Atorvastatin, etanercept and the nephrogenic cardiac sympathetic remodeling in chronic renal failure rats

BACKGROUND Chronic renal failure(CRF) patients are predisposed to arrhythmias, while the detailed mechanisms are unclear. We hypothesized the chronic inflammatory state of CRF patients may lead to cardiac sympathetic remodeling, increasing the incidence of ventricular arrhythmia(VA) and sudden cardiac death. And explored the role of atorvastatin and etanercept in this process.METHODS A total of 48 rats were randomly divided into sham operation group(Sham group), CRF group, CRF + atorvastatin group(CRF + statin group), and CRF + etanercept group(CRF + rhTNFR-Fcgroup). Sympathetic nerve remodeling was assessed by immunofluorescence of growth-associated protein 43(GAP-43) and tyrosine hydroxylase positive area fraction. Electrophysiological testing was performed to assess the incidence of VA by assessing the ventricular effective refractory period and ventricular fibrillation threshold. The levels of tumor necrosis factor-alpha(TNF-α) and interleukin-1beta were determined by Western blotting and enzyme-linked immunosorbent assay.RESULTS Echocardiogram showed that compared with the Sham group, left ventricular end-systolic diameter and ventricular weight/body weight ratio were significantly higher in the CRF group. Hematoxylin-eosin and Masson staining indicated that myocardial fibers were broken, disordered, and fibrotic in the CRF group. Western blotting, enzyme-linked immunosorbent assay,immunofluorescence and electrophysiological examination suggested that compared with the Sham group, GAP-43 and TNF-α proteins were significantly upregulated, GAP-43 and tyrosine hydroxylase positive nerve fiber area was increased, and ventricular fibrillation threshold was significantly decreased in the CRF group. The above effects were inhibited in the CRF + statin group and the CRF + rhTNFR-Fcgroup.CONCLUSIONS In CRF rats, TNF-α was upregulated, cardiac sympathetic remodeling was more severe, and the nephrogenic cardiac sympathetic remodeling existed. Atorvastatin and etanercept could downregulate the expression of TNF-α or inhibit its activity, thus inhibited the above effects, and reduced the occurrence of VA and sudden cardiac death.

Mufangji tang ameliorates pulmonary arterial hypertension through improving vascular remodeling,inhibiting inflammatory response and oxidative stress,and inducing apoptosis

Background:Mufangji tang(MFJT)is composed of Ramulus Cinnamomi,Radix Ginseng,Cocculus orbiculatus(Linn.)DC.,and Gypsum.In clinical settings,MFJT has been effectively employed in addressing a range of respiratory disorders,notably including pulmonary arterial hypertension(PAH).However,the mechanism of action of MFJT on PAH remains unknown.Methods:In this study,a monocrotaline-induced PAH rat model was established and treated with MFJT.The therapeutic effects of MFJT on PAH rat model were evaluated.Network pharmacology was conducted to screen the possible targets for MFJT on PAH,and the molecular docking between the main active components and the core targets was carried out.The key targets identified from network pharmacology were tested.Results:Results showed significant therapeutic effects of MFJT on PAH rat model.Analysis of network pharmacology revealed several potential targets related to apoptosis,inflammation,oxidative stress,and vascular remodeling.Molecular docking showed that the key components were well docked with the core targets.Further experimental validation results that MFJT treatment induced apoptosis(downregulated Bcl-2 levels and upregulated Bax levels in lung tissue),inhibited inflammatory response and oxdative stress(decreased the levels of IL-1β,TNF-α,inducible NOS,and malondialdehyde,and increased the levels of endothelial nitric oxide synthase,nitric oxide,glutathione and superoxide dismutase),reduced the proliferation of pulmonary arterial smooth muscle cells(downregulated ET-1 andβ-catenin levels and ERK1/2 phosphorylation,increased GSK3βlevels).Conclusion:Our study revealed MFJT treatment could alleviate PAH in rats via induction of apoptosis,inhibition of inflammation and oxidative stress,and the prevention of vascular remodeling.

Investigating the relationship between intracranial atherosclerotic plaque remodelling and diabetes using high-resolution vessel wall imaging

BACKGROUND Intracranial atherosclerosis,a leading cause of stroke,involves arterial plaque formation.This study explores the link between plaque remodelling patterns and diabetes using high-resolution vessel wall imaging(HR-VWI).AIM To investigate the factors of intracranial atherosclerotic remodelling patterns and the relationship between intracranial atherosclerotic remodelling and diabetes mellitus using HR-VWI.METHODS Ninety-four patients diagnosed with middle cerebral artery or basilar artery INTRODUCTION Intracranial atherosclerotic disease is one of the main causes of ischaemic stroke in the world,accounting for approx-imately 10%of transient ischaemic attacks and 30%-50%of ischaemic strokes[1].It is the most common factor among Asian people[2].The adaptive changes in the structure and function of blood vessels that can adapt to changes in the internal and external environment are called vascular remodelling,which is a common and important pathological mechanism in atherosclerotic diseases,and the remodelling mode of atherosclerotic plaques is closely related to the occurrence of stroke.Positive remodelling(PR)is an outwards compensatory remodelling where the arterial wall grows outwards in an attempt to maintain a constant lumen diameter.For a long time,it was believed that the degree of stenosis can accurately reflect the risk of ischaemic stroke[3-5].Previous studies have revealed that lesions without significant luminal stenosis can also lead to acute events[6,7],as summarized in a recent meta-analysis study in which approximately 50%of acute/subacute ischaemic events were due to this type of lesion[6].Research[8,9]has pointed out that the PR of plaques is more dangerous and more likely to cause acute ischaemic stroke.Previous studies[10-13]have found that there are specific vascular remodelling phenomena in the coronary and carotid arteries of diabetic patients.However,due to the deep location and small lumen of intracranial arteries and limitations of imaging techniques,the relationship between intracranial arterial remodelling and diabetes is still unclear.In recent years,with the development of magnetic resonance technology and the emergence of high-resolution(HR)vascular wall imaging,a clear and multidimensional display of the intracranial vascular wall has been achieved.Therefore,in this study,HR wall imaging(HR-VWI)was used to display the remodelling characteristics of bilateral middle cerebral arteries and basilar arteries and to explore the factors of intracranial vascular remodelling and its relationship with diabetes.

Evidence-Based Complementary and Alternative Medicine Effects of Capybara Oil on Cardiac Remodeling of C57bl/6 Mice

Cardiovascular diseases are the main cause of morbidity and mortality in the world, and obesity and the metabolic syndrome are risk factors for its development. One of the therapies to reduce cardiovascular risk is the use of polyunsaturated fatty acids. In Brazil, a source of such acid is the oil extracted from the fat of the capybara. The objective of this work is to study the effects of the capybara oil on lipid and glucose metabolism, as well as its effects on the adipose tissue and cardiac remodeling. We assessed the effects of capybara oil treatment on body mass, lipid and carbohydrate metabolism, systolic blood pressure, adipose tissue and cardiac remodeling, and performed an ultrastructural evaluation of the myocardium in C57Bl/6 mice treated with high-fat diet. Treatment with capybara oil reduced total cholesterol and triglyceride levels, systolic blood pressure, visceral and subcutaneous adipose tissue, and adipocyte diameter. In addition, cardiac remodeling was attenuated, preserving cardiomyocytes, increasing vascularization, reducing cardiomyocyte hypertrophy and the extracellular matrix, and preserving the morphological integrity of mitochondria. Capybara oil has several beneficial effects on the cardiovascular and metabolic system, and further studies are needed to better understand its role in the prevention or treatment of cardiovascular diseases.

Mechanism of Yanghe Pingchaun granules on airway remodeling in asthmatic rats based on IL-6/JAK2/STAT3 signaling axis

Objective: To investigate the effects of Yanghe Pingchuan Granules on airway remodeling in asthmatic rats, and to explore the mechanism of Interleukin-6/Janus kinase 2/ Signal transducing activator of transcription 3(IL-6/JAK2/STAT3) signal axis. Methods: We separated 42 healthy male SD rats into two groups, a control group (7) and a model group (35).The model group was sensitized with a combination of ovalbumin (OVA) and aluminum hydroxide for 2 weeks, while the control group was given an equal amount of physiological saline.After 2 weeks, the modeling group was randomly divided into Model group, Yanghe Pingchuan Granules high, medium and low dose groups and Dexamethasone group, each group consisted of 7 animals. After 4 weeks, OVA atomization and gavage were used for stimulation and treatment. Yanghe Pingchuan Granules high, middle and low groups were given 15.48, 7.74, 3.87 g∙kg-1 Yanghe Pingchuan Granules daily, dexamethasone group was given 0.0625 mg∙kg-1 dexamethasone daily, and the other groups were given the same amount of normal saline. HE, PAS and Masson staining were used to observe the lung histopathological changes in rats. The levels of interleukin-6, IL-23 and IL-17A were detected by ELISA. The expression levels of JAK-2, P-JAK2, STAT3 and P-STAT3 in lung tissues were detected by Western blot. Real-time quantitative polymerase chain reaction (qRT-PCR) was used to detect the mRNA expression levels of IL-6, JAK2 and STAT3 in rat lung tissue. Results: The lung tissue structure of the model group was severely damaged compared to the control group, accompanied by a great many of inflammatory cell infiltration, goblet cell hyperplasia, subepithelial collagen fiber deposition and airway epithelial thickening were more obvious. The expressions of IL-6, IL- 23 and IL-17A in serum were significantly increased (P<0.01), the protein expression levels of JAK-2, P-JAK2, STAT3 and P-STAT3 and the mRNA expression levels of IL-6, JAK2 and STAT3 in lung tissue were significantly increased (P<0.01);Compared with the model group, inflammatory cell infiltration, goblet cell proliferation, subepithelial collagen fiber deposition and airway epithelial thickening were significantly reduced in each administration group, and the expressions of IL-6, IL-23 and IL-17A in serum were significantly decreased (P< 0.01). The protein expression levels of JAK-2, P-JAK2, STAT3 and P-STAT3 and mRNA expression levels of IL-6, JAK2 and STAT3 in lung tissue were significantly decreased (P<0.01). Conclusion: Yanghe Pingchuan Granules can significantly alleviate airway remodeling in asthmatic rats, and its mechanism may be through inhibiting the IL-6/JAK2/STAT3 signal axis.

Modulation of bone remodeling by the gut microbiota:a new therapy for osteoporosis

The gut microbiota(GM)plays a crucial role in maintaining the overall health and well-being of the host.Recent studies have demonstrated that the GM may significantly influence bone metabolism and degenerative skeletal diseases,such as osteoporosis(OP).Interventions targeting GM modification,including probiotics or antibiotics,have been found to affect bone remodeling.This review provides a comprehensive summary of recent research on the role of GM in regulating bone remodeling and seeks to elucidate the regulatory mechanism from various perspectives,such as the interaction with the immune system,interplay with estrogen or parathyroid hormone(PTH),the impact of GM metabolites,and the effect of extracellular vesicles(EVs).Moreover,this review explores the potential of probiotics as a therapeutic approach for OP.The insights presented may contribute to the development of innovative GM-targeted therapies for OP.

Treadmill exercise exerts a synergistic effect with bone marrow mesenchymal stem cell-derived exosomes on neuronal apoptosis and synaptic-axonal remodeling

Treadmill exercise and mesenchymal stem cell transplantation are both practical and effective methods for the treatment of cerebral ischemia.However,whether there is a synergistic effect between the two remains unclear.In this study,we established rat models of ischemia/reperfusion injury by occlusion of the middle cerebral artery for 2 hours and reperfusion for 24 hours.Rat models were perfused with bone marrow mesenchymal stem cell-derived exosomes(MSC-exos)via the tail vein and underwent 14 successive days of treadmill exercise.Neurological assessment,histopathology,and immunohistochemistry results revealed decreased neuronal apoptosis and cerebral infarct volume,evident synaptic formation and axonal regeneration,and remarkably recovered neurological function in rats subjected to treadmill exercise and MSC-exos treatment.These effects were superior to those in rats subjected to treadmill exercise or MSC-exos treatment alone.Mechanistically,further investigation revealed that the activation of JNK1/c-Jun signaling pathways regulated neuronal apoptosis and synaptic-axonal remodeling.These findings suggest that treadmill exercise may exhibit a synergistic effect with MSC-exos treatment,which may be related to activation of the JNK1/c-Jun signaling pathway.This study provides novel theoretical evidence for the clinical application of treadmill exercise combined with MSC-exos treatment for ischemic cerebrovascular disease.

A mutation in the ZNF687 gene that is responsible for the severe form of Paget's disease of bone causes severely altered bone remodeling and promotes hepatocellular carcinoma onset in a knock-in mouse model

Paget’s disease(PDB)is a late-onset bone remodeling disorder with a broad spectrum of symptoms and complications.One of the most aggressive forms is caused by the P937R mutation in the ZNF687 gene.Although the genetic involvement of ZNF687 in PDB has been extensively studied,the molecular mechanisms underlying this association remain unclear.Here,we describe the first Zfp687 knock-in mouse model and demonstrate that the mutation recapitulates the PDB phenotype,resulting in severely altered bone remodeling.Through microcomputed tomography analysis,we observed that 8-month-old mutant mice showed a mainly osteolytic phase,with a significant decrease in the trabecular bone volume affecting the femurs and the vertebrae.Conversely,osteoblast activity was deregulated,producing disorganized bone.Notably,this phenotype became pervasive in 16-month-old mice,where osteoblast function overtook bone resorption,as highlighted by the presence of woven bone in histological analyses,consistent with the PDB phenotype.Furthermore,we detected osteophytes and intervertebral disc degeneration,outlining for the first time the link between osteoarthritis and PDB in a PDB mouse model.RNA sequencing of wild-type and Zfp687 knockout RAW264.7 cells identified a set of genes involved in osteoclastogenesis potentially regulated by Zfp687,e.g.,Tspan7,Cpe,Vegfc,and Ggt1,confirming its role in this process.Strikingly,in this mouse model,the mutation was also associated with a high penetrance of hepatocellular carcinomas.Thus,this study established an essential role of Zfp687 in the regulation of bone remodeling,offering the potential to therapeutically treat PDB,and underlines the oncogenic potential of ZNF687.

The roles of bone remodeling in normal hematopoiesis and age-related hematological malignancies

Prior research establishing that bone interacts in coordination with the bone marrow microenvironment(BMME)to regulate hematopoietic homeostasis was largely based on analyses of individual bone-associated cell populations.Recent advances in intravital imaging has suggested that the expansion of hematopoietic stem cells(HSCs)and acute myeloid leukemia cells is restricted to bone marrow microdomains during a distinct stage of bone remodeling.These findings indicate that dynamic bone remodeling likely imposes additional heterogeneity within the BMME to yield differential clonal responses.A holistic understanding of the role of bone remodeling in regulating the stem cell niche and how these interactions are altered in age-related hematological malignancies will be critical to the development of novel interventions.To advance this understanding,herein,we provide a synopsis of the cellular and molecular constituents that participate in bone turnover and their known connections to the hematopoietic compartment.Specifically,we elaborate on the coupling between bone remodeling and the BMME in homeostasis and age-related hematological malignancies and after treatment with bone-targeting approaches.We then discuss unresolved questions and ambiguities that remain in the field.

The impact of aging on cardiac remodeling in chronic mitral regurgitation

BACKGROUND Chronic mitral regurgitation(MR)is a volume overload state that causes dilatation of the left sided cardiac chambers.The presence of significant dilatation is considered an indication for mitral valve intervention,however,aging may affect left ventricular(LV)remodeling independently of valvular disease.The objective of this study was to examine age-related changes in cardiac remodeling in a broad population of patients with chronic MR.METHODS Consecutive subjects that underwent echocardiography examinations recorded in the echocardiography database of a university-affiliated laboratory were retrieved.Subjects were categorized into none/mild,moderate or severe MR.For purposes of analysis of differences with aging,the population was divided into groups above and below 70 years of age and standard echocardiographic measurements were compared between the groups.RESULTS A total of 3492 subjects with at least moderate MR(mean age:76 years,52%female)were included in the study and compared to 18,250 subjects with none or mild MR.Older patients had significantly smaller LV end-diastolic diameters and volumes and significantly larger left atrial(LA)volumes when compared to the younger group.LA volume index increased in both age groups as MR severity increased,while LV end-diastolic volume increased with increasing MR only in the younger population.CONCLUSIONS Cardiac remodeling in chronic MR is significantly influenced by age.Guideline based recommendations of timing of mitral valve interventions in asymptomatic MR patients,based on assessment of LA and LV remodeling,may need to take age into account.

Adjusting phosphate feeding regimen according to daily rhythm increases eggshell quality via enhancing medullary bone remodeling in laying hens

Background Body phosphorus metabolism exhibits a circadian rhythm over the 24-h daily cycle.The egg laying behavior makes laying hens a very special model for investigating phosphorus circadian rhythms.There is lack of information about the impact of adjusting phosphate feeding regimen according to daily rhythm on the phosphorus homeostasis and bone remodeling of laying hens.Methods and results Two experiments were conducted.In Exp.1,Hy-Line Brown laying hens(n=45)were sampled according the oviposition cycle(at 0,6,12,and 18 h post-oviposition,and at the next oviposition,respectively;n=9 at each time point).Diurnal rhythms of body calcium/phosphorus ingestions and excretions,serum calcium/phosphorus levels,oviduct uterus calcium transporter expressions,and medullary bone(MB)remodeling were illustrated.In Exp.2,two diets with different phosphorus levels(0.32%and 0.14%non-phytate phosphorus(NPP),respectively)were alternately presented to the laying hens.Briefly,four phosphorus feeding regimens in total(each included 6 replicates of 5 hens):(1)fed 0.32%NPP at both 09:00 and 17:00;(2)fed 0.32%NPP at 09:00 and 0.14%NPP at 17:00;(3)fed 0.14%NPP at 09:00 and 0.32%NPP at 17:00;(4)fed 0.14%NPP at both 09:00 and 17:00.As a result,the regimen fed 0.14%NPP at 09:00 and 0.32%NPP at 17:00,which was designed to strengthen intrinsic phosphate circadian rhythms according to the findings in Exp.1,enhanced(P<0.05)MB remodeling(indicated by histological images,serum markers and bone mineralization gene expressions),elevated(P<0.05)oviduct uterus calcium transportation(indicated by transient receptor potential vanilloid 6 protein expression),and subsequently increased(P<0.05)eggshell thickness,eggshell strength,egg specific gravity and eggshell index in laying hens.Conclusions These results underscore the importance of manipulating the sequence of daily phosphorus ingestion,instead of simply controlling dietary phosphate concentrations,in modifying the bone remodeling process.Body phosphorus rhythms will need to be maintained during the daily eggshell calcification cycle.

Fractional Order Nonlinear Bone Remodeling Dynamics Using the Supervised Neural Network

This study aims to solve the nonlinear fractional-order mathematical model(FOMM)by using the normal and dysregulated bone remodeling of themyeloma bone disease(MBD).For themore precise performance of the model,fractional-order derivatives have been used to solve the disease model numerically.The FOMM is preliminarily designed to focus on the critical interactions between bone resorption or osteoclasts(OC)and bone formation or osteoblasts(OB).The connections of OC and OB are represented by a nonlinear differential system based on the cellular components,which depict stable fluctuation in the usual bone case and unstable fluctuation through the MBD.Untreated myeloma causes by increasing the OC and reducing the osteoblasts,resulting in net bone waste the tumor growth.The solutions of the FOMM will be provided by using the stochastic framework based on the Levenberg-Marquardt backpropagation(LVMBP)neural networks(NN),i.e.,LVMBPNN.The mathematical performances of three variations of the fractional-order derivative based on the nonlinear disease model using the LVMPNN.The static structural performances are 82%for investigation and 9%for both learning and certification.The performances of the LVMBPNN are authenticated by using the results of the Adams-Bashforth-Moulton mechanism.To accomplish the capability,steadiness,accuracy,and ability of the LVMBPNN,the performances of the error histograms(EHs),mean square error(MSE),recurrence,and state transitions(STs)will be provided.

Meta-analysis of statin combined with trimetazidine on the regulation of inflammatory factors in coronary atherosclerotic heart disease and improvement of ventricular remodeling

Objective:To systematically evaluate the effects of statins combined with trimetazidine on the regulation of inflammatory factors and the improvement of ventricular remodeling in coronary atherosclerotic heart disease based on the inflammasomes/immune damage response theory.Methods:Using computer to search for EMbase,The Cochrane Library,Web of Science,MEDLINE,PubMed,WanFang Data,CNKI,China Biomedical Document Service System(CBM),VIP database(VIP),9 databases in total.The search time limit is from the inception of the databases to June 7,2021.All reference documents included in the study were manually searched.According to the Cochrane systematic review method,the information on atorvastatin combined with trimetazidine and conventional treatment(antiplatelet,control blood pressure,diuresis,coronary artery dilation and other expectant treatments)contrast the use of trimetazidine or stains combined with expectant treatment of coronary atherosclerotic heart disease patients in Chinese and English randomized controlled trials(RCT),and conduct the extraction and quality evaluation of the included literature data,using RevMan5.4 software for Meta analysis.Outcome indicators include inflammatory factors:C-reactive protein(CRP),IL-6(interleukin 6),tumor necrosis factor(TNF-α),and ventricular remodeling related outcome indicators:left ventricular end diastolic diameter(LVEDD),left Ventricular end systolic diameter(LVESD).Results:12 randomized controlled trials were included,a total of 1120 patients with coronary heart disease.Meta-analysis results:(1)inflammatory factors:the statin combined with trimetazidine group can significantly reduce the CRP,IL-6,TNF-α’s expression degree in the blood of patients with coronary heart disease compared with the control group(only statins or trimetazidine).CRP[n=770,SMD=-2.70,95%CI(-2.55,-1.40),P<-0.00001],TNF-α[n=678,SMD=-2.25,95%CI(-3.39,-1.12),P<-0.0001],IL-6[n=770,SMD=-2.10,95%CI(-3.10,-1.10),P<0.00001].(2)Ventricular remodeling:Compared with the control group(using statins or trimetazidine alone),the statin combined with trimetazidine group can significantly reduce the left ventricular end-systolic diameter of patients with coronary heart disease before treatment[n=626,SMD=-1.55,95%CI(-2.10,-0.99),P<-0.00001]and leftVentricular end diastolic diameter[n=626,SMD=-1.18,95%CI(-1.56,-0.80),P<-0.00001].Conclusion:Compared with the control group,statins combined with trimetazidine can significantly reduce the level of inflammatory factors based on the inflammasomes/immune injury response theory,and improve the ventricular remodeling in patients with coronary heart disease.

The role of exosomes in bone remodeling and osseointegration of implants

Dental implant is an effective method in the treatment of missing teeth.The process of osseointegration of implant teeth involves the coordinated operation of immune system and bone system.The interaction between cells is closely related to bone formation and repair.Exosomes are important intercellular communication molecules.They were originally found in the supernatant of sheep erythrocytes cultured in vitro.They are micro vesicles with a diameter of 40~150 nm.They exist in a variety of cells and body fluids.They enter the target cells by endocytosis and transport,affecting the expression of cell genes and changing the fate of cells.It has an important regulatory function in the microenvironment of implant bone binding.It plays a role in bone remodeling through small molecular RNA,specific proteins and other growth factors secreted by different cells.This article reviews the role of bone derived cellderived exosomes in bone remodeling and their function in implant osseointegration.

Shengmai Yin formula promotes ventricular remodeling in chronic heart failure rats by inhibiting excessive autophagy via activating AKT/mTOR pathway

Background:Shengmai Yin(SMY)formula,a traditional Chinese medicine,shows a definite therapeutic effect on chronic heart failure(CHF)in clinical practice,but the molecular mechanism remains largely unknown.The PI3K/Akt/mTOR pathway is a classic pathway of autophagy and plays a pivotal role in the occurrence and development of CHF.Here,we aimed to investigate whether SMY formula treat CHF rats by inhibiting excessive autophagy.Methods:Echocardiography was conducted to evaluate cardiac function.Transmission electron microscopy was used to observe the arrangement of myocardial cells.Enzyme linked immunosorbent assay analysis was performed to quantitative detecting the content of N-terminal pro-B-type natriuretic peptide,stromelysin-2,TNF-α in rat serum.Western blotting was used to detect the expression of AKT,p-AKT,mTOR,p-mTOR,light chain 3(LC3),and p62.In vitro,myocardial cells were treated with hypoxia reoxygenation and then intervened with SMY.Cell counting kit-8 method was used to measure the cell viability.The immunofluorescence expression of LC3 protein were also examined.Results:In vivo,SMY intervention assisted in the ventricular remodeling,reduced the levels of N-terminal pro-B-type natriuretic peptide,stromelysin-2,TNF-αin serum,and recovered myocardial cell structure in CHF rats.Treatment with SMY significantly promoted the ratio of p-AKT/AKT,p-mTOR/mTOR,and down-regulated the expression level of p62 and the ratio of LC3-Ⅱ/LC3-Ⅰ.In vitro,when the concentration of SMY containing serum reached 40% in the medium,the activity of myocardial cells reached the highest at 135.14%.SMY inhibited the expression of LC3 in hypoxic-reoxygenation embryonic ventricular myocytes cells.When the hypoxic reoxygenation cells treated with p-mTOR inhibitor,rapamycin,or p-AKT inhibitor,API-1,SMY could also down-regulated the LC3 expression level.Conclusions:SMY formula functions in restoring cardiac function and promoting myocardial ultrastructural recovery by reducing autophagy activity through up-regulating the ratio of p-AKT/AKT,p-mTOR/mTOR,and down-regulating the expression level of p62 and the ratio of LC3-Ⅱ/LC3-Ⅰ in CHF rats.

Effect of spironolactone on cardiac remodeling after acute myocardial infarction

BACKGROUND:Few studies have reported the effect of aldosterone receptor antagonist(ARA) on myocardial remodeling after acute myocardial infarction(AMI).This study was undertaken to investigate the preventive effect of ARA on myocardial remodeling after AMI.METHODS:A total of 616 patients who had been admitted into the CCU of the First Affiliated Hospital of Harbin Medical University from January 2008 to January 2010 were studied prospectively.Only 528 patients were observed completely,including 266 of the control group and 262 of the treatment group.There was no statistical difference in age,gender,medical history,admission situation,and treatment between the two groups(P>0.05).The preventive effects of spironolactone on cardiac remodeling,left ventricular function,renal function and blood levels of potassium were evaluated by echocardiography,serum potassium and serum creatinine at one-month and one-year follow-up.RESULTS:The echocardiography indicators such as LVESD,LVEDD,LVEF,LAD-ML and LADSI were significantly improved in the treatment group compared with the control group at one year(P<0.05).In the treatment group,LVESD,LVEDD,LVPWT,LVEF,LAD-ML and LAD-SI were more significantly improved at one year than one month(P<0.05,P=0.007 to LVEF),and in the control group LVEF was more significantly improved at one year than one month(P=0.0277).There were no significant differences in serum potassium and serum creatinine levels between the two groups.CONCLUSION:On the basis of conventional treatment,the early combination of low-dose spironolactone(20 mg/d) could inhibit cardiac remodeling at late stage and prevent heart fadure.

Cardiac remodeling and physical training post myocardial infarction

After myocardial infarction(MI), the heart undergoes extensive myocardial remodeling through the accumulation of fibrous tissue in both the infarcted and noninfarcted myocardium, which distorts tissue structure, increases tissue stiffness, and accounts for ventricular dysfunction. There is growing clinical consensus that exercise training may beneficially alter the course of post-MI myocardial remodeling and improve cardiac function. This review summarizes the present state of knowledge regarding the effect of post-MI exercise training on infarcted hearts. Due to the degree of difficulty to study a viable human heart at both protein and molecular levels, most of the detailed studies have been performed by using animal models. Although there are some negative reports indicating that post-MI exercise may further cause deterioration of the wounded hearts, a growing body of research from both human and animal experiments demonstrates that post-MI exercise may beneficially alter the course of wound healing and improve cardiac function. Furthermore, the improved function is likely due to exercise training-induced mitigation of reninangiotensin-aldosterone system, improved balance between matrix metalloproteinase-1 and tissue inhibitor of matrix metalloproteinase-1, favorable myosin heavy chain isoform switch, diminished oxidative stress, enhanced antioxidant capacity, improved mitochondrial calcium handling, and boosted myocardial angiogenesis. Additionally, meta-analyses revealed that exercise-based cardiac rehabilitation has proven to be effective, and remains one of the least expensive therapies for both the prevention and treatment of cardiovascular disease, and prevents re-infarction.

Xinfuli Granule improves post-myocardial infarction ventricular remodelingand myocardial fibrosis in rats by regulating TGF-β/Smads signaling pathway

Background Recent clinical and experimental studies have confirmed the effects of Xinfuli Granule （XG）, a compound Chinesemedicine in the prevention and treatment of heart failure （HF）. This study aimed to investigate the effects and the mechanisms of XG onventricular reconstruction in rats with acute myocardial infarction （AMI）. Methods Sprague-Dawley rats were subjected to left anteriordescending branch ligation. The rats that survived 24 h were randomly assigned to five groups： medium-dose of XG group （MI＋XGM）,high-dose of XG group （MI＋XGH）, carvedilol group （MI＋C）, medium-dose of XG ＋ carvedilol group （MI＋C＋XGM）. Fourteen rats under-went identical surgical procedures without artery ligation, serving as sham controls. At 28 days, left ventricular weight to body weight（LVW/BW） and heart weight to body weight （HW/BW） were calculated; left ventricular ejection fraction （LVEF）, left ventricular shorteningfraction （LVFS）, left ventricular internal diameter at systole （LVIDS） were measured by ultrasound; HE staining, Masson staining, and Siriusred staining were used to assess the myocardial pathological and physiological changes as well as myocardial fibrosis area and non-infarctzone Ⅰ/Ⅲ collagen ratio. Expression of Smad3 were detected and analyzed by Western blot, immunohistochemistry and immunofluorescenceP-Smad3, Smad2 and Smad7 in the TGF-13/Smads signaling pathway were also analyzed by Western blot. Results The LVIDS （P 〈 0.01）,HW/BW （P 〈 0.05）, type UIII collagen ratio （P 〈 0.01） and myocardial collagen （P 〈 0.01） decreased significantly while the LVW/BW,LVFS （P 〈 0.05） increased significantly in MI＋XGM group as compared with those in other groups. The expression of key signal moleculesof the TGF-β/Smads signaling pathway, including Smad3, P-Smad3 and Smad2 protein were decreased, while the expression of Smad7 in-creased in both XG and carvedilol treatment groups as compared to those of the MI group （all P 〈 0.01）. Immunohistochemistry and im-munofluorescence further confirmed the down-regulated Smad3 expression. Conclusion XG can improve ventricular reconstruction andinhibit myocardial fibrosis in rats with AMI by regulating TGF-β/Smads signaling pathway.

Stem cell mechanisms during left ventricular remodeling post-myocardial infarction:Repair and regeneration

Post-myocardial infarction(MI),the left ventricle(LV)undergoes a series of events collectively referred to as remodeling.As a result,damaged myocardium is replaced with fibrotic tissue consequently leading to contractile dysfunction and ultimately heart failure.LV remodeling post-MI includes inflammatory,fibrotic,and neovascularization responses that involve regulated cell recruitment and function.Stem cells(SCs)have been transplanted post-MI for treatment of LV remodeling and shown to improve LV function by reduction in scar tissue formation in humans and animal models of MI.The promising results obtained from the application of SCs post-MI have sparked a massive effort to identify the optimal SC for regeneration of cardiomyocytes and the paradigm for clinical applications.Although SC transplantations are generally associated with new tissue formation,SCs also secrete cytokines,chemokines and growth factors that robustly regulate cell behavior in a paracrine fashion during the remodeling process.In this review,the different types of SCs used for cardiomyogenesis,markers of differentiation,paracrine factor secretion,and strategies for cell recruitment and delivery are addressed.

Expression and role of specificity protein 1 in the sclera remodeling of experimental myopia in guinea pigs

AIM：To study the expression of collagen I and transcription factor specificity protein 1（Sp1）,a transforming growth factor-β1（TGF-β1） downstream target,and reveal the impact of the TGF-β1-Sp1 signaling pathway on collagen remodeling in myopic sclera.METHODS：Seventy-five 1-week-old guinea pigs were randomly divided into normal control,form deprivation myopia（FDM）,and self-control groups.FDM was induced for different times using coverage with translucent latex balloons and FDM recovery was performed for 1wk after 4wk treatment;then,changes in refractive power and axial length were measured.Immunohistochemistry and reverse transcription-polymerase chain reaction were used to evaluate dynamic changes in collagen I and Sp1 expression in the sclera of guinea pigs with emmetropia and experimental myopia,and the relationship between collagen I and Sp1 levels was analyzed.RESULTS：In the FDM group,the refractive power was gradually changed（from 2.09±0.30 D at week 0 to-1.23±0.69 D,-4.17±0.59 D,-7.07±0.56 D,and-4.30±0.58 D at weeks 2,4,6,and 1wk after 4wk,respectively;P〈0.05）,indicating deepening of myopia.The axial length was increased（from 5.92±0.39 mm at week 0 to 6.62±0.36 mm,7.30±0.34 mm,7.99±0.32 mm,and 7.41±0.36 mm at weeks 2,4,6,and 1wk after 4wk;P〈0.05）.The m RNA and protein expression of Sp1 and collagen I in the sclera of the FDM group was lower than that of the control groups（P〈0.05）,and the reduction was eye-coverage time-dependent.Furthermore,correlation between Sp1 and collagen I down-regulation in the myopic sclera was observed.CONCLUSION：Our data indicate that transcription factor Sp1 may be involved in the regulation of type I collagensynthesis/degradation during myopic sclera remodeling,suggesting that TGF-β1 signaling plays a role in the development and progression of myopia.