factors for mediating the up-regulation of beta 1 receptor in myocardial cell membrane in early stage of acute myocardial ischemia.
Finally, it should be noted that: the above embodiments are only used to illustrate the technical solution of the present invention, and not to limit the same; while the invention has been described in detail and with reference to the foregoing embodiments, it will be understood by those skilled in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some or all of the technical features may be equivalently replaced; and the modifications or the substitutions do not make the essence of the corresponding technical solutions depart from the scope of the technical solutions of the embodiments of the present invention.
Reference documents:
【7】 Study on changes of serum endogenous orphan enkephalin and C-reactive protein levels of elderly patients with atrial fibrillation before joint replacement [ J ] Tianjin medicine, 2019,47 (12):1230-1234.
【8】Liu EH, Li C, Govindasamy M, et al. Elevated prepronociceptin, nociceptin/orphanin FQ and nocistatin concentrations in rat chronic constriction nerve injury and diabetic neuropathic pain models. Neurosci Lett. 2012. 506(1): 104-6.
【9】Zingale GA, Bellia F, Ahmed I, Mielczarek P, Silberring J, Grasso G. IDE Degrades Nociceptin/Orphanin FQ through an Insulin Regulated Mechanism. Int J Mol Sci. 2019. 20(18).
【10】Sliepen S, Korioth J, Christoph T, et al. The nociceptin/orphanin FQ receptor system as a target to alleviate cancer-induced bone pain in rats: Model validation and pharmacological evaluation. Br J Pharmacol. 2019 .
【11】Micioni Di Bonaventura MV, Micioni Di Bonaventura E, Cifani C, Polidori C. N/OFQ-NOP System in Food Intake. Handb Exp Pharmacol. 2019. 254: 279-295.
【12】Han RW, Tian AW, Lin HR, et al. Nociceptin impairs acquisition of novel object recognition memory in perirhinal cortex. Neurobiol Learn Mem. 2019. 162: 9-14.
【13】 Chang bear, Han Yi, Guo Zheng endogenous orphan enkephalin influences the rat ischemic arrhythmia by regulating beta 1 adrenergic receptors [ J ] Tianjin medicine, 2019,47(03): 245-.
Claims (5)
1. Use of endogenous orphan enkephalin N/OFQ, characterized in that: the amino acid sequence of the endogenous orphan enkephalin N/OFQ is as follows: Phe-Gly-Gly-Phe-Thr-Gly-Ala-Arg-Lys-Ser-Ala-Arg-Lys-Leu-Ala-Asn-Gln; the endogenous orphan enkephalin is used for preparing a diagnostic reagent or a kit for detecting diabetes combined with asymptomatic myocardial ischemia.
2. Use according to claim 1, characterized in that: the detection refers to endogenous orphan enkephalin N/OFQ in serum of a tested individual.
3. A diagnostic reagent for detecting diabetes mellitus associated with silent myocardial ischemia, comprising: the reagents comprise reagents for detecting the expression of endogenous orphan enkephalin.
4. A diagnostic kit for detecting diabetes mellitus combined with asymptomatic myocardial ischemia is characterized in that: the kit comprises a reagent for detecting the expression of endogenous orphan enkephalin, namely N/OFQ.
5. Use according to claim 1 or 2, characterized in that: the diagnostic critical point of the N/OFQ is 5.184ng/L, and the suspicious value range is 4.437ng/L-5.863 ng/L.
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