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
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
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
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
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
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
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
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...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.展开更多
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, incre...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.展开更多
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 investi...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.展开更多
Type 2 diabetes(T2 D) is associated with systemic abnormal bone remodeling and bone loss. Meanwhile,abnormal subchondral bone remodeling induces cartilage degradation, resulting in osteoarthritis(OA).Accordingly, we i...Type 2 diabetes(T2 D) is associated with systemic abnormal bone remodeling and bone loss. Meanwhile,abnormal subchondral bone remodeling induces cartilage degradation, resulting in osteoarthritis(OA).Accordingly, we investigated alterations in subchondral bone remodeling, microstructure and strength in knees from T2 D patients and their association with cartilage degradation. Tibial plateaus were collected from knee OA patients undergoing total knee arthroplasty and divided into non-diabetic(n = 70) and diabetes(n = 51) groups. Tibial plateaus were also collected from cadaver donors(n = 20) and used as controls.Subchondral bone microstructure was assessed using micro-computed tomography. Bone strength was evaluated by micro-finite-element analysis. Cartilage degradation was estimated using histology. The expression of tartrate-resistant acidic phosphatase(TRAP), osterix, and osteocalcin were calculated using immunohistochemistry. Osteoarthritis Research Society International(OARSI) scores of lateral tibial plateau did not differ between non-diabetic and diabetes groups, while higher OARSI scores on medial side were detected in diabetes group. Lower bone volume fraction and trabecular number and higher structure model index were found on both sides in diabetes group. These microstructural alterations translated into lower elastic modulus in diabetes group. Moreover, diabetes group had a larger number of TRAP^+ osteoclasts and lower number of Osterix^+ osteoprogenitors and Osteocalcin^+ osteoblasts. T2 D knees are characterized by abnormal subchondral bone remodeling and microstructural and mechanical impairments, which were associated with exacerbated cartilage degradation. In regions with intact cartilage the underlying bone still had abnormal remodeling in diabetes group, suggesting that abnormal bone remodeling may contribute to the early pathogenesis of T2 D-associated knee OA.展开更多
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 contract...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.展开更多
Tumor growth and metastasis depend on the establishment of tumor vasculature to provide oxygen,nutrients,and other essential factors.The well-known vascular endothelial growth factor(VEGF) signaling is crucial for spr...Tumor growth and metastasis depend on the establishment of tumor vasculature to provide oxygen,nutrients,and other essential factors.The well-known vascular endothelial growth factor(VEGF) signaling is crucial for sprouting angiogenesis as well as recruitment of circulating progenitor endothelial cells to tumor vasculature,which has become therapeutic targets in clinical practice.However,the survival benefits gained from targeting VEGF signaling have been very limited,with the inevitable development of treatment resistance.In this article,we discuss the most recent findings and understanding on how solid tumors evade VEGF-targeted therapy,with a special focus on vessel co-option,vessel remodeling,and tumor cell-derived vasculature establishment.Vessel co-option may occur in tumors independently of sprouting angiogenesis,and sprouting angiogenesis is not always required for tumor growth.The differences between vessel-like structure and tubule-like structure formed by tumor cells are also introduced.The exploration of the underlying mechanisms of these alternative angiogenic approaches would not only widen our knowledge of tumor angiogenesis but also provide novel therapeutic targets for better controlling cancer growth and metastasis.展开更多
Elevated concentrations of plasma fatty acids in transition dairy cows are significantly associated with increased disease susceptibility and poor lactation performance. The main source of plasma fatty acids throughou...Elevated concentrations of plasma fatty acids in transition dairy cows are significantly associated with increased disease susceptibility and poor lactation performance. The main source of plasma fatty acids throughout the transition period is lipolysis from adipose tissue depots. During this time, plasma fatty acids serve as a source of calories mitigating the negative energy balance prompted by copious milk synthesis and limited dry matter intake.Past research has demonstrated that lipolysis in the adipose organ is a complex process that includes not only the activation of lipolytic pathways in response to neural, hormonal, or paracrine stimuli, but also important changes in the structure and cellular distribution of the tissue in a process known as adipose tissue remodeling. This process involves an inflammatory response with immune cell migration, proliferation of the cellular components of the stromal vascular fraction, and changes in the extracellular matrix. This review summarizes current knowledge on lipolysis in dairy cattle, expands on the new field of adipose tissue remodeling, and discusses how these biological processes affect transition cow health and productivity.展开更多
Stroke remains the leading cause of long-term disability.Hemiparesis is one of the most common post-stroke motor deficits and is largely attributed to loss or disruption of the motor signals from the affected motor co...Stroke remains the leading cause of long-term disability.Hemiparesis is one of the most common post-stroke motor deficits and is largely attributed to loss or disruption of the motor signals from the affected motor cortex.As the only direct descending motor pathway,the corticospinal tract(CST)is the primary pathway to innervate spinal motor neurons,and thus,forms the neuroanatomical basis to control the peripheral muscles for voluntary movements.Here,we review evidence from both experimental animals and stroke patients,regarding CST axonal damage,functional contribution of CST axonal integrity and remodeling to neurological recovery,and therapeutic approaches aimed to enhance CST axonal remodeling after stroke.The new insights gleaned from preclinical and clinical studies may encourage the development of more rational therapeutics with a strategy targeted to promote axonal rewiring for corticospinal innervation,which will significantly impact the current clinical needs of subacute and chronic stroke treatment.展开更多
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.
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 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 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.
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.
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.
基金supported by a grant from Science and Technology Planning Project of Heilongjiang Province,China(GB08C402-01)
文摘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.
文摘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.
文摘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.
基金supported by National Natural Science Foundation of China(NSFC Nos.81601930 and U1613224)Natural Science Foundation of Guangxi(2016JJB140050)+1 种基金Research Grant Council of Hong Kong(HKU715213 and 17206916)Shenzhen Peacock Project
文摘Type 2 diabetes(T2 D) is associated with systemic abnormal bone remodeling and bone loss. Meanwhile,abnormal subchondral bone remodeling induces cartilage degradation, resulting in osteoarthritis(OA).Accordingly, we investigated alterations in subchondral bone remodeling, microstructure and strength in knees from T2 D patients and their association with cartilage degradation. Tibial plateaus were collected from knee OA patients undergoing total knee arthroplasty and divided into non-diabetic(n = 70) and diabetes(n = 51) groups. Tibial plateaus were also collected from cadaver donors(n = 20) and used as controls.Subchondral bone microstructure was assessed using micro-computed tomography. Bone strength was evaluated by micro-finite-element analysis. Cartilage degradation was estimated using histology. The expression of tartrate-resistant acidic phosphatase(TRAP), osterix, and osteocalcin were calculated using immunohistochemistry. Osteoarthritis Research Society International(OARSI) scores of lateral tibial plateau did not differ between non-diabetic and diabetes groups, while higher OARSI scores on medial side were detected in diabetes group. Lower bone volume fraction and trabecular number and higher structure model index were found on both sides in diabetes group. These microstructural alterations translated into lower elastic modulus in diabetes group. Moreover, diabetes group had a larger number of TRAP^+ osteoclasts and lower number of Osterix^+ osteoprogenitors and Osteocalcin^+ osteoblasts. T2 D knees are characterized by abnormal subchondral bone remodeling and microstructural and mechanical impairments, which were associated with exacerbated cartilage degradation. In regions with intact cartilage the underlying bone still had abnormal remodeling in diabetes group, suggesting that abnormal bone remodeling may contribute to the early pathogenesis of T2 D-associated knee OA.
文摘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.
基金supported by grants from the National Natural Science Foundation of China(No.81472386,81472380,81272340,and 81030043)the National High Technology Research and Development Program of China (863 Program,No.2012AA02A501)
文摘Tumor growth and metastasis depend on the establishment of tumor vasculature to provide oxygen,nutrients,and other essential factors.The well-known vascular endothelial growth factor(VEGF) signaling is crucial for sprouting angiogenesis as well as recruitment of circulating progenitor endothelial cells to tumor vasculature,which has become therapeutic targets in clinical practice.However,the survival benefits gained from targeting VEGF signaling have been very limited,with the inevitable development of treatment resistance.In this article,we discuss the most recent findings and understanding on how solid tumors evade VEGF-targeted therapy,with a special focus on vessel co-option,vessel remodeling,and tumor cell-derived vasculature establishment.Vessel co-option may occur in tumors independently of sprouting angiogenesis,and sprouting angiogenesis is not always required for tumor growth.The differences between vessel-like structure and tubule-like structure formed by tumor cells are also introduced.The exploration of the underlying mechanisms of these alternative angiogenic approaches would not only widen our knowledge of tumor angiogenesis but also provide novel therapeutic targets for better controlling cancer growth and metastasis.
基金supported in part by USDA-NIFA(Washington,DC)grants 2014-68004-21972 and 2015-67015-23207Department of Large Animal Clinical Sciences(East Lansing,MI)+2 种基金the Michigan State University Elwood Kirkpatrick Dairy Science Research Endowment(East Lansing,MI)Michigan Alliance for Animal Agriculture(East Lansing,Michigan)Michigan Animal Health Foundation
文摘Elevated concentrations of plasma fatty acids in transition dairy cows are significantly associated with increased disease susceptibility and poor lactation performance. The main source of plasma fatty acids throughout the transition period is lipolysis from adipose tissue depots. During this time, plasma fatty acids serve as a source of calories mitigating the negative energy balance prompted by copious milk synthesis and limited dry matter intake.Past research has demonstrated that lipolysis in the adipose organ is a complex process that includes not only the activation of lipolytic pathways in response to neural, hormonal, or paracrine stimuli, but also important changes in the structure and cellular distribution of the tissue in a process known as adipose tissue remodeling. This process involves an inflammatory response with immune cell migration, proliferation of the cellular components of the stromal vascular fraction, and changes in the extracellular matrix. This review summarizes current knowledge on lipolysis in dairy cattle, expands on the new field of adipose tissue remodeling, and discusses how these biological processes affect transition cow health and productivity.
文摘Stroke remains the leading cause of long-term disability.Hemiparesis is one of the most common post-stroke motor deficits and is largely attributed to loss or disruption of the motor signals from the affected motor cortex.As the only direct descending motor pathway,the corticospinal tract(CST)is the primary pathway to innervate spinal motor neurons,and thus,forms the neuroanatomical basis to control the peripheral muscles for voluntary movements.Here,we review evidence from both experimental animals and stroke patients,regarding CST axonal damage,functional contribution of CST axonal integrity and remodeling to neurological recovery,and therapeutic approaches aimed to enhance CST axonal remodeling after stroke.The new insights gleaned from preclinical and clinical studies may encourage the development of more rational therapeutics with a strategy targeted to promote axonal rewiring for corticospinal innervation,which will significantly impact the current clinical needs of subacute and chronic stroke treatment.
