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Eight triterpenes were isolated from the methanol extract of Galbanum by various chromatographic methods including silica gel, ODS opening column, recrystallization and semi-preparative HPLC. Their structures were determined by spectroscopic methods and physicochemical properties as 3β,19α,21α-trihydroxyl-12-en-28-oic acid (1), sumaresinolic acid (2), 3β,19α-dihydroxyl-12-en-28-oic acid (3), oleanolic acid (4), 3β,6β,19α-trihydroxyl-12-en-28-oic acid (5), 19α-hydroxy oleanonic acid (6), 6α-hydroxy oleanonic acid (7), and (11R,12R)-3α,6α-dihydroxy-epoxyolean-28α,13α-olide (8). Among them, compound 1 is a new compound, while compounds 2-8 were newly isolated from the Apiaceae family. The ability of compounds 1-8 to inhibit cholinesterase was determined with an improved Ellman method. Compound 1 showed strong inhibitory activity against butyrylcholinesterase. The molecular docking results indicated that Trp82, His438, Phe329 and Ala328 played an important role in the binding of compound 1 to butyrylcholinesterase.
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Long noncoding RNAs (lncRNAs) are a class of RNAs that are more than 200 nucleotides in length with no protein coding property. LncRNAs are involved in almost every cellular process through multiple mechanisms. LncRNAs can directly bind to molecules in cells such as proteins, RNA, and DNA, to regulate cellular functions by influencing processes including transcription, translation, and molecular transporting. Recent researches showed lncRNAs are key regulators of serious cardiac diseases, especially in development and progression of cardiac ischemia, arrhythmia, cardiac fibrosis, and heart failure. This article mainly summarizes the function and mechanism of lncRNAs in cardiac diseases and gives reasonable prospect of lncRNAs in the future.
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Drug-induced cardiotoxicity is recently a major concern. Cardiotoxicity is the leading cause of drug withdrawal from the market. Long-QT syndrome is one of the most important manifestations of cardiotoxicity. hERG potassium channel is an important target of drug-induced arrhythmia and antiarrhythmia drugs. Traditional Chinese medicine is a traditional medicine in China with a long history and a wide range of clinical use. However, the multi-organ toxicity caused by traditional Chinese medicine is still a problem to be solved. Some traditional Chinese medicines already in clinical use have been withdrawn from the market because of their potential cardiotoxicity or severe arrhythmias. The cardiac toxicity of more than 50 kinds of traditional Chinese medicines causing arrhythmia was reported, while more than 20 of them are induced by affecting on the hERG potassium channels. Therefore, finding out the mechanism of drug-induced long-QT syndrome and the regulatory target of drug intervention is the key research goal in today's medical field. In this paper, we summarized the mechanisms of long-QT syndrome induced by traditional Chinese medicine with Ikr/hERG potassium channel as the main target. It provides a theoretical basis for the rational use of related traditional Chinese medicine in clinical practice, the avoidance of cardiac toxicity and the development of regulatory targets for drug intervention.
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OBJECTIVE To explore the protection mechanism of metformin and tanshinone IIA on myocardial injury. METHODS The cultured neonatal rat ventricular cells (NRVCs) were exposed to 100 μmol·L-1H2O2to simulate the in vitro model of ischemia-reperfusion injury.MTT,TUNEL and Viability/Cytotoxicity Assay were used to evaluate the effect of metformin on the viability of cardiomyocytes after treated with H2O2. The target of miR-1 was verified by Dual luciferase reporter assay. ChIP analyses was adopted to reveal the relationship between C/EBP β and miR-1.Tanshinone IIA was administrated daily for 7 d before ligation of the left anterior descending artery (LAD) and lasted for 3 months after LAD.Whole-cell patch-clamp techniques were used to measure the inward rectifying K+current(IK1)in rat isolated ventricular myocytes.GRP94,p-AMPKα,C/EBP β,CHOP,Caspase-3,Kir2.1,p38 MAPK, Cx43, MEF2 and SRF levels were analyzed by Western blot and miR-1 level was quantified by Real-time PCR.RESULTS The expression of miR-1 was significantly increased in NRVCs exposed to H2O2 in vitro. miR-1 was shown to target the 3′-untranslated region (UTR) of GRP94, which results in the accumulation of un/misfolded proteins,leading to the endoplasmic reticulum(ER)stress.C/EBP β directly induces the upregulation of miR-1 by binding to its promoter.Furthermore,metformin,a direct allosteric AMPK activator, significantly reduces C/EBP β and miR-1 levels comparing with control group. Similarly, tanshinone IIA decreased the incidence of arrhythmias and relieved ischemia-induced injury.Moreover, tanshinone IIA depressed the elevated miR-1 level and inhibited the activation of p38 MAPK and heart special transcription factors SRF and MEF2 in ischemic cardiomyocytes. CONCLUSION Metformin protects cardiomyocytes against H2O2damage through AMPK/C/EBPβ/miR-1/GRP94 pathway.Tanshi-none IIA play a role in protection cardiomyocytes from ischemic injury based on inhibiting miR-1 expres-sion through p38 MAPK signal pathway.
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OBJECTIVE To investigate the anti-pyroptotic effects of melatonin in atherosclerotic endothelium and to elucidate the potential mechanisms.METHODS ApoE-/-mice were randomly divid-ed into four groups (n=8): the normal-diet group (ND), the normal-diet group treated with melatonin (10 mg·kg-1)(ND+MLT),the high-fat-diet group(HFD),and the high-fat-diet group treated with melatonin (HFD+MLT).After 12 weeks,the expression levels of pyroptosis related genes including NLRP3,ASC, cleaved-caspase 1,GSDMD-N,IL-1β and IL-18 were examined in aortic endothelium by Western blotting, qRT-PCR and immunofluorescent staining.Besides,levels of MEG3 and miR-223 were also tested by qRT-PCR.The interaction between MEG3 and miR-223 was detected by luciferase assay.For in vitro study,human aortic endothelial cells(HAECs)were transiently transfected with miR-223 mimic,miR-223 inhibitor (AMO-223), MEG3-overexpressing plasmid or negative controls. After 6 h of transfection, the medium was replaced by fresh medium with or without ox-LDL(25 μg·mL-1)for 24 h and then treated with or without melatonin (10 μmol·L-1) for 48 h. Cell pyroptosis was evaluated by Hoechst 33342/PI staining and differentially expressed pyroptosis related genes. RESULTS Melatonin markedly reduced the atherosclerotic plaque in aorta of ApoE-/- mice. Meanwhile, melatonin also attenuated the expression NLRP3, ASC, cleaved-caspase1, NF-κB/GSDMD, GSDMD-N termini, IL-1β, and IL-18 in aortic endo-thelium.Consistent anti-pyroptotic effects were also observed in ox-LDL-treated HAECs.We found that lncRNAMEG3 enhanced pyroptosis in HAECs. Moreover, MEG3 acted as an endogenous sponge by sequence complementarity to suppress the function of miR-223 and to increase NLRP3expression and enhance endothelial cell pyroptosis. Furthermore, knockdown of miR-223 blocked the anti-pyroptotic actions of melatonin in ox-LDL-treated HAECs. CONCLUSION Melatonin prevents endothelial cell pyroptosis via MEG3/miR-223/NLRP3 axis in atherosclerosis and therefore melatonin replacement might be considered a new strategy for protecting endothelium against pyroptosis thereby for the treat-ment of atherosclerosis associated with pyroptosis.
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Anthocyanin is a water-soluble flavonoid pigment which is widely found in plants. Studies showed that anthocyanin had protective effect on vision. However, whether anthocyanin has therapeutic effect on cataract remain unclear. In this study, we established the age-related and posterior capsule opacification cataract cell models through inducing oxidative damage of human lens epithelial cells (HLECs) by H2O2 and inducing epithelial-mesenchymal transition (EMT) by transforming growth factor β2 (TGF-β2). The preventative effects of anthocyanin on markers of oxidative damage and EMT were determined by respective assay kits and PCR analysis. Anthocyanin was beneficial to reduce oxidative stress of HLECs, protecting cells from H2O2 induced damage and increasing α-crystallin expression. The potential mechanisms might be that anthocyanin increased the activities of SOD and GSH-Px, which contributes to reduce cellular ROS and MDA level. Besides, anthocyanin inhibited Ca2+ overload, which contributes to protection of cell from apoptosis. Meanwhile, anthocyanin had inhibitory effect on EMT, slowed down cell proliferation, migration caused by TGF-β2 through decreasing mRNA expression levels of EMT markers including COL1A1, COL1A2, COL3, COL4, Fn and α-SMA. The results suggest that anthocyanin could protect HLECs from oxidative damage induced by H2O2 and cell proliferation, migration and EMT induced by TGF-β2, which indicated that anthocyanin may have protective and therapeutic effects on age-related cataract and posterior capsule opacification.
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Ten triterpenes compounds were isolated from the methanol extraction of the latex of Euphorbia resinifera by means of various chromatographic methods such as silica gel, ODS and semi-preparative HPLC, Their structures were identified by spectroscopic methods and physicochemical properties. These isolated compounds were identified as 3-hydroxy-25,26,27-trinor eupha-8-ene-24-oate (1), iso-maticadienediol (2), 25,26,27-trinorTirucall-8-ene-3-ol-4-acid (3), dammarendiol Ⅱ (4), eupha-8,24-diene-3-ol-26-al (5), lnonotusane C (6), eupha-8,24-diene-3-ol-7,11-dione (7), inoterpene A (8), inoterpene B (9), and eupha-24-methylene-8-ene-3-ol-7,11-dione (10). Among them, compound 1 was a new natural product, compounds 2-4 were firstly isolated from the Euphorbiaceae and compounds 5 and 6 were isolated from the genus Euphorbia for the first time. The cytotoxicity of the compounds 1-10 against MCF-7, U937 and C6 cancer cell lines was evaluated, but none of the compounds was active.
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The morbidity of diabetes has been increasing rapidly in recent years. Delayed wound healing has become a common complication in diabetes, which seriously affects the orthobiosis of patients. Exploring and finding the molecular mechanisms of diabetic wound healing and the effective therapies to promote wound healing have important clinical significances. Stem cells transplant has become a research hotspot in accelerating diabetic wound healing. This article reviewed the present approaches concerning stem cells transplant in diabetic wound healing both at domestic and abroad, and looked forward the clinical therapy of stem cells on diabetic wound healing.
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Humans , Diabetes Mellitus , Therapeutics , Stem Cell Transplantation , Stem Cells , Wound HealingABSTRACT
Cardiovascular disease, with high morbidity and mortality, has been threatening the health of human beings. Therefore, expecting to find a more effective therapeutic method, a plenty of researchers devote themselves to the study of the cardiovascular disease all the time. Since discovered on the heart, M3 receptor of muscarinic acetylcholine receptor (mAchR, M receptor) became a new starting point of the research of the cardiovascular disease. With more and more investigation, many people found that M3 receptor could protect the heart from kinds of cardiovascular disease, which may make it a new hopeful therapeutic point. So, expecting to give support to the reference and encouragement for the study of disease related to M3 receptor in future, this review expounds M3 receptor on the heart from the main following aspects: the effect on the heart, the influence on the cardiovascular disease and the mechanism of M3 receptor involved.
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Humans , Cardiovascular Diseases , Heart , Physiology , Receptor, Muscarinic M3 , PhysiologyABSTRACT
<p><b>OBJECTIVE</b>To study the clinicopathologic characteristics of peripheral neuroblastic tumors and to evaluate the prognostic significance of these features.</p><p><b>METHODS</b>The clinical and pathologic findings were retrospectively reviewed in 121 cases of peripheral neuroblastic tumor. The clinical outcomes of patients were evaluated. The three-year event-free survival rate was analyzed, with respect to age of patients, Evan's staging, International Neuroblastoma Pathology Classification and mitosis-karyorrhexis index.</p><p><b>RESULTS</b>The median age at diagnosis was 2.7 years; and 96 cases (79.3%) occurred in patients younger than 5 years old. The number of cases in Evan's staging I, II, III, IV and IVs was 24, 39, 24, 29 and 5, respectively. There were 82 cases of neuroblastoma (NB) (including 2 cases of undifferentiated NB, 52 cases of poorly differentiated NB and 28 cases of differentiating NB), 9 cases of ganglioneuroblastoma, intermixed type (GNBi), 19 cases of ganglioneuroma, maturing type (GN) and 11 cases of ganglioneuroblastoma, nodular type (GNBn). Forty-nine cases were in the favorable histology subgroup and 72 cases in the unfavorable histology subgroup. The overall three-year event-free survival rate of the 121 cases was 73.0% ± 4.3%. The three-year event-free survival rates were associated with age (P = 0.002), Evan's staging (P = 0.000), histologic category (P = 0.000), mitosis-karyorrhexis index (P = 0.043), prognostic subgroup (P = 0.000).</p><p><b>CONCLUSIONS</b>Most of the peripheral neuroblastic tumors occur in the children younger than 5 years old. It is composed of NB, GNBi, GN and GNBn. The three-year event-free survival rate is approximately 70%. Significant prognostic parameters include age of patients, Evan's staging, International Neuroblastoma Pathology Classification and mitosis-karyorrhexis index.</p>
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Child , Child, Preschool , Female , Humans , Infant , Infant, Newborn , Male , Age Factors , Antigens, Nuclear , Metabolism , Disease-Free Survival , Ganglioneuroblastoma , Metabolism , Pathology , General Surgery , Ganglioneuroma , Metabolism , Pathology , General Surgery , Neoplasm Staging , Nerve Tissue Proteins , Metabolism , Nestin , Metabolism , Neuroblastoma , Metabolism , Pathology , General Surgery , Peripheral Nervous System Neoplasms , Metabolism , Pathology , General Surgery , Phosphopyruvate Hydratase , Metabolism , Retrospective Studies , S100 Proteins , MetabolismABSTRACT
Neuropeptide Y (NPY), a sympathetic neurotransmitter, is highly associated with baroreflex dysfunction and multiple cardiac diseases such as diabetic myocardiopathy. In the present study, we aimed to explore the role of peripheral NPY Y1 receptor (Y1R) and Y2 receptor (Y2R), which are dominantly present in peripheral cardiovascular control, in baroreflex sensitivity (BRS) of streptozotocin (STZ)-induced diabetic rats. Peripheral Y1R and Y2R were antagonized by specific antagonists (BIBP 3226 and BIIE 0246, respectively) from subcutaneously implanted ALZET mini-osmotic pump in STZ-induced diabetic rats for 4 weeks. Then baseline systolic blood pressure, heart rate, cardiac function, BRS, plasma NPY and lipid levels were evaluated. We found that STZ led to increased plasma NPY and lipid level. And the STZ-increased lipid levels were reduced by BIBP 3226 and BIIE 0246. BIBP 3226 ameliorated the aberrant BRS, but had little effect on the impaired cardiac function of the STZ rats. BIIE 0246 alleviated sodium nitroprusside (SNP)-induced but not phenylephrine (PE)-induced aberrant baroreflex control of heart rate in the STZ rats. In addition, BIIE 0246 alleviated the bradycardia, but further impaired cardiac contractility in the STZ rats. These results suggest that peripheral Y1R and Y2R play different roles in STZ-induced impairment of BRS.
Subject(s)
Animals , Rats , Arginine , Pharmacology , Baroreflex , Benzazepines , Pharmacology , Blood Pressure , Bradycardia , Diabetes Mellitus, Experimental , Drug Therapy , Heart Rate , Myocardial Contraction , Neuropeptide Y , Blood , Receptors, Neuropeptide Y , StreptozocinABSTRACT
Translational medicine is a novel concept about combination of basic research and clinical application. The aim of translational medicine is to realize the translation of basic research into clinical practice. microRNAs (miRNAs) are non-coding single-stranded RNAs with 21-25 nucleotides in length as newly discovered factors in regulating gene expression. Recently, the key regulatory role of miRNA in the cardiovascular system has been elucidated and amount of remarkable results has been achieved, particularly in the regulation of cardiac arrhythmias. A series of studies demonstrate that miRNAs are involved in the regulation of expression of a variety of proteins associated with cardiac electrical activity, and are the potential targets of occurrence of cardiac arrhythmias and anti-arrhythmic drugs. miRNAs as a therapeutic target regulate the stability of mRNAs of target genes or play an inhibitory role in the translation process. Stability of the corresponding miRNA expression levels in the target organ may be a new approach for the disease therapy. Regarding the dysfunction of miRNA, we employed miRNA re-expression strategy and anti-miRNA strategy to correct target protein function and provide a new entry for the therapy of arrhythmia. With the technology of miRNA mimics and antagomirs, miRNAs are expected to treat various cardiovascular diseases and will provide a fresh impetus to achieve transform medicine.
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Animals , Humans , Anti-Arrhythmia Agents , Therapeutic Uses , Arrhythmias, Cardiac , Therapeutics , Gene Expression Regulation , Ion Channels , Metabolism , MicroRNAs , Genetics , Metabolism , Physiology , RNA Interference , Translational Research, BiomedicalABSTRACT
Arrhythmia is a common complication of cardiovascular diseases and a risk factor for human health. Especially, ventricular tachycardia and ventricular fibrillation may not only exacerbate original heart diseases, but also cause cardiac sudden death which has been an mportant death reason in China. However, anti-arrhythmic drugs nowadays cannot effectively treat these arrhythmias, with an efficiency of only 30%-60%, which indicates that our knowledge about arrhythmias is limited. Hence, to explore the potential mechanism, look for novel targets, and develop drugs with multiple-channel action are the focus of the research direction. Recent studies displayed that the atrial-specific potassium channels such as IKur and IKAch were involved in atrial fibrillation, which provided a prospective target for atrial fibrillation treatment. Calcium leak, gap junction protein and autoantibody against ICaL channel were shown to participate in arrhythmogenesis. These findings provided a theoretical basis for the development of more effective anti-arrhythmic drugs. Remarkably, as a kind of mportant RNA regulating gene expression, microRNA (miRNA) was shown to possess anti-arrhythmic activities which may prevent cardiac sudden death. miR-1, miR-133 and miR-590 regulated the arrhythmia in various types of animal models. Because of the multiple-gene regulation actions of miRNA, it has the potential to be developed as novel anti-arrhythmic target.
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microRNAs are one kind of endogenous no-encoding RNA with about 22 nucleotides in length, and inhibited the translation of mRNAs by partially complementary binding to the 3' UTR of target mRNAs in the post-transcriptional level. Recent research shows that miRNAs function in the physiological and pathological processes of heart, especially involved in the occurrence and progress of arrhythmias. Abnormal miRNAs alters the protein expression of ion channels, causes the cardiac dysfunction, and triggers heart arrhythmias. The article summarized recent advances about roles of miRNA in arrhythmias and related cardiomyopathy, and discussed the therapeutic potential of miRNAs for heart diseases.
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Humans , Arrhythmias, Cardiac , Genetics , Metabolism , Cardiomyopathies , Genetics , Metabolism , MicroRNAs , Genetics , MetabolismABSTRACT
<p><b>OBJECTIVE</b>To investigate the effects of carnitine on cardiac function, collagen contents, peroxisome proliferator-activated receptor alpha (PPARalpha) and retinoid X receptor alpha (RXRct) expressions in a rat alcoholic cardiomyopathy modeL.</p><p><b>METHODS</b>Adult male Wistar rats were randomly divided into alcohol group (A) , alcohol/carnitine group (B) and control group. Six months later, protein expressions of collagen I, collagen III, matrix metalloproteinase-9 (MMP-9) and Smad-3 were determined by immunohistochemical staining. Protein expressions of PPARalpha and RXRalpha were detected by Western blot.</p><p><b>RESULTS</b>Expressions of collagen I, collagen III, MMP-9 and Smad-3 were significantly increased in groups A and B compared to group C (P < 0.01 or P < 0.05). Expressions of PPARalpha and RXRalpha (0.156 and 0.192, respectively, in group A; 0.248 and 0.385, respectively, in group B) were decreased compared to group C (P < 0.01 or P < 0.05). These changes were significantly attenuated by carnitine (all P < 0.05, group B vs. group A). Moreover, PPARalpha and RXRalpha positively correlated with EF and FS, and negatively correlated LVEDd, collagen I , collagen III, MMP-9 and Smad-3 (all P < 0.01).</p><p><b>CONCLUSION</b>PPARalpha and RXRalpha downregulation is significantly correlated with cardiac dysfunction in this alcoholic cardiomyopathy model, carnitine ameliorated the cardiac fibrosis and remodeling possibly through upregulating the metabolic pathways of PPARalpha and RXRalpha.</p>
Subject(s)
Animals , Male , Rats , Cardiomyopathy, Alcoholic , Metabolism , Pathology , Carnitine , Therapeutic Uses , Myocardium , Metabolism , Pathology , PPAR alpha , Metabolism , Rats, Wistar , Retinoid X Receptor alpha , MetabolismABSTRACT
<p><b>BACKGROUND</b>Poly (ADP-ribose) polymerase (PARP) plays an important role in cell survival and death. However, the mechanisms involved are not fully understood. Therefore, we investigated the effect of inhibition of PARP on acute myocardial infarction (AMI) at different time points in rats.</p><p><b>METHODS</b>AMI was induced in rats by ligating the left anterior descending coronary artery. One group received 3-aminobenzamide (3-AB, a kind of PARP inhibitor) (30 mg/kg) by intraperitoneal injection. The changes of ultramicrostructure of cardiocytes in infarction region were noted, PARP cleavage was measured by Western blotting, and expressions of protein of PARP and apoptosis inducing factor (AIF) were measured by immunohistochemical staining after treatment with 3-AB for 2 hours, 4 hours, 6 hours, 1 week, 4 weeks and 8 weeks.</p><p><b>RESULTS</b>Few damages to the ultramicrostructure of cardiocytes were observed after treatment with 3-AB. PARP cleavage was detected as early as 4 hours and markedly increased by 6 hours following AMI without 3-AB, but was not found until 6 hours following AMI treated with 3-AB. There were significant differences between 3-AB and AMI groups at the same time points. The expression of PARP was observed gradually increased, but that of AIF was suppressed for 6 hours after treatment of 3-AB, compared with AMI groups in positive cells at the same time points. There was significantly less cleavage of PARP and more PARP expression in 3-AB treated group compared with AMI and control groups at all matched time points.</p><p><b>CONCLUSIONS</b>Our results suggest that 3-AB inhibits degradation of PARP, increases the expression of PARP protein, and suppresses the expression of AIF protein. Inhibition of PARP activity may protect cardiocytes in rats with AMI and reduce apoptosis.</p>
Subject(s)
Animals , Male , Rats , Apoptosis Inducing Factor , Metabolism , Benzamides , Pharmacokinetics , Blotting, Western , Enzyme Inhibitors , Pharmacology , Immunohistochemistry , Myocardial Infarction , Metabolism , Myocytes, Cardiac , Metabolism , Poly(ADP-ribose) Polymerases , Metabolism , Rats, WistarABSTRACT
<p><b>BACKGROUND</b>We hypothesize that increased atrial oxidative stress and inflammation may play an important role in atrial nerve sprouting and heterogeneous sympathetic hyperinnervation during atrial fibrillation (AF). To test the hypothesis, we examined whether the antioxidant and anti-inflammatory treatment with probucol attenuates atrial autonomic remodeling in a canine model of AF produced by prolonged rapid right atrial pacing.</p><p><b>METHODS</b>Twenty-one dogs were divided into a sham-operated group, a control group and a probucol group. Dogs in the control group and probucol group underwent right atrial pacing at 400 beats per minute for 6 weeks, and those in the probucol group received probucol 1 week before rapid atrial pacing until pacing stopped. After 6-week rapid atrial pacing, general properties including left atrial structure and function, atrial hemodynamics and the inducibility and duration of AF were measured in all the groups. Atrial oxidative stress markers and serum C-reactive protein (CRP) concentration were estimated. The degree of nerve sprouting and sympathetic innervation at the right atrial anterior wall (RAAW) and the left atrial anterior wall (LAAW) were quantified by immunohistochemistry, atrial norepinephrine contents were also detected. Atrial beta-nerve growth factor (beta-NGF) mRNA and protein expression at the RAAW and LAAW were assessed by real-time quantitative RT-PCR and Western blotting respectively.</p><p><b>RESULTS</b>Atrial tachypacing induced significant nerve sprouting and heterogeneous sympathetic hyperinnervation, and the magnitude of nerve sprouting and hyperinnervation was higher in the RAAW than in the LAAW. Atrial beta-NGF mRNA and protein levels were significantly increased at the RAAW and LAAW, and the upregulation of beta-NGF expression was greater at the RAAW than at the LAAW in the control group. The beta-NGF protein level was positively correlated with the density of sympathetic nerves in all groups. Probucol decreased the increase of CRP concentration and attenuated atrial oxidative stress caused by atrial tachypacing. In addition, probucol could effectively inhibit atrial beta-NGF upregulation, significantly attenuate atrial nerve sprouting and heterogeneous sympathetic hyperinnervation, and dramatically reduce the inducibility and duration of AF.</p><p><b>CONCLUSIONS</b>The atrial over-expression of beta-NGF possibly caused by increased oxidative stress and inflammation may be the main mechanism underlying atrial autonomic remodeling during AF. Probucol attenuates atrial autonomic remodeling possibly by its antioxidant and anti-inflammatory actions.</p>
Subject(s)
Animals , Dogs , Female , Male , Antioxidants , Therapeutic Uses , Atrial Fibrillation , Drug Therapy , Blotting, Western , C-Reactive Protein , Metabolism , Cardiac Pacing, Artificial , Disease Models, Animal , Electrocardiography , Heart Atria , Immunohistochemistry , Nerve Growth Factor , Genetics , Metabolism , Norepinephrine , Metabolism , Probucol , Therapeutic Uses , Reverse Transcriptase Polymerase Chain ReactionABSTRACT
Objective To study the level of serum lipids and body-fat content of high-fat diet induced pbesity rats(DIO).explore the relationship between intracellular caleium and ventrieufar arrhythmia.Methods Sixty male Sprague-Dawley(SD)rats were divided into control group(15)and experiment group(45),high-fat diet was administrated for 12 weeks to established obesity model,15 rats were selected into obesity group according to their body weight gain.The standard 2-lead electrocardiograph was used to detect the incidence and scores of arrhythmia induced by barium chloride(BaCl2,0.1 mg/kg)for 1 hour on every 8 rats from different groups respectively.Body-fat content.the level of serum total cholesterol(TC),triglyceride(TG),low density lipopmtein cholesterol (LDL-C) and high density lipopmtein cholesterol (HDL-C)were measured.The epididymal(EP),retroperitoneal (RE) and mesenteric(ME)white adipose pads was measured to obtain the body fat content.Single ventricular myrocytes of rats were isolated by enzymatic dissociation.The confocal laser scanning microscope was used to record basic intraceUular calcium level([Ca2+]i).Results The body-fat content in obesity group[(7.71±0.74)%] was significantly higher than control group[(4.69±0.37)%](t＝3.650,P＜0.05).The level of serum TC,TGand LDL-C were significantly higher(t＝3.801,2.778,3.536.P＜0.05) in obesity group[(1.26±0.04),(0.58±0.10),(0.51±0.04)mmol/L]than those in control group[(0.92±0.08),(0.29+0.03),(0.31±0.04) mmol/L].The level of serum HDL-C wa8 decreased gradually from control group[(0.53±0.05)mmol/L] toobesity group[(0.52±0.02)mmol/L],but there waft no significant difference between them(t＝0.186,P＞0.05).The incidence of arrhythmia induced by BaCl2(0.1 mg/kg)in obesity group was significantly higher than controlgroup(X2＝5.333,P＜0.05),and the scores of arrhythmla was increased in obesity group(2.5±0.6)too.The fluorescence intensity standing for[Ca2+]i was increased significantly(t＝2.409,P＜0.05)from obesity group(247.96±20.03)to control group (174.25±23.13).Conclusion As the free cytosolic calcium begin to accumulate,the arrhythmia morbidity is increased in obesity rats.
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Objective To observe the therapeutic action of choline on As2O3 induced electrecardiogram (ECG)QT interval prolongation and to further explore molecular biological mechanisms.Methods 40 guinea pigs were divided into 5 groups randomly with 8 rats in each group:control group intravenously injected with saline, experimental group with 0.4,0.8,1.6 ms/kg of choline and As2O3 group with 8 mg/kg choline plus 1.6 mg/kg As2O3.After a series of concentration of As2O3 was intravenously given,ECG was monitored at different time(0,10, 30,60,90,120 min),and corrected QT interval(QTc)was studied.Total RNA Wa$abstracted from the guinea pigs hearts after 6 h,and the effects of choline on altered L-type calcium channel α1c and potassium channel GPERG mRNA expression caused by As2O3 in cardiomyocytes of guinea pig were studied by the method of reverse transcription polyme,chain reaction(RT-PCR).Results In 0.8 mg/kg As2O3 group,the value of QTc at 60, 90 and 120 min respectively being 354 ±22.366± 31 and 368 ±29 waa significantly higher than that of control groups[(325±26,336 ±26 and 324 ±20)at same time] with a significant difference(P<0.05 or<0.01);the value of QTc at 90 and 120 rain was significantly higher than that of O min group(334 ±12),the difference being statistically significant(P<0.05).In 1.6 mg/kg As2O3 group,the value of QTc at 10,30,60,90 and 120 min respectively being 362±33,380±21,382±35,388±39 and 388 ±31 was significantly higher than that of control groups[(328 ±20.324 ±25,325 ±26,336±26 and 324 ±20)at same time]with a significant difference (P<0.05 or<0.01);the value of QTc at 10,30,60,90 and 120 min Was significantly higher than that of O min group(329 ±31),the difference being statistically significant(P<0.05).In choline+As2O3group,the value of qrc at 30,60,90 and 120 min was 337 ±17,341±15,344 ±22 and 343 ±19,significantly lower than that of 1.6 mg/kg As2O3 group,the difference being statistically significant(P<0.05 or<0.01).The RT-PCR results indicated that the value of L-type calcium channel α1c mRNA expression at the concentration of 1.6 mg/kg As2O3 was 1.27±0.14 vs 1.02±0.12 of control group(P<0.01),and it was 1.10 ±0.13 in choline+As2O3 group(P<0.05 Vs 1.6 mg/kg As2O3 group).The value of potassium channel GPERG mRNA expression were 1.29 ±0.11,1.22±0.12 and 1.27±0.16 at the dose of 0.4,0.8,1.6 mg/kg As2O3(P>0.05 VS 1.23±0.08 of control group).In choline+ As2O3 group,the value was 1.30±0.14(compared with 1.6 mg/kg As2O3 group,P>0.05).Conclusions Choline normalizes QTc abnormality during As2O3 application,and modulating changed calcium channel mRNA expression induced by As2O3 may be one of the mechanisms.
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<p><b>BACKGROUND</b>Atrial fibrillation (AF) is accompanied by atrial structural remodeling. Calpain activity is induced during AF. To test a causal relationship between calpain activation and atrial structural changes, N-acetyl-Leu-Leu-Met (ALLM), a calpain inhibitor, was utilized in a canine AF model.</p><p><b>METHODS</b>Fifteen dogs were randomly divided into 3 groups: sham-operated group, control group and calpain inhibitor group; each with 5 dogs. Sustained AF was induced by rapid right atrium pacing at 600 beats per minute for 3 weeks. ALLM was administered at a dosage of 1.0 mg x kg(-1) x d(-1) in the calpain inhibitor group. Three weeks later, the proteolysis, protein expression of TnT and myosin, calpain I localization and expression and structural changes were examined in left atrial free walls, right atrial free walls and the interatrial septum respectively. Atrial size and contractile function were also measured by echocardiography.</p><p><b>RESULTS</b>Long-term rapid atrial pacing induced marked structural changes such as enlarged atrial volume, myolysis, degradation of TnT and myosin, accumulation of glycogen and changes in mitochondrial shape and size, which were paralleled by an increase in calpain activity. The positive correlation between calpain activity and the degree of myolysis (r(s) = 0.90 961, P < 0.0001) was demonstrated. In addition to structural abnormalities, pacing-induced atrial contractile dysfunction was observed in this study. The pacing-induced atrial structural alterations and loss of contractility were partially prevented by the calpain inhibitor ALLM.</p><p><b>CONCLUSIONS</b>Activation of calpain represents key features in the progression towards overt structural remodeling. Calpain inhibitor, ALLM, suppressed the increased calpain activity and reversed structural remodeling caused by sustained atrial fibrillation in the present model. Calpain inhibition may therefore provide a possibility for therapeutic intervention in AF.</p>