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 ...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.展开更多
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 disor...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.展开更多
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(...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.展开更多
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 th...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.展开更多
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 unclea...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.展开更多
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 skeleta...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.展开更多
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 geneti...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.展开更多
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 o...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.展开更多
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,fractio...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.展开更多
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 populat...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.展开更多
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 inter...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.展开更多
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...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.展开更多
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 cell...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.展开更多
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...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.展开更多
目的探讨免疫调节分子IL-33对绝经后骨质疏松症(postmenopausal osteoporosis,PMOP)模型鼠RANKL/c-Fos/NFATc1信号轴的调控作用及藤黄健骨胶囊(Tenghuang Jiangu capsule,TJC)的干预机制。方法构建PMOP大鼠模型,设置假手术组、PMOP模型...目的探讨免疫调节分子IL-33对绝经后骨质疏松症(postmenopausal osteoporosis,PMOP)模型鼠RANKL/c-Fos/NFATc1信号轴的调控作用及藤黄健骨胶囊(Tenghuang Jiangu capsule,TJC)的干预机制。方法构建PMOP大鼠模型,设置假手术组、PMOP模型组、阳性对照组(0.09 mg/kg)和TJC高、中、低剂量组(0.36、0.18、0.09 g/kg),灌胃给药,每天1次,持续8周。从大鼠末次给药后体质量、骨密度(bone mineral density,BMD)及股骨组织微结构等方面评价TJC的疗效;通过ELISA分析TJC对大鼠血清免疫调节因子IL-33、IL-1、IL-31变化;运用qPCR和Western blotting分析TJC对大鼠股骨OPG、RANKL、RANK、c-Fos、NFATc1表达量的影响。结果与假手术组相比,PMOP模型组大鼠的体质量、骨髓脂肪组织相对面积(relative area of bone marrow adipose tissue,BMAT),IL-1、IL-31变化,RANKL、RANK、c-Fos、NFATc1的表达均出现了明显升高的趋势,而BMD、IL-33变化、OPG的表达则出现了明显下降的趋势(P<0.01);与PMOP模型组相比,TJC高剂量组大鼠体质量出现显著下降趋势、IL-33变化出现显著升高趋势(P<0.01),TJC中、高剂量组大鼠BMAT、RANK的表达出现显著下降趋势、OPG的表达出现显著升高趋势(P<0.05或P<0.01),TJC各剂量组大鼠IL-1、IL-31变化,RANKL、c-Fos、NFATc1出现显著降低趋势,BMD出现显著增加趋势(P<0.05或P<0.01)。结论TJC能够提高PMOP大鼠免疫调控分子IL-33含量,抑制免疫调控分子IL-1、IL-31含量和破骨细胞分化标志分子NFATc1的表达,其机制可能与RANKL/c-Fos/NFATc1抑制骨代谢通路密切相关。展开更多
基金supported by the Key Project of Tianjin Natural Science Foundation (No.21JCZDJC01080)the Tianjin Key Medical Discipline (Specialty) (TJYXZDX K-029A)+1 种基金the Academic Backbone of “Clinical Talent Training and Climbing Plan” of Tianjin Medical University and the Tianjin Health Research ProjectScience and Technology Development Fund of Nanjing Medical University (NMUB20210180)。
文摘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.
基金supported by the Qingdao Medical Research Guidance Plan(2020-WJZD049).
文摘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.
基金The Sixth Batch of Special Support Plans in Anhui Province(No.dlPtzjh20200050)Key Natural Science Research Project of Higher Education Institutions in Anhui Province(No.KJ2020A0426)。
文摘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.
文摘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.
基金supported by the National Natural Science Foundation of China,No.81772452(to NL)the Fujian Province Joint Funds for the Innovation of Science and Technology,No.2020Y9065(to NL)+1 种基金Fujian Province Special Foundation for Natural Science Innovation Project,No.2016B014(to NL)the Natural Science Foundation of Fujian Province,No.2019J01160(to XHJ).
文摘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.
基金supported by the National Key Research and Development Program of China (2022YFD1300400)the 2115 Talent Development Program of China Agricultural University。
文摘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.
基金Italian Association for Cancer Research(AIRC)under IG 2020-ID.25110 projectPOR Campania FESR 2014/2020(Project SATIN)+1 种基金Progetto MISE(F/050011/02/X32)–P.I.Fernando Gianfrancescofunding from the European Calcified Tissue Society(ECTS)and the Italian Society for Osteoporosis,Mineral Metabolism and Skeletal Diseases(SIOMMMS)。
文摘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.
基金supported by National Natural Science Foundation of China (32172759)Shaanxi Provincial Science and Technology Department (2022QFY11-05,2021KJXX-97,2021TD-30).
文摘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.
基金Thailand Science Research and Innovation(TSRI).Contract No.FRB650059/NMA/10the NSRF via the Program Management Unit for Human Resources&Institutional Development,Research and Innovation(grant number B05F640092).
文摘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.
基金supported by awards from the National Institute of Health R21AR069789&R01 AG059775(to LX),R01 AG076786&R01 AG079556The Henry and Marilyn Taub Foundation+4 种基金the Edward P.Evans Foundationthe Mangurian Foundationthe National Aeronautics and Space Administration(to LMC)NIH R21 AR081050,R01 AR056702,P30 AR069655&P50 AR072000(to EMS)University of Rochester Aging Institute and the Dresner MDS foundation(to SY)。
文摘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.
文摘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.
基金General Project of the National Natural Science Foundation of China(81973686)National Key Research and Development Program Project(2019YFC0840608)。
文摘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.
基金Scientific Research Project of Hainan Provincial Department of Education (No.Hnky2018ZD-7)。
文摘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.
基金financially supported by Foundation of Tianjin Municipal Education Commission(2019KJ058).
文摘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.
文摘目的探讨免疫调节分子IL-33对绝经后骨质疏松症(postmenopausal osteoporosis,PMOP)模型鼠RANKL/c-Fos/NFATc1信号轴的调控作用及藤黄健骨胶囊(Tenghuang Jiangu capsule,TJC)的干预机制。方法构建PMOP大鼠模型,设置假手术组、PMOP模型组、阳性对照组(0.09 mg/kg)和TJC高、中、低剂量组(0.36、0.18、0.09 g/kg),灌胃给药,每天1次,持续8周。从大鼠末次给药后体质量、骨密度(bone mineral density,BMD)及股骨组织微结构等方面评价TJC的疗效;通过ELISA分析TJC对大鼠血清免疫调节因子IL-33、IL-1、IL-31变化;运用qPCR和Western blotting分析TJC对大鼠股骨OPG、RANKL、RANK、c-Fos、NFATc1表达量的影响。结果与假手术组相比,PMOP模型组大鼠的体质量、骨髓脂肪组织相对面积(relative area of bone marrow adipose tissue,BMAT),IL-1、IL-31变化,RANKL、RANK、c-Fos、NFATc1的表达均出现了明显升高的趋势,而BMD、IL-33变化、OPG的表达则出现了明显下降的趋势(P<0.01);与PMOP模型组相比,TJC高剂量组大鼠体质量出现显著下降趋势、IL-33变化出现显著升高趋势(P<0.01),TJC中、高剂量组大鼠BMAT、RANK的表达出现显著下降趋势、OPG的表达出现显著升高趋势(P<0.05或P<0.01),TJC各剂量组大鼠IL-1、IL-31变化,RANKL、c-Fos、NFATc1出现显著降低趋势,BMD出现显著增加趋势(P<0.05或P<0.01)。结论TJC能够提高PMOP大鼠免疫调控分子IL-33含量,抑制免疫调控分子IL-1、IL-31含量和破骨细胞分化标志分子NFATc1的表达,其机制可能与RANKL/c-Fos/NFATc1抑制骨代谢通路密切相关。