| BackgroundMyocardial infarction is the ischemic necrosis of myocardial tissue.It has the characteristics of rapid onset and high morbidity.It is an important cause of death from cardiovascular disease,and it seriously endangers human health.After myocardial infarction,the tissue gradually necroses and the heart becomes hypertrophic.During the process of heart self-repair,myocardial remodeling will occur,and the energy consumption of the heart will increase at this time.Since the heart itself is a high energy-consuming organ,in this ischemia and hypoxia environment,the myocardial tissue will appear "energy starvation".The function gradually deteriorates,energy metabolism is disordered,resulting in abnormal myocardial structure and function,and myocardial fibrosis is aggravated.It has become a major cause of heart failure.Therefore,relevant research on energy metabolites in myocardial infarction is carried out to find drugs and targets that regulate energy metabolites,and optimize the phenotype of myocardial energy metabolism,which may provide new ideas and directions for the treatment of myocardial infarction.After myocardial infarction,the cardiac function gradually deteriorates.If there is no timely drug intervention,it will gradually develop into heart failure with the development of the disease.Heart failure is the terminal stage of the development of various cardiovascular diseases,and clinically manifests as dyspnea,fatigue,edema and other symptoms.Symptoms of heart failure patients are prone to repeated attacks,a long course of disease,and in severe cases,physical activity is limited,and even life is unable to take care of themselves.Patients with heart failure not only face physical damage but also have a heavy psychological burden,so patients with heart failure are often accompanied by depression in the later stage.The appearance of depression affects the effect of re-treatment of patients,and increases the risk of readmission for patients.At the same time,the deepening of the degree of heart failure will also increase the possibility of depression,aggravate the degree of depression,and the mutual influence between heart failure and depression.circulation,thereby increasing patient mortality.Naoxintong Recipe originated from the classic traditional Chinese medicine"Buyang Huanwu Decoction",which is the representative formula of Yiqi Huoxue Recipe.The curative effect is remarkable,and it has always been in the forefront of the drugs for cardiovascular and cerebrovascular diseases.However,it is rarely reported whether Naoxintong recipe can improve the cardiac function of myocardial infarction from the perspective of energy metabolism and the depression caused by heart failure.The two models of different pathological stages of heart failure and heart failure,carried out in-depth research at the animal level,and explained the mechanism of Naoxintong formula in the treatment of myocardial infarction by regulating energy metabolism and improving depression caused by heart failure,and then from "heart damage to brain".The scientific connotation of "Naoxin Tongzhi" of Naoxintong prescription is explained from the perspective of Naoxintong prescriptionContent and ResultsPart 1 Study on pharmacodynamics and energy metabolism of Naoxintong formula in the treatment of myocardial infarctionObjective:To explore the mechanism of Naoxintong Capsule in the treatment of myocardial infarction from the perspective of energy metabolism by establishing myocardial infarction model.Methods:The myocardial infarction model was established by ligation of the left anterior descending coronary artery,and the rats were randomly divided into sham operation,model,Naoxintong capsule low-dose,Naoxintong capsule high-dose groups(NXT-L,NXT-H)and valsarta group(Val).Evaluated cardiac functional and structural changes of the heart by color doppler ultrasonography;immunohistochemical method was used to detect the expression of inflammatory factors TNF-α and IL-6 in myocardial tissue;hematoxylin-eosin(HE)and Masson’s trichrome staining(Masson)were used to observe the pathological changes of rat myocardial tissue;ELISA was used to detect serum cardiac troponin T(cTnT)content was used to assess myocardial injury;UPLC-QQQ-MS was used to target and analyze the content of 29 energy metabolites in myocardial tissue to study the changes in energy metabolism after myocardial infarction and the effect of Naoxintong capsule.Results:1 Compared with the sham group,the left ventricular short-axis shortening rate(LVFS)and left ventricular ejection fraction(LVEF)of rats’ myocardial tissuewere decreased,with statistical difference(P<0.05).Compared with the model group,the LVEF and LVFS of the drug group were increased.Compared with the sham-operated group,the serum cTnT level in the model group was significantly increased(P<0.05).After administration,the content of each administration group decreased with a statistical difference(P<0.05).2 HE and Masson staining showed that the myocardial tissue of the rats in the sham operation group was regularly arranged and closely,the myocardial cell morphology was complete,and there was no collagen deposition;the myocardial tissue of the model group showed irregular distribution,inflammatory cell infiltration,a large number of collagen deposition,and myocardial fibrosis.The severity was severe,and the infarct area increased(P<0.05);the results of immunohistochemistry showed that compared with the sham group,the expression of IL-6 in the model group was significantly decreased;In the administration group,the myocardial tissue was densely arranged,the inflammatory infiltration was not obvious,and a small amount of collagen fibers were proliferated.The muscle fibers were arranged more completely,and the infarct area was significantly reduced(P<0.05).myocardial tissue damage was improved.3 Through targeted analysis of the levels of 29 energy metabolites,it was found that after myocardial infarction,4 compounds of 3-phospho-D-glyceric acid,dihydroxyacetone phosphate,phosphoenolpyruvate and pyruvic acid in glycolytic metabolism,4 compounds of alpha-ketoglutaric acid,thiamine pyrophosphate,succinic acid and oxaloacetic acid in tricarboxylic acid cycle,3 compounds of flavin mononucleotide,NAD and ADP in oxidative phosphorylation,and 4 compounds of GMP,AMP,cyclic AMP and GTP in purine metabolism,2 compounds of NADP and NADPH in glutathione metabolism.A total of 17 different energy metabolism pathways had significant changes in metabolite levels,and these disturbances can be reversed by the intervention of Naoxintong capsule,indicating that the therapeutic effect of Naoxintong may be originating from interference with energy metabolism.Part 2 Effect of Naoxintong Formula on Improving Depression-like Behavior after Heart FailureObjective:To explore the changes of brain morphology and function in rats after heart failure from the perspectives of behavior,pathological histomorphology,molecular biology,etc.by establishing a heart failure model;Improvement in cardiac function and depressive disorder in rats after heart failure.Methods:A model of heart failure caused by myocardial infarction was established by ligating the left anterior coronary artery,and echocardiography was performed after 4W.The ejection fraction<50%was used as the model’s success standard.For the sham operation,model group,NXT-L,NXT-H and Val a total of five groups,continuous gavage for 7W.Echocardiography was used to detect LVEF,LVFS and cardiac output(CO)in rats;HE staining and Masson staining were used to observe the pathological conditions of myocardial tissue;sugar water preference test and Morris water maze test were used to detect behavioral changes;ELISA was used to detect adrenal stimulation Corticosteroid-releasing hormone(CRH),adrenocorticotropic hormone(ACTH),brain-derived neurotrophic factor(BDNF);glutamate(GLU),epinephrine(AD),norepinephrine(NA),dopamine(DA),serotonin(5-HT),acetylcholine(ACH),γ-aminobutyric acid(GABA)content changes;transmission electron microscopy was used to observe the ultrastructure of neurons in hippocampal CA1area.Results:1 Compared with the sham group,the LVEF,LVFS and CO in the model group were decreased,with a statistical difference(P<0.05);Compared with the model group,the LVEF,LVFS and CO in treatment groups increased,with statistical differences(P<0.05);2 HE and Masson staining showed that the myocardial tissue of the rats in the sham operation group was closely and regularly arranged,the myocardial cell morphology was complete,and there was no collagen deposition;the myocardial tissue of the model group showed irregular distribution,inflammatory cell infiltration,a large number of collagen deposition,and myocardial fibrosis.In the administration group,the arrangement of myocardial tissue was relatively dense,the inflammatory infiltration was not obvious,and a small amount of collagen fiber hyperplasia was seen,the arrangement of muscle fibers was relatively complete,and the myocardial tissue damage was improved.3 In the sugar water preference experiment,the sugar water preference rate of the model group was lower than that of the sham operation group,and the difference was statistically significant.After administration,the NXT-L group and the NXT-H group could significantly increase the sugar water preference rate(P<0.05),while the Val group did not have the same preference rate(P>0.05);In the Morris water maze test,the escape latency of the Model group was longer than that of the sham group,the number of crossings was less than that of the sham group and the difference was significant(P<0.05);Compared with the Model group,the escape latency of the NXT-H and Val groups was shortened and the number of crossings was increased,with statistical difference(P<0.05)4 ELISA results showed that compared with the sham operation group,the contents of CRH and ACTH were significantly increased,and the contents of BDNF were decreased,with statistical differences(P<0.05).Compared with the model group,the contents of CRH and ACTH in the NXT-L,NXT-H and Val groups were decreased,with a statistical difference(P<0.05),and the content of BDNF in the NXT-H group was increased,with a statistical difference(P<0.05).Although the content of BDNF in NXT-L and Val group increased,there were no statistical difference.5 Through the detection of 7 neurotransmitters such as dopamine,acetylcholine,serotonin,and norepinephrine,it was found that compared with the sham operation group,the contents of serotonin,dopamine and γ-aminobutyric acid were decreased,and there was a statistical difference(P<0.05).The changes of norepinephrine,epinephrine,glutamate and acetylcholine were not statistically different.Compared with the model group,the contents of dopamine and γ-aminobutyric acid in the high-dose Naoxintong capsule group were significantly increased,with a statistical difference(P<0.05).Although the content of dopamine in NXT-L and Val groups increased,there were no statistical significance difference(P>0.05).6 The ultrastructure of hippocampal CA1 region showed that the overall structure of nerve cells in the sham-operated group was acceptable,with complete cell membrane,complete nuclear membrane,uniform chromatin,large nucleolus,compact structure,no obvious swelling of mitochondria,and parallel mitochondrial cristae.There was no autophagic structure in the cells;In the model group,nerve cells appeared edema,the cell membrane was partially damaged,most of the organelles disintegrated,the mitochondria were swollen,the mitochondrial cristae were broken,and autophagy-lysosomes appeared;In the administration group,the nerve cells showed mild edema,the cell membrane was intact,and the intracellular organelles were abundant.The nucleus is slightly sunken locally,the nuclear membrane is clear,and the chromatin is uniform.Mitochondria were slightly swollen,most mitochondrial cristae were present,and some mitochondrial cristae were reduced.Autophagolysosomes were not observed in NXT-H.group,but autophagolysosomes were found in Val group.Conclusion1 Naoxintong formula has a protective effect on myocardial infarction ratsNaoxintong Capsule can effectively reduce the infiltration of inflammatory cells,improve myocardial fibrosis,reduce the infarct size,relieve myocardial injury in rats with myocardial infarction,enhance cardiac function,and explain its regulatory mechanism from the perspective of energy metabolism.At the same time,it also provides a theoretical basis for finding new targets and new drugs.2 Naoxintong formula has a protective effect on rats with heart failureNaoxintong capsule has protective effect on heart failure rats.Rat cardiac function is reduced after heart failure.Naoxintong Capsule can improve cardiac function in rats by increasing LVEF,LVFS and CO,and play a protective role against cardiac injury.3 Naoxintong formula can improve depressive disorder caused by heart failureIn rats after heart failure,CRH and ACTH levels increased,HPA axis hyperactivity,BDNF level decreased,sugar water preference decreased,anhedonia,decreased learning and memory ability,abnormal changes in neurotransmitters,ultrastructure showed that after heart failure there is a certain degree of damage to the brain tissue.The above results all showed that the rats after heart failure had obvious depression,which reflected "heart damage brain" to a certain extent.NaoxintongFormula can not only improve heart function,but also improve and regulate depressive behavior,brain ultrastructural damage,neurotransmitter changes and HPA axis hyperactivity caused by heart failure.Innovation point of the study1 In the first part of the experiment,the targeted metabolomics method was used to accurately detect the changes of metabolites related to energy metabolism after myocardial infarction,and the intervention effect of Naoxintong Formula was studied.This provides a theoretical basis for the treatment of myocardial infarction from metabolic therapy through optimizing energy metabolism.2 In the second part of the experiment of this paper,the model of depressive disorder induced by heart failure in rats is highly similar to the clinical situation of patients with depression after heart failure.There is less research aboutI the therapeutic effect of Naoxintong capsule on depressive disorder caused by heart failure.At the animal level,this part of the experiment studies and explains the"psycho-cardiology" therapeutic effect of Naoxintong Recipe from heart failure to depression,from heart to psychology,and provides a theoretical basis for expanding the clinical application of traditional Chinese medicine. |
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