BACKGROUND Intracranial atherosclerosis,a leading cause of stroke,involves arterial plaque formation.This study explores the link between plaque remodelling patterns and diabetes using high-resolution vessel wall imag...BACKGROUND Intracranial atherosclerosis,a leading cause of stroke,involves arterial plaque formation.This study explores the link between plaque remodelling patterns and diabetes using high-resolution vessel wall imaging(HR-VWI).AIM To investigate the factors of intracranial atherosclerotic remodelling patterns and the relationship between intracranial atherosclerotic remodelling and diabetes mellitus using HR-VWI.METHODS Ninety-four patients diagnosed with middle cerebral artery or basilar artery INTRODUCTION Intracranial atherosclerotic disease is one of the main causes of ischaemic stroke in the world,accounting for approx-imately 10%of transient ischaemic attacks and 30%-50%of ischaemic strokes[1].It is the most common factor among Asian people[2].The adaptive changes in the structure and function of blood vessels that can adapt to changes in the internal and external environment are called vascular remodelling,which is a common and important pathological mechanism in atherosclerotic diseases,and the remodelling mode of atherosclerotic plaques is closely related to the occurrence of stroke.Positive remodelling(PR)is an outwards compensatory remodelling where the arterial wall grows outwards in an attempt to maintain a constant lumen diameter.For a long time,it was believed that the degree of stenosis can accurately reflect the risk of ischaemic stroke[3-5].Previous studies have revealed that lesions without significant luminal stenosis can also lead to acute events[6,7],as summarized in a recent meta-analysis study in which approximately 50%of acute/subacute ischaemic events were due to this type of lesion[6].Research[8,9]has pointed out that the PR of plaques is more dangerous and more likely to cause acute ischaemic stroke.Previous studies[10-13]have found that there are specific vascular remodelling phenomena in the coronary and carotid arteries of diabetic patients.However,due to the deep location and small lumen of intracranial arteries and limitations of imaging techniques,the relationship between intracranial arterial remodelling and diabetes is still unclear.In recent years,with the development of magnetic resonance technology and the emergence of high-resolution(HR)vascular wall imaging,a clear and multidimensional display of the intracranial vascular wall has been achieved.Therefore,in this study,HR wall imaging(HR-VWI)was used to display the remodelling characteristics of bilateral middle cerebral arteries and basilar arteries and to explore the factors of intracranial vascular remodelling and its relationship with diabetes.展开更多
In China, there are approximately 20 million people suffering from peripheral nerve injury and this number is increasing at a rate of 2 million per year. These patients cannot live or work independently and are a heav...In China, there are approximately 20 million people suffering from peripheral nerve injury and this number is increasing at a rate of 2 million per year. These patients cannot live or work independently and are a heavy responsibility on both family and society because of extreme disability and dysfunction caused by peripheral nerve injury (PNI). Thus, repair of PNI has become a major public health issue in China.展开更多
This imaginary transformation from Sméagol to Gollum is a dramatization of the illusive repercussions of mechanical stress affecting bone. This paper presents the main ideas of mechanical stress and bone remodell...This imaginary transformation from Sméagol to Gollum is a dramatization of the illusive repercussions of mechanical stress affecting bone. This paper presents the main ideas of mechanical stress and bone remodelling from a novel’s perspective. The object of this study is to provide evidence for new ways to explore bone’s functional adaptation to mechanical stress made through the copious interpretation and integration of new and existing literature. It tackles the underlying biology of bone cells and how they detect and react to strain stimuli. The different types of mechanical demands in daily activities are sifted through and any misconceptions found fallible in literature are refined. A personal experience of a stress fracture is reviewed to parallel the implications that lead to the incident with the findings on the link between mechanical stress and bone remodelling. Some factors regarding age, gender and ethnicity and the interplay with mechanical stress influencing bone remodelling are considered. Brief overviews of three new medical novelties in bone healing are outlined, hoping that these interventions of proper medical techniques can be a change for the better: one from Gollum to Sméagol rather than vice versa.展开更多
Atrial fibrillation(AF) is the most commonly encountered clinical arrhythmia associated with pronounced mortality and morbidity, which are related to palpitations, fainting, congestive heart failure, and stroke. Prolo...Atrial fibrillation(AF) is the most commonly encountered clinical arrhythmia associated with pronounced mortality and morbidity, which are related to palpitations, fainting, congestive heart failure, and stroke. Prolonged episodes of AF promote AF persistence mainly due to electrical remodelling that alters ion-channel expression and/or function. Micro RNAs(mi RNAs), a new class of noncoding mR NAs of around 22 nucleotides in length, have recently emerged as one of the key players in the geneexpression regulatory networks. The potential roles of miR NAs in controlling AF have recently been investigated. Several recent studies have provided promising results for a better understanding of the molecular mechanisms of AF. In this review, we summarize the mechanism of miR NAs as regulators of ion-channel gene expression and their role in causing AF through electrical remodelling.展开更多
Ventricular remodelling is the main trigger of the development of heart failure. Therefore, the reduction of structural remodelling is known to prevent the development of heart failure. The aim of the present study wa...Ventricular remodelling is the main trigger of the development of heart failure. Therefore, the reduction of structural remodelling is known to prevent the development of heart failure. The aim of the present study was to investigate the effects of OMACOR?, a well known mixture of EPA and DHA in an experimental model of heart failure induced by occlusion of left descending coronary artery and the reperfusion within 2 months. After a long term treatment of 2 months;OMACOR? (100 mg/kg) statistically significantly reduced the expansion of infarcted zone (35% ± 4%, P ± 3% in the vehicle group). The phosphorylation of Cx43 as biomarker of the cardiac remodelling was visualised by immunofluorescence in rat’s heart at the end of the study. In the vehicle-infarcted group, a significant de-phosphorylation of Cx43 was observed (8.2 ± 1.0 u.a, n = 8 compared to 11.8 ± 1.3 u.a in the sham group, n = 9) confirming a remodelling process in the infarcted group. In the group treated with OMACOR?,the de-phosphorylation of Cx43 was no longer observed compared to the sham group (16.4 ± 2.9 u.a, n = 9, NS). The present results demonstrate that a long term treatment with OMA-COR? reduced the infarcted size in experimental models of heart failure and that these anti-remodelling effects are due at least in part by resynchronizing the gap junction activity.展开更多
The present study is to determine the effects of captoprll treatment on myocyte hypertropay. collagen concentration, the total collagen content, type Ⅰ and type,Ⅲ collaged Protein ratio[Ⅰ / Ⅲ (p)] and their mRNA r...The present study is to determine the effects of captoprll treatment on myocyte hypertropay. collagen concentration, the total collagen content, type Ⅰ and type,Ⅲ collaged Protein ratio[Ⅰ / Ⅲ (p)] and their mRNA ratio [Ⅰ / Ⅲ (R)]3 In non-infarcted area(NⅡA), infarcted area(ⅡA) ofleft ventricle (LV) and right ventricle(RV) rollowing myocardial inrarction (MⅡ) in rats. The results showed: ①Captopril treatment can prevent myocyte hypertrophy in CⅡA and RV, but its effectson biochemical remodelling or collaged in CⅡA, RV and ⅡA were different. In NⅡA, the total collagencontent, collagen concentration and the Ⅰ /Ⅲ (P) were returned to their control values respectively.However, captopril treatment only decreased the total collagen content in RV and had no significanteffects on the total collagen content, collagen concentration and Ⅰ /Ⅲ (P) in ⅡA; ② The changes ofⅠ /Ⅲ (R) In CⅡA, ⅡA aam RV showed similar patterns to their Ⅰ /Ⅲ (P) respctily The resultssuggest:① The adulatory mechanism of collageu remodelling may be different in various hypertrophy models. Accompanied'by the regression of myocyte hypertrophy, the changes of collagen matrixmay not occur concurrently; ② The efects of captopril treatment on collagen remodelling may bedue to its decreasing angiotensiu Ⅱ level, and then influencing collagen synthesis of cardiac fibroblast on the level of gene expression.展开更多
Background Nifekalant may prevent atrial fibrillation (AF) and possibly be useful in treatment of atrial tachyarrhythmia in patients with severe heart failure. This study investigated the electophysiologic effect of...Background Nifekalant may prevent atrial fibrillation (AF) and possibly be useful in treatment of atrial tachyarrhythmia in patients with severe heart failure. This study investigated the electophysiologic effect of nifekalant on the acute atrial remodeling in rapid atrial pacing (RAP) model of canine. Methods Twelve mongrel dogs subjected to rapid stimulation (400 beats/min) at left atrial appendage (LAA) for 24 hours, were randomized into the control group (rapid pacing only, n=6) and the nifekalant group (intravenous nifekalant therapy immediately after RAP, n=6). Atrial electrophysiological parameters were measured in right atrium, coronary sinus, LAA, posterior wall of left atrium (PWLA) and left superior pulmonary vein (LSPV), before and after the RAP. Results In the control group, the effective refractory periods (ERP) were shortened greatly at all sites, paced dogs had substantially shorter ERPs in the high right atrium, LAA, and LSPV, but fewer changes in the PWLA, the coefficient variation of ERP (COV ERP) was increased significantly. After rapid atrial stimulation, the inducibility of AF increased significantly [induction number: pre-RAP vs post-RAP, 1.00 ± 0.89 vs 8.17 ± 2.79, P〈0.01; duration of AF: pre-RAP vs post-RAP, (450.34± 362.59) ms vs (9975.77±4376.99) ms, P〈0.01]. In the nifekalant group, although the ERPs were prolonged at all sites compared with those in pre-RAP state, only the value at LSPV differed significantly from that in pre-RAP state [pre-RAP vs post-RAP, (102.50±5.24) ms vs (132.51 ±5.20) ms, P〈0.01]; the COV ERP did not change statistically in this group. The inducibility of AF slightly increased but insignificantly after pacing [induction number: pre-RAP vs post-RAP, 0.83 ±0.75 vs 1.67±0.82, P=0.19; duration of AF: pre-RAP vs post-RAP, (378.67±317.88) ms vs (1124.08± 1109.77) ms, P=0.06]. Conduction time values did not alter significantly in either of the two groups after RAP. Condusions In canine RAP model, nifekalant inhibited ERP shortening and ERP heterogeneity increasing, decreased AF induction. Nifekalant can reverse acute electrical remodeling effect in this model.展开更多
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
Axonal remodeling is a critical aspect of ischemic brain repair processes and contributes to spontaneous functional recovery.Our previous in vitro study demonstrated that exosomes/small extracellular vesicles(sEVs)iso...Axonal remodeling is a critical aspect of ischemic brain repair processes and contributes to spontaneous functional recovery.Our previous in vitro study demonstrated that exosomes/small extracellular vesicles(sEVs)isolated from cerebral endothelial cells(CEC-sEVs)of ischemic brain promote axonal growth of embryonic cortical neurons and that microRNA 27a(miR-27a)is an elevated miRNA in ischemic CEC-sEVs.In the present study,we investigated whether normal CEC-sEVs engineered to enrich their levels of miR-27a(27a-sEVs)further enhance axonal growth and improve neurological outcomes after ischemic stroke when compared with treatment with non-engineered CEC-sEVs.27a-sEVs were isolated from the conditioned medium of healthy mouse CECs transfected with a lentiviral miR-27a expression vector.Small EVs isolated from CECs transfected with a scramble vector(Scra-sEVs)were used as a control.Adult male mice were subjected to permanent middle cerebral artery occlusion and then were randomly treated with 27a-sEVs or Scra-sEVs.An array of behavior assays was used to measure neurological function.Compared with treatment of ischemic stroke with Scra-sEVs,treatment with 27a-sEVs significantly augmented axons and spines in the peri-infarct zone and in the corticospinal tract of the spinal grey matter of the denervated side,and significantly improved neurological outcomes.In vitro studies demonstrated that CEC-sEVs carrying reduced miR-27a abolished 27a-sEV-augmented axonal growth.Ultrastructural analysis revealed that 27a-sEVs systemically administered preferentially localized to the pre-synaptic active zone,while quantitative reverse transcription-polymerase chain reaction and Western Blot analysis showed elevated miR-27a,and reduced axonal inhibitory proteins Semaphorin 6A and Ras Homolog Family Member A in the peri-infarct zone.Blockage of the Clathrin-dependent endocytosis pathway substantially reduced neuronal internalization of 27a-sEVs.Our data provide evidence that 27a-sEVs have a therapeutic effect on stroke recovery by promoting axonal remodeling and improving neurological outcomes.Our findings also suggest that suppression of axonal inhibitory proteins such as Semaphorin 6A may contribute to the beneficial effect of 27a-sEVs on axonal remodeling.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
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
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
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
The mature seed of Paris polyphylla var.chinensis(PPC)is morphophysiologically dormant and develops differently under warm and cold temperatures.To elucidate the molecular mechanisms underlying temperature-dependent r...The mature seed of Paris polyphylla var.chinensis(PPC)is morphophysiologically dormant and develops differently under warm and cold temperatures.To elucidate the molecular mechanisms underlying temperature-dependent regulation of PPC seed dormancy and germination,we investigated the dynamic changes in PPC seed transcript levels under warm and cold temperature stratifications(WS and CS,respectively)by time-resolved RNA sequencing,focusing on genes related to hormone metabolism and signaling and cell wall remodeling(CWRM)and encoding transcription factors/regulators(TFs/TRs).A total of 48765 and 47836 differentially expressed genes(DEGs)were associated with WS and CS,respectively.Of these,17581 and 16652 DEGs,respectively,unique to WS and CS,and 5386 were common to both temperature stratifications across nine analyzed growth stages.The expression of hormone metabolism and signaling,TF/TR,and CWRM genes were closely associated with temperature.More genes related to gibberellin(GA),cytokinin,auxin,and brassinosteroid biosynthetic were upregulated in WS as compared to CS seeds,while genes related to dormancy release and germination were downregulated in WS seeds.However,only GA and abscisic acid levels were altered in PPC seeds breaking morphophysiological dormancy(MPD).Overall,37 TF and five TR families were upregulated whereas 24 TF and 16 TR families were downregulated in WS as compared to CS seeds.Most CWRM families were highly expressed under WS as compared to CS,suggesting that they promote endosperm weakening and embryo growth of WS seeds and facilitate MPD release and germination.A coexpression analysis revealed positive correlations between TFs/TRs and DEGs involved in hormone metabolism and signaling and CWRM.These results provided a basis for investigating the interaction between the endosperm and underdeveloped embryo in the regulation of PPC seed germination and seedling emergence.展开更多
Ischemic stroke is one of the most common causes of mortality and disability worldwide.However,treatment efficacy and the progress of research remain unsatisfactory.As the critical support system and essential compone...Ischemic stroke is one of the most common causes of mortality and disability worldwide.However,treatment efficacy and the progress of research remain unsatisfactory.As the critical support system and essential components in neurovascular units,glial cells and blood vessels(including the bloodbrain barrier)together maintain an optimal microenvironment for neuronal function.They provide nutrients,regulate neuronal excitability,and prevent harmful substances from entering brain tissue.The highly dynamic networks of this support system play an essential role in ischemic stroke through processes including brain homeostasis,supporting neuronal function,and reacting to injuries.However,most studies have focused on postmortem animals,which inevitably lack critical information about the dynamic changes that occur after ischemic stroke.Therefore,a high-precision technique for research in living animals is urgently needed.Two-photon fluorescence laser-scanning microscopy is a powerful imaging technique that can facilitate live imaging at high spatiotemporal resolutions.Twophoton fluorescence laser-scanning microscopy can provide images of the whole-cortex vascular 3D structure,information on multicellular component interactions,and provide images of structure and function in the cranial window.This technique shifts the existing research paradigm from static to dynamic,from flat to stereoscopic,and from single-cell function to multicellular intercommunication,thus providing direct and reliable evidence to identify the pathophysiological mechanisms following ischemic stroke in an intact brain.In this review,we discuss exciting findings from research on the support system after ischemic stroke using two-photon fluorescence laser-scanning microscopy,highlighting the importance of dynamic observations of cellular behavior and interactions in the networks of the brain’s support systems.We show the excellent application prospects and advantages of two-photon fluorescence laser-scanning microscopy and predict future research developments and directions in the study of ischemic stroke.展开更多
The majority of inherited retinal degenerative diseases and dry age-related macular degeneration are characterized by decay of the outer retina and photoreceptors,which leads to progressive loss of vision.The inner re...The majority of inherited retinal degenerative diseases and dry age-related macular degeneration are characterized by decay of the outer retina and photoreceptors,which leads to progressive loss of vision.The inner retina,including second-and third-order retinal neurons,also shows aberrant structural changes at all stages of degeneration.Müller glia,the major glial cells maintain retinal homeostasis,activating and rearranging immediately in response to photoreceptor stress.These phenomena are collectively known as retinal remodeling and are anatomically well described,but their impact on visual function is less well characterized.Retinal remodeling has traditionally been considered a detrimental chain of events that decreases visual function.However,emerging evidence from functional assays suggests that remodeling could also be a part of a survival mechanism wherein the inner retina responds plastically to outer retinal degeneration.The visual system’s first synapses between the photoreceptors and bipolar cells undergo rewiring and functionally compensate to maintain normal signal output to the brain.Distinct classes of retinal ganglion cells remain even after the massive loss of photoreceptors.Müller glia possess the regenerative potential for retinal recovery and possibly exert adaptive transcriptional changes in response to neuronal loss.These types of homeostatic changes could potentially explain the well-maintained visual function observed in patients with inherited retinal degenerative diseases who display prominent anatomic retinal pathology.This review will focus on our current understanding of retinal neuronal and Müller glial adaptation for the potential preservation of retinal activity during photoreceptor degeneration.Targeting retinal self-compensatory responses could help generate universal strategies to delay sensory disease progression.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
基金Supported by National Natural Science Foundation of China,No.82071871Guangdong Basic and Applied Basic Research Foundation,No.2021A1515220131+1 种基金Guangdong Medical Science and Technology Research Fund Project,No.2022111520491834Clinical Research Project of Shenzhen Second People's Hospital,No.20223357022。
文摘BACKGROUND Intracranial atherosclerosis,a leading cause of stroke,involves arterial plaque formation.This study explores the link between plaque remodelling patterns and diabetes using high-resolution vessel wall imaging(HR-VWI).AIM To investigate the factors of intracranial atherosclerotic remodelling patterns and the relationship between intracranial atherosclerotic remodelling and diabetes mellitus using HR-VWI.METHODS Ninety-four patients diagnosed with middle cerebral artery or basilar artery INTRODUCTION Intracranial atherosclerotic disease is one of the main causes of ischaemic stroke in the world,accounting for approx-imately 10%of transient ischaemic attacks and 30%-50%of ischaemic strokes[1].It is the most common factor among Asian people[2].The adaptive changes in the structure and function of blood vessels that can adapt to changes in the internal and external environment are called vascular remodelling,which is a common and important pathological mechanism in atherosclerotic diseases,and the remodelling mode of atherosclerotic plaques is closely related to the occurrence of stroke.Positive remodelling(PR)is an outwards compensatory remodelling where the arterial wall grows outwards in an attempt to maintain a constant lumen diameter.For a long time,it was believed that the degree of stenosis can accurately reflect the risk of ischaemic stroke[3-5].Previous studies have revealed that lesions without significant luminal stenosis can also lead to acute events[6,7],as summarized in a recent meta-analysis study in which approximately 50%of acute/subacute ischaemic events were due to this type of lesion[6].Research[8,9]has pointed out that the PR of plaques is more dangerous and more likely to cause acute ischaemic stroke.Previous studies[10-13]have found that there are specific vascular remodelling phenomena in the coronary and carotid arteries of diabetic patients.However,due to the deep location and small lumen of intracranial arteries and limitations of imaging techniques,the relationship between intracranial arterial remodelling and diabetes is still unclear.In recent years,with the development of magnetic resonance technology and the emergence of high-resolution(HR)vascular wall imaging,a clear and multidimensional display of the intracranial vascular wall has been achieved.Therefore,in this study,HR wall imaging(HR-VWI)was used to display the remodelling characteristics of bilateral middle cerebral arteries and basilar arteries and to explore the factors of intracranial vascular remodelling and its relationship with diabetes.
基金supported by grants from the National Program on Key Basic Research Project of China(973 Program),No.2014CB542200Program for Innovative Research Team in University of Ministry of Education of China,No.IRT1201+1 种基金the National Natural Science Foundation of China,No.31271284,31171150,81171146,30971526,31100860,31040043Program for New Century Excellent Talents in University of Ministry of Education of China,No.BMU20110270
文摘In China, there are approximately 20 million people suffering from peripheral nerve injury and this number is increasing at a rate of 2 million per year. These patients cannot live or work independently and are a heavy responsibility on both family and society because of extreme disability and dysfunction caused by peripheral nerve injury (PNI). Thus, repair of PNI has become a major public health issue in China.
文摘This imaginary transformation from Sméagol to Gollum is a dramatization of the illusive repercussions of mechanical stress affecting bone. This paper presents the main ideas of mechanical stress and bone remodelling from a novel’s perspective. The object of this study is to provide evidence for new ways to explore bone’s functional adaptation to mechanical stress made through the copious interpretation and integration of new and existing literature. It tackles the underlying biology of bone cells and how they detect and react to strain stimuli. The different types of mechanical demands in daily activities are sifted through and any misconceptions found fallible in literature are refined. A personal experience of a stress fracture is reviewed to parallel the implications that lead to the incident with the findings on the link between mechanical stress and bone remodelling. Some factors regarding age, gender and ethnicity and the interplay with mechanical stress influencing bone remodelling are considered. Brief overviews of three new medical novelties in bone healing are outlined, hoping that these interventions of proper medical techniques can be a change for the better: one from Gollum to Sméagol rather than vice versa.
基金Supported by Grants BFU2012-38111(Ministerio de Economíay Competitividad,Gobierno de Espaa),Nos.CTS-1614,P08-CTS-03878,BIO-302(Junta de Andalucia)and AFM2012-16074(AFM)
文摘Atrial fibrillation(AF) is the most commonly encountered clinical arrhythmia associated with pronounced mortality and morbidity, which are related to palpitations, fainting, congestive heart failure, and stroke. Prolonged episodes of AF promote AF persistence mainly due to electrical remodelling that alters ion-channel expression and/or function. Micro RNAs(mi RNAs), a new class of noncoding mR NAs of around 22 nucleotides in length, have recently emerged as one of the key players in the geneexpression regulatory networks. The potential roles of miR NAs in controlling AF have recently been investigated. Several recent studies have provided promising results for a better understanding of the molecular mechanisms of AF. In this review, we summarize the mechanism of miR NAs as regulators of ion-channel gene expression and their role in causing AF through electrical remodelling.
文摘Ventricular remodelling is the main trigger of the development of heart failure. Therefore, the reduction of structural remodelling is known to prevent the development of heart failure. The aim of the present study was to investigate the effects of OMACOR?, a well known mixture of EPA and DHA in an experimental model of heart failure induced by occlusion of left descending coronary artery and the reperfusion within 2 months. After a long term treatment of 2 months;OMACOR? (100 mg/kg) statistically significantly reduced the expansion of infarcted zone (35% ± 4%, P ± 3% in the vehicle group). The phosphorylation of Cx43 as biomarker of the cardiac remodelling was visualised by immunofluorescence in rat’s heart at the end of the study. In the vehicle-infarcted group, a significant de-phosphorylation of Cx43 was observed (8.2 ± 1.0 u.a, n = 8 compared to 11.8 ± 1.3 u.a in the sham group, n = 9) confirming a remodelling process in the infarcted group. In the group treated with OMACOR?,the de-phosphorylation of Cx43 was no longer observed compared to the sham group (16.4 ± 2.9 u.a, n = 9, NS). The present results demonstrate that a long term treatment with OMA-COR? reduced the infarcted size in experimental models of heart failure and that these anti-remodelling effects are due at least in part by resynchronizing the gap junction activity.
文摘The present study is to determine the effects of captoprll treatment on myocyte hypertropay. collagen concentration, the total collagen content, type Ⅰ and type,Ⅲ collaged Protein ratio[Ⅰ / Ⅲ (p)] and their mRNA ratio [Ⅰ / Ⅲ (R)]3 In non-infarcted area(NⅡA), infarcted area(ⅡA) ofleft ventricle (LV) and right ventricle(RV) rollowing myocardial inrarction (MⅡ) in rats. The results showed: ①Captopril treatment can prevent myocyte hypertrophy in CⅡA and RV, but its effectson biochemical remodelling or collaged in CⅡA, RV and ⅡA were different. In NⅡA, the total collagencontent, collagen concentration and the Ⅰ /Ⅲ (P) were returned to their control values respectively.However, captopril treatment only decreased the total collagen content in RV and had no significanteffects on the total collagen content, collagen concentration and Ⅰ /Ⅲ (P) in ⅡA; ② The changes ofⅠ /Ⅲ (R) In CⅡA, ⅡA aam RV showed similar patterns to their Ⅰ /Ⅲ (P) respctily The resultssuggest:① The adulatory mechanism of collageu remodelling may be different in various hypertrophy models. Accompanied'by the regression of myocyte hypertrophy, the changes of collagen matrixmay not occur concurrently; ② The efects of captopril treatment on collagen remodelling may bedue to its decreasing angiotensiu Ⅱ level, and then influencing collagen synthesis of cardiac fibroblast on the level of gene expression.
文摘Background Nifekalant may prevent atrial fibrillation (AF) and possibly be useful in treatment of atrial tachyarrhythmia in patients with severe heart failure. This study investigated the electophysiologic effect of nifekalant on the acute atrial remodeling in rapid atrial pacing (RAP) model of canine. Methods Twelve mongrel dogs subjected to rapid stimulation (400 beats/min) at left atrial appendage (LAA) for 24 hours, were randomized into the control group (rapid pacing only, n=6) and the nifekalant group (intravenous nifekalant therapy immediately after RAP, n=6). Atrial electrophysiological parameters were measured in right atrium, coronary sinus, LAA, posterior wall of left atrium (PWLA) and left superior pulmonary vein (LSPV), before and after the RAP. Results In the control group, the effective refractory periods (ERP) were shortened greatly at all sites, paced dogs had substantially shorter ERPs in the high right atrium, LAA, and LSPV, but fewer changes in the PWLA, the coefficient variation of ERP (COV ERP) was increased significantly. After rapid atrial stimulation, the inducibility of AF increased significantly [induction number: pre-RAP vs post-RAP, 1.00 ± 0.89 vs 8.17 ± 2.79, P〈0.01; duration of AF: pre-RAP vs post-RAP, (450.34± 362.59) ms vs (9975.77±4376.99) ms, P〈0.01]. In the nifekalant group, although the ERPs were prolonged at all sites compared with those in pre-RAP state, only the value at LSPV differed significantly from that in pre-RAP state [pre-RAP vs post-RAP, (102.50±5.24) ms vs (132.51 ±5.20) ms, P〈0.01]; the COV ERP did not change statistically in this group. The inducibility of AF slightly increased but insignificantly after pacing [induction number: pre-RAP vs post-RAP, 0.83 ±0.75 vs 1.67±0.82, P=0.19; duration of AF: pre-RAP vs post-RAP, (378.67±317.88) ms vs (1124.08± 1109.77) ms, P=0.06]. Conduction time values did not alter significantly in either of the two groups after RAP. Condusions In canine RAP model, nifekalant inhibited ERP shortening and ERP heterogeneity increasing, decreased AF induction. Nifekalant can reverse acute electrical remodeling effect in this model.
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 NIH grants,R01 NS111801(to ZGZ)American Heart Association 16SDG29860003(to YZ)。
文摘Axonal remodeling is a critical aspect of ischemic brain repair processes and contributes to spontaneous functional recovery.Our previous in vitro study demonstrated that exosomes/small extracellular vesicles(sEVs)isolated from cerebral endothelial cells(CEC-sEVs)of ischemic brain promote axonal growth of embryonic cortical neurons and that microRNA 27a(miR-27a)is an elevated miRNA in ischemic CEC-sEVs.In the present study,we investigated whether normal CEC-sEVs engineered to enrich their levels of miR-27a(27a-sEVs)further enhance axonal growth and improve neurological outcomes after ischemic stroke when compared with treatment with non-engineered CEC-sEVs.27a-sEVs were isolated from the conditioned medium of healthy mouse CECs transfected with a lentiviral miR-27a expression vector.Small EVs isolated from CECs transfected with a scramble vector(Scra-sEVs)were used as a control.Adult male mice were subjected to permanent middle cerebral artery occlusion and then were randomly treated with 27a-sEVs or Scra-sEVs.An array of behavior assays was used to measure neurological function.Compared with treatment of ischemic stroke with Scra-sEVs,treatment with 27a-sEVs significantly augmented axons and spines in the peri-infarct zone and in the corticospinal tract of the spinal grey matter of the denervated side,and significantly improved neurological outcomes.In vitro studies demonstrated that CEC-sEVs carrying reduced miR-27a abolished 27a-sEV-augmented axonal growth.Ultrastructural analysis revealed that 27a-sEVs systemically administered preferentially localized to the pre-synaptic active zone,while quantitative reverse transcription-polymerase chain reaction and Western Blot analysis showed elevated miR-27a,and reduced axonal inhibitory proteins Semaphorin 6A and Ras Homolog Family Member A in the peri-infarct zone.Blockage of the Clathrin-dependent endocytosis pathway substantially reduced neuronal internalization of 27a-sEVs.Our data provide evidence that 27a-sEVs have a therapeutic effect on stroke recovery by promoting axonal remodeling and improving neurological outcomes.Our findings also suggest that suppression of axonal inhibitory proteins such as Semaphorin 6A may contribute to the beneficial effect of 27a-sEVs on axonal remodeling.
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 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 CAMS Innovation Fund for Medical Sciences (CIFMS) (2017-I2M-3-013)the National Key Research and Development Program of China (Grant No. 2017YFC1700706)the National Natural Science Foundation of China (Grant No. 31471575).
文摘The mature seed of Paris polyphylla var.chinensis(PPC)is morphophysiologically dormant and develops differently under warm and cold temperatures.To elucidate the molecular mechanisms underlying temperature-dependent regulation of PPC seed dormancy and germination,we investigated the dynamic changes in PPC seed transcript levels under warm and cold temperature stratifications(WS and CS,respectively)by time-resolved RNA sequencing,focusing on genes related to hormone metabolism and signaling and cell wall remodeling(CWRM)and encoding transcription factors/regulators(TFs/TRs).A total of 48765 and 47836 differentially expressed genes(DEGs)were associated with WS and CS,respectively.Of these,17581 and 16652 DEGs,respectively,unique to WS and CS,and 5386 were common to both temperature stratifications across nine analyzed growth stages.The expression of hormone metabolism and signaling,TF/TR,and CWRM genes were closely associated with temperature.More genes related to gibberellin(GA),cytokinin,auxin,and brassinosteroid biosynthetic were upregulated in WS as compared to CS seeds,while genes related to dormancy release and germination were downregulated in WS seeds.However,only GA and abscisic acid levels were altered in PPC seeds breaking morphophysiological dormancy(MPD).Overall,37 TF and five TR families were upregulated whereas 24 TF and 16 TR families were downregulated in WS as compared to CS seeds.Most CWRM families were highly expressed under WS as compared to CS,suggesting that they promote endosperm weakening and embryo growth of WS seeds and facilitate MPD release and germination.A coexpression analysis revealed positive correlations between TFs/TRs and DEGs involved in hormone metabolism and signaling and CWRM.These results provided a basis for investigating the interaction between the endosperm and underdeveloped embryo in the regulation of PPC seed germination and seedling emergence.
基金supported by grants from the National Natural Science Foundation of China,Nos.92148206,82071330(to ZPT)82201745(to HN)the Natural Science Foundation of Hubei Province,China,Nos.2021BCA109(to ZPT)and 2021CFB067(to HN)。
文摘Ischemic stroke is one of the most common causes of mortality and disability worldwide.However,treatment efficacy and the progress of research remain unsatisfactory.As the critical support system and essential components in neurovascular units,glial cells and blood vessels(including the bloodbrain barrier)together maintain an optimal microenvironment for neuronal function.They provide nutrients,regulate neuronal excitability,and prevent harmful substances from entering brain tissue.The highly dynamic networks of this support system play an essential role in ischemic stroke through processes including brain homeostasis,supporting neuronal function,and reacting to injuries.However,most studies have focused on postmortem animals,which inevitably lack critical information about the dynamic changes that occur after ischemic stroke.Therefore,a high-precision technique for research in living animals is urgently needed.Two-photon fluorescence laser-scanning microscopy is a powerful imaging technique that can facilitate live imaging at high spatiotemporal resolutions.Twophoton fluorescence laser-scanning microscopy can provide images of the whole-cortex vascular 3D structure,information on multicellular component interactions,and provide images of structure and function in the cranial window.This technique shifts the existing research paradigm from static to dynamic,from flat to stereoscopic,and from single-cell function to multicellular intercommunication,thus providing direct and reliable evidence to identify the pathophysiological mechanisms following ischemic stroke in an intact brain.In this review,we discuss exciting findings from research on the support system after ischemic stroke using two-photon fluorescence laser-scanning microscopy,highlighting the importance of dynamic observations of cellular behavior and interactions in the networks of the brain’s support systems.We show the excellent application prospects and advantages of two-photon fluorescence laser-scanning microscopy and predict future research developments and directions in the study of ischemic stroke.
基金supported by NIH R01EY032492Boston Children’s Hospital(OFD/BTREC/CTREC Faculty Career Development Grant 97906,Pilot Grant 92214,and Ophthalmology Foundation 85010)+5 种基金Mass Lions Eye Foundation 87820Blind Children’s Center 89282(to ZF)Academy of Finland grant 346295Finnish Eye and Tissue Bank FoundationRetina Registered Association(Finland)Sokeain Yst?v?t/De Blindas V?nner Registered Association(to HOL)。
文摘The majority of inherited retinal degenerative diseases and dry age-related macular degeneration are characterized by decay of the outer retina and photoreceptors,which leads to progressive loss of vision.The inner retina,including second-and third-order retinal neurons,also shows aberrant structural changes at all stages of degeneration.Müller glia,the major glial cells maintain retinal homeostasis,activating and rearranging immediately in response to photoreceptor stress.These phenomena are collectively known as retinal remodeling and are anatomically well described,but their impact on visual function is less well characterized.Retinal remodeling has traditionally been considered a detrimental chain of events that decreases visual function.However,emerging evidence from functional assays suggests that remodeling could also be a part of a survival mechanism wherein the inner retina responds plastically to outer retinal degeneration.The visual system’s first synapses between the photoreceptors and bipolar cells undergo rewiring and functionally compensate to maintain normal signal output to the brain.Distinct classes of retinal ganglion cells remain even after the massive loss of photoreceptors.Müller glia possess the regenerative potential for retinal recovery and possibly exert adaptive transcriptional changes in response to neuronal loss.These types of homeostatic changes could potentially explain the well-maintained visual function observed in patients with inherited retinal degenerative diseases who display prominent anatomic retinal pathology.This review will focus on our current understanding of retinal neuronal and Müller glial adaptation for the potential preservation of retinal activity during photoreceptor degeneration.Targeting retinal self-compensatory responses could help generate universal strategies to delay sensory disease progression.
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.