Attempts have been made to use cell transplantation and biomaterials to promote cell proliferation,differentiation,migration,and survival,as well as angiogenesis,in the context of brain injury.However,whether bioactiv...Attempts have been made to use cell transplantation and biomaterials to promote cell proliferation,differentiation,migration,and survival,as well as angiogenesis,in the context of brain injury.However,whether bioactive materials can repair the damage caused by ischemic stroke by activating endogenous neurogenesis and angiogenesis is still unknown.In this study,we applied chitosan gel loaded with basic fibroblast growth factor to the stroke cavity 7 days after ischemic stroke in rats.The gel slowly released basic fibroblast growth factor,which improved the local microenvironment,activated endogenous neural stem/progenitor cells,and recruited these cells to migrate toward the penumbra and stroke cavity and subsequently differentiate into neurons,while enhancing angiogenesis in the penumbra and stroke cavity and ultimately leading to partial functional recovery.This study revealed the mechanism by which bioactive materials repair ischemic strokes,thus providing a new strategy for the clinical application of bioactive materials in the treatment of ischemic stroke.展开更多
Endorepellin plays a key role in the regulation of angiogenesis,but its effects on angiogenesis after traumatic brain injury are unclear.This study explored the effects of endorepellin on angiogenesis and neurobehavio...Endorepellin plays a key role in the regulation of angiogenesis,but its effects on angiogenesis after traumatic brain injury are unclear.This study explored the effects of endorepellin on angiogenesis and neurobehavioral outcomes after traumatic brain injury in mice.Mice were randomly divided into four groups:sham,controlled cortical impact only,adeno-associated virus(AAV)-green fluorescent protein,and AAV-shEndorepellin-green fluorescent protein groups.In the controlled cortical impact model,the transduction of AAV-shEndorepellin-green fluorescent protein downregulated endorepellin while increasing the number of CD31+/Ki-67+proliferating endothelial cells and the functional microvessel density in mouse brain.These changes resulted in improved neurological function compared with controlled cortical impact mice.Western blotting revealed increased expression of vascular endothelial growth factor and angiopoietin-1 in mice treated with AAV-shEndorepellin-green fluorescent protein.Synchrotron radiation angiography showed that endorepellin downregulation promoted angiogenesis and increased cortical neovascularization,which may further improve neurobehavioral outcomes.Furthermore,an in vitro study showed that downregulation of endorepellin increased tube formation by human umbilical vein endothelial cells compared with a control.Mechanistic analysis found that endorepellin downregulation may mediate angiogenesis by activating vascular endothelial growth factor-and angiopoietin-1-related signaling pathways.展开更多
BACKGROUND Hepatic arterial infusion chemotherapy(HAIC)has been proven to be an ideal choice for treating unresectable hepatocellular carcinoma(uHCC).HAIC-based treatment showed great potential for treating uHCC.Howev...BACKGROUND Hepatic arterial infusion chemotherapy(HAIC)has been proven to be an ideal choice for treating unresectable hepatocellular carcinoma(uHCC).HAIC-based treatment showed great potential for treating uHCC.However,large-scale studies on HAIC-based treatments and meta-analyses of first-line treatments for uHCC are lacking.AIM To investigate better first-line treatment options for uHCC and to assess the safety and efficacy of HAIC combined with angiogenesis inhibitors,programmed cell death of protein 1(PD-1)and its ligand(PD-L1)blockers(triple therapy)under real-world conditions.METHODS Several electronic databases were searched to identify eligible randomized controlled trials for this meta-analysis.Study-level pooled analyses of hazard ratios(HRs)and odds ratios(ORs)were performed.This was a retrospective single-center study involving 442 patients with uHCC who received triple therapy or angiogenesis inhibitors plus PD-1/PD-L1 blockades(AIPB)at Sun Yat-sen University Cancer Center from January 2018 to April 2023.Propensity score matching(PSM)was performed to balance the bias between the groups.The Kaplan-Meier method and cox regression were used to analyse the survival data,and the log-rank test was used to compare the suvival time between the groups.RESULTS A total of 13 randomized controlled trials were included.HAIC alone and in combination with sorafenib were found to be effective treatments(P values for ORs:HAIC,0.95;for HRs:HAIC+sorafenib,0.04).After PSM,176 HCC patients were included in the analysis.The triple therapy group(n=88)had a longer median overall survival than the AIPB group(n=88)(31.6 months vs 14.6 months,P<0.001)and a greater incidence of adverse events(94.3%vs 75.4%,P<0.001).CONCLUSION This meta-analysis suggests that HAIC-based treatments are likely to be the best choice for uHCC.Our findings confirm that triple therapy is more effective for uHCC patients than AIPB.展开更多
Hepatocellular carcinoma(HCC)is the fourth leading cause of cancer-associated death worldwide.Angiogenesis,the process of formation of new blood vessels,is required for cancer cells to obtain nutrients and oxygen.HCC ...Hepatocellular carcinoma(HCC)is the fourth leading cause of cancer-associated death worldwide.Angiogenesis,the process of formation of new blood vessels,is required for cancer cells to obtain nutrients and oxygen.HCC is a typical hypervascular solid tumor with an aberrant vascular network and angiogenesis that contribute to its growth,progression,invasion,and metastasis.Current anti-angiogenic therapies target mainly tyrosine kinases,vascular endothelial growth factor receptor(VEGFR),and plateletderived growth factor receptor(PDGFR),and are considered effective strategies for HCC,particularly advanced HCC.However,because the survival benefits conferred by these anti-angiogenic therapies are modest,new anti-angiogenic targets must be identified.Several recent studies have determined the underlying molecular mechanisms,including pro-angiogenic factors secreted by HCC cells,the tumor microenvironment,and cancer stem cells.In this review,we summarize the roles of pro-angiogenic factors;the involvement of endothelial cells,hepatic stellate cells,tumor-associated macrophages,and tumor-associated neutrophils present in the tumor microenvironment;and the regulatory influence of cancer stem cells on angiogenesis in HCC.Furthermore,we discuss some of the clinically approved anti-angiogenic therapies and potential novel therapeutic targets for angiogenesis in HCC.A better understanding of the mechanisms underlying angiogenesis may lead to the development of more optimized anti-angiogenic treatment modalities for HCC.展开更多
Treatment with metformin can lead to the recovery of pleiotropic biological activities after spinal cord injury.However,its effect on spinal cord injury in aged mice remains unclear.Considering the essential role of a...Treatment with metformin can lead to the recovery of pleiotropic biological activities after spinal cord injury.However,its effect on spinal cord injury in aged mice remains unclear.Considering the essential role of angiogenesis during the regeneration process,we hypothesized that metformin activates the adenosine monophosphate-activated protein kinase/endothelial nitric oxide synthase pathway in endothelial cells,thereby promoting microvascular regeneration in aged mice after spinal cord injury.In this study,we established young and aged mouse models of contusive spinal cord injury using a modified Allen method.We found that aging hindered the recovery of neurological function and the formation of blood vessels in the spinal cord.Treatment with metformin promoted spinal cord microvascular endothelial cell migration and blood vessel formation in vitro.Furthermore,intraperitoneal injection of metformin in an in vivo model promoted endothelial cell proliferation and increased the density of new blood vessels in the spinal cord,thereby improving neurological function.The role of metformin was reversed by compound C,an adenosine monophosphate-activated protein kinase inhibitor,both in vivo and in vitro,suggesting that the adenosine monophosphate-activated protein kinase/endothelial nitric oxide synthase pathway likely regulates metformin-mediated angiogenesis after spinal cord injury.These findings suggest that metformin promotes vascular regeneration in the injured spinal cord by activating the adenosine monophosphate-activated protein kinase/endothelial nitric oxide synthase pathway,thereby improving the neurological function of aged mice after spinal cord injury.展开更多
Promotion of new blood vessel formation is a new strategy for treating ischemic stroke.Non-coding miRNAs have been recently considered potential therapeutic targets for ischemic stroke.miR-181b has been shown to promo...Promotion of new blood vessel formation is a new strategy for treating ischemic stroke.Non-coding miRNAs have been recently considered potential therapeutic targets for ischemic stroke.miR-181b has been shown to promote angiogenesis in hypoxia and traumatic brain injury model,while its effect on ischemic stroke remains elusive.In this study,we found that overexpression of miR-181b in brain microvascular endothelial cells subjected to oxygen-glucose deprivation in vitro restored cell prolife ration and enhanced angiogenesis.In rat models of focal cerebral ischemia,ove rexpression of miR-181b reduced infarction volume,promoted angiogenesis in ischemic penumbra,and improved neurological function.We further investigated the molecular mechanism by which miR-181b participates in angiogenesis after ischemic stroke and found that miR-181b directly bound to the 3’-UTR of phosphatase and tensin homolog(PTEN) mRNA to induce PTEN downregulation,leading to activation of the protein kinase B(Akt) pathway,upregulated expression of vascular endothelial growth facto rs,down-regulated expression of endostatin,and promoted angiogenesis.Taken togethe r,these results indicate that exogenous miR-181b exhibits neuroprotective effects on ischemic stro ke through activating the PTEN/Akt signal pathway and promoting angiogenesis.展开更多
Neoplasms can be considered as a group of aberrant cells that need more vascular supply to fulfill all their functions.Therefore,they promote angiogenesis through the same neovascularization pathway used physiological...Neoplasms can be considered as a group of aberrant cells that need more vascular supply to fulfill all their functions.Therefore,they promote angiogenesis through the same neovascularization pathway used physiologically.Angiogenesis is a process characterized by a heterogeneous distribution of oxygen caused by the tumor and oxidative stress;the latter being one of the most powerful stimuli of angiogenesis.As a result of altered tumor metabolism due to hypoxia,acidosis occurs.The angiogenic process and oxidative stress can be detected by measuring serum and tissue biomarkers.The study of the mechanisms underlying angiogenesis and oxidative stress could lead to the identification of new biomarkers,ameliorating the selection of patients with neoplasms and the prediction of their response to possible anti-tumor therapies.In particular,in the treatment of patients with similar clinical tumor phenotypes but different prognoses,the new biomarkers could be useful.Moreover,they may lead to a better understanding of the mechanisms underlying drug resistance.Experimental studies show that blocking the vascular supply results in antiproliferative activity in vivo in neuroendocrine tumor cells,which require a high vascular supply.展开更多
Background: Improving the mechanical properties and angiogenesis of acellular scaffolds before transplantation is an important challenge facing the development of acellular liver grafts. The present study aimed to eva...Background: Improving the mechanical properties and angiogenesis of acellular scaffolds before transplantation is an important challenge facing the development of acellular liver grafts. The present study aimed to evaluate the cytotoxicity and angiogenesis of polyethylene glycol(PEG) crosslinked decellularized single liver lobe scaffolds(DLSs), and establish its suitability as a graft for long-term liver tissue engineering. Methods: Using mercaptoacrylate produced by the Michael addition reaction, DLSs were first modified using N-succinimidyl S-acetylthioacetate(SATA), followed by cross-linking with PEG as well as vascular endothelial growth factor(VEGF). The optimal concentration of agents and time of the individual steps were identified in this procedure through biomechanical testing and morphological analysis. Subsequently, human umbilical vein endothelial cells(HUVECs) were seeded on the PEG crosslinked scaffolds to detect the proliferation and viability of cells. The scaffolds were then transplanted into the subcutaneous tissue of Sprague-Dawley rats to evaluate angiogenesis. In addition, the average number of blood vessels was evaluated in the grafts with or without PEG at days 7, 14, and 21 after implantation. Results: The PEG crosslinked DLS maintained their three-dimensional structure and were more translucent after decellularization than native DLS, which presented a denser and more porous network structure. The results for Young’s modulus proved that the mechanical properties of 0.5 PEG crosslinked DLS were the best and close to that of native livers. The PEG-VEGF-DLS could better promote cell proliferation and differentiation of HUVECs compared with the groups without PEG cross-linking. Importantly, the average density of blood vessels was higher in the PEG-VEGF-DLS than that in other groups at days 7, 14, and 21 after implantation in vivo. Conclusions: The PEG crosslinked DLS with VEGF could improve the biomechanical properties of native DLS, and most importantly, their lack of cytotoxicity provides a new route to promote the proliferation of cells in vitro and angiogenesis in vivo in liver tissue engineering.展开更多
Large bone defect regeneration has always been recognized as a challenging clinical problem due to the difficulty of revascularization.Conventional treatments exhibit certain inherent disadvantages(e.g.,secondary inju...Large bone defect regeneration has always been recognized as a challenging clinical problem due to the difficulty of revascularization.Conventional treatments exhibit certain inherent disadvantages(e.g.,secondary injury,immunization,and potential infections).However,three-dimensional(3D)printing technology as an emerging field can serve as an effective approach to achieve satisfactory revascularization while making up for the above limitations.A wide variety of methods can be used to facilitate blood supply during the design of a 3D-printed scaffold.Importantly,the scaffold structure lays a foundation for the entire printing object;any method to promote angiogenesis can be effective only if it is based on well-designed scaffolds.In this review,different designs related to angiogenesis are summarized by collecting the literature from recent years.The 3D-printed scaffolds are classified into four major categories and discussed in detail,from elementary porous scaffolds to the most advanced bone-like scaffolds.Finally,structural design suggestions to achieve rapid angiogenesis are proposed by analyzing the above architectures.This review can provide a reference for organizations or individual academics to achieve improved bone defect repair and regeneration using 3D printing.展开更多
Background:Pathological angiogenesis and blood–brain barrier damage may play an important role in Alzheimer's disease(AD).ACE2 is mainly expressed on the surface of endothelial cells in brain.Recent studies have ...Background:Pathological angiogenesis and blood–brain barrier damage may play an important role in Alzheimer's disease(AD).ACE2 is mainly expressed on the surface of endothelial cells in brain.Recent studies have shown that the expression of ACE2 in AD is reduced,but its role in AD is still unclear.Method:We induced AD damage in endothelial cells using Aβ25-35 and overexpressed ACE2 in bEend.3 cells through lentiviral transfection.We detected the effect of Aβ25-35 on cell viability using the CCK-8 assay and examined the effect of overexpressing ACE2 on angiogenesis using an angiogenesis assay.We used western blot and cell immunofluorescence to detect changes in the expression of the VEGF/VEGFR2 pathway,tight junction protein,and NF-κB pathway.Results:Aβ25-35 treatment significantly decreased the expression of ACE2 and reduced cell viability.ACE2 overexpression(1)reduced the number of branches and junctions in tube formation,(2)inhibited the activation of the VEGF/VEGFR2 pathway induced by Aβ25-35,(3)increased the expression of TJPs,including ZO-1 and claudin-5,and(4)restored Aβ25-35-induced activation of the NF-κB pathway.Conclusion:Overexpression of ACE2 can improve pathological angiogenesis and blood–brain barrier damage in AD models in vitro by inhibiting NF-κB/VEGF/VEGFR2 pathway activity.ACE2 may therefore represent a therapeutic target for endothelial cell dysfunction in AD.展开更多
BACKGROUND As a novel endogenous anti-angiogenic molecule, vasohibin 1(VASH1) is not only expressed in tumor stroma, but also in tumor tissue. Moreover, studies have shown that VASH1 may be a prognostic marker in colo...BACKGROUND As a novel endogenous anti-angiogenic molecule, vasohibin 1(VASH1) is not only expressed in tumor stroma, but also in tumor tissue. Moreover, studies have shown that VASH1 may be a prognostic marker in colorectal cancer(CRC). Knockdown of VASH1 enhanced transforming growth factor-β1(TGF-β1)/Smad3 pathway activity and type Ⅰ/Ⅲ collagen production. Our previous findings suggest that ELL-associated factor 2(EAF2) may play a tumor suppressor and protective role in the development and progression of CRC by regulating signal transducer and activator of transcription 3(STAT3)/TGF-β1 signaling pathway. However, the functional role and mechanism of VASH1-mediated TGF-β1 related pathway in CRC has not been elucidated.AIM To investigate the expression of VASH1 in CRC and its correlation with the expression of EAF2. Furthermore, we studied the functional role and mechanism of VASH1 involved in the regulation and protection of EAF2 in CRC cells in vitro.METHODS We collected colorectal adenocarcinoma and corresponding adjacent tissues to investigate the clinical expression of EAF2 protein and VASH1 protein in patients with advanced CRC. Following, we investigated the effect and mechanism of EAF2 and VASH1 on the invasion, migration and angiogenesis of CRC cells in vitro using plasmid transfection.RESULTS Our findings indicated that EAF2 was down-regulated and VASH1 was upregulated in advanced CRC tissue compared to normal colorectal tissue. KaplanMeier survival analysis showed that the higher EAF2 Level group and the lower VASH1 Level group had a higher survival rate. Overexpression of EAF2 might inhibit the activity of STAT3/TGF-β1 pathway by up-regulating the expression of VASH1, and then weaken the invasion, migration and angiogenesis of CRC cells.CONCLUSION This study suggests that EAF2 and VASH1 may serve as new diagnostic and prognostic markers for CRC, and provide a clinical basis for exploring new biomarkers for CRC. This study complements the mechanism of EAF2 in CRC cells, enriches the role and mechanism of CRC cellderived VASH1, and provides a new possible subtype of CRC as a therapeutic target of STAT3/TGF-β1 pathway.展开更多
Objective:The main characteristics of diabetic nephropathy(DN)at the early stage are abnormal angiogenesis of glomerular endothelial cells(GECs)and macrophage infiltration.Galectin-3 plays a pivotal role in the pathog...Objective:The main characteristics of diabetic nephropathy(DN)at the early stage are abnormal angiogenesis of glomerular endothelial cells(GECs)and macrophage infiltration.Galectin-3 plays a pivotal role in the pathogenesis of DN via binding with its ligand,advanced glycation end products(AGEs).Catalpol,an iridoid glucoside extracted from Rehmannia glutinosa,has been found to ameliorate vascular inflammation,reduce endothelial permeability,and protect against endothelial damage in diabetic milieu.However,little is known about whether catalpol could exert an anti-angiogenesis and anti-inflammation effect induced by AGEs.Methods:Mouse GECs(mGECs)and RAW 264.7 macrophages were treated with different concentrations of AGEs(0,50,100,200 and 400μg/mL)for different time(0,6,12,24 and 48 h)to determine the optimal concentration of AGEs and treatment time.Cells were treated with catalpol(10μmol/L),GB1107(1μmol/L,galectin-3 inhibitor),PX-478(50μmol/L,HIF-1αinhibitor),adenovirus-green fluorescent protein(Ad-GFP)[3×10^(7)plaque-forming unit(PFU)/mL]or Ad-galectin-3-GFP(2×10^(8)PFU/mL),which was followed by incubation with 50μg/mL AGEs.The levels of galectin-3,vascular endothelial growth factor A(VEGFA)and pro-angiogenic factors angiopoietin-1(Ang-1),angiopoietin-2(Ang-2),tunica interna endothelial cell kinase-2(Tie-2)were detected by enzyme-linked immunosorbent assay(ELISA).Cell counting kit-8(CCK-8)assay was used to evaluate the proliferation of these cells.The expression levels of galectin-3,vascular endothelial growth factor receptor 1(VEGFR1),VEGFR2,and hypoxia-inducible factor-1α(HIF-1α)in mGECs and those of galectin-3 and HIF-1αin RAW 264.7 macrophages were detected by Western blotting and immunofluorescence(IF)staining.The rat DN model was established.Catalpol(100 mg/kg)or GB1107(10 mg/kg)was administered intragastrically once a day for 12 weeks.Ad-galectin-3-GFP(6×10^(7)PFU/mL,0.5 mL)or Ad-GFP(6×10^(6)PFU/mL,0.5 mL)was injected into the tail vein of rats 48 h before the sacrifice of the animals.The expression of galectin-3,VEGFR1,.VEGFR2,and HIF-1αin renal cortices was analyzed by Western blotting.The expression of galectin-3,F4/80(a macrophage biomarker),and CD34(an endothelium biomarker)in renal cortices was detected by IF staining,and collagen accumulation by Masson staining.Results:The expression levels of galectin-3 and VEGFA were significantly higher in mGECs and RAW 264.7 macrophages treated with 50μg/mL AGEs for 48 h than those in untreated cells.Catalpol and GB1107 could block the AGEs-induced proliferation of mGECs and RAW 264.7 macrophages.Over-expression of galectin-3 was found to reduce the inhibitory effect of catalpol on the proliferation of cells.Catalpol could significantly decrease the levels of Ang-1,Ang-2 and Tie-2 released by AGEs-treated mGECs,which could be reversed by over-expression of galectin-3.Catalpol could significantly inhibit AGEs-induced expression of galectin-3,HIF-1α,VEGFR1,and VEGFR2 in mGECs.The inhibitory effect of catalpol on galectin-3 in AGEs-treated mGECs was impaired by PX-478.Moreover,catalpol attenuated the AGEs-activated HIF-1α/galectin-3 pathway in RAW 264.7 macrophages,which was weakened by PX-478.Additionally,catalpol significantly inhibited the expression of galectin-3,macrophage infiltration,collagen accumulation,and angiogenesis in the kidney of diabetic rats.Over-expression of galectin-3 could antagonize these inhibitory effects of catalpol.Conclusion:Catalpol prevented the angiogenesis of mGECs and macrophage proliferation via inhibiting galectin-3.It could prevent the progression of diabetes-induced renal damage.展开更多
BACKGROUND The development of new vasculatures(angiogenesis)is indispensable in supplying oxygen and nutrients to fuel tumor growth.Epigenetic dysregulation in the tumor vasculature is critical to colorectal cancer(CR...BACKGROUND The development of new vasculatures(angiogenesis)is indispensable in supplying oxygen and nutrients to fuel tumor growth.Epigenetic dysregulation in the tumor vasculature is critical to colorectal cancer(CRC)progression.Sirtuin(SIRT)enzymes are highly expressed in blood vessels.BZD9L1 benzimidazole analogue is a SIRT 1 and 2 inhibitor with reported anticancer activities in CRC.However,its role has yet to be explored in CRC tumor angiogenesis.AIM To investigate the anti-angiogenic potential of BZD9L1 on endothelial cells(EC)in vitro,ex vivo and in HCT116 CRC xenograft in vivo models.METHODS EA.hy926 EC were treated with half inhibitory concentration(IC50)(2.5μM),IC50(5.0μM),and double IC50(10.0μM)of BZD9L1 and assessed for cell proliferation,adhesion and SIRT 1 and 2 protein expression.Next,2.5μM and 5.0μM of BZD9L1 were employed in downstream in vitro assays,including cell cycle,cell death and sprouting in EC.The effect of BZD9L1 on cell adhesion molecules and SIRT 1 and 2 were assessed via real-time quantitative polymerase chain reaction(qPCR).The growth factors secreted by EC post-treatment were evaluated using the Quantibody Human Angiogenesis Array.Indirect co-culture with HCT116 CRC cells was performed to investigate the impact of growth factors modulated by BZD9L1-treated EC on CRC.The effect of BZD9L1 on sprouting impediment and vessel regression was determined using mouse choroids.HCT116 cells were also injected subcutaneously into nude mice and analyzed for the outcome of BZD9L1 on tumor necrosis,Ki67 protein expression indicative of proliferation,cluster of differentiation 31(CD31)and CD34 EC markers,and SIRT 1 and 2 genes via hematoxylin and eosin,immunohistochemistry and qPCR,respectively.RESULTS BZD9L1 impeded EC proliferation,adhesion,and spheroid sprouting through the downregulation of intercellular adhesion molecule 1,vascular endothelial cadherin,integrin-alpha V,SIRT1 and SIRT2 genes.The compound also arrested the cells at G1 phase and induced apoptosis in the EC.In mouse choroids,BZD9L1 inhibited sprouting and regressed sprouting vessels compared to the negative control.Compared to the negative control,the compound also reduced the protein levels of angiogenin,basic fibroblast growth factor,platelet-derived growth factor and placental growth factor,which then inhibited HCT116 CRC spheroid invasion in co-culture.In addition,a significant reduction in CRC tumor growth was noted alongside the downregulation of human SIRT1(hSIRT1),hSIRT2,CD31,and CD34 EC markers and murine SIRT2 gene,while the murine SIRT1 gene remained unaffected,compared to vehicle control.Histology analyses revealed that BZD9L1 at low(50 mg/kg)and high(250 mg/kg)doses reduced Ki-67 protein expression,while BZD9L1 at the high dose diminished tumor necrosis compared to vehicle control.CONCLUSION These results highlighted the anti-angiogenic potential of BZD9L1 to reduce CRC tumor progression.Furthermore,together with previous anticancer findings,this study provides valuable insights into the potential of BZD9L1 to co-target CRC tumor vasculatures and cancer cells via SIRT1 and/or SIRT2 down-regulation to improve the therapeutic outcome.展开更多
Angiogenesis plays a significant role in the occurrence and development of inflammatory bowel disease(IBD).The aim of this study is to explore potential angiogenesis related genes(ARGs)in IBD through bioinformatics an...Angiogenesis plays a significant role in the occurrence and development of inflammatory bowel disease(IBD).The aim of this study is to explore potential angiogenesis related genes(ARGs)in IBD through bioinformatics analysis and in vivo experiments.Methods:GSE57945,GSE87466,and GSE36807 were obtained from the Gene Expression Omnibus database.GSE57945 was used as the training set,while GSE87466 and GSE36807 were used as the validation set.The key ARGs associated with IBD were identified using the least absolute shrinkage and selection operator(LASSO)and random forest methods.These identified ARGs were then utilized to construct a diagnostic model for IBD.The Single-Sample Genome Enrichment Analysis,Cibersort,and Xcell methods were used to evaluate the immune infiltration.Expression of amyloid beta precursor protein(APP)was verified in the IBD mouse model induced by dextran sulfate sodium using immunohistochemistry(IHC).Results:The receiver operating curve area of GSE57945 was 0.948.Two distinct clusters were identified using consensus clustering and non-negative matrix factorization clustering.Subsequent analyses revealed significant differences in immune levels and functional enrichment between the two clusters.The successful construction of the animal model for the IBD was evident by hematoxylin and eosin staining,while IHC results showed a high expression of APP in IBD and a low expression in normal tissues.Conclusion:Our findings provide new insights into the diagnosis of IBD by ARGs,and APP could be a potential novel biomarker for IBD and promising therapeutic targets.展开更多
Objective:Inhibition of tumor angiogenesis has become a new targeted tumor therapy.In this study,we established a micellar carrier with a tumor neovascularization-targeting effect modified by the neovascularization-ta...Objective:Inhibition of tumor angiogenesis has become a new targeted tumor therapy.In this study,we established a micellar carrier with a tumor neovascularization-targeting effect modified by the neovascularization-targeting peptide NGR.Methods:The targeted polymer poly(ethylene glycol)-b-poly(lactide-co-glycolide)(PEG-PLGA)modified with Asn–Gly–Arg(NGR)peptide was prepared and characterized by 1H nuclear magnetic resonance and Fourier-transform infrared spectrometry.NGR-PEG-PLGA was used to construct curcumin(Cur)-loaded micelles by the solvent evaporation method.The physicochemical properties of the micelles were also investigated.Additionally,we evaluated the antitumor efficacy of the polymer micelles(PM)using in vitro cytology experiments and in vivo animal studies.Results:The particle size of Cur-NGR-PM was 139.70±2.51 nm,and the drug-loading capacity was 14.37±0.06%.In vitro cytological evaluation showed that NGR-modified micelles showed higher cellular uptake through receptor-mediated endocytosis pathways than did unmodified micelles,leading to the apoptosis of tumor cells.Then,in vivo antitumor experiments showed that the modified micelles significantly inhibited tumor growth and were safe.Conclusions:NGR-modified micelles significantly optimized the therapeutic efficacy of Cur.This strategy offers a viable avenue for cancer treatment.展开更多
BACKGROUND Ultrasound is a vital tool for the diagnosis and management of colorectal cancer(CRC).Contrast-enhanced ultrasound(CEUS)is a non-invasive,safe,and cost-effective method for evaluating tumour blood vessels,t...BACKGROUND Ultrasound is a vital tool for the diagnosis and management of colorectal cancer(CRC).Contrast-enhanced ultrasound(CEUS)is a non-invasive,safe,and cost-effective method for evaluating tumour blood vessels,that play a crucial role in tumour growth and progression.AIM To explore CEUS’s role in the quantitative evaluation of CRC blood vessels and their correlation with angiogenesis markers and prognosis.METHODS This study prospectively enrolled 100 patients with CRC confirmed by histo-pathology.All patients received preoperative CEUS examinations.Quantitative parameters,such as peak intensity(PI),time to peak(TTP),and area under the curve(AUC),were derived from time-intensity curve(TIC)analysis.Tumour tissue samples were obtained during surgery and examined immunohistochem-ically to assess the expression of angiogenesis markers,including vascular endo-thelial growth factor(VEGF)and microvessel density(MVD).The correlation between CEUS parameters,angiogenesis markers,and clinicopathological features was evaluated using appropriate statistical tests.RESULTS Quantitative CEUS parameters(PI,TTP,and AUC)showed significant correlations with VEGF expression(P<0.001)and MVD(P<0.001),indicating a strong link between tumour blood vessels and angiogenesis.Increased PI,reduced TTP,and expanded AUC values were significantly related to higher tumour stage(P<0.001),lymph node metastasis(P<0.001),and distant metastasis(P<0.001).Furthermore,these parameters were recognized as independent predictors of overall survival and disease-free survival in multivariate analysis(P<0.001).CONCLUSION CEUS has a high potential in guiding treatment planning and predicting patient outcomes.However,more com-prehensive,multicentre studies are required to validate the clinical utility of CEUS in CRC management.展开更多
[Objectives]This study was conducted to clarify the action mechanism of Pseudostellariae Radix in regulating angiogenesis by using network pharmacology and a dual-screening system,and to provide a basis for its clinic...[Objectives]This study was conducted to clarify the action mechanism of Pseudostellariae Radix in regulating angiogenesis by using network pharmacology and a dual-screening system,and to provide a basis for its clinical treatment of cardiovascular diseases.[Methods]The TCMSP database was used for preliminary screening to obtain the active compounds of Pseudostellariae Radix and the protein targets of its action.GeneCards and OMIM databases were used to search for targets related to angiogenesis.Cytoscape 3.9.1 was used to construct a drug-target network and protein interaction network of Pseudostellariae Radix in angiogenesis.The GO enrichment analysis and KEGG pathway analysis of the targets of Pseudostellariae Radix in angiogenesis were carried out on Metascape platform.The effects of the screened active compounds were verified using a dual-screening system.[Results]Six active components of Pseudostellariae Radix,luteolin,acetin,beta-sitosterol,linarin,schottenol and 1-monolinolein,were screened by TCMSP database;and the six active components were predicted with 78 common target proteins related to angiogenesis,of which 19 were core targets.Pseudostellariae Radix mainly intervened in angiogenesis through domain specific binding,ubiquitin-like protein ligase binding,kinase binding and other molecular functions to regulate biological processes such as membrane microdomain,plasma membrane raft and caveola.The results of KEGG enrichment indicated that pathways in cancer,lipid and atherosclerosis,hepatitis B,apoptosis,toxoplasmosis and other key pathways might be the mechanism for the intervention of angiogenesis.The results of the dual-screening system showed that luteolin,acacetin,beta-sitosterol and linarin protected HUVECs and promoted zebrafish angiogenesis.[Conclusions]This study preliminarily demonstrated that luteolin,acacetin,beta-sitosterol and linarin could intervene in angiogenesis through multiple targets and multiple pathways,providing ideas and a scientific basis for the treatment of cardiovascular diseases.展开更多
Lymph node metastasis is the hallmark of colon cancer progression,and is considered one of the most important prognostic factors.Recently,there has been growing evidence that tumor lymphangiogenesis(formation of new l...Lymph node metastasis is the hallmark of colon cancer progression,and is considered one of the most important prognostic factors.Recently,there has been growing evidence that tumor lymphangiogenesis(formation of new lymphatic vessels) plays an important role in this process.Here,we review the latest f indings of the role of lymphangiogenesis in colorectal cancer progression,and discuss its clinical application as a biomarker and target for new therapy.Understanding the molecular pathways that regulate lymphangiogenesis is mandatory to pave the way for the development of new therapies for cancer.In the future,tailored treatments consisting of combinations of chemotherapy,other targeted therapies,and anti-lymphangiogenesis agents will hopefully improve patient outcomes.This progression to the clinic must be guided by new avenues of research,such as the identif ication of biomarkers that predict response to treatment.展开更多
Despite improvements in the early diagnosis,prognosis and therapeutic strategies for gastric cancer(GC),human GC remains one of the most frequently diagnosed malignant tumors in the world,and the survival rate of GC p...Despite improvements in the early diagnosis,prognosis and therapeutic strategies for gastric cancer(GC),human GC remains one of the most frequently diagnosed malignant tumors in the world,and the survival rate of GC patients remains very poor.Thus,a suitable therapeutic strategy for GC is important for prolonging survival.Both tumor cells themselves and the tumor microenvironment play an important role in tumorigenesis,including angiogenesis,inflammation,immunosuppression and metastasis.Importantly,these cells contribute to gastric carcinogenesis by altering the angiogenic phenotype switch.The development,relapse and spreading of tumors depend on new vessels that provide the nutrition,growth factors and oxygen required for continuous tumor growth.Therefore,a state of tumor dormancy could be induced by blocking tumor-associated angiogenesis.Recently,several antiangiogenic agents have been identified,and their potential for the clinical management of GC has been tested.Here,we provide an up-to-date summary of angiogenesis and the angiogenic factors associated with tumor progression in GC.We also review antiangiogenic agents with a focus on the anti-vascular endothelial growth factor receptor(VEGFR)-mediated pathway for endothelial cell growth and their angiogenesis ability in GC.However,most antiangiogenic agents have reported no benefit to overall survival(OS)compared to chemotherapy alone in local or advanced GC.In phase III clinical trials,only ramucirumab(anti-VEGFR blocker)and apatinib(VEGFR-TKI blocker)have reported an improved median overall response rate and prolonged OS and progression-free survival outcomes as a 2 nd-line agent combined with chemotherapy treatment in advanced GC.By providing insights into the molecular mechanisms of angiogenesis associated with tumor progression in GC,this review will hopefully aid the optimization of antiangiogenesis strategies for GC therapy in combination with chemotherapy and adjuvant treatment.展开更多
The cornea is maintained in an avascular state by maintaining an environment whereby anti-angiogenic factors take the upper hand over factors promoting angiogenesis. Many of the common pathologies affecting the cornea...The cornea is maintained in an avascular state by maintaining an environment whereby anti-angiogenic factors take the upper hand over factors promoting angiogenesis. Many of the common pathologies affecting the cornea involve the disruption of such equilibrium and the shift towards new vessel formation, leading to corneal opacity and eventually-vision loss. Therefore it is of paramount importance that the molecular underpinnings of corneal neovascularization(CNV) be clearly understood, in order to develop better targeted treatments. This article is a review of the literature on the recent discoveries regarding pro-angiogenic factors of the cornea(such as vascular endothelial growth factors,fibroblast growth factor and matrix metalloproteinases)and anti-angiogenic factors of the cornea(such as endostatins and neostatins). Further, we review the molecular underpinnings of lymphangiogenesis, a process now known to be almost separate from(yet related to) hemangiogenesis.展开更多
基金supported by the National Natural Science Foundation of China,Nos.81941011(to XL),31771053(to HD),31730030(to XL),31971279(to ZY),31900749(to PH),31650001(to XL),31320103903(to XL),31670988(to ZY)the Natural Science Foundation of Beijing,Nos.7222004(to HD)+1 种基金a grant from Ministry of Science and Technology of China,Nos.2017YFC1104002(to ZY),2017YFC1104001(to XL)a grant from Beihang University,No.JKF-YG-22-B001(to FH)。
文摘Attempts have been made to use cell transplantation and biomaterials to promote cell proliferation,differentiation,migration,and survival,as well as angiogenesis,in the context of brain injury.However,whether bioactive materials can repair the damage caused by ischemic stroke by activating endogenous neurogenesis and angiogenesis is still unknown.In this study,we applied chitosan gel loaded with basic fibroblast growth factor to the stroke cavity 7 days after ischemic stroke in rats.The gel slowly released basic fibroblast growth factor,which improved the local microenvironment,activated endogenous neural stem/progenitor cells,and recruited these cells to migrate toward the penumbra and stroke cavity and subsequently differentiate into neurons,while enhancing angiogenesis in the penumbra and stroke cavity and ultimately leading to partial functional recovery.This study revealed the mechanism by which bioactive materials repair ischemic strokes,thus providing a new strategy for the clinical application of bioactive materials in the treatment of ischemic stroke.
基金supported by the National Natural Science Foundation of China,Nos.81801236(to ZX),81974189(to HT)a grant from Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine,No.ynlc201719(to QZ).
文摘Endorepellin plays a key role in the regulation of angiogenesis,but its effects on angiogenesis after traumatic brain injury are unclear.This study explored the effects of endorepellin on angiogenesis and neurobehavioral outcomes after traumatic brain injury in mice.Mice were randomly divided into four groups:sham,controlled cortical impact only,adeno-associated virus(AAV)-green fluorescent protein,and AAV-shEndorepellin-green fluorescent protein groups.In the controlled cortical impact model,the transduction of AAV-shEndorepellin-green fluorescent protein downregulated endorepellin while increasing the number of CD31+/Ki-67+proliferating endothelial cells and the functional microvessel density in mouse brain.These changes resulted in improved neurological function compared with controlled cortical impact mice.Western blotting revealed increased expression of vascular endothelial growth factor and angiopoietin-1 in mice treated with AAV-shEndorepellin-green fluorescent protein.Synchrotron radiation angiography showed that endorepellin downregulation promoted angiogenesis and increased cortical neovascularization,which may further improve neurobehavioral outcomes.Furthermore,an in vitro study showed that downregulation of endorepellin increased tube formation by human umbilical vein endothelial cells compared with a control.Mechanistic analysis found that endorepellin downregulation may mediate angiogenesis by activating vascular endothelial growth factor-and angiopoietin-1-related signaling pathways.
基金Supported by Natural Science Foundation of Guangdong Province,No.2020A1515011539.
文摘BACKGROUND Hepatic arterial infusion chemotherapy(HAIC)has been proven to be an ideal choice for treating unresectable hepatocellular carcinoma(uHCC).HAIC-based treatment showed great potential for treating uHCC.However,large-scale studies on HAIC-based treatments and meta-analyses of first-line treatments for uHCC are lacking.AIM To investigate better first-line treatment options for uHCC and to assess the safety and efficacy of HAIC combined with angiogenesis inhibitors,programmed cell death of protein 1(PD-1)and its ligand(PD-L1)blockers(triple therapy)under real-world conditions.METHODS Several electronic databases were searched to identify eligible randomized controlled trials for this meta-analysis.Study-level pooled analyses of hazard ratios(HRs)and odds ratios(ORs)were performed.This was a retrospective single-center study involving 442 patients with uHCC who received triple therapy or angiogenesis inhibitors plus PD-1/PD-L1 blockades(AIPB)at Sun Yat-sen University Cancer Center from January 2018 to April 2023.Propensity score matching(PSM)was performed to balance the bias between the groups.The Kaplan-Meier method and cox regression were used to analyse the survival data,and the log-rank test was used to compare the suvival time between the groups.RESULTS A total of 13 randomized controlled trials were included.HAIC alone and in combination with sorafenib were found to be effective treatments(P values for ORs:HAIC,0.95;for HRs:HAIC+sorafenib,0.04).After PSM,176 HCC patients were included in the analysis.The triple therapy group(n=88)had a longer median overall survival than the AIPB group(n=88)(31.6 months vs 14.6 months,P<0.001)and a greater incidence of adverse events(94.3%vs 75.4%,P<0.001).CONCLUSION This meta-analysis suggests that HAIC-based treatments are likely to be the best choice for uHCC.Our findings confirm that triple therapy is more effective for uHCC patients than AIPB.
基金supported by the National Key Research and Development Program of China(Grant No.2020YFA0803700)the National Natural Science Foundation of China(Grant Nos.91639108,81770272,and 81970425)+1 种基金the Beijing Natural Science Foundation(Grant No.7212044)the Beijing Hospital Authority Youth Program(Grant No.QML20190306)。
文摘Hepatocellular carcinoma(HCC)is the fourth leading cause of cancer-associated death worldwide.Angiogenesis,the process of formation of new blood vessels,is required for cancer cells to obtain nutrients and oxygen.HCC is a typical hypervascular solid tumor with an aberrant vascular network and angiogenesis that contribute to its growth,progression,invasion,and metastasis.Current anti-angiogenic therapies target mainly tyrosine kinases,vascular endothelial growth factor receptor(VEGFR),and plateletderived growth factor receptor(PDGFR),and are considered effective strategies for HCC,particularly advanced HCC.However,because the survival benefits conferred by these anti-angiogenic therapies are modest,new anti-angiogenic targets must be identified.Several recent studies have determined the underlying molecular mechanisms,including pro-angiogenic factors secreted by HCC cells,the tumor microenvironment,and cancer stem cells.In this review,we summarize the roles of pro-angiogenic factors;the involvement of endothelial cells,hepatic stellate cells,tumor-associated macrophages,and tumor-associated neutrophils present in the tumor microenvironment;and the regulatory influence of cancer stem cells on angiogenesis in HCC.Furthermore,we discuss some of the clinically approved anti-angiogenic therapies and potential novel therapeutic targets for angiogenesis in HCC.A better understanding of the mechanisms underlying angiogenesis may lead to the development of more optimized anti-angiogenic treatment modalities for HCC.
基金supported by the Natural Nature Science Foundation of China,Nos.82030071,81874004the Science and Technology Major Project of Changsha,No.kh2103008(all to JZH).
文摘Treatment with metformin can lead to the recovery of pleiotropic biological activities after spinal cord injury.However,its effect on spinal cord injury in aged mice remains unclear.Considering the essential role of angiogenesis during the regeneration process,we hypothesized that metformin activates the adenosine monophosphate-activated protein kinase/endothelial nitric oxide synthase pathway in endothelial cells,thereby promoting microvascular regeneration in aged mice after spinal cord injury.In this study,we established young and aged mouse models of contusive spinal cord injury using a modified Allen method.We found that aging hindered the recovery of neurological function and the formation of blood vessels in the spinal cord.Treatment with metformin promoted spinal cord microvascular endothelial cell migration and blood vessel formation in vitro.Furthermore,intraperitoneal injection of metformin in an in vivo model promoted endothelial cell proliferation and increased the density of new blood vessels in the spinal cord,thereby improving neurological function.The role of metformin was reversed by compound C,an adenosine monophosphate-activated protein kinase inhibitor,both in vivo and in vitro,suggesting that the adenosine monophosphate-activated protein kinase/endothelial nitric oxide synthase pathway likely regulates metformin-mediated angiogenesis after spinal cord injury.These findings suggest that metformin promotes vascular regeneration in the injured spinal cord by activating the adenosine monophosphate-activated protein kinase/endothelial nitric oxide synthase pathway,thereby improving the neurological function of aged mice after spinal cord injury.
基金supported by the National Natural Science Foundation of China,Nos.81801169 (to LXX),82071404 (to HC),81870952 (to HMW)。
文摘Promotion of new blood vessel formation is a new strategy for treating ischemic stroke.Non-coding miRNAs have been recently considered potential therapeutic targets for ischemic stroke.miR-181b has been shown to promote angiogenesis in hypoxia and traumatic brain injury model,while its effect on ischemic stroke remains elusive.In this study,we found that overexpression of miR-181b in brain microvascular endothelial cells subjected to oxygen-glucose deprivation in vitro restored cell prolife ration and enhanced angiogenesis.In rat models of focal cerebral ischemia,ove rexpression of miR-181b reduced infarction volume,promoted angiogenesis in ischemic penumbra,and improved neurological function.We further investigated the molecular mechanism by which miR-181b participates in angiogenesis after ischemic stroke and found that miR-181b directly bound to the 3’-UTR of phosphatase and tensin homolog(PTEN) mRNA to induce PTEN downregulation,leading to activation of the protein kinase B(Akt) pathway,upregulated expression of vascular endothelial growth facto rs,down-regulated expression of endostatin,and promoted angiogenesis.Taken togethe r,these results indicate that exogenous miR-181b exhibits neuroprotective effects on ischemic stro ke through activating the PTEN/Akt signal pathway and promoting angiogenesis.
文摘Neoplasms can be considered as a group of aberrant cells that need more vascular supply to fulfill all their functions.Therefore,they promote angiogenesis through the same neovascularization pathway used physiologically.Angiogenesis is a process characterized by a heterogeneous distribution of oxygen caused by the tumor and oxidative stress;the latter being one of the most powerful stimuli of angiogenesis.As a result of altered tumor metabolism due to hypoxia,acidosis occurs.The angiogenic process and oxidative stress can be detected by measuring serum and tissue biomarkers.The study of the mechanisms underlying angiogenesis and oxidative stress could lead to the identification of new biomarkers,ameliorating the selection of patients with neoplasms and the prediction of their response to possible anti-tumor therapies.In particular,in the treatment of patients with similar clinical tumor phenotypes but different prognoses,the new biomarkers could be useful.Moreover,they may lead to a better understanding of the mechanisms underlying drug resistance.Experimental studies show that blocking the vascular supply results in antiproliferative activity in vivo in neuroendocrine tumor cells,which require a high vascular supply.
基金supported by grants from Natural Science Foundation of Zhejiang Province (LY20H180011)National Natural Science Foundation of China (81970653)Medical and Health Science and Technology project of Zhejiang (2016KYA061)
文摘Background: Improving the mechanical properties and angiogenesis of acellular scaffolds before transplantation is an important challenge facing the development of acellular liver grafts. The present study aimed to evaluate the cytotoxicity and angiogenesis of polyethylene glycol(PEG) crosslinked decellularized single liver lobe scaffolds(DLSs), and establish its suitability as a graft for long-term liver tissue engineering. Methods: Using mercaptoacrylate produced by the Michael addition reaction, DLSs were first modified using N-succinimidyl S-acetylthioacetate(SATA), followed by cross-linking with PEG as well as vascular endothelial growth factor(VEGF). The optimal concentration of agents and time of the individual steps were identified in this procedure through biomechanical testing and morphological analysis. Subsequently, human umbilical vein endothelial cells(HUVECs) were seeded on the PEG crosslinked scaffolds to detect the proliferation and viability of cells. The scaffolds were then transplanted into the subcutaneous tissue of Sprague-Dawley rats to evaluate angiogenesis. In addition, the average number of blood vessels was evaluated in the grafts with or without PEG at days 7, 14, and 21 after implantation. Results: The PEG crosslinked DLS maintained their three-dimensional structure and were more translucent after decellularization than native DLS, which presented a denser and more porous network structure. The results for Young’s modulus proved that the mechanical properties of 0.5 PEG crosslinked DLS were the best and close to that of native livers. The PEG-VEGF-DLS could better promote cell proliferation and differentiation of HUVECs compared with the groups without PEG cross-linking. Importantly, the average density of blood vessels was higher in the PEG-VEGF-DLS than that in other groups at days 7, 14, and 21 after implantation in vivo. Conclusions: The PEG crosslinked DLS with VEGF could improve the biomechanical properties of native DLS, and most importantly, their lack of cytotoxicity provides a new route to promote the proliferation of cells in vitro and angiogenesis in vivo in liver tissue engineering.
基金supported by the Zhejiang Province Key Research and Development Program(No.2021C03059)。
文摘Large bone defect regeneration has always been recognized as a challenging clinical problem due to the difficulty of revascularization.Conventional treatments exhibit certain inherent disadvantages(e.g.,secondary injury,immunization,and potential infections).However,three-dimensional(3D)printing technology as an emerging field can serve as an effective approach to achieve satisfactory revascularization while making up for the above limitations.A wide variety of methods can be used to facilitate blood supply during the design of a 3D-printed scaffold.Importantly,the scaffold structure lays a foundation for the entire printing object;any method to promote angiogenesis can be effective only if it is based on well-designed scaffolds.In this review,different designs related to angiogenesis are summarized by collecting the literature from recent years.The 3D-printed scaffolds are classified into four major categories and discussed in detail,from elementary porous scaffolds to the most advanced bone-like scaffolds.Finally,structural design suggestions to achieve rapid angiogenesis are proposed by analyzing the above architectures.This review can provide a reference for organizations or individual academics to achieve improved bone defect repair and regeneration using 3D printing.
基金Peking Union Medical CollegeCAMS initiative for Innovative Medicine of ChinaGrant/Award Number:2021-I2M-1-034
文摘Background:Pathological angiogenesis and blood–brain barrier damage may play an important role in Alzheimer's disease(AD).ACE2 is mainly expressed on the surface of endothelial cells in brain.Recent studies have shown that the expression of ACE2 in AD is reduced,but its role in AD is still unclear.Method:We induced AD damage in endothelial cells using Aβ25-35 and overexpressed ACE2 in bEend.3 cells through lentiviral transfection.We detected the effect of Aβ25-35 on cell viability using the CCK-8 assay and examined the effect of overexpressing ACE2 on angiogenesis using an angiogenesis assay.We used western blot and cell immunofluorescence to detect changes in the expression of the VEGF/VEGFR2 pathway,tight junction protein,and NF-κB pathway.Results:Aβ25-35 treatment significantly decreased the expression of ACE2 and reduced cell viability.ACE2 overexpression(1)reduced the number of branches and junctions in tube formation,(2)inhibited the activation of the VEGF/VEGFR2 pathway induced by Aβ25-35,(3)increased the expression of TJPs,including ZO-1 and claudin-5,and(4)restored Aβ25-35-induced activation of the NF-κB pathway.Conclusion:Overexpression of ACE2 can improve pathological angiogenesis and blood–brain barrier damage in AD models in vitro by inhibiting NF-κB/VEGF/VEGFR2 pathway activity.ACE2 may therefore represent a therapeutic target for endothelial cell dysfunction in AD.
基金the Natural Science Foundation of Liaoning Province,No.2023-MS-149.
文摘BACKGROUND As a novel endogenous anti-angiogenic molecule, vasohibin 1(VASH1) is not only expressed in tumor stroma, but also in tumor tissue. Moreover, studies have shown that VASH1 may be a prognostic marker in colorectal cancer(CRC). Knockdown of VASH1 enhanced transforming growth factor-β1(TGF-β1)/Smad3 pathway activity and type Ⅰ/Ⅲ collagen production. Our previous findings suggest that ELL-associated factor 2(EAF2) may play a tumor suppressor and protective role in the development and progression of CRC by regulating signal transducer and activator of transcription 3(STAT3)/TGF-β1 signaling pathway. However, the functional role and mechanism of VASH1-mediated TGF-β1 related pathway in CRC has not been elucidated.AIM To investigate the expression of VASH1 in CRC and its correlation with the expression of EAF2. Furthermore, we studied the functional role and mechanism of VASH1 involved in the regulation and protection of EAF2 in CRC cells in vitro.METHODS We collected colorectal adenocarcinoma and corresponding adjacent tissues to investigate the clinical expression of EAF2 protein and VASH1 protein in patients with advanced CRC. Following, we investigated the effect and mechanism of EAF2 and VASH1 on the invasion, migration and angiogenesis of CRC cells in vitro using plasmid transfection.RESULTS Our findings indicated that EAF2 was down-regulated and VASH1 was upregulated in advanced CRC tissue compared to normal colorectal tissue. KaplanMeier survival analysis showed that the higher EAF2 Level group and the lower VASH1 Level group had a higher survival rate. Overexpression of EAF2 might inhibit the activity of STAT3/TGF-β1 pathway by up-regulating the expression of VASH1, and then weaken the invasion, migration and angiogenesis of CRC cells.CONCLUSION This study suggests that EAF2 and VASH1 may serve as new diagnostic and prognostic markers for CRC, and provide a clinical basis for exploring new biomarkers for CRC. This study complements the mechanism of EAF2 in CRC cells, enriches the role and mechanism of CRC cellderived VASH1, and provides a new possible subtype of CRC as a therapeutic target of STAT3/TGF-β1 pathway.
基金supported by grants from the National Natural Science Foundation of China(No.81374029,No.81073111,No.81874359)Natural Science Foundation of the Higher Education Institutions of Jiangsu Province(No.18KJD360002)+1 种基金a Project Funded by Jiangsu Agri-animal Husbandry Vocational College(No.NSF2021CB04)a Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD)(No.JKLPSE201604).
文摘Objective:The main characteristics of diabetic nephropathy(DN)at the early stage are abnormal angiogenesis of glomerular endothelial cells(GECs)and macrophage infiltration.Galectin-3 plays a pivotal role in the pathogenesis of DN via binding with its ligand,advanced glycation end products(AGEs).Catalpol,an iridoid glucoside extracted from Rehmannia glutinosa,has been found to ameliorate vascular inflammation,reduce endothelial permeability,and protect against endothelial damage in diabetic milieu.However,little is known about whether catalpol could exert an anti-angiogenesis and anti-inflammation effect induced by AGEs.Methods:Mouse GECs(mGECs)and RAW 264.7 macrophages were treated with different concentrations of AGEs(0,50,100,200 and 400μg/mL)for different time(0,6,12,24 and 48 h)to determine the optimal concentration of AGEs and treatment time.Cells were treated with catalpol(10μmol/L),GB1107(1μmol/L,galectin-3 inhibitor),PX-478(50μmol/L,HIF-1αinhibitor),adenovirus-green fluorescent protein(Ad-GFP)[3×10^(7)plaque-forming unit(PFU)/mL]or Ad-galectin-3-GFP(2×10^(8)PFU/mL),which was followed by incubation with 50μg/mL AGEs.The levels of galectin-3,vascular endothelial growth factor A(VEGFA)and pro-angiogenic factors angiopoietin-1(Ang-1),angiopoietin-2(Ang-2),tunica interna endothelial cell kinase-2(Tie-2)were detected by enzyme-linked immunosorbent assay(ELISA).Cell counting kit-8(CCK-8)assay was used to evaluate the proliferation of these cells.The expression levels of galectin-3,vascular endothelial growth factor receptor 1(VEGFR1),VEGFR2,and hypoxia-inducible factor-1α(HIF-1α)in mGECs and those of galectin-3 and HIF-1αin RAW 264.7 macrophages were detected by Western blotting and immunofluorescence(IF)staining.The rat DN model was established.Catalpol(100 mg/kg)or GB1107(10 mg/kg)was administered intragastrically once a day for 12 weeks.Ad-galectin-3-GFP(6×10^(7)PFU/mL,0.5 mL)or Ad-GFP(6×10^(6)PFU/mL,0.5 mL)was injected into the tail vein of rats 48 h before the sacrifice of the animals.The expression of galectin-3,VEGFR1,.VEGFR2,and HIF-1αin renal cortices was analyzed by Western blotting.The expression of galectin-3,F4/80(a macrophage biomarker),and CD34(an endothelium biomarker)in renal cortices was detected by IF staining,and collagen accumulation by Masson staining.Results:The expression levels of galectin-3 and VEGFA were significantly higher in mGECs and RAW 264.7 macrophages treated with 50μg/mL AGEs for 48 h than those in untreated cells.Catalpol and GB1107 could block the AGEs-induced proliferation of mGECs and RAW 264.7 macrophages.Over-expression of galectin-3 was found to reduce the inhibitory effect of catalpol on the proliferation of cells.Catalpol could significantly decrease the levels of Ang-1,Ang-2 and Tie-2 released by AGEs-treated mGECs,which could be reversed by over-expression of galectin-3.Catalpol could significantly inhibit AGEs-induced expression of galectin-3,HIF-1α,VEGFR1,and VEGFR2 in mGECs.The inhibitory effect of catalpol on galectin-3 in AGEs-treated mGECs was impaired by PX-478.Moreover,catalpol attenuated the AGEs-activated HIF-1α/galectin-3 pathway in RAW 264.7 macrophages,which was weakened by PX-478.Additionally,catalpol significantly inhibited the expression of galectin-3,macrophage infiltration,collagen accumulation,and angiogenesis in the kidney of diabetic rats.Over-expression of galectin-3 could antagonize these inhibitory effects of catalpol.Conclusion:Catalpol prevented the angiogenesis of mGECs and macrophage proliferation via inhibiting galectin-3.It could prevent the progression of diabetes-induced renal damage.
基金Supported by the Ministry of Higher Education Malaysia for the Fundamental Research Grant Scheme,No. FRGS/1/2021/SKK06/USM/02/7
文摘BACKGROUND The development of new vasculatures(angiogenesis)is indispensable in supplying oxygen and nutrients to fuel tumor growth.Epigenetic dysregulation in the tumor vasculature is critical to colorectal cancer(CRC)progression.Sirtuin(SIRT)enzymes are highly expressed in blood vessels.BZD9L1 benzimidazole analogue is a SIRT 1 and 2 inhibitor with reported anticancer activities in CRC.However,its role has yet to be explored in CRC tumor angiogenesis.AIM To investigate the anti-angiogenic potential of BZD9L1 on endothelial cells(EC)in vitro,ex vivo and in HCT116 CRC xenograft in vivo models.METHODS EA.hy926 EC were treated with half inhibitory concentration(IC50)(2.5μM),IC50(5.0μM),and double IC50(10.0μM)of BZD9L1 and assessed for cell proliferation,adhesion and SIRT 1 and 2 protein expression.Next,2.5μM and 5.0μM of BZD9L1 were employed in downstream in vitro assays,including cell cycle,cell death and sprouting in EC.The effect of BZD9L1 on cell adhesion molecules and SIRT 1 and 2 were assessed via real-time quantitative polymerase chain reaction(qPCR).The growth factors secreted by EC post-treatment were evaluated using the Quantibody Human Angiogenesis Array.Indirect co-culture with HCT116 CRC cells was performed to investigate the impact of growth factors modulated by BZD9L1-treated EC on CRC.The effect of BZD9L1 on sprouting impediment and vessel regression was determined using mouse choroids.HCT116 cells were also injected subcutaneously into nude mice and analyzed for the outcome of BZD9L1 on tumor necrosis,Ki67 protein expression indicative of proliferation,cluster of differentiation 31(CD31)and CD34 EC markers,and SIRT 1 and 2 genes via hematoxylin and eosin,immunohistochemistry and qPCR,respectively.RESULTS BZD9L1 impeded EC proliferation,adhesion,and spheroid sprouting through the downregulation of intercellular adhesion molecule 1,vascular endothelial cadherin,integrin-alpha V,SIRT1 and SIRT2 genes.The compound also arrested the cells at G1 phase and induced apoptosis in the EC.In mouse choroids,BZD9L1 inhibited sprouting and regressed sprouting vessels compared to the negative control.Compared to the negative control,the compound also reduced the protein levels of angiogenin,basic fibroblast growth factor,platelet-derived growth factor and placental growth factor,which then inhibited HCT116 CRC spheroid invasion in co-culture.In addition,a significant reduction in CRC tumor growth was noted alongside the downregulation of human SIRT1(hSIRT1),hSIRT2,CD31,and CD34 EC markers and murine SIRT2 gene,while the murine SIRT1 gene remained unaffected,compared to vehicle control.Histology analyses revealed that BZD9L1 at low(50 mg/kg)and high(250 mg/kg)doses reduced Ki-67 protein expression,while BZD9L1 at the high dose diminished tumor necrosis compared to vehicle control.CONCLUSION These results highlighted the anti-angiogenic potential of BZD9L1 to reduce CRC tumor progression.Furthermore,together with previous anticancer findings,this study provides valuable insights into the potential of BZD9L1 to co-target CRC tumor vasculatures and cancer cells via SIRT1 and/or SIRT2 down-regulation to improve the therapeutic outcome.
基金funded by the Nanjing Tianqing Research Fund Project(Grant Serial Number:HX202334)the Institute Fund from First Affliated Hospital of Xi’an Jiaotong University(Grant Serial Number:2022MS-17).
文摘Angiogenesis plays a significant role in the occurrence and development of inflammatory bowel disease(IBD).The aim of this study is to explore potential angiogenesis related genes(ARGs)in IBD through bioinformatics analysis and in vivo experiments.Methods:GSE57945,GSE87466,and GSE36807 were obtained from the Gene Expression Omnibus database.GSE57945 was used as the training set,while GSE87466 and GSE36807 were used as the validation set.The key ARGs associated with IBD were identified using the least absolute shrinkage and selection operator(LASSO)and random forest methods.These identified ARGs were then utilized to construct a diagnostic model for IBD.The Single-Sample Genome Enrichment Analysis,Cibersort,and Xcell methods were used to evaluate the immune infiltration.Expression of amyloid beta precursor protein(APP)was verified in the IBD mouse model induced by dextran sulfate sodium using immunohistochemistry(IHC).Results:The receiver operating curve area of GSE57945 was 0.948.Two distinct clusters were identified using consensus clustering and non-negative matrix factorization clustering.Subsequent analyses revealed significant differences in immune levels and functional enrichment between the two clusters.The successful construction of the animal model for the IBD was evident by hematoxylin and eosin staining,while IHC results showed a high expression of APP in IBD and a low expression in normal tissues.Conclusion:Our findings provide new insights into the diagnosis of IBD by ARGs,and APP could be a potential novel biomarker for IBD and promising therapeutic targets.
基金supported by Scientific Research Project of Tianjin Municipal Education Commission (No.2019KJ080).
文摘Objective:Inhibition of tumor angiogenesis has become a new targeted tumor therapy.In this study,we established a micellar carrier with a tumor neovascularization-targeting effect modified by the neovascularization-targeting peptide NGR.Methods:The targeted polymer poly(ethylene glycol)-b-poly(lactide-co-glycolide)(PEG-PLGA)modified with Asn–Gly–Arg(NGR)peptide was prepared and characterized by 1H nuclear magnetic resonance and Fourier-transform infrared spectrometry.NGR-PEG-PLGA was used to construct curcumin(Cur)-loaded micelles by the solvent evaporation method.The physicochemical properties of the micelles were also investigated.Additionally,we evaluated the antitumor efficacy of the polymer micelles(PM)using in vitro cytology experiments and in vivo animal studies.Results:The particle size of Cur-NGR-PM was 139.70±2.51 nm,and the drug-loading capacity was 14.37±0.06%.In vitro cytological evaluation showed that NGR-modified micelles showed higher cellular uptake through receptor-mediated endocytosis pathways than did unmodified micelles,leading to the apoptosis of tumor cells.Then,in vivo antitumor experiments showed that the modified micelles significantly inhibited tumor growth and were safe.Conclusions:NGR-modified micelles significantly optimized the therapeutic efficacy of Cur.This strategy offers a viable avenue for cancer treatment.
文摘BACKGROUND Ultrasound is a vital tool for the diagnosis and management of colorectal cancer(CRC).Contrast-enhanced ultrasound(CEUS)is a non-invasive,safe,and cost-effective method for evaluating tumour blood vessels,that play a crucial role in tumour growth and progression.AIM To explore CEUS’s role in the quantitative evaluation of CRC blood vessels and their correlation with angiogenesis markers and prognosis.METHODS This study prospectively enrolled 100 patients with CRC confirmed by histo-pathology.All patients received preoperative CEUS examinations.Quantitative parameters,such as peak intensity(PI),time to peak(TTP),and area under the curve(AUC),were derived from time-intensity curve(TIC)analysis.Tumour tissue samples were obtained during surgery and examined immunohistochem-ically to assess the expression of angiogenesis markers,including vascular endo-thelial growth factor(VEGF)and microvessel density(MVD).The correlation between CEUS parameters,angiogenesis markers,and clinicopathological features was evaluated using appropriate statistical tests.RESULTS Quantitative CEUS parameters(PI,TTP,and AUC)showed significant correlations with VEGF expression(P<0.001)and MVD(P<0.001),indicating a strong link between tumour blood vessels and angiogenesis.Increased PI,reduced TTP,and expanded AUC values were significantly related to higher tumour stage(P<0.001),lymph node metastasis(P<0.001),and distant metastasis(P<0.001).Furthermore,these parameters were recognized as independent predictors of overall survival and disease-free survival in multivariate analysis(P<0.001).CONCLUSION CEUS has a high potential in guiding treatment planning and predicting patient outcomes.However,more com-prehensive,multicentre studies are required to validate the clinical utility of CEUS in CRC management.
基金Supported by Project of Science and Technology Department of Guizhou Province(ZK[2021]-546)Project of Science and Technology Department of Guizhou Province([2019]1401)+1 种基金Guizhou Administration of Traditional Chinese Medicine(QZYY-2021-03)Guizhou Provincial Health Commission(gzwkj2021-464).
文摘[Objectives]This study was conducted to clarify the action mechanism of Pseudostellariae Radix in regulating angiogenesis by using network pharmacology and a dual-screening system,and to provide a basis for its clinical treatment of cardiovascular diseases.[Methods]The TCMSP database was used for preliminary screening to obtain the active compounds of Pseudostellariae Radix and the protein targets of its action.GeneCards and OMIM databases were used to search for targets related to angiogenesis.Cytoscape 3.9.1 was used to construct a drug-target network and protein interaction network of Pseudostellariae Radix in angiogenesis.The GO enrichment analysis and KEGG pathway analysis of the targets of Pseudostellariae Radix in angiogenesis were carried out on Metascape platform.The effects of the screened active compounds were verified using a dual-screening system.[Results]Six active components of Pseudostellariae Radix,luteolin,acetin,beta-sitosterol,linarin,schottenol and 1-monolinolein,were screened by TCMSP database;and the six active components were predicted with 78 common target proteins related to angiogenesis,of which 19 were core targets.Pseudostellariae Radix mainly intervened in angiogenesis through domain specific binding,ubiquitin-like protein ligase binding,kinase binding and other molecular functions to regulate biological processes such as membrane microdomain,plasma membrane raft and caveola.The results of KEGG enrichment indicated that pathways in cancer,lipid and atherosclerosis,hepatitis B,apoptosis,toxoplasmosis and other key pathways might be the mechanism for the intervention of angiogenesis.The results of the dual-screening system showed that luteolin,acacetin,beta-sitosterol and linarin protected HUVECs and promoted zebrafish angiogenesis.[Conclusions]This study preliminarily demonstrated that luteolin,acacetin,beta-sitosterol and linarin could intervene in angiogenesis through multiple targets and multiple pathways,providing ideas and a scientific basis for the treatment of cardiovascular diseases.
基金Supported by SUMITOMO Life Social Welfare Services Foundation (to Nagahashi M)Virginia Commonwealth University Grant BIRCWH K12HD055881,and Susan G Komen for the Cure Career Catalyst Research Grant KG090510 (to Takabe K)
文摘Lymph node metastasis is the hallmark of colon cancer progression,and is considered one of the most important prognostic factors.Recently,there has been growing evidence that tumor lymphangiogenesis(formation of new lymphatic vessels) plays an important role in this process.Here,we review the latest f indings of the role of lymphangiogenesis in colorectal cancer progression,and discuss its clinical application as a biomarker and target for new therapy.Understanding the molecular pathways that regulate lymphangiogenesis is mandatory to pave the way for the development of new therapies for cancer.In the future,tailored treatments consisting of combinations of chemotherapy,other targeted therapies,and anti-lymphangiogenesis agents will hopefully improve patient outcomes.This progression to the clinic must be guided by new avenues of research,such as the identif ication of biomarkers that predict response to treatment.
基金Supported by the Ministry of Science and Technology,Taiwan,No.MOST 106-2320-B-255-005 and No.MOST 107-2320-B-255-003Chang Gung Medical Research Foundation,Taoyuan,Taiwan,No.CMRPF1G0011,No.CMRPF1G0251,No.CMRPF1I0031,No.CMRPF1H0051,and No.CMRPF1I0041Chang Gung University of Science and Technology,Taoyuan,Taiwan,No.ZRRPF3H0131
文摘Despite improvements in the early diagnosis,prognosis and therapeutic strategies for gastric cancer(GC),human GC remains one of the most frequently diagnosed malignant tumors in the world,and the survival rate of GC patients remains very poor.Thus,a suitable therapeutic strategy for GC is important for prolonging survival.Both tumor cells themselves and the tumor microenvironment play an important role in tumorigenesis,including angiogenesis,inflammation,immunosuppression and metastasis.Importantly,these cells contribute to gastric carcinogenesis by altering the angiogenic phenotype switch.The development,relapse and spreading of tumors depend on new vessels that provide the nutrition,growth factors and oxygen required for continuous tumor growth.Therefore,a state of tumor dormancy could be induced by blocking tumor-associated angiogenesis.Recently,several antiangiogenic agents have been identified,and their potential for the clinical management of GC has been tested.Here,we provide an up-to-date summary of angiogenesis and the angiogenic factors associated with tumor progression in GC.We also review antiangiogenic agents with a focus on the anti-vascular endothelial growth factor receptor(VEGFR)-mediated pathway for endothelial cell growth and their angiogenesis ability in GC.However,most antiangiogenic agents have reported no benefit to overall survival(OS)compared to chemotherapy alone in local or advanced GC.In phase III clinical trials,only ramucirumab(anti-VEGFR blocker)and apatinib(VEGFR-TKI blocker)have reported an improved median overall response rate and prolonged OS and progression-free survival outcomes as a 2 nd-line agent combined with chemotherapy treatment in advanced GC.By providing insights into the molecular mechanisms of angiogenesis associated with tumor progression in GC,this review will hopefully aid the optimization of antiangiogenesis strategies for GC therapy in combination with chemotherapy and adjuvant treatment.
文摘The cornea is maintained in an avascular state by maintaining an environment whereby anti-angiogenic factors take the upper hand over factors promoting angiogenesis. Many of the common pathologies affecting the cornea involve the disruption of such equilibrium and the shift towards new vessel formation, leading to corneal opacity and eventually-vision loss. Therefore it is of paramount importance that the molecular underpinnings of corneal neovascularization(CNV) be clearly understood, in order to develop better targeted treatments. This article is a review of the literature on the recent discoveries regarding pro-angiogenic factors of the cornea(such as vascular endothelial growth factors,fibroblast growth factor and matrix metalloproteinases)and anti-angiogenic factors of the cornea(such as endostatins and neostatins). Further, we review the molecular underpinnings of lymphangiogenesis, a process now known to be almost separate from(yet related to) hemangiogenesis.
