Drug development for Alzheimer’s disease is extremely challenging,as demonstrated by the repeated failures of amyloid-β-targeted therapeutics and the controversies surrounding the amyloid-βcascade hypothesis.More r...Drug development for Alzheimer’s disease is extremely challenging,as demonstrated by the repeated failures of amyloid-β-targeted therapeutics and the controversies surrounding the amyloid-βcascade hypothesis.More recently,advances in the development of Lecanemab,an anti-amyloid-βmonoclonal antibody,have shown positive results in reducing brain A burden and slowing cognitive decline in patients with early-stage Alzheimer’s disease in the Phase Ⅲ clinical trial(Clarity Alzheimer’s disease).Despite these promising results,side effects such as amyloid-related imaging abnormalities(ARIA)may limit its usage.ARIA can manifest as ARIA-E(cerebral edema or effusions)and ARIA-H(microhemorrhages or superficial siderosis)and is thought to be caused by increased vascular permeability due to inflammatory responses,leading to leakages of blood products and protein-rich fluid into brain parenchyma.Endothelial dysfunction is an early pathological feature of Alzheimer’s disease,and the blood-brain barrier becomes increasingly leaky as the disease progresses.In addition,APOE4,the strongest genetic risk factor for Alzheimer’s disease,is associated with higher vascular amyloid burden,increased ARIA incidence,and accelerated blood-brain barrier disruptions.These interconnected vascular abnormalities highlight the importance of vascular contributions to the pathophysiology of Alzheimer’s disease.Here,we will closely examine recent research evaluating the heterogeneity of brain endothelial cells in the microvasculature of different brain regions and their relationships with Alzheimer’s disease progression.展开更多
Dengue fever is an acute infectious disease caused by the dengue virus and transmitted by mosquito vectors[1].Its clinical manifestations include high fever,headache,muscle and joint pain,and rash.It holds a significa...Dengue fever is an acute infectious disease caused by the dengue virus and transmitted by mosquito vectors[1].Its clinical manifestations include high fever,headache,muscle and joint pain,and rash.It holds a significant position in global public health.In recent years,its incidence has continued to rise worldwide[2],making it one of the major diseases threatening human health.The disease course of dengue fever is divided into three typical phases:the acute febrile phase,the critical phase,and the recovery phase.While most patients experience mild symptoms,some may progress to severe dengue and potentially fatal outcomes if not promptly and effectively treated during the critical phase.展开更多
Repairing the endothelial barrier is essential for maintaining pulmonary fuid balance and regulating leukocyte infiltration during sepsis[1].Tissue kallikrein-related peptidases(KLKs)are secreted serine proteases invo...Repairing the endothelial barrier is essential for maintaining pulmonary fuid balance and regulating leukocyte infiltration during sepsis[1].Tissue kallikrein-related peptidases(KLKs)are secreted serine proteases involved in angiogenesis[2].However,their involvement in regulating endothelial regeneration remains largely unknown.展开更多
Introduction Fuchs endothelial corneal dystrophy(FECD)is an inherited,degenerative disease of the corneal endothelial cells(CECs).It is characterized by a progressive deterioration of endothelial cells,altered extrace...Introduction Fuchs endothelial corneal dystrophy(FECD)is an inherited,degenerative disease of the corneal endothelial cells(CECs).It is characterized by a progressive deterioration of endothelial cells,altered extracellular matrix(ECM)production,and development of guttae(1,2).The presence of guttae has been shown to significantly impair corneal endothelial function,leading to corneal oedema and visual impairment.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
AIM: To establish the role of vascular endothelial growth factor (VEGF) in the oncogenesis of human gastric carcinoma more directly. METHODS: The expression of VEGF and its receptor kinase-domain insert containing rec...AIM: To establish the role of vascular endothelial growth factor (VEGF) in the oncogenesis of human gastric carcinoma more directly. METHODS: The expression of VEGF and its receptor kinase-domain insert containing receptor (KDR) in human gastric cancer tissue were observed by immunohistochemical staining. VEGF levels were manipulated in human gastric cancer cell using eukaryotic expression constructs designed to express the complete VEGF(165) complimentary DNA in either the sense or antisense orientation. The biological changes of the cells were observed in which VEGF was up-regulated or down-regulated. RESULTS: VEGF-positive rate was 50%, and VEGF was mainly localized in the cytoplasm and membrane of the tumor cells, while KDR was mainly located in the membrane of vascular endothelial cells in gastric cancer tissues and peri-cancerous tissue. In 2 cases of 50 specimens, the gastric cancer cells expressed KDR, localized in both the cytoplasm and membrane. Introduction of VEGF(165) antisense into human gastric cancer cells (SGC-7901, immunofluorescence intensity, 31.6%)) resulted in a significant reduction in VEGF-specific messenger RNA and total and cell surface VEGF protein (immunofluorescence intensity, 8.9%) (P【0.05). Conversely, stable integration of VEGF(165) in the sense orientation resulted in an increase in cellular and cell surface VEGF (immunofluorescence intensity, 75.4%) (P【0.05). Lowered VEGF levels were associated with a marked decrease in the growth of nude mouse xenografted tumor (at 33 days postimplantation, tumor volume: 345.40 +/- 136.31 mm3)(P【0.05 vs control SGC-7901 group: 1534.40 +/- 362.88 mm3), whereas up-regulation of VEGF resulted in increased xenografted tumor size (at 33 days postimplantation, tumor volume: 2350.50 +/- 637.70 mm3) (P【0.05 vs control SGC-7901 group). CONCLUSION: This study provides direct evidence that VEGF plays an important role in the oncogenesis of human gastric cancer.展开更多
The endothelium modulates vascular homeostasis owing to a variety of vasoconstrictors and vasodilators.Endothelial dysfunction(ED),characterized by impaired vasodilation,inflammation,and thrombosis,triggers future car...The endothelium modulates vascular homeostasis owing to a variety of vasoconstrictors and vasodilators.Endothelial dysfunction(ED),characterized by impaired vasodilation,inflammation,and thrombosis,triggers future cardiovascular(CV)diseases.Chronic kidney disease,a state of chronic inflammation caused by oxidative stress,metabolic abnormalities,infection,and uremic toxins damages the endothelium.ED is also associated with a decline in estimated glomerular filtration rate.After kidney transplantation,endothelial functions undergo immediate but partial restoration,promising graft longevity and enhanced CV health.However,the anticipated CV outcomes do not happen due to various transplant-related and unrelated risk factors for ED,culminating in poor CV health and graft survival.ED in kidney transplant recipients is an underrecognized and poorly studied entity.CV diseases are the leading cause of death among kidney transplant candidates with functioning grafts.ED contributes to the pathogenesis of many of the CV diseases.Various biomarkers and vasoreactivity tests are available to study endothelial functions.With an increasing number of transplants happening every year,and improved graft rejection rates due to the availability of effective immunosuppressants,the focus has now shifted to endothelial protection for the prevention,early recognition,and treatment of CV diseases.展开更多
Exosomes have shown good potential in ischemic injury disease treatments.However,evidence about their effect and molecular mechanisms in osteonecrosis of femoral head(ONFH)treatment is still limited.Here,we revealed t...Exosomes have shown good potential in ischemic injury disease treatments.However,evidence about their effect and molecular mechanisms in osteonecrosis of femoral head(ONFH)treatment is still limited.Here,we revealed the cell biology characters of ONFH osteonecrosis area bone tissue in single cell scale and thus identified a novel ONFH treatment approach based on M2 macrophages-derived exosomes(M2-Exos).We further show that M2-Exos are highly effective in the treatment of ONFH by modulating the phenotypes communication between neutrophil and endothelium including neutrophil extracellular traps formation and endothelial phenotype transition.Additionally,we identified that M2-Exos’therapeutic effect is attributed to the high content of miR-93-5p and constructed miR-93-5p overexpression model in vitro and in vivo based on lentivirus and adenoassociated virus respectively.Then we found miR-93-5p can not only reduce neutrophil extracellular traps formation but also improve angiogenic ability of endothelial cells.These results provided a new theoretical basis for the clinical application of ONFH therapeutic exosomes.展开更多
AIM:To assess the relationship between serological parameters and the prognosis of young patients with retinal vein occlusion(RVO)after intravitreal conbercept injection(IVC).METHODS:This study enrolled 100 young pati...AIM:To assess the relationship between serological parameters and the prognosis of young patients with retinal vein occlusion(RVO)after intravitreal conbercept injection(IVC).METHODS:This study enrolled 100 young patients(≤50 years old)diagnosed with RVO-related macular edema(RVO-ME)who had been undergoing IVC at the 474 Hospital in Xinjiang between January 2022 and October 2023.Patients were categorized into two groups:70 eyes in the effective group and 30 eyes in the ineffective group.The effective group comprised patients exhibiting a visual acuity improvement of≥2 lines at the last follow-up,with resolved ME and central macular thickness(CMT)<300μm.Conversely,the ineffective group included patients with visual acuity improvement of<1 line,persistent ME,and CMT≥300μm at the last follow-up.Serological parameters,including white blood cell count,neutrophil count,lymphocyte count,monocyte count,and mean platelet volume were assessed before treatment.The correlation between bestcorrected visual acuity(BCVA)and neutrophil-to-lymphocyte ratio(NLR),platelet-to-lymphocyte ratio(PLR),systemic immune inflammation index(SII),and systemic immune response index(SIRI)was analyzed.Additionally,the association between these serological parameters and the efficacy of IVC was explored.RESULTS:Three months after treatment,the effective group demonstrated a significant improvement in BCVA from 0.82±0.20 to 0.36±0.10,with a concurrent decrease in CMT from 661.28±163.90 to 200.61±82.45μm(P<0.001).Conversely,the ineffective group exhibited minimal changes in BCVA(0.86±0.25 to 0.82±0.14)and CMT(669.84±164.95 to 492.13±138.67μm,P<0.001).The differences in BCVA and CMT between the two groups were statistically significant(P<0.001).According to subgroup analysis,in patients with central RVO(CRVO),BCVA improved from 0.82±0.23 to 0.49±0.12 in the effective group and from 0.80±0.18 to 0.76±0.22 in the ineffective group(P<0.001).The CMT changes followed a similar pattern.In patients with branch RVO(BRVO),comparable trends in BCVA and CMT changes were observed between the effective and ineffective groups(P<0.001).Additionally,the effective group exhibited higher PLR and SII values than the ineffective group(P<0.05).Further CRVO and BRVO subgroups analysis exhibited consistent PLR and SII value trends.CONCLUSION:Compared to other inflammatory factors,elevated PLR and SII levels before treatment are better predictors of outcomes in young RVO-ME patients undergoing IVC treatment.展开更多
AIM:To determine the therapeutic benefits of fenofibrate(Feno)on the dysfunction of high glucose(HG)-induced human retinal microvascular endothelial cells(HRMECs)and to elucidate the underlying molecular mechanism.MET...AIM:To determine the therapeutic benefits of fenofibrate(Feno)on the dysfunction of high glucose(HG)-induced human retinal microvascular endothelial cells(HRMECs)and to elucidate the underlying molecular mechanism.METHODS:HRMEC dysfunction model was established by 48h glucose(30 mmol/L)treatment and treated with Feno/NOD-like receptor thermal protein domain associated protein 3(NLRP3)inflammasome activator(Nigericin).Cell viability/apoptosis were assessed by cell counting kit-8(CCK-8)/terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay(TUNEL)staining and flow cytometry assays.Levels of apoptosis-(Bcl-2-associated X protein,Bax/B-cell lymphoma 2,Bcl-2),vascular permeability-(vascular endothelial growth factor,VEGF)and inflammasome activation-related proteins(NLRP3/cleaved caspase-1/apoptosis-associated speck-like protein containing a CARD,ASC),as well as inflammatory factors(interleukin,IL-6/IL-1β/tumor necrosis factor,TNF-α/IL-18)were determined with Western blot/enzyme linked immunosorbent assay(ELISA).Cell permeability/reactive oxygen species(ROS)level/superoxide dismutase(SOD)activity/malondialdehyde(MDA)content were assessed by Evans blue staining/2',7'-dichlorodihydrofluorescein diacetate(DCFH-DA)fluorescent probe/SOD kit/MDA kit.RESULTS:HRMEC dysfunction was successfully induced by HG,evidenced by decreased viability(P<0.001),increased apoptosis(P<0.001),permeability(P<0.001),and inflammatory factor levels(P<0.001).Feno treatment significantly ameliorated HG-induced HRMEC dysfunction(P<0.01).Meanwhile,HG induction increased ROS production(P<0.001)and MDA content(P<0.001)in HRMECs,while reducing SOD activity(P<0.001),indicative of oxidative stress.This was,however,abolished by Feno(P<0.05).Moreover,Feno eliminated activation of NLRP3 inflammasomes(P<0.05)in HG-induced HRMECs.Strikingly,activation of NLRP3 inflammasomes partially averted the inhibition of Feno on HG-induced HRMEC dysfunction(P<0.05).CONCLUSION:Feno represses oxidative stress and NLRP3 inflammasome activation,consequently alleviating HG-induced HRMEC dysfunction.展开更多
After brain damage,regenerative angiogenesis and neurogenesis have been shown to occur simultaneously in mammals,suggesting a close link between these processes.However,the mechanisms by which these processes interact...After brain damage,regenerative angiogenesis and neurogenesis have been shown to occur simultaneously in mammals,suggesting a close link between these processes.However,the mechanisms by which these processes interact are not well understood.In this work,we aimed to study the correlation between angiogenesis and neurogenesis after a telencephalic stab wound injury.To this end,we used zebrafish as a relevant model of neuroplasticity and brain repair mechanisms.First,using the Tg(fli1:EGFP×mpeg1.1:mCherry)zebrafish line,which enables visualization of blood vessels and microglia respectively,we analyzed regenerative angiogenesis from 1 to 21 days post-lesion.In parallel,we monitored brain cell proliferation in neurogenic niches localized in the ventricular zone by using immunohistochemistry.We found that after brain damage,the blood vessel area and width as well as expression of the fli1 transgene and vascular endothelial growth factor(vegfaa and vegfbb)were increased.At the same time,neural stem cell proliferation was also increased,peaking between 3 and 5 days post-lesion in a manner similar to angiogenesis,along with the recruitment of microglia.Then,through pharmacological manipulation by injecting an anti-angiogenic drug(Tivozanib)or Vegf at the lesion site,we demonstrated that blocking or activating Vegf signaling modulated both angiogenic and neurogenic processes,as well as microglial recruitment.Finally,we showed that inhibition of microglia by clodronate-containing liposome injection or dexamethasone treatment impairs regenerative neurogenesis,as previously described,as well as injury-induced angiogenesis.In conclusion,we have described regenerative angiogenesis in zebrafish for the first time and have highlighted the role of inflammation in this process.In addition,we have shown that both angiogenesis and neurogenesis are involved in brain repair and that microglia and inflammation-dependent mechanisms activated by Vegf signaling are important contributors to these processes.This study paves the way for a better understanding of the effect of Vegf on microglia and for studies aimed at promoting angiogenesis to improve brain plasticity after brain injury.展开更多
Drug-eluting magnesium(Mg)alloy stents have a slower degradation rate and lower restenosis rate compared with uncoated stents,demonstrating good clinical efficacy.However,the release of anti-hyperplasia drugs from coa...Drug-eluting magnesium(Mg)alloy stents have a slower degradation rate and lower restenosis rate compared with uncoated stents,demonstrating good clinical efficacy.However,the release of anti-hyperplasia drugs from coatings delays endothelial tissue repair,thus leading to late stent thrombosis.To address these issues,a dual self-healed coating with various biological properties was fabricated on magnesium fluoride/polydopamine(MgF_(2)/PDA)-treated Mg alloys by spraying-assisted layer-by-layer(LBL)self-assembly of chitosan(CS),gallic acid(GA),and 3-aminobenzeneboronic acid-modified hyaluronic acid(HA-ABBA).The LBL coating,approximately 1.50μm thick,exhibited a uniform morphology with good adhesion strength(~1065 mN).The annual corrosion rate(Pi)of LBL samples was~1400 times slower than that of the Mg substrate,due to the physical barrier function provided by MgF_(2)/PDA layers and the dual self-healed ability of LBL layers.The rapid self-healing ability(with a healing period of~4 h under dynamic/static conditions)resulted from the synergistic interplay between the recombination of diverse chemical bonds within the LBL coating and the coordination of LBL-released GA with Mg2+,as corroborated by computer simulations.Compared with the drug-eluting coatings,the LBL sample demonstrated substantial advantages in anti-oxidation,anti-denaturation of fibrinogen,anti-platelet adhesion,anti-inflammation,anti-hyperplasia,and promoted-endothelialization.These benefits effectively address the limitations associated with drug-eluting coatings.展开更多
In patients with Alzheimer’s disease,gamma-glutamyl transferase 5(GGT5)expression has been observed to be downregulated in cerebrovascular endothelial cells.However,the functional role of GGT5 in the development of A...In patients with Alzheimer’s disease,gamma-glutamyl transferase 5(GGT5)expression has been observed to be downregulated in cerebrovascular endothelial cells.However,the functional role of GGT5 in the development of Alzheimer’s disease remains unclear.This study aimed to explore the effect of GGT5 on cognitive function and brain pathology in an APP/PS1 mouse model of Alzheimer’s disease,as well as the underlying mechanism.We observed a significant reduction in GGT5 expression in two in vitro models of Alzheimer’s disease(Aβ_(1-42)-treated hCMEC/D3 and bEnd.3 cells),as well as in the APP/PS1 mouse model.Additionally,injection of APP/PS1 mice with an adeno-associated virus encoding GGT5 enhanced hippocampal synaptic plasticity and mitigated cognitive deficits.Interestingly,increasing GGT5 expression in cerebrovascular endothelial cells reduced levels of both soluble and insoluble amyloid-βin the brains of APP/PS1 mice.This effect may be attributable to inhibition of the expression ofβ-site APP cleaving enzyme 1,which is mediated by nuclear factor-kappa B.Our findings demonstrate that GGT5 expression in cerebrovascular endothelial cells is inversely associated with Alzheimer’s disease pathogenesis,and that GGT5 upregulation mitigates cognitive deficits in APP/PS1 mice.These findings suggest that GGT5 expression in cerebrovascular endothelial cells is a potential therapeutic target and biomarker for Alzheimer’s disease.展开更多
Objective To investigate the structural changes of rat thoracic aorta and changes in expression levels of Bmal1 and cyclins in thoracic aorta endothelial cells following heat stress.Methods Twenty male SD rats were ra...Objective To investigate the structural changes of rat thoracic aorta and changes in expression levels of Bmal1 and cyclins in thoracic aorta endothelial cells following heat stress.Methods Twenty male SD rats were randomized equally into control group and heat stress group.After exposure to 32℃for 2 weeks in the latter group,the rats were examined for histopathological changes and Bmal1 expression in the thoracic aorta using HE staining and immunohistochemistry.In the cell experiments,cultured rat thoracic aortic endothelial cells(RTAECs)were incubated at 40℃for 12 h with or without prior transfection with a Bmal1-specific small interfering RNA(si-Bmal1)or a negative sequence.In both rat thoracic aorta and RTAECs,the expressions of Bmal1,the cell cycle proteins CDK1,CDK4,CDK6,and cyclin B1,and apoptosis-related proteins Bax and Bcl-2 were detected using Western blotting.TUNEL staining was used to detect cell apoptosis in rat thoracic aorta,and the changes in cell cycle distribution and apoptosis in RTAECs were analyzed with flow cytometry.Results Compared with the control rats,the rats exposed to heat stress showed significantly increased blood pressures and lowered heart rate with elastic fiber disruption and increased expressions of Bmal1,cyclin B1 and CDK1 in the thoracic aorta(P<0.05).In cultured RTAECs,heat stress caused significant increase of Bmal1,cyclin B1 and CDK1 protein expression levels,which were obviously lowered in cells with prior si-Bmal1 transfection.Bmal1 knockdown also inhibited heat stress-induced increase of apoptosis in RTAECs as evidenced by decreased expression of Bax and increased expression of Bcl-2.Conclusion Heat stress upregulates Bmal1 expression and causes alterations in expressions of cyclins to trigger apoptosis of rat thoracic aorta endothelial cells,which can be partly alleviated by suppressing Bmal1 expression.展开更多
In the version of the article initially published,in Figure 6,the image of the kidney from mice treated with the CD31-PILs-AUF1 group was inadvertently used.The updated images were listed below.The authors declared th...In the version of the article initially published,in Figure 6,the image of the kidney from mice treated with the CD31-PILs-AUF1 group was inadvertently used.The updated images were listed below.The authors declared that this error does not change any of the descriptions or conclusions in the article.展开更多
Background:Fluorescein is commonly used in ophthalmology for the assessment of ocular surface integrity.There have been limited studies on the effects of fluorescein on corneal endothelial cells.This study aims to ass...Background:Fluorescein is commonly used in ophthalmology for the assessment of ocular surface integrity.There have been limited studies on the effects of fluorescein on corneal endothelial cells.This study aims to assess the effect of the widely used fluorescein dye on human corneal endothelial cells(HCEnCs)in vitro at different concentrations and exposure times.Methods:B4G12,an immortalized human corneal endothelium cell line was cultured on pre-coated tissue culture flask with human endothelial-serum free medium(SFM)supplemented with 10 ng/mL basic fibroblast growth factor(bFGF).The fully confluent B4G12 cell monolayers in 96 well plates were treated with water as control,or fluorescein at various concentrations and exposure times.Cell viability was assessed using two techniques:Alamar Blue assay and cell morphology assessment with an inverted phase-contrast microscopy.Results:Short-term exposure to fluorescein(0.01-0.2%)for up to 30 minutes did not affect cell viability.Continuous fluorescein exposure however significantly reduced the viability of the cells with a notable reduction in cell metabolic activity with fluorescein treatments of 0.001%,0.01% and 0.05% for 1 day(and up to 4 days).Conclusions:Short-term exposure to fluorescein for up to 30 minutes in concentrations commonly used in clinical practice did not affect HCEnC viability.However,fluorescein exposure for longer durations can be detrimental to corneal endothelial cell health.Future studies should evaluate the effects of longer-term fluorescein exposure on endothelial function especially in susceptible patients including the elderly and patients with epithelial defects that enable diffusion of fluorescein towards the endothelium.展开更多
AIM:To assess tomographic changes and subclinical edema detection in Fuchs’endothelial corneal dystrophy(FECD)through Scheimpflug tomography in a group of phakic patients contemplating cataract surgery.METHODS:A retr...AIM:To assess tomographic changes and subclinical edema detection in Fuchs’endothelial corneal dystrophy(FECD)through Scheimpflug tomography in a group of phakic patients contemplating cataract surgery.METHODS:A retrospective study was conducted on 30 phakic eyes from patients diagnosed with FECD but without clinical edema,and 59 phakic eyes from a control group without corneal alterations.Comprehensive ophthalmic examinations were conducted,including slitlamp biomicroscopy,corneal specular microscopy(CSM),and Scheimpflug tomography.RESULTS:The study encompassed 30 phakic eyes with FECD(mean age 59.8±13.1y)and 59 control eyes(mean age 61.3±7.7y).The best-corrected visual acuity was higher in the control group compared to the FECD group[0(0,0.08)vs 0.05(0,0.15)logMAR;P=0.042].CSM revealed significant differences between the FECD and control groups in several parameters:number of analyzed cells(26±13 vs 135±42,P<0.001),cell density(2049±376 vs 2479±225 cells/mm2,P<0.001),mean cell area[463(434,544)vs 397(383,431)μm2;P<0.001],coefficient of variation(54.8%±18.7%vs 41.0%±7.2%,P<0.001),and hexagonal cells[0(0,47%)vs 47%(40%,53%),P<0.001].Although often used as a clinical parameter for detecting edema,central corneal thickness measured by CSM showed no significant difference between the FECD and control groups(530±57 vs 546±30μm,P=0.179).Significant differences were noted in various Pentacam measurements between the groups.Specifically,parameters like loss of parallel isopachs(13 vs 0 eyes,P<0.001),displacement of the thinnest point(11 vs 0 eyes,P<0.001),posterior focal depression(25 vs 7 eyes,P<0.001),and increased light scatter[21.4(17.6;23.9)vs 18.0(16.8,21.8),P=0.01]were significantly more prevalent in FECD eyes,reflecting the presence of subclinical edema and loss of corneal transparency.CONCLUSION:Scheimpflug tomography allows for an objective assessment of FECD,offering the capability to detect subclinical edema at an early stage,monitor disease progression,and serve as a predictor of corneal decompensation following cataract surgery.展开更多
Elevated homocysteine is a clinically relevantmetabolic signal in chronic obstructive pulmonary disease(COPD).Higher circulating levels track with oxidative stress,endothelial dysfunction,mitochondrial impairment,and ...Elevated homocysteine is a clinically relevantmetabolic signal in chronic obstructive pulmonary disease(COPD).Higher circulating levels track with oxidative stress,endothelial dysfunction,mitochondrial impairment,and pulmonary vascular remodeling,rise with disease severity,and may contribute to the excess cardiovascular risk—although effect sizes and causality remain uncertain.This review centers on the homocysteine–carnitine relationship in COPD pathophysiology.Carnitine deficiency,prevalent in COPD,can worsen mitochondrial bioenergetics,promote accumulation of acyl intermediates,and reduce nitric oxide bioavailability via endothelial nitric oxide synthase uncoupling(eNOS).Conversely,restoring carnitine status in experimental and early clinical settings has been associated with lower homocysteine,improved nitric oxide signaling,and attenuation of vascular remodeling,suggesting a reciprocal link rather than a one-way pathway.We review existing evidence on various COPD phenotypes and severities,delineate mechanisms that connect homocysteine,carnitine metabolism,mitochondria,redox balance and eNOS uncoupling,and evaluate therapeutic strategies—ranging from lowering homocysteine with B-group vitamins to integrated approaches that also supportmitochondrial function and redox homeostasis,including targeted carnitine supplementation.The role of L-carnitine as a potential therapeutic agent for lowering homocysteine and improving mitochondrial and vascular function warrants further investigation,as it may help slow the progression of COPD and its related comorbidities.展开更多
Background Abdominal aortic aneurysm(AAA)is a life-threatening vascular disease associated with endothelial cell senescence.Resveratrol(RSV),a natural polyphenol,exerts potent anti-senescent and anti-inflammatory effe...Background Abdominal aortic aneurysm(AAA)is a life-threatening vascular disease associated with endothelial cell senescence.Resveratrol(RSV),a natural polyphenol,exerts potent anti-senescent and anti-inflammatory effects.However,its molecular mechanism in treating AAA remains unclear.Methods An AAA model was established in mice via angiotensin Ⅱ(AngⅡ)infusion[1000 ng/(kg·min)],with a subset receiving RSV treatment[100 mg/(kg·day)by gavage].Aortic diameter was measured,and histopathological changes were assessed by Hematoxylin-Eosin(HE)and Elastica Van Gieson(EVG)staining.Vascular aging was evaluated by senescence-associatedβ-galactosidase(SA-β-gal)activity and pulse wave velocity(PWV).In vitro,human umbilical vein endothelial cells(HUVECs)were treated with AngⅡ(10-6 M)with or without RSV(40μM)and/or the sirtuin 1(SIRT1)inhibitor EX527(10μM).Senescence markers,senescence-associated secretory phenotype(SASP)factor expression[interleukin-1 beta(IL-1β),interleukin-6(IL-6),tumor necrosis factor-alpha(TNF-α)],and SIRT1/p21 pathway proteins were analyzed.Results In vivo,RSV significantly attenuated Ang Ⅱ-induced AAA formation,reducing aortic diameter,preserving elastic fiber integrity,and suppressing vascular senescence and stiffness.In HUVECs,Ang Ⅱ-induced senescence and SASP expression were markedly inhibited by RSV.However,these protective effects were abolished by EX527.Mechanistically,RSV reversed the Ang Ⅱ-induced downregulation of SIRT1 and upregulation of p21,which was also blocked by SIRT1 inhibition.Conclusions RSV effectively prevented experimental AAA formation by alleviating vascular aging and endothelial cell senescence.This protective effect was abrogated by the SIRT1 inhibitor EX527,confirming that RSV mitigated AAA development and vascular senescence through the SIRT1/p21 signaling pathway.These findings highlighted RSV as a promising therapeutic candidate for AAA treatment.展开更多
BACKGROUND:The present study aims to investigate whether mannitol facilitates central nervous system(CNS) entry of vancomycin and alleviates methicillin-resistant Staphylococcus aureus(MRSA)intracranial infection.METH...BACKGROUND:The present study aims to investigate whether mannitol facilitates central nervous system(CNS) entry of vancomycin and alleviates methicillin-resistant Staphylococcus aureus(MRSA)intracranial infection.METHODS:Blood-brain barrier(BBB) permeability was assessed by measuring the concentration of sodium fl uorescein(NaF) in the brain tissues of rats and fl uorescein isothiocyanate-dextran(FITC-dextran)in a single-cell layer model.Neutrophil infiltration in the brain tissue,inflammatory cytokine levels in the serum,neurological function,and 7-day survival rates were used to evaluate therapeutic eff ects of mannitol and vancomycin in MRSA-infected rats.Syndecan-1 and fi lamentous actin(F-actin) levels were measured,and the relationship between F-actin and the endothelial glycocalyx layer(EGL) was explored via the depolymerization agent cytochalasin D and the polymerization agent jasplakinolide.RESULTS:Following mannitol administration,the NaF and vancomycin concentrations in the brain tissue increased rapidly within 5 min and remained stable for 30 min,indicating that mannitol increased BBB permeability for 30 min.In vitro,mannitol treatment led to significantly greater FITC-dextran permeation through a single-cell layer compared to controls.In the MRSA intracranial infection model,rats treated with mannitol and vancomycin simultaneously presented less infl ammation,improved neurological function,and increased 7-day survival rate compared to rats treated with vancomycin and mannitol at 10-hour intervals.Further experiments revealed that mannitol decreased the expression of syndecan-1 in brain tissues,which was confi rmed by in vitro experiments showing that mannitol signifi cantly decreased syndecan-1 via F-actin depolymerization.CONCLUSION:Mannitol may enhance the therapeutic effi cacy of vancomycin against intracranial MRSA infection by decreasing the endothelial glycocalyx of the BBB via F-actin depolymerization.展开更多
基金supported by the National Natural Science Foundation of China,Nos.82404892(to QY),82061160374(to ZZ)the Science and Technology Development Fund,Macao Special Administrative Region,China,Nos.0023/2020/AFJ,0035/2020/AGJ+2 种基金the University of Macao Research Grant,Nos.MYRG2022-00248-ICMS,MYRG-CRG2022-00010-ICMS(to MPMH)the Natural Science Foundation of Guangdong Province,No.2024A1515012818(to ZZ)the Fundamental Research Funds for the Central Universities,No.21623114(to ZZ).
文摘Drug development for Alzheimer’s disease is extremely challenging,as demonstrated by the repeated failures of amyloid-β-targeted therapeutics and the controversies surrounding the amyloid-βcascade hypothesis.More recently,advances in the development of Lecanemab,an anti-amyloid-βmonoclonal antibody,have shown positive results in reducing brain A burden and slowing cognitive decline in patients with early-stage Alzheimer’s disease in the Phase Ⅲ clinical trial(Clarity Alzheimer’s disease).Despite these promising results,side effects such as amyloid-related imaging abnormalities(ARIA)may limit its usage.ARIA can manifest as ARIA-E(cerebral edema or effusions)and ARIA-H(microhemorrhages or superficial siderosis)and is thought to be caused by increased vascular permeability due to inflammatory responses,leading to leakages of blood products and protein-rich fluid into brain parenchyma.Endothelial dysfunction is an early pathological feature of Alzheimer’s disease,and the blood-brain barrier becomes increasingly leaky as the disease progresses.In addition,APOE4,the strongest genetic risk factor for Alzheimer’s disease,is associated with higher vascular amyloid burden,increased ARIA incidence,and accelerated blood-brain barrier disruptions.These interconnected vascular abnormalities highlight the importance of vascular contributions to the pathophysiology of Alzheimer’s disease.Here,we will closely examine recent research evaluating the heterogeneity of brain endothelial cells in the microvasculature of different brain regions and their relationships with Alzheimer’s disease progression.
文摘Dengue fever is an acute infectious disease caused by the dengue virus and transmitted by mosquito vectors[1].Its clinical manifestations include high fever,headache,muscle and joint pain,and rash.It holds a significant position in global public health.In recent years,its incidence has continued to rise worldwide[2],making it one of the major diseases threatening human health.The disease course of dengue fever is divided into three typical phases:the acute febrile phase,the critical phase,and the recovery phase.While most patients experience mild symptoms,some may progress to severe dengue and potentially fatal outcomes if not promptly and effectively treated during the critical phase.
基金supported by the National Natural Science Foundation of China(Grant Nos.:32171124,31871156,31971101,32271180,82272229,and 81471852)Hunan Provincial Natural Science Foundation of China(Grant No.:2021JJ31058).
文摘Repairing the endothelial barrier is essential for maintaining pulmonary fuid balance and regulating leukocyte infiltration during sepsis[1].Tissue kallikrein-related peptidases(KLKs)are secreted serine proteases involved in angiogenesis[2].However,their involvement in regulating endothelial regeneration remains largely unknown.
文摘Introduction Fuchs endothelial corneal dystrophy(FECD)is an inherited,degenerative disease of the corneal endothelial cells(CECs).It is characterized by a progressive deterioration of endothelial cells,altered extracellular matrix(ECM)production,and development of guttae(1,2).The presence of guttae has been shown to significantly impair corneal endothelial function,leading to corneal oedema and visual impairment.
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.
文摘AIM: To establish the role of vascular endothelial growth factor (VEGF) in the oncogenesis of human gastric carcinoma more directly. METHODS: The expression of VEGF and its receptor kinase-domain insert containing receptor (KDR) in human gastric cancer tissue were observed by immunohistochemical staining. VEGF levels were manipulated in human gastric cancer cell using eukaryotic expression constructs designed to express the complete VEGF(165) complimentary DNA in either the sense or antisense orientation. The biological changes of the cells were observed in which VEGF was up-regulated or down-regulated. RESULTS: VEGF-positive rate was 50%, and VEGF was mainly localized in the cytoplasm and membrane of the tumor cells, while KDR was mainly located in the membrane of vascular endothelial cells in gastric cancer tissues and peri-cancerous tissue. In 2 cases of 50 specimens, the gastric cancer cells expressed KDR, localized in both the cytoplasm and membrane. Introduction of VEGF(165) antisense into human gastric cancer cells (SGC-7901, immunofluorescence intensity, 31.6%)) resulted in a significant reduction in VEGF-specific messenger RNA and total and cell surface VEGF protein (immunofluorescence intensity, 8.9%) (P【0.05). Conversely, stable integration of VEGF(165) in the sense orientation resulted in an increase in cellular and cell surface VEGF (immunofluorescence intensity, 75.4%) (P【0.05). Lowered VEGF levels were associated with a marked decrease in the growth of nude mouse xenografted tumor (at 33 days postimplantation, tumor volume: 345.40 +/- 136.31 mm3)(P【0.05 vs control SGC-7901 group: 1534.40 +/- 362.88 mm3), whereas up-regulation of VEGF resulted in increased xenografted tumor size (at 33 days postimplantation, tumor volume: 2350.50 +/- 637.70 mm3) (P【0.05 vs control SGC-7901 group). CONCLUSION: This study provides direct evidence that VEGF plays an important role in the oncogenesis of human gastric cancer.
文摘The endothelium modulates vascular homeostasis owing to a variety of vasoconstrictors and vasodilators.Endothelial dysfunction(ED),characterized by impaired vasodilation,inflammation,and thrombosis,triggers future cardiovascular(CV)diseases.Chronic kidney disease,a state of chronic inflammation caused by oxidative stress,metabolic abnormalities,infection,and uremic toxins damages the endothelium.ED is also associated with a decline in estimated glomerular filtration rate.After kidney transplantation,endothelial functions undergo immediate but partial restoration,promising graft longevity and enhanced CV health.However,the anticipated CV outcomes do not happen due to various transplant-related and unrelated risk factors for ED,culminating in poor CV health and graft survival.ED in kidney transplant recipients is an underrecognized and poorly studied entity.CV diseases are the leading cause of death among kidney transplant candidates with functioning grafts.ED contributes to the pathogenesis of many of the CV diseases.Various biomarkers and vasoreactivity tests are available to study endothelial functions.With an increasing number of transplants happening every year,and improved graft rejection rates due to the availability of effective immunosuppressants,the focus has now shifted to endothelial protection for the prevention,early recognition,and treatment of CV diseases.
基金the support of the National Natural Science Foundation of China (Grant No.82272503)Natural Science Foundation of Zhejiang Province (Grant No. LQN25H060006)
文摘Exosomes have shown good potential in ischemic injury disease treatments.However,evidence about their effect and molecular mechanisms in osteonecrosis of femoral head(ONFH)treatment is still limited.Here,we revealed the cell biology characters of ONFH osteonecrosis area bone tissue in single cell scale and thus identified a novel ONFH treatment approach based on M2 macrophages-derived exosomes(M2-Exos).We further show that M2-Exos are highly effective in the treatment of ONFH by modulating the phenotypes communication between neutrophil and endothelium including neutrophil extracellular traps formation and endothelial phenotype transition.Additionally,we identified that M2-Exos’therapeutic effect is attributed to the high content of miR-93-5p and constructed miR-93-5p overexpression model in vitro and in vivo based on lentivirus and adenoassociated virus respectively.Then we found miR-93-5p can not only reduce neutrophil extracellular traps formation but also improve angiogenic ability of endothelial cells.These results provided a new theoretical basis for the clinical application of ONFH therapeutic exosomes.
基金Supported by Youth Cultivation Research Program of Beijing Road Medical Area,Xinjiang Military Region General Hospital,Xinjiang,China(No.2022jzbj105)Science and Technology Program of Urumqi Municipal Health and Wellness Commission(No.202360).
文摘AIM:To assess the relationship between serological parameters and the prognosis of young patients with retinal vein occlusion(RVO)after intravitreal conbercept injection(IVC).METHODS:This study enrolled 100 young patients(≤50 years old)diagnosed with RVO-related macular edema(RVO-ME)who had been undergoing IVC at the 474 Hospital in Xinjiang between January 2022 and October 2023.Patients were categorized into two groups:70 eyes in the effective group and 30 eyes in the ineffective group.The effective group comprised patients exhibiting a visual acuity improvement of≥2 lines at the last follow-up,with resolved ME and central macular thickness(CMT)<300μm.Conversely,the ineffective group included patients with visual acuity improvement of<1 line,persistent ME,and CMT≥300μm at the last follow-up.Serological parameters,including white blood cell count,neutrophil count,lymphocyte count,monocyte count,and mean platelet volume were assessed before treatment.The correlation between bestcorrected visual acuity(BCVA)and neutrophil-to-lymphocyte ratio(NLR),platelet-to-lymphocyte ratio(PLR),systemic immune inflammation index(SII),and systemic immune response index(SIRI)was analyzed.Additionally,the association between these serological parameters and the efficacy of IVC was explored.RESULTS:Three months after treatment,the effective group demonstrated a significant improvement in BCVA from 0.82±0.20 to 0.36±0.10,with a concurrent decrease in CMT from 661.28±163.90 to 200.61±82.45μm(P<0.001).Conversely,the ineffective group exhibited minimal changes in BCVA(0.86±0.25 to 0.82±0.14)and CMT(669.84±164.95 to 492.13±138.67μm,P<0.001).The differences in BCVA and CMT between the two groups were statistically significant(P<0.001).According to subgroup analysis,in patients with central RVO(CRVO),BCVA improved from 0.82±0.23 to 0.49±0.12 in the effective group and from 0.80±0.18 to 0.76±0.22 in the ineffective group(P<0.001).The CMT changes followed a similar pattern.In patients with branch RVO(BRVO),comparable trends in BCVA and CMT changes were observed between the effective and ineffective groups(P<0.001).Additionally,the effective group exhibited higher PLR and SII values than the ineffective group(P<0.05).Further CRVO and BRVO subgroups analysis exhibited consistent PLR and SII value trends.CONCLUSION:Compared to other inflammatory factors,elevated PLR and SII levels before treatment are better predictors of outcomes in young RVO-ME patients undergoing IVC treatment.
基金Supported by grants from the Tianjin Key Medical Discipline(Specialty)Construction Project(No.TJYXZDXK-037A).
文摘AIM:To determine the therapeutic benefits of fenofibrate(Feno)on the dysfunction of high glucose(HG)-induced human retinal microvascular endothelial cells(HRMECs)and to elucidate the underlying molecular mechanism.METHODS:HRMEC dysfunction model was established by 48h glucose(30 mmol/L)treatment and treated with Feno/NOD-like receptor thermal protein domain associated protein 3(NLRP3)inflammasome activator(Nigericin).Cell viability/apoptosis were assessed by cell counting kit-8(CCK-8)/terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay(TUNEL)staining and flow cytometry assays.Levels of apoptosis-(Bcl-2-associated X protein,Bax/B-cell lymphoma 2,Bcl-2),vascular permeability-(vascular endothelial growth factor,VEGF)and inflammasome activation-related proteins(NLRP3/cleaved caspase-1/apoptosis-associated speck-like protein containing a CARD,ASC),as well as inflammatory factors(interleukin,IL-6/IL-1β/tumor necrosis factor,TNF-α/IL-18)were determined with Western blot/enzyme linked immunosorbent assay(ELISA).Cell permeability/reactive oxygen species(ROS)level/superoxide dismutase(SOD)activity/malondialdehyde(MDA)content were assessed by Evans blue staining/2',7'-dichlorodihydrofluorescein diacetate(DCFH-DA)fluorescent probe/SOD kit/MDA kit.RESULTS:HRMEC dysfunction was successfully induced by HG,evidenced by decreased viability(P<0.001),increased apoptosis(P<0.001),permeability(P<0.001),and inflammatory factor levels(P<0.001).Feno treatment significantly ameliorated HG-induced HRMEC dysfunction(P<0.01).Meanwhile,HG induction increased ROS production(P<0.001)and MDA content(P<0.001)in HRMECs,while reducing SOD activity(P<0.001),indicative of oxidative stress.This was,however,abolished by Feno(P<0.05).Moreover,Feno eliminated activation of NLRP3 inflammasomes(P<0.05)in HG-induced HRMECs.Strikingly,activation of NLRP3 inflammasomes partially averted the inhibition of Feno on HG-induced HRMEC dysfunction(P<0.05).CONCLUSION:Feno represses oxidative stress and NLRP3 inflammasome activation,consequently alleviating HG-induced HRMEC dysfunction.
基金supported by European Regional Development Funds RE0022527 ZEBRATOX(EU-Région Réunion-French State national counterpart,to Nicolas Diotel and Jean-Loup Bascands).
文摘After brain damage,regenerative angiogenesis and neurogenesis have been shown to occur simultaneously in mammals,suggesting a close link between these processes.However,the mechanisms by which these processes interact are not well understood.In this work,we aimed to study the correlation between angiogenesis and neurogenesis after a telencephalic stab wound injury.To this end,we used zebrafish as a relevant model of neuroplasticity and brain repair mechanisms.First,using the Tg(fli1:EGFP×mpeg1.1:mCherry)zebrafish line,which enables visualization of blood vessels and microglia respectively,we analyzed regenerative angiogenesis from 1 to 21 days post-lesion.In parallel,we monitored brain cell proliferation in neurogenic niches localized in the ventricular zone by using immunohistochemistry.We found that after brain damage,the blood vessel area and width as well as expression of the fli1 transgene and vascular endothelial growth factor(vegfaa and vegfbb)were increased.At the same time,neural stem cell proliferation was also increased,peaking between 3 and 5 days post-lesion in a manner similar to angiogenesis,along with the recruitment of microglia.Then,through pharmacological manipulation by injecting an anti-angiogenic drug(Tivozanib)or Vegf at the lesion site,we demonstrated that blocking or activating Vegf signaling modulated both angiogenic and neurogenic processes,as well as microglial recruitment.Finally,we showed that inhibition of microglia by clodronate-containing liposome injection or dexamethasone treatment impairs regenerative neurogenesis,as previously described,as well as injury-induced angiogenesis.In conclusion,we have described regenerative angiogenesis in zebrafish for the first time and have highlighted the role of inflammation in this process.In addition,we have shown that both angiogenesis and neurogenesis are involved in brain repair and that microglia and inflammation-dependent mechanisms activated by Vegf signaling are important contributors to these processes.This study paves the way for a better understanding of the effect of Vegf on microglia and for studies aimed at promoting angiogenesis to improve brain plasticity after brain injury.
基金supported by the National Key Research and Development Program of China(No.2021YFC2400703)the Key Scientific and Technological Research Projects in Henan Province(Nos.232102311155 and 232102230106)Zhengzhou University Major Project Cultivation Special Project(No.125-32214076).
文摘Drug-eluting magnesium(Mg)alloy stents have a slower degradation rate and lower restenosis rate compared with uncoated stents,demonstrating good clinical efficacy.However,the release of anti-hyperplasia drugs from coatings delays endothelial tissue repair,thus leading to late stent thrombosis.To address these issues,a dual self-healed coating with various biological properties was fabricated on magnesium fluoride/polydopamine(MgF_(2)/PDA)-treated Mg alloys by spraying-assisted layer-by-layer(LBL)self-assembly of chitosan(CS),gallic acid(GA),and 3-aminobenzeneboronic acid-modified hyaluronic acid(HA-ABBA).The LBL coating,approximately 1.50μm thick,exhibited a uniform morphology with good adhesion strength(~1065 mN).The annual corrosion rate(Pi)of LBL samples was~1400 times slower than that of the Mg substrate,due to the physical barrier function provided by MgF_(2)/PDA layers and the dual self-healed ability of LBL layers.The rapid self-healing ability(with a healing period of~4 h under dynamic/static conditions)resulted from the synergistic interplay between the recombination of diverse chemical bonds within the LBL coating and the coordination of LBL-released GA with Mg2+,as corroborated by computer simulations.Compared with the drug-eluting coatings,the LBL sample demonstrated substantial advantages in anti-oxidation,anti-denaturation of fibrinogen,anti-platelet adhesion,anti-inflammation,anti-hyperplasia,and promoted-endothelialization.These benefits effectively address the limitations associated with drug-eluting coatings.
基金supported by STI2030-Major Projects,No.2021ZD 0201801(to JG)Shanxi Province Basic Research Program,No.20210302123429(to QS).
文摘In patients with Alzheimer’s disease,gamma-glutamyl transferase 5(GGT5)expression has been observed to be downregulated in cerebrovascular endothelial cells.However,the functional role of GGT5 in the development of Alzheimer’s disease remains unclear.This study aimed to explore the effect of GGT5 on cognitive function and brain pathology in an APP/PS1 mouse model of Alzheimer’s disease,as well as the underlying mechanism.We observed a significant reduction in GGT5 expression in two in vitro models of Alzheimer’s disease(Aβ_(1-42)-treated hCMEC/D3 and bEnd.3 cells),as well as in the APP/PS1 mouse model.Additionally,injection of APP/PS1 mice with an adeno-associated virus encoding GGT5 enhanced hippocampal synaptic plasticity and mitigated cognitive deficits.Interestingly,increasing GGT5 expression in cerebrovascular endothelial cells reduced levels of both soluble and insoluble amyloid-βin the brains of APP/PS1 mice.This effect may be attributable to inhibition of the expression ofβ-site APP cleaving enzyme 1,which is mediated by nuclear factor-kappa B.Our findings demonstrate that GGT5 expression in cerebrovascular endothelial cells is inversely associated with Alzheimer’s disease pathogenesis,and that GGT5 upregulation mitigates cognitive deficits in APP/PS1 mice.These findings suggest that GGT5 expression in cerebrovascular endothelial cells is a potential therapeutic target and biomarker for Alzheimer’s disease.
文摘Objective To investigate the structural changes of rat thoracic aorta and changes in expression levels of Bmal1 and cyclins in thoracic aorta endothelial cells following heat stress.Methods Twenty male SD rats were randomized equally into control group and heat stress group.After exposure to 32℃for 2 weeks in the latter group,the rats were examined for histopathological changes and Bmal1 expression in the thoracic aorta using HE staining and immunohistochemistry.In the cell experiments,cultured rat thoracic aortic endothelial cells(RTAECs)were incubated at 40℃for 12 h with or without prior transfection with a Bmal1-specific small interfering RNA(si-Bmal1)or a negative sequence.In both rat thoracic aorta and RTAECs,the expressions of Bmal1,the cell cycle proteins CDK1,CDK4,CDK6,and cyclin B1,and apoptosis-related proteins Bax and Bcl-2 were detected using Western blotting.TUNEL staining was used to detect cell apoptosis in rat thoracic aorta,and the changes in cell cycle distribution and apoptosis in RTAECs were analyzed with flow cytometry.Results Compared with the control rats,the rats exposed to heat stress showed significantly increased blood pressures and lowered heart rate with elastic fiber disruption and increased expressions of Bmal1,cyclin B1 and CDK1 in the thoracic aorta(P<0.05).In cultured RTAECs,heat stress caused significant increase of Bmal1,cyclin B1 and CDK1 protein expression levels,which were obviously lowered in cells with prior si-Bmal1 transfection.Bmal1 knockdown also inhibited heat stress-induced increase of apoptosis in RTAECs as evidenced by decreased expression of Bax and increased expression of Bcl-2.Conclusion Heat stress upregulates Bmal1 expression and causes alterations in expressions of cyclins to trigger apoptosis of rat thoracic aorta endothelial cells,which can be partly alleviated by suppressing Bmal1 expression.
文摘In the version of the article initially published,in Figure 6,the image of the kidney from mice treated with the CD31-PILs-AUF1 group was inadvertently used.The updated images were listed below.The authors declared that this error does not change any of the descriptions or conclusions in the article.
文摘Background:Fluorescein is commonly used in ophthalmology for the assessment of ocular surface integrity.There have been limited studies on the effects of fluorescein on corneal endothelial cells.This study aims to assess the effect of the widely used fluorescein dye on human corneal endothelial cells(HCEnCs)in vitro at different concentrations and exposure times.Methods:B4G12,an immortalized human corneal endothelium cell line was cultured on pre-coated tissue culture flask with human endothelial-serum free medium(SFM)supplemented with 10 ng/mL basic fibroblast growth factor(bFGF).The fully confluent B4G12 cell monolayers in 96 well plates were treated with water as control,or fluorescein at various concentrations and exposure times.Cell viability was assessed using two techniques:Alamar Blue assay and cell morphology assessment with an inverted phase-contrast microscopy.Results:Short-term exposure to fluorescein(0.01-0.2%)for up to 30 minutes did not affect cell viability.Continuous fluorescein exposure however significantly reduced the viability of the cells with a notable reduction in cell metabolic activity with fluorescein treatments of 0.001%,0.01% and 0.05% for 1 day(and up to 4 days).Conclusions:Short-term exposure to fluorescein for up to 30 minutes in concentrations commonly used in clinical practice did not affect HCEnC viability.However,fluorescein exposure for longer durations can be detrimental to corneal endothelial cell health.Future studies should evaluate the effects of longer-term fluorescein exposure on endothelial function especially in susceptible patients including the elderly and patients with epithelial defects that enable diffusion of fluorescein towards the endothelium.
文摘AIM:To assess tomographic changes and subclinical edema detection in Fuchs’endothelial corneal dystrophy(FECD)through Scheimpflug tomography in a group of phakic patients contemplating cataract surgery.METHODS:A retrospective study was conducted on 30 phakic eyes from patients diagnosed with FECD but without clinical edema,and 59 phakic eyes from a control group without corneal alterations.Comprehensive ophthalmic examinations were conducted,including slitlamp biomicroscopy,corneal specular microscopy(CSM),and Scheimpflug tomography.RESULTS:The study encompassed 30 phakic eyes with FECD(mean age 59.8±13.1y)and 59 control eyes(mean age 61.3±7.7y).The best-corrected visual acuity was higher in the control group compared to the FECD group[0(0,0.08)vs 0.05(0,0.15)logMAR;P=0.042].CSM revealed significant differences between the FECD and control groups in several parameters:number of analyzed cells(26±13 vs 135±42,P<0.001),cell density(2049±376 vs 2479±225 cells/mm2,P<0.001),mean cell area[463(434,544)vs 397(383,431)μm2;P<0.001],coefficient of variation(54.8%±18.7%vs 41.0%±7.2%,P<0.001),and hexagonal cells[0(0,47%)vs 47%(40%,53%),P<0.001].Although often used as a clinical parameter for detecting edema,central corneal thickness measured by CSM showed no significant difference between the FECD and control groups(530±57 vs 546±30μm,P=0.179).Significant differences were noted in various Pentacam measurements between the groups.Specifically,parameters like loss of parallel isopachs(13 vs 0 eyes,P<0.001),displacement of the thinnest point(11 vs 0 eyes,P<0.001),posterior focal depression(25 vs 7 eyes,P<0.001),and increased light scatter[21.4(17.6;23.9)vs 18.0(16.8,21.8),P=0.01]were significantly more prevalent in FECD eyes,reflecting the presence of subclinical edema and loss of corneal transparency.CONCLUSION:Scheimpflug tomography allows for an objective assessment of FECD,offering the capability to detect subclinical edema at an early stage,monitor disease progression,and serve as a predictor of corneal decompensation following cataract surgery.
基金financed by the Ryazan StateMedical University intra-university grant:Agreement No.1A/25 for the implementation of research on the topic:“Metabolic Markers of Impaired Adaptation to Hypoxia in COPD:The Role of Hyperhomocysteinemia and Carnitine Deficiency”dated 09 April 2025.
文摘Elevated homocysteine is a clinically relevantmetabolic signal in chronic obstructive pulmonary disease(COPD).Higher circulating levels track with oxidative stress,endothelial dysfunction,mitochondrial impairment,and pulmonary vascular remodeling,rise with disease severity,and may contribute to the excess cardiovascular risk—although effect sizes and causality remain uncertain.This review centers on the homocysteine–carnitine relationship in COPD pathophysiology.Carnitine deficiency,prevalent in COPD,can worsen mitochondrial bioenergetics,promote accumulation of acyl intermediates,and reduce nitric oxide bioavailability via endothelial nitric oxide synthase uncoupling(eNOS).Conversely,restoring carnitine status in experimental and early clinical settings has been associated with lower homocysteine,improved nitric oxide signaling,and attenuation of vascular remodeling,suggesting a reciprocal link rather than a one-way pathway.We review existing evidence on various COPD phenotypes and severities,delineate mechanisms that connect homocysteine,carnitine metabolism,mitochondria,redox balance and eNOS uncoupling,and evaluate therapeutic strategies—ranging from lowering homocysteine with B-group vitamins to integrated approaches that also supportmitochondrial function and redox homeostasis,including targeted carnitine supplementation.The role of L-carnitine as a potential therapeutic agent for lowering homocysteine and improving mitochondrial and vascular function warrants further investigation,as it may help slow the progression of COPD and its related comorbidities.
基金supported by the grant from the Fujian Province Natural Science Foundation(No.2024J01608)。
文摘Background Abdominal aortic aneurysm(AAA)is a life-threatening vascular disease associated with endothelial cell senescence.Resveratrol(RSV),a natural polyphenol,exerts potent anti-senescent and anti-inflammatory effects.However,its molecular mechanism in treating AAA remains unclear.Methods An AAA model was established in mice via angiotensin Ⅱ(AngⅡ)infusion[1000 ng/(kg·min)],with a subset receiving RSV treatment[100 mg/(kg·day)by gavage].Aortic diameter was measured,and histopathological changes were assessed by Hematoxylin-Eosin(HE)and Elastica Van Gieson(EVG)staining.Vascular aging was evaluated by senescence-associatedβ-galactosidase(SA-β-gal)activity and pulse wave velocity(PWV).In vitro,human umbilical vein endothelial cells(HUVECs)were treated with AngⅡ(10-6 M)with or without RSV(40μM)and/or the sirtuin 1(SIRT1)inhibitor EX527(10μM).Senescence markers,senescence-associated secretory phenotype(SASP)factor expression[interleukin-1 beta(IL-1β),interleukin-6(IL-6),tumor necrosis factor-alpha(TNF-α)],and SIRT1/p21 pathway proteins were analyzed.Results In vivo,RSV significantly attenuated Ang Ⅱ-induced AAA formation,reducing aortic diameter,preserving elastic fiber integrity,and suppressing vascular senescence and stiffness.In HUVECs,Ang Ⅱ-induced senescence and SASP expression were markedly inhibited by RSV.However,these protective effects were abolished by EX527.Mechanistically,RSV reversed the Ang Ⅱ-induced downregulation of SIRT1 and upregulation of p21,which was also blocked by SIRT1 inhibition.Conclusions RSV effectively prevented experimental AAA formation by alleviating vascular aging and endothelial cell senescence.This protective effect was abrogated by the SIRT1 inhibitor EX527,confirming that RSV mitigated AAA development and vascular senescence through the SIRT1/p21 signaling pathway.These findings highlighted RSV as a promising therapeutic candidate for AAA treatment.
基金supported by the National Natural Science Foundation for Young Scientists of China (grant no.2002074)the Natural Science Foundation of Guangdong Province(2023A1515010267, 2023A1515012665, 2024A1515010073)+1 种基金the China International Medical Foundation Cerebrovascular Disease Youth Innovation Fund (Z-2016-20-2201)the Medical Leading Talents Fund of Guangdong Province (KJ012019430)。
文摘BACKGROUND:The present study aims to investigate whether mannitol facilitates central nervous system(CNS) entry of vancomycin and alleviates methicillin-resistant Staphylococcus aureus(MRSA)intracranial infection.METHODS:Blood-brain barrier(BBB) permeability was assessed by measuring the concentration of sodium fl uorescein(NaF) in the brain tissues of rats and fl uorescein isothiocyanate-dextran(FITC-dextran)in a single-cell layer model.Neutrophil infiltration in the brain tissue,inflammatory cytokine levels in the serum,neurological function,and 7-day survival rates were used to evaluate therapeutic eff ects of mannitol and vancomycin in MRSA-infected rats.Syndecan-1 and fi lamentous actin(F-actin) levels were measured,and the relationship between F-actin and the endothelial glycocalyx layer(EGL) was explored via the depolymerization agent cytochalasin D and the polymerization agent jasplakinolide.RESULTS:Following mannitol administration,the NaF and vancomycin concentrations in the brain tissue increased rapidly within 5 min and remained stable for 30 min,indicating that mannitol increased BBB permeability for 30 min.In vitro,mannitol treatment led to significantly greater FITC-dextran permeation through a single-cell layer compared to controls.In the MRSA intracranial infection model,rats treated with mannitol and vancomycin simultaneously presented less infl ammation,improved neurological function,and increased 7-day survival rate compared to rats treated with vancomycin and mannitol at 10-hour intervals.Further experiments revealed that mannitol decreased the expression of syndecan-1 in brain tissues,which was confi rmed by in vitro experiments showing that mannitol signifi cantly decreased syndecan-1 via F-actin depolymerization.CONCLUSION:Mannitol may enhance the therapeutic effi cacy of vancomycin against intracranial MRSA infection by decreasing the endothelial glycocalyx of the BBB via F-actin depolymerization.
