Recent advances in surface endothelialization of the magnesium alloy stent materials

Magnesium and its alloy have good mechanical properties and biodegradability,and have become the hotspot of the next-generation biodegradable vascular stent materials.However,their rapid degradation in vivo and poor biocompatibility are still the bottlenecks of clinical applications for the cardiovascular stents.In particular,how to induce the repair and regeneration of the vascular endothelial with normal physiological functions on the surface of the magnesium alloy stent materials represents the key to its clinical application in the field of cardiovascular stents.It has been believed that it is an ideal way to completely solve the postoperative complications through constructing the multifunctional anti-corrosive bioactive coating on the magnesium alloy surface to induce the formation of vascular endothelium with normal physiological functions.However,how to construct a corrosion-resistant multifunctional bioactive coating with the good endothelial regeneration abilities on the magnesium alloy surface still faces a great challenge.This paper mainly focused on highlighting and summarizing the recent advances in the surface endothelialization of the magnesium alloy materials for the vascular stent,including the bio-inert coating,in-situ immobilization of bioactive molecules on the surface,polymer coating loaded with bioactive factors,novel multifunctional polymer coating,bioactive micropatterns,bioactive layer with glycocalyx-like structure,NO-releasing coating and bioactive sol-gel coating.The advantages and disadvantages of these strategies were discussed and analyzed.Finally,in the senses of future development and clinical application,this paper analyzed and summarized the development direction and prospect of surface endothelialization of the magnesium alloy vascular stents.It is anticipated that this review can give the new cues to the surface endothelialization of the cardiovascular magnesium alloy stents and promote future advancements in this field.

A biomimetic basementmembrane consisted of hybrid aligned nanofibers andmicrofibers with immobilized collagen IV and laminin for rapid endothelialization

Rapid formation of a continuous endothelial cell(EC)monolayer with healthy endothelium function on the luminal surface of vascular implants is imperative to improve the longtime patency of small-diameter vascular implants.In the present study,we combined the contact guidance effects of aligned nanofibers,which enhance EC adhesion and proliferation because of its similar fiber scale with native vascular basement membranes,and aligned microfibers,which could induce EC elongation effectively and allow ECs infiltration.It was followed by successive immobilization of collagen IV and laminin to fabricate a biomimetic basement membrane(BBM)with structural and compositional biomimicry.The hemolysis assay and platelet adhesion results showed that the BBM exhibited excellent hemocompatibility.Meanwhile,the adhered human umbilical vein endothelial cells(HUVECs)onto theBBMaligned along the orientation of the microfibers with an elongated morphology,and the data demonstrated that the BBM showed favorable effects on EC attachment,proliferation,and viability.The oriented EC monolayer formed on the BBM exhibited improved antithrombotic capability as indicated by higher production of nitric oxide and prostacyclin(PGI2).Furthermore,fluorescence images indicated that HUVECs could infiltrate into the BBM,implying theBBM’s ability to enhance transmural endothelialization.Hence,theBBMpossessed the properties to regulate ECbehaviors and allow transmural ingrowth,demonstrating the potential to be applied as the luminal surface of small-diameter vascular implants for rapid endothelialization.

Fucoidan and topography modification improved in situ endothelialization on acellular synthetic vascular grafts

Thrombogenesis remains the primary failure of synthetic vascular grafts.Endothelial coverage is crucial to provide an antithrombogenic surface.However,most synthetic materials do not support cell adhesion,and transanastomotic endothelial migration is limited.Here,a surface modification strategy using fucoidan and topography was developed to enable fast in situ endothelialization of polyvinyl alcohol,which is not endothelial cell-adhesive.Among three different immobilization approaches compared,conjugation of aminated-fucoidan promoted endothelial monolayer formation while minimizing thrombogenicity in both in vitro platelet rich plasma testing and ex vivo non-human primate shunt assay.Screening of six topographical patterns showed that 2μm gratings increased endothelial cell migration without inducing inflammation responses of endothelial cells.Mechanistic studies demonstrated that fucoidan could attract fibronectin,enabling integrin binding and focal adhesion formation and activating focal adhesion kinase(FAK)signaling,and 2μm gratings further enhanced FAK-mediated cell migration.In a clinically relevant rabbit carotid artery end-to-side anastomosis model,60%in situ endothelialization was observed throughout the entire lumen of 1.7 mm inner diameter modified grafts,compared to 0%of unmodified graft,and the four-week graft patency also increased.This work presents a promising strategy to stimulate in situ endothelialization on synthetic materials for improving long-term performance.

Degradation and biocompatibility of one-step electrodeposited magnesium thioctic acid/magnesium hydroxide hybrid coatings on ZE21B alloys for cardiovascular stents

Constructing a functional hybrid coating appears to be a promising strategy for addressing the poor corrosion resistance and insufficient endothelialization of Mg-based stents.Nevertheless,the steps for preparing composite coatings are usually complicated and time-consuming.Herein,a novel composite coating,composed of bioactive magnesium thioctic acid(MTA)layer formed by deposition and corrosion-resistant magnesium hydroxide(Mg(OH)_(2))layer grown in situ,is simply fabricated on ZE21B alloys via one-step electrodeposition.Scanning electron microscopy(SEM)shows that the electrodeposited coating has a compact and uniform structure.And the high adhesion of the MTA/Mg(OH)_(2)hybrid coating is also confirmed by the micro-scratch test.Electrochemical test,scanning kelvin probe(SKP),and hydrogen evolution measurement indicate that the hybrid coating effectively reduces the degradation rate of Mg substrates.Haemocompatibility experiment and cell culture trial detect that the composite coating is of fine biocompatibility.Finally,the preparation mechanism of MTA/Mg(OH)_(2)hybrid coatings is discussed and proposed.This coating shows a great potential application for cardiovascular stents.

Sustained release of vascular endothelial growth factor A and basic fibroblast growth factor from nanofiber membranes reduces oxygen/glucose deprivation-induced injury to neurovascular units

Upregulation of vascular endothelial growth factor A/basic fibroblast growth factor(VEGFA/b FGF)expression in the penumbra of cerebral ischemia can increase vascular volume,reduce lesion volume,and enhance neural cell proliferation and differentiation,thereby exerting neuroprotective effects.However,the beneficial effects of endogenous VEGFA/b FGF are limited as their expression is only transiently increased.In this study,we generated multilayered nanofiber membranes loaded with VEGFA/b FGF using layer-by-layer self-assembly and electrospinning techniques.We found that a membrane containing 10 layers had an ideal ultrastructure and could efficiently and stably release growth factors for more than 1 month.This 10-layered nanofiber membrane promoted brain microvascular endothelial cell tube formation and proliferation,inhibited neuronal apoptosis,upregulated the expression of tight junction proteins,and improved the viability of various cellular components of neurovascular units under conditions of oxygen/glucose deprivation.Furthermore,this nanofiber membrane decreased the expression of Janus kinase-2/signal transducer and activator of transcription-3(JAK2/STAT3),Bax/Bcl-2,and cleaved caspase-3.Therefore,this nanofiber membrane exhibits a neuroprotective effect on oxygen/glucose-deprived neurovascular units by inhibiting the JAK2/STAT3 pathway.

Challenges and strategies for in situ endothelialization and long-term lumen patency of vascular grafts

Vascular diseases are the most prevalent cause of ischemic necrosis of tissue and organ,which even result in dysfunction and death.Vascular regeneration or artificial vascular graft,as the conventional treatment modality,has received keen attentions.However,small-diameter(diameter<4 mm)vascular grafts have a high risk of thrombosis and intimal hyperplasia(IH),which makes long-term lumen patency challengeable.Endothelial cells(ECs)form the inner endothelium layer,and are crucial for anti-coagulation and thrombogenesis.Thus,promoting in situ endothelialization in vascular graft remodeling takes top priority,which requires recruitment of endothelia progenitor cells(EPCs),migration,adhesion,proliferation and activation of EPCs and ECs.Chemotaxis aimed at ligands on EPC surface can be utilized for EPC homing,while nanofibrous structure,biocompatible surface and cell-capturing molecules on graft surface can be applied for cell adhesion.Moreover,cell orientation can be regulated by topography of scaffold,and cell bioactivity can be modulated by growth factors and therapeutic genes.Additionally,surface modification can also reduce thrombogenesis,and some drug release can inhibit IH.Considering the influence of macrophages on ECs and smooth muscle cells(SMCs),scaffolds loaded with drugs that can promote M2 polarization are alternative strategies.In conclusion,the advanced strategies for enhanced long-term lumen patency of vascular grafts are summarized in this review.Strategies for recruitment of EPCs,adhesion,proliferation and activation of EPCs and ECs,anti-thrombogenesis,anti-IH,and immunomodulation are discussed.Ideal vascular grafts with appropriate surface modification,loading and fabrication strategies are required in further studies.

Distinctive effects of CD34- and CD133-specific antibody-coated stents on re-endothelialization and in-stent restenosis at the early phase of vascular injury

It is not clear what effects of CD34-and CD133-specific antibody-coated stents have on reendothelialization and in-stent restenosis(ISR)at the early phase of vascular injury.This study aims at determining the capabilities of different coatings on stents(e.g.gelatin,anti-CD133 and anti-CD34 antibodies)to promote adhesion and proliferation of endothelial progenitor cells(EPCs).The in vitro study revealed that the adhesion force enabled the EPCs coated on glass slides to withstand flow-induced shear stress,so that allowing for the growth of the cells on the slides for 48 h.The in vivo experiment using a rabbit model in which the coated stents with different substrates were implanted showed that anti-CD34 and anti-CD133 antibody-coated stents markedly reduced the intima area and restenosis than bare mental stents(BMS)and gelatin-coated stents.Compared with the anti-CD34 antibody-coated stents,the time of cells adhesion was longer and earlier present in the anti-CD133 antibody-coated stents and anti-CD133 antibody-coated stents have superiority in re-endothelialization and inhibition of ISR.In conclusion,this study demonstrated that anti-CD133 antibody as a stent coating for capturing EPCs is better than anti-CD34 antibody in promoting endothelialization and reducing ISR.

Coaxial-printed small-diameter polyelectrolyte-based tubes with an electrostatic self-assembly of heparin and YIGSR peptide for antithrombogenicity and endothelialization

Low patency ratio of small-diameter vascular grafts remains a major challenge due to the occurrence of thrombosis formation and intimal hyperplasia after transplantation.Although developing the functional coating with release of bioactive molecules on the surface of small-diameter vascular grafts are reported as an effective strategy to improve their patency ratios,it is still difficult for current functional coatings cooperating with spatiotemporal control of bioactive molecules release to mimic the sequential requirements for antithrombogenicity and endothelialization.Herein,on basis of 3D-printed polyelectrolyte-based vascular grafts,a biologically inspired release system with sequential release in spatiotemporal coordination of dual molecules through an electrostatic self-assembly was first described.A series of tubes with tunable diameters were initially fabricated by a coaxial extrusion printing method with customized nozzles,in which a polyelectrolyte ink containing of ε-polylysine and sodium alginate was used.Further,dual bioactive molecules,heparin with negative charges and Tyr-Ile-Gly-Ser-Arg(YIGSR)peptide with positive charges were layer-by-layer assembled onto the surface of these 3D-printed tubes.Due to the electrostatic interaction,the sequential release of heparin and YIGSR was demonstrated and could construct a dynamic microenvironment that was thus conducive to the antithrombogenicity and endothelialization.This study opens a new avenue to fabricate a small-diameter vascular graft with a biologically inspired release system based on electrostatic interaction,revealing a huge potential for development of small-diameter artificial vascular grafts with good patency.

In vivo degradation and endothelialization of an iron bioresorbable scaffold

Detection of in vivo biodegradation is critical for development of next-generation medical devices such as bioresorbable stents or scaffolds(BRSs).In particular,it is urgent to establish a nondestructive approach to examine in vivo degradation of a new-generation coronary stent for interventional treatment based on mammal experiments;otherwise it is not available to semi-quantitatively monitor biodegradation in any clinical trial.Herein,we put forward a semi-quantitative approach to measure degradation of a sirolimus-eluting iron bioresorbable scaffold(IBS)based on optical coherence tomography(OCT)images;this approach was confirmed to be consistent with the present weight-loss measurements,which is,however,a destructive approach.The IBS was fabricated by a metal-polymer composite technique with a polylactide coating on an iron stent.The efficacy as a coronary stent of this new bioresorbable scaffold was compared with that of a permanent metal stent with the name of trade mark Xience,which has been widely used in clinic.The endothelial coverage on IBS was found to be greater than on Xience after implantation in a rabbit model;and our well-designed ultrathin stent exhibited less individual variation.We further examined degradation of the IBSs in both minipig coronary artery and rabbit abdominal aorta models.The present result indicated much faster iron degradation of IBS in the rabbit model than in the porcine model.The semi-quantitative approach to detect biodegradation of IBS and the finding of the species difference might be stimulating for fundamental investigation of biodegradable implants and clinical translation of the next-generation coronary stents.

Preparation and Endothelialization of Multi-level Vessel-like Network in Enzymated Gelatin Scaffolds

Loss of function of large tissues is an urgent clinical problem. Although the artificial microfluidic network fabricated in large tis- sue-engineered constructs has great promise, it is still difficult to develop an efficient vessel-like design to meet the requirements of the biomimetic vascular network for tissue engineering applications. In this study, we used a facile approach to fabricate a branched and multi-level vessel-like network in a large muscle scaffolds by combining stereolithography （SL） technology and enzymatic crosslinking mechanism. The morphology of microchannel cross-sections was characterized using micro-computed tomography. The square cross-sections were gradually changed to a seamless circular microfluidic network, which is similar to the natural blood vessel. In the different micro-channels, the velocity greatly affected the attachment and spread of Human Umbilical Vein Endothelial Cell （HUVEC）-Green Fluorescent Protein （GFP）. Our study demonstrated that the branched and multi-level microchannel network simulates biomimetic microenvironments to promote endothelialization. The gelatin scaffolds in the circular vessel-like networks will likely support myoblast and surrounding tissue for clinical use.

Covalent functionalization of decellularized tissues accelerates endothelialization

In the field of tissue regeneration,the lack of a stable endothelial lining may affect the hemocompatibility of both synthetic and biological replacements.These drawbacks might be prevented by specific biomaterial functionalization to induce selective endothelial cell(EC)adhesion.Decellularized bovine pericardia and porcine aortas were selectively functionalized with a REDV tetrapeptide at 10^(-5)M and 10^(-6)M working concentrations.The scaffold-bound peptide was quantified and REDV potential EC adhesion enhancement was evaluated in vitro by static seeding of human umbilical vein ECs.The viable cells and MTS production were statistically higher in functionalized tissues than in control.Scaffold histoarchitecture,geometrical features,and mechanical properties were unaffected by peptide anchoring.The selective immobilization of REDV was effective in accelerating ECs adhesion while promoting proliferation in functionalized decellularized tissues intended for blood-contacting applications.

Effect of VEGF/GREDVY Modified Surface on Vascular Cells Behavior

We synthesized B-He/B-GREDVY and immobilized them on avidin-coated surfaces.To examine the immobilization of molecules in the material, the following experiments were performed:fluorescein isothiocyanate(FITC) fluorescence staining, water contact angle and atomic force microscopy(AFM) measurements. Besides, the biological evaluation experiments were also performed, such as platelets adhesion and activation, the culturing of smooth muscle cells(SMC) and endothelial cells(EC). These experimental results show that the modified surfaces could prevent the hyperproliferation of SMC, and promote the proliferation and migration of EC and EPC. Furthermore, the adding of VEGF improved the EC adhesion in a dynamic environment. Generally, it is expected that the modified surfaces could be used to accelerate the formation of the newly endothelial layer for the construction of platforms for coronary artery stent therapy.

Trimethylamine N-oxide aggravates vascular permeability and endothelial cell dysfunction under diabetic condition:in vitro and in vivo study

AIM:To provide the direct evidence for the crucial role of trimethylamine N-oxide(TMAO)in vascular permeability and endothelial cell dysfunction under diabetic condition.METHODS:The role of TMAO on the in vitro biological effect of human retinal microvascular endothelial cells(HRMEC)under high glucose conditions was tested by a cell counting kit,wound healing,a transwell and a tube formation assay.The inflammation-related gene expression affected by TMAO was tested by real-time polymerase chain reaction(RT-PCR).The expression of the cell junction was measured by Western blotting(WB)and immunofluorescence staining.In addition,two groups of rat models,diabetic and non-diabetic,were fed with normal or 0.1%TMAO for 16wk,and their plasma levels of TMAO,vascular endothelial growth factor(VEGF),interleukin(IL)-6 and tumor necrosis factor(TNF)-αwere tested.The vascular permeability of rat retinas was measured using FITC-Dextran,and the expression of zonula occludens(ZO)-1 and claudin-5 in rat retinas was detected by WB or immunofluorescence staining.RESULTS:TMAO administration significantly increased the cell proliferation,migration,and tube formation of primary HRMEC either in normal or high-glucose conditions.RT-PCR showed elevated inflammation-related gene expression of HRMEC under TMAO stimulation,while WB or immunofluorescence staining indicated decreased cell junction ZO-1 and occludin expression after high-glucose and TMAO treatment.Diabetic rats showed higher plasma levels of TMAO as well as retinal vascular leakage,which were even higher in TMAO-feeding diabetic rats.Furthermore,TMAO administration increased the rat plasma levels of VEGF,IL-6 and TNF-αwhile decreasing the retinal expression levels of ZO-1 and claudin-5.CONCLUSION:TMAO enhances the proliferation,migration,and tube formation of HRMEC,as well as destroys their vascular integrity and tight connection.It also regulates the expression of VEGF,IL-6,and TNF-α.

Ghrelin inhibits autophagy mediated by AKT/mTOR pathway to ameliorate retinal angiogenesis induced by high glucose stress

AIM:To observe the effect of ghrelin,a growth hormonereleasing peptide,on retinal angiogenesis in vitro under high glucose(HG)stress and to explore the possible mechanism of autophagy.METHODS:Human retinal microvascular endothelial cells(HRMECs)were treated with high concentration of glucose alone or in combination with ghrelin.The cell migration,tube formation and the expression of the autophagy-related proteins LC3-II/I,Beclin-1,p62,phosphorylated AKT(p-AKT)/AKT and phosphorylated mammalian target of rapamycin(p-mTOR)/mTOR were detected.Then,to clarify the correlation between ghrelin effect and autophagy,AKT inhibitor VIII was adopted to treat HRMECs,and cell migration,tube formation as well as the protein expressions of LC3-II/I,Beclin-1 and p62 were observed.RESULTS:Under HG stress,ghrelin inhibited migration and tube formation of HRMECs.Ghrelin inhibited the increases in the protein levels of LC3-II/I,Beclin-1 and the decreases in the protein levels of p62,p-AKT/AKT and p-mTOR/mTOR induced by HG stress.Moreover,under the action of AKT/mTOR pathway inhibitors,the effects of ghrelin on migration and tube formation were both reduced.In addition,the expression of LC3-II/I and Beclin-1 were significantly up-regulated and the expression of p62 was down-regulated.CONCLUSION:Retinal angiogenesis under in vitro HG stress can be inhibited by ghrelin through activating AKT/mTOR pathway to inhibit autophagy.

Membrane vesicles derived from Streptococcus suis serotype 2 induce cell pyroptosis in endothelial cells via the NLRP3/Caspase-1/GSDMD pathway

Streptococcus suis serotype 2(S.suis 2)is a zoonotic pathogen that clinically causes severe swine and human infections(such as meningitis,endocarditis,and septicemia).In order to cause widespread diseases in different organs,S.suis 2 must colonize the host,break the blood barrier,and cause exaggerated inflammation.In the last few years,most studies have focused on a single virulence factor and its influences on the host.Membrane vesicles(MVs)can be actively secreted into the extracellular environment contributing to bacteria-host interactions.Gram-negative bacteria-derived outer membrane vesicles(OMVs)were recently shown to activate host Caspase-11-mediated non-canonical inflammasome pathway via deliverance of OMV-bound lipopolysaccharide(LPS),causing host cell pyroptosis.However,little is known about the effect of the MVs from S.suis 2(Gram-positive bacteria without LPS)on cell pyroptosis.Thus,we investigated the molecular mechanism by which S.suis 2 MVs participate in endothelial cell pyroptosis.In this study,we used proteomics,electron scanning microscopy,fluorescence microscope,Western blotting,and bioassays,to investigate the MVs secreted by S.suis 2.First,we demonstrated that S.suis 2 secreted MVs with an average diameter of 72.04 nm,and 200 proteins in MVs were identified.Then,we showed that MVs were transported to cells via mainly dynamin-dependent endocytosis.The S.suis 2 MVs activated NLRP3/Caspase-1/GSDMD canonical inflammasome signaling pathway,resulting in cell pyroptosis,but it did not activate the Caspase-4/-5 pathway.More importantly,endothelial cells produce large amounts of reactive oxygen species(ROS)and lost their mitochondrial membrane potential under induction by S.suis 2 MVs.The results in this study suggest for the first time that MVs from S.suis 2 were internalized by endothelial cells via mainly dynamin-dependent endocytosis and might promote NLRP3/Caspase-1/GSDMD pathway by mitochondrial damage,which produced mtDNA and ROS under induction,leading to the pyroptosis of endothelial cells.

Small extracellular vesicles derived from cerebral endothelial cells with elevated microRNA 27a promote ischemic stroke recovery

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.

Xuebijing improves intestinal microcirculation dysfunction in septic rats by regulating the VEGF-A/PI3K/Akt signaling pathway

BACKGROUND:This study aims to explore whether Xuebijing(XBJ) can improve intestinal microcirculation dysfunction in sepsis and its mechanism.METHODS:A rat model of sepsis was established by cecal ligation and puncture(CLP).A total of 30 male SD rats were divided into four groups:sham group,CLP group,XBJ + axitinib group,and XBJ group.XBJ was intraperitoneally injected 2 h before CLP.Hemodynamic data(blood pressure and heart rate) were recorded.The intestinal microcirculation data of the rats were analyzed via microcirculation imaging.Enzyme-linked immunosorbent assay(ELISA) kits were used to detect the serum levels of interleukin-6(IL-6),C-reactive protein(CRP),and tumor necrosis factor-α(TNF-α) in the rats.Histological analysis and transmission electron microscopy were used to analyze the injury of small intestinal microvascular endothelial cells and small intestinal mucosa in rats.The expression of vascular endothelial growth factor A(VEGF-A),phosphoinositide 3-kinase(PI3K),phosphorylated PI3K(p-PI3K),protein kinase B(Akt),and phosphorylated Akt(p-Akt) in the small intestine was analyzed via Western blotting.RESULTS:XBJ improved intestinal microcirculation dysfunction in septic rats,alleviated the injury of small intestinal microvascular endothelial cells and small intestinal mucosa,and reduced the systemic inflammatory response.Moreover,XBJ upregulated the expression of VEGF-A,p-PI3K/total PI3K,and p-Akt/total Akt in the rat small intestine.CONCLUSION:XBJ may improve intestinal microcirculation dysfunction in septic rats possibly through the VEGF-A/PI3K/Akt signaling pathway.

Neural stem cell-derived exosomes regulate cell proliferation,migration,and cell death of brain microvascular endothelial cells via the miR-9/Hes1 axis under hypoxia

Background:Our previous study found that mouse embryonic neural stem cell(NSC)-derived exosomes(EXOs)regulated NSC differentiation via the miR-9/Hes1 axis.However,the effects of EXOs on brain microvascular endothelial cell(BMEC)dysfunction via the miR-9/Hes1 axis remain unknown.Therefore,the current study aimed to determine the effects of EXOs on BMEC proliferation,migration,and death via the miR-9/Hes1 axis.Methods:Immunofluorescence,quantitative real-time polymerase chain reaction,cell counting kit-8 assay,wound healing assay,calcein-acetoxymethyl/propidium iodide staining,and hematoxylin and eosin staining were used to determine the role and mechanism of EXOs on BMECs.Results:EXOs promoted BMEC proliferation and migration and reduced cell death under hypoxic conditions.The overexpression of miR-9 promoted BMEC prolifera-tion and migration and reduced cell death under hypoxic conditions.Moreover,miR-9 downregulation inhibited BMEC proliferation and migration and also promoted cell death.Hes1 silencing ameliorated the effect of amtagomiR-9 on BMEC proliferation and migration and cell death.Hyperemic structures were observed in the regions of the hippocampus and cortex in hypoxia-induced mice.Meanwhile,EXO treatment improved cerebrovascular alterations.Conclusion:NSC-derived EXOs can promote BMEC proliferation and migra-tion and reduce cell death via the miR-9/Hes1 axis under hypoxic conditions.Therefore,EXO therapeutic strategies could be considered for hypoxia-induced vascular injury.

The emerging role of nitric oxide in the synaptic dysfunction of vascular dementia

With an increase in global aging,the number of people affected by cerebrovascular diseases is also increasing,and the incidence of vascular dementia-closely related to cerebrovascular risk-is increasing at an epidemic rate.However,few therapeutic options exist that can markedly improve the cognitive impairment and prognosis of vascular dementia patients.Similarly in Alzheimer’s disease and other neurological disorders,synaptic dysfunction is recognized as the main reason for cognitive decline.Nitric oxide is one of the ubiquitous gaseous cellular messengers involved in multiple physiological and pathological processes of the central nervous system.Recently,nitric oxide has been implicated in regulating synaptic plasticity and plays an important role in the pathogenesis of vascular dementia.This review introduces in detail the emerging role of nitric oxide in physiological and pathological states of vascular dementia and summarizes the diverse effects of nitric oxide on different aspects of synaptic dysfunction,neuroinflammation,oxidative stress,and blood-brain barrier dysfunction that underlie the progress of vascular dementia.Additionally,we propose that targeting the nitric oxide-sGC-cGMP pathway using certain specific approaches may provide a novel therapeutic strategy for vascular dementia.

Close relationship between mediators of inflammation and pancreatic cancer:Our experience

In this editorial,we focus specifically on the mechanisms by which pancreatic inflammation affects pancreatic cancer.Cancer of the pancreas remains one of the deadliest cancer types.The highest incidence and mortality rates of pancreatic cancer are found in developed countries.Trends of pancreatic cancer incidence and mortality vary considerably worldwide.A better understanding of the etiology and identification of the risk factors is essential for the primary prevention of this disease.Pancreatic tumors are characterized by a complex microenvironment that orchestrates metabolic alterations and supports a milieu of interactions among various cell types within this niche.In this editorial,we highlight the foundational studies that have driven our understanding of these processes.In our experimental center,we have carefully studied the mechanisms of that link pancreatic inflammation and pancreatic cancer.We focused on the role of mast cells(MCs).MCs contain pro-angiogenic factors,including tryptase,that are associated with increased angiogenesis in various tumors.In this editorial,we address the role of MCs in angiogenesis in both pancreatic ductal adenocarcinoma tissue and adjacent normal tissue.The assessment includes the density of c-Kit receptor-positive MCs,the density of tryptase-positive MCs,the area of tryptasepositive MCs,and angiogenesis in terms of microvascularization density.