Efecto modulador de los glucocorticoides sobre la angiogénesis mediada porPI3K/Akt activada por α7-nAChR: Una revisión narrativa

Introducción: los glucocorticoides (GC) han sido ampliamente utilizados en el tratamiento de patologías oculares debido a sus efectos antiinflamatorios y anti-angiogénicos. Se ha sugerido que el mecanismo de acción anti-angiogénico de los GC puede estar relacionado con la enzima fosfatidilinositol-3-cinasa (PI3K), la cual desempeña un papel crucial en la angiogénesis mediada por el receptor de acetilcolina nicotínico alfa 7 (α7-nAChR). La PI3K es una enzima lipoproteica heterodimérica compuesta por las subunidades; reguladora (p85) y catalítica (p110). Objetivo: esta revisión examina la evidencia de cómo los GC modulan la vía de señalización de PI3K activada por α7-nAChR en el proceso de angiogénesis in vitro. Metodología: se realizó una revisión bibliográfica utilizando los motores de búsqueda PubMed y Web of Science, relacionando los conceptos "endothelial cell", "α7-nAChR", "PI3K" y "glucocorticoid". Resultados: se seleccionaron 30 artículos que informaron sobre la expresión de α7-nAChR y PI3K en células endoteliales humanas. Además, del efecto de dexametasona sobre las subunidades de PI3K y Akt (proteína cinasa B) en modelos humano, murino y porcino. A partir de estos hallazgos, se propuso un mecanismo mediante el cual los GC ejercen su efecto anti-angiogénico a través de la modulación en la expresión de la subunidad inhibitoria p85 de PI3K activada por α7-nAChR en células endoteliales humanas. Conclusión: los antecedentes evidencian que dexametasona, ejerce su mecanismo de acción anti-angiogénico mediante el incremento de la expresión de la subunidad inhibitoria p85 de PI3K activada por α7-nAChR.

Introduction: glucocorticoids (GC) have been widely used in the treatment of ocular pathologies due to their anti-inflammatory and anti-angiogenic effects. It has been suggested that the anti-angiogenic mechanism of GC may be related to the enzyme phosphatidylinositol-3-kinase (PI3K), which plays a crucial role in angiogenesis mediated by the alpha 7 nicotinic acetylcholine receptor (α7-nAChR). PI3K is a heterodimeric lipoprotein enzyme composed of regulatory (p85) and catalytic (p110) subunits. Objective: this review examines the evidence of how the GC modulate the PI3K signaling pathway activated by α7-nAChR in the process of in vitro angiogenesis. Methodology: a literature search was conducted using the PubMed and Web of Science search engines, relating the concepts of "endothelial cell," "α7-nAChR," "PI3K," and "glucocorticoid." Results: thirty-two articles were selected that reported on the expression of α7-nAChR and PI3K in human endothelial cells. Furthermore, the effect of dexamethasone on PI3K and Akt (protein kinase B) subunits was documented in human, murine, and porcine models. Based on these findings, a mechanism was proposed whereby GC exert their anti-angiogenic effect through modulation of the expression of the inhibitory p85 subunit of PI3K activated by α7-nAChR in human endothelial cells. Conclusion: background evidence suggests that dexamethasone exerts its anti-angiogenic mechanism of action by increasing the expression of the α7-nAChR-activated PI3K inhibitory subunit p85

Celecoxib: Antiangiogenic and Antitumoral Action / Celecoxib: Acción Antiangiogénica y Antitumoral

SUMMARY: Angiogenesis, a process by which new blood vessels are generated from pre-existing ones, is significantly compromised in tumor development, given that due to the nutritional need of tumor cells, pro-angiogenic signals will be generated to promote this process and thus receive the oxygen and nutrients necessary for its development, in addition to being a key escape route for tumor spread. Although there is currently an increase in the number of studies of various anti-angiogenic therapies that help reduce tumor progression, it is necessary to conduct a review of existing studies of therapeutic alternatives to demonstrate their importance.

La angiogénesis, proceso por el cual se generan nuevos vasos sanguíneos a partir de otros preexistentes, se encuentra comprometida de forma importante en el desarrollo tumoral, dado que por necesidad nutritiva de las células tumorales se generarán señales pro angiogénicas para promover este proceso y así recibir el oxígeno y los nutrientes necesarios para su desarrollo, además de ser una ruta de escape clave para la diseminación tumoral. Si bien, actualmente existe un aumento en la cantidad de estudios de diversas terapias anti angiogénicas que ayudan a reducir el avance tumoral, es necesario realizar una revisión de los estudios existentes de alternativas terapéuticas para demostrar su importancia.

Effect and Mechanism of Sishenjian on Synovial Lesions in Knee Osteoarthritis Rats / 中国实验方剂学杂志

ObjectiveTo explore the effect and mechanism of Sishenjian on synovial lesions induced by monosodium iodoacetate （MIA） in rats with knee osteoarthritis （KOA）. MethodSixty female Sprague-Dawley （SD） rats were randomly divided into the following six groups： normal group， model group， celecoxib group， and high-， medium-， and low-dose Sishenjian group. The KOA rat model was established by intra-articular injection of MIA. Celecoxib （18 mg·kg-1） and Sishenjian （14.4， 7.2， 3.6 g·kg-1） were administered by gavage according to the groups. All rats were euthanized after four weeks of continuous administration. The transverse diameter of the bilateral knee joints of rats was measured， and gross observation of the knee joint was performed. Pathological changes in knee joint synovial tissue were observed by hematoxylin-eosin （HE） staining and picrosirius red staining. Immunohistochemistry （IHC） was used to detect the expression of vascular endothelial growth factor A （VEGFA） in synovial tissue. The levels of inflammatory cytokines in the joint synovial fluid were detected by enzyme-linked immunosorbent assay （ELISA）. Real-time quantitative polymerase chain reaction （Real-time PCR） and Western blot were used to detect the expression of mRNA and proteins related to the transforming growth factor-β1 （TGF-β1）/Smad2/3 pathway in knee joint synovium. ResultCompared with the normal group， the transverse diameter of the knee joint in the model group significantly increased （P<0.01）. Compared with the model group， the transverse diameter of the knee joint in rats of each Sishenjian group significantly decreased （P<0.01）. Compared with the normal group， the expression levels of interleukin-1β （IL-1β） and tumor necrosis factor-α （TNF-α） in the knee joint synovial fluid of model group significantly increased （P<0.01）. Compared with the model group， the expression levels of IL-1β and TNF-α in the knee joint synovial fluid of rats in each Sishenjian group significantly decreased （P<0.01）. Compared with the normal group， the expression levels of TGF-β1， Smad2/3， phosphorylation（p）-Smad2/3， type Ⅰ collagen α1 （ColⅠα1）， type Ⅲ collagen α1 （ColⅢα1）， VEGFA proteins and TGF-β1， Smad2/3， ColⅠα1， ColⅢα1 mRNA in knee joint synovium of model group significantly increased （P<0.01）. Compared with the model group， the expression levels of TGF-β1， Smad2/3， phosphorylation （p）-Smad2/3， ColⅠα1， ColⅢα1， VEGFA proteins and TGF-β1， Smad2/3， ColⅠα1， ColⅢα1 mRNA in knee joint synovium of rats in each Sishenjian group significantly decreased （P<0.05， P<0.01）. ConclusionSishenjian can inhibit synovial inflammation and angiogenesis， and may become a potential drug for treating synovial lesions in KOA by regulating the TGF-β1/Smad2/3 pathway.

Effect of siRNA-mediated α-TAT1 gene silencing on migration behavior of endothelial cells in rats with hepatopulmonary syndrome / 陆军军医大学学报

Objective To investigate the effect of silencing alpha tubulin acetyltransferase 1(α-TAT1)on migration behavior of endothelial cells induced by hepatopulmonary syndrome(HPS).Methods Online database Tabula Muris was used to analyze the expression of α-TAT1 in various cell subsets in the lungs.Twenty-four male SD rats were randomly divided into control group(Sham group,n=6)and common bile duct ligation group(HPS group,n=18).The rats in HPS group were euthanasized at 2 and 4 weeks after modelling,and then the expression of α-TAT1 in pulmonary vascular endothelial cells was detected by immunofluorescence colocalization.The sera from the Sham and HPS rats were used to stimulate human umbilical vein endothelial cells(HUVECs)for 12 and 24 h,respectively.Then the obtained HUVECs were divided into 4 groups:Sham serum+siRNA NC group,Sham serum+siRNA α-TAT1 group,HPS serum+siRNA NC group,HPS serum+siRNA α-TAT1 group.The expression levels of α-TAT1 and Ace-α-tubulin in HUVECs were detected by Western blotting.Immunofluorescence assay was applied to observe the levels of polymerized microtubules of α-Tubulin in HUVECs after nocodazole(10 μmol/L)pretreatment to evaluate the stability of microtubule structure.Cell scratch assay combined with cell immunofluorescence assay was employed to observe the nuclear localization of Golgi apparatus and cell migration ability of HUVECs.The angiogenesis ability of HUVECs was tested by in vitro angiogenesis test.Results In vivo and in vitro experiments showed that the expression of α-TAT1 in endothelial cells was significantly increased after HPS inducement.The expression levels of α-TAT1 and Ace-α-tubulin were significantly down-regulated,and the stability of microtubules was weakened in the siRNA α-TAT1 interference group(P＜0.01).In addition,the distribution of GM 130 labeled Golgi apparatus in the protrusion of HUVECs was down-regulated in the siRNAα-TAT1 interference group,as well as the migration ability(P＜0.01).And the length of angiogenesis and network level were also significantly declined(P＜0.01).Conclusion Silencing α-TAT1 reduces the migrαtion and angiogenesis of endothelial cells in HPS,which was associated with weakened stabilization of microtubule.

Research progress of myeloid-derived suppressor cells in tumor angiogenesis / 国际肿瘤学杂志

As a kind of immunosuppressive cells, myeloid-derived suppressor cells (MDSCs) are an important component of the immune microenvironment. MDSCs play a significant role in promoting tumor immune escape. In addition, non-immunological functions such as promoting angiogenesis can also promote tumor development with the deepening of research. MDSCs can promote tumor angiogenesis directly through vascular endothelial growth factor signaling pathway, or promote tumor growth and angiogenesis by secreting cytokines such as matrix metalloprotein-9, basic fibroblast growth factor, angiogenic peptide Bv8, platelet derived growth factor, exosomes, or interacting with other cells. Exploring the expansion, activation, recruitment and angiogenesis mechanism of MDSCs will provide new ideas for regulating the individualized diagnosis and treatment based on targeted MDSCs.

A Review of Research Status for the Anti-tumor Mechanism of Shanxian Granule / 广州中医药大学学报

In this article,the mechanism of Shanxian Granule in inhibiting liver cancer,lung cancer,sarcoma,melanoma and other tumors was reviewed,with a view to providing a theoretical basis for the clinical research of Shanxian Granules in the treatment of malignant tumors.Shanxian Granule are the pure Chinese medicine preparation for counteracting malignant tumor developed by the Oncology Research Team of Shaanxi University of Chinese Medicine on the basis of the theory of traditional Chinese medicine syndrome differentiation and treatment combined with decades of clinical experience as well as the achievements of modern pharmacological research.Shanxian Granule are mainly composed of Crataegi Fructus,Agrimoniae Herba,Panacis Quinquefolii Radix,Curcumae Rhizoma,Testudinis Carapax et Plastrum,Trionycis Carapax,Corydalis Rhizoma,and Polyporus,and have the actions of benefiting qi and nourishing yin,supporting healthy-qi and cultivating the essence,activating blood and removing stasis,and eliminating swelling and counteracting cancer.The compatibility of Shanxian Granule embodies the principle of supporting healthy-qi but avoiding maintaining pathogens,and eliminating pathogens but avoiding injuring healthy-qi.The granules can effectively inhibit the growth and metastasis of liver cancer,lung cancer,sarcoma,melanoma and other tumors both in vivo and in vitro,alleviate the clinical symptoms of tumor patients,and improve their prognosis.The anti-tumor mechanism of Shanxian Granules is related to the enhancement of body immune function,inhibition of tumor cell proliferation,enhancement of tumor cell apoptosis,inhibition of tumor cell invasion and metastasis as well as the tumor angiogenesis.

Effect of catgut implantation at acupoint on the learning and memory function and hippocampal microangiogenesis in vascular dementia rats / 解剖学报

Objective To observe the effect of catgut implantation at acupoint(CIAA)on the learning and memory function,hippocampal microangiogenesis,and the mRNA and protein expression of angiopoietin-1(Ang-1)/vascular endothelialgrowth factor(VEGF)and its receptor TEK tyrosine kinase(TIE2)/VEGF receptor 2(VEGFR2)in rats with vascular dementia(VD).To explore the mechanism of catgut implantation at acupoint in preventing and treating VD.Methods Using a random number table,VD rats were divided into a model group,a nimodipine group,and an catgut implantation at acupoint group,and a sham operation group was set up,with 10 rats in each group.On the 7th day after surgery,the treatment groups were given catgut implantation at acupoint and nimodipine gastric lavage for 21 days.After treatment,Morris water maze behavioral test was performed.HE staining was used to observe hippocampal CA1 tissue.CD34 immunohistochemical staining was used to detect hippocampal microvascular density(MVD).Real-time PCR and Western blotting were used to detect the mRNA and protein expression of Ang-1/VEGF and its receptor TIE2/VEGFR2 in the hippocampus.Results Compared with the model group,the average escape latency of the other groups was significantly shortened,and the target quadrant residence time was significantly prolonged(P<0.01,P<0.05).Compared with the model group,the number of nucleolus and well-formed pyramidal cells in hippocampal CA1 area of the catgut implantation at acupoint group and the nimodipine group increased in varying degrees,and they were arranged more closely,with only a few cells scattered and swollen.In the sham surgery group,a few CD34 positive cells were scattered.The treatment groups had more closely distributed CD34 positive cells with significant staining compared to the model group.The MVD of the model group was significantly higher than that of the sham surgery group(P<0.01).Both nimodipine group and catgut implantation at acupoint group had higher MVD than the model group(P<0.05,P<0.01).Compared with the sham surgery group,the mRNA and protein expression of Ang-1/VEGF and its receptor TIE2/VEGFR2 in the model group increased significantly(P<0.01,P<0.05).Compared with the model group,both nimodipine group and catgut implantation at acupoint group had higher mRNA and protein expression of Ang-1/VEGF and its receptor TIE2/VEGFR2(P<0.01,P<0.05).Conclusion Catgut implantation at acupoint can improve the learning and memory abilities in VD rats,promote hippocampal microvascular angiogenesis,which may be related to the up-regulation of Ang-1/VEGF and its receptor TIE2/VEGFR2 mRNA and protein expression.

Establishment and application of animal models of myocardial infarction / 解剖学报

Myocardial infarction is one of the severe cardiovascular diseases.The patients with myocardial infarction die of heart failure or arrhythmia.In recent years,the studies in myocardial infarction therapies have advanced greatly,especially the preclinical experimental studies.The experimental studies of myocardial infarction often rely on animal models.Therefore,successful establishment of the myocardial infarction models has important application value in exploring the new techniques and measures for repairing the infarcted myocardium.In this paper,the techniques in establishment of the myocardial infarction models and strategies of their application are summarized.

Application progress of mesenchymal stem cells in islet transplantation for type 1 diabetes mellitus / 器官移植

Islet transplantation is considered as one of the most effective approach for type 1 diabetes mellitus, although its efficacy is limited by several factors. Anoxia, stress and rejection occurring during the isolation, culturing and transplantation of islets may have impact on the outcome of the islet transplantation. Due to the biological properties such as anti-inflammation, angiogenetic promotion and immune regulation, mesenchymal stem cells (MSCs) are all the way focused by researchers. Additionally, exosome, a derivative of MSC, also plays an import role in regulating anoxia-induced oxidative stress modulation, angiogenetic promotion, and immune regulation. MSC-based islet transplantation may be a useful therapeutic tool in treating type 1 diabetes. Therefore, in this review, the potential effect of MSC prior and posterior to the operation of the islet transplantation, its clinical application as well as its limitations were reviewed, aiming to offer insights into the future application of islet transplantation in treating type 1 diabetes.

Inhibition of HSP70 release by geniposide improves angiogenesis in moist heat arthralgia spasm syndrome collagen induced arthritis rats / 中国药理学通报

Aim To investigate the relation between the effect of geniposide (GE) in improving angiogenesis in arthralgia spasm syndrome collagen induced arthritis (CIA) rats and the modulation of heat shock proteins 70 (HSP70) release. Methods A CIA model was constructed by multiple intradermal injections of complete Freund's adjuvant (CFA) and an equal volume mixture of chicken type II collagen (CCII) into the dorsal and caudal root regions of rats, on the basis of which a rheumatic fever stimulus was given to build up a moist heat arthralgia spasm syndrome in CIA rats. After successful modeling, the groups were randomly grouped, and the administered groups were gavaged with GE (60, 120 mg · kg

Bioceramic scaffolds with two-step internal/external modification of copper-containing polydopamine enhance antibacterial and alveolar bone regeneration capability / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Magnesium-doped calcium silicate (CS) bioceramic scaffolds have unique advantages in mandibular defect repair; however, they lack antibacterial properties to cope with the complex oral microbiome. Herein, for the first time, the CS scaffold was functionally modified with a novel copper-containing polydopamine (PDA(Cu2+‍)) rapid deposition method, to construct internally modified (*P), externally modified (@PDA), and dually modified (*P@PDA) scaffolds. The morphology, degradation behavior, and mechanical properties of the obtained scaffolds were evaluated in vitro. The results showed that the CS*P@PDA had a unique micro-/nano-structural surface and appreciable mechanical resistance. During the prolonged immersion stage, the release of copper ions from the CS*P@PDA scaffolds was rapid in the early stage and exhibited long-term sustained release. The in vitro evaluation revealed that the release behavior of copper ions ascribed an excellent antibacterial effect to the CS*P@PDA, while the scaffolds retained good cytocompatibility with improved osteogenesis and angiogenesis effects. Finally, the PDA(Cu2+)-modified scaffolds showed effective early bone regeneration in a critical-size rabbit mandibular defect model. Overall, it was indicated that considerable antibacterial property along with the enhancement of alveolar bone regeneration can be imparted to the scaffold by the two-step PDA(Cu2+) modification, and the convenience and wide applicability of this technique make it a promising strategy to avoid bacterial infections on implants.

LAMP3 inhibited the proliferation,metastatic and PC-3-induced vasculogenesis of HUVEC by regulating VEGF/AKT signaling / 实用医学杂志

Objective To explore the impactof Lysosome-Associated Membrane Protein 3(LAMP3)on theproliferation,migration and angiogenesis of PC-3 cells.Methods LAMP3 expression in normal prostate epithelial cells and prostate cancer bone metastasis cells was detected using western blot and RT-PCR.Stable LAMP3-silenced PC-3 cells were constructed,and the effects of LAMP3 on proliferation,invasion,and migration of PC-3 cells were assessed using CCK8,scratch assay,and transwell assay,respectively.ELISA and angiogenesis assays were employed to examine the expression of VEGF and MMP9,as well as angiogenesis of HUVEC cells induced by PC-3 cells.Finally,WB and RT-PCR were used to detect the expression of VEGF,AKT/p-AKT.Results Our findings showed that the expression level of LAMP3 was significantly higherin prostate cellsthan in normal prostate epithelial cells,especially in PC-3 cells(P<0.05).We also found that silencing LAMP3 could inhibit the proliferation,migration and invasion of PC-3 cells,along with the expression of VEGF and MMP9 and the PC-3 cells-induced angiogenesis,and these results were statistically significant(P<0.05).Furthermore,LAMP3 downregulated the expression of VEGF and AKT/p-AKT in PC-3 cells.Conclusion LAMP3 can affect the proliferation,migrationand angiogenesis of PC-3 cells through the regulation of VEGF/AKT pathway.Thus,LAMP3 might be a potential thera-peutic target for prostate cancer bone metastasis.

Tumor endothelial markers1 mediate endothelial cell angiogenesis and heart failure myocardial remodeling via MAPKs pathway / 实用医学杂志

Objective To explore the role of endothelial cells in angiogenesis and myocardial remodeling in heart failure based on MAPKs pathway mediated by tumor endothelial marker 1(TEM1).Methods Sixty-four mice were equally randomized into four groups:sham operation,myocardial infarction(MI),MI+sh-NC and MI+ sh-TEM1.On the 7th day after MI,the changes of EndMT in the infarct border area were detected by immunofluo-rescence staining,and the cardiac function of mice was evaluated by echocardiography on the 28th day.Mouse aortic endothelial cells(MAECs)were divided into three groups:control,Vector and rTEM1.In addition,MAECs were pretreated with MAPK inhibitor SB203580,and the cells were treated with rTEM1 for 48 h.The changes of EndMT and MAPKs signaling pathways in endothelial cells were evaluated by Western blot.Results In the myocardium at the border of infarction,the level of TEM1-1 increased slightly on the 1st day after MI,reached the peak on the 7th day,and then decreased on the 28th day.Compared with Vector group,the expression of VE-Cadherin protein in the rTEM1 group decreased significantly(P<0.05),and the levels of α-SMA and vimentin,relative migration distance,the number of invading cells,and the number of branching formation increased signifi-cantly(P<0.05).SB203580 reversed these changes of MAECs induced by rTEM1.Compared with the MI group,the co-staining level of CD31+Vimentin+ in the MI+sh-TEM1 group decreased significantly(P<0.01).On the 28th day,the LVEF and LVFS in the MI+sh-TEM1 group were significantly higher than those in MI group(P<0.05).Compared with the MI group,the expressions of p-P38/P38 and p-JNK/JNK in the endothelial cells of the MI+sh-TEM1 group decreased.Conclusion EndMT and angiogenesis induced by TEM1 participate in the pathogenesis of cardiac fibroblasts induced by MI,which may be mechanically related to the activation of MAPKs signaling pathway.

Research Progress on the Mechanism of Type H Blood Vessels Promoting Angiogenesis-osteogenesis Coupling in Fracture Healing / 华中科技大学学报(医学版)

Fracture is a common orthopedic disease in clinical practice,and the resulting nonunion or delayed union of frac-tures is a major challenge in clinical treatment.In the process of fracture healing,there is a complex interaction between angio-genesis and osteogenesis,which is called the"angiogenesis-osteogenesis coupling"mechanism.In recent years,a new capillary subtype characterized by high expression of platelet endothelial cell adhesion molecule-1(PECAM-1/CD31)and salivary glyco-protein(EMCN),namely type H blood vessel,has been identified and found to play an important role in regulation of the angio-genesis-osteogenesis coupling.In this review,the mechanism of type H blood vessels promoting angiogenesis-osteogenesis cou-pling,the related molecules and signal pathways regulating type H blood vessels regeneration were discussed,in order to provide new ideas and methods for promoting fracture healing.

The effects of exercise preconditioning on angiogenesis and protein expression after cerebral ischemia and reperfusion / 中华物理医学与康复杂志

Objective:To observe any effect of exercise preconditioning on the levels of hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) in the brain tissue of rats after induced cerebral ischemia and reperfusion, and how it might promote angiogenesis.Methods:Thirty-six male Sprague-Dawley rats were randomly divided into a sham-operation group, a model group and an exercise preconditioning group, each of 12. After adaptive running training for 3 days, the exercise preconditioning group ran daily for 30 minutes at 15m/min for 14 days, while the other two groups did not exercise. Middle cerebral artery occlusion and reperfusion were then induced in the model and exercise preconditioning groups using the modified Zea-Longa suture method. Rats in the sham-operation group were only cut open to expose the right carotid artery. Right after the modeling, and again 24 hours later neurological deficit was evaluated using the Zea-Longa score and modified neurological severity scoring (mNSS). Infarct sizes were measured using 2, 3, 5-triphenyl tetrazolium chloride staining. Any morphological changes were noted using hematoxylin and eosin (HE) staining, and the expression of CD31 protein, hypoxia-inducible factor-1α and vascular endothelial growth factor in the ischemic cerebral cortex were quantified immunohistochemically.Results:Right after the modelling, compared with the sham-operation group, the average Zea-Longa scores of the model and exercise groups had increased significantly, but were not significantly different from each other. Twenty-four hours later the average Zea-Longa score, mNSS score and relative cerebral infarction area of the model group had increased significantly compared with the sham-operation group, while the exercise preconditioning group′s averages had decreased significantly. The HE staining showed that compared with the sham-operation group, pathological changes such as loose tissue, reduced number of nerve cells, nucleolysis, and vacuolization of the cerebral cortex on the ischemic side were found in the model group. Compared with the model group, the pathological changes in the exercise preconditioning group were less serious. The levels of CD31 protein, HIF-1α and VEGF in the ischemic cerebral cortexes of the model group had by then increased significantly. But compared with the model group, those levels had increased more in the exercise preconditioning group.Conclusion:Exercise preconditioning can effectively promote angiogenesis after cerebral ischemia and reduce chronic injury. That may be related to the activation of the HIF-1α and/or VEGF signaling pathways.

Pachymic acid exerts antitumor activities by modulating the Wnt/β-catenin signaling pathway via targeting PTP1B

@#Objective: To determine the inhibitory effects of pachymic acid on lung adenocarcinoma (LUAD) cells and elucidate its underlying mechanism. Methods: CCK-8, wound healing, Transwell, Western blot, tube formation, and immunofluorescence assays were carried out to measure the effects of various concentrations of pachymic acid on LUAD cell proliferation, metastasis, angiogenesis as well as autophagy. Subsequently, molecular docking technology was used to detect the potential targeted binding association between pachymic acid and protein tyrosine phosphatase 1B (PTP1B). Moreover, PTP1B was overexpressed in A549 cells to detect the specific mechanisms of pachymic acid. Results: Pachymic acid suppressed LUAD cell viability, metastasis as well as angiogenesis while inducing cell autophagy. It also targeted PTP1B and lowered PTP1B expression. However, PTP1B overexpression reversed the effects of pachymic acid on metastasis, angiogenesis, and autophagy as well as the expression of Wnt3a and β-catenin in LUAD cells. Conclusions: Pachymic acid inhibits metastasis and angiogenesis, and promotes autophagy in LUAD cells by modulating the Wnt/ β-catenin signaling pathway via targeting PTP1B.

The roles of LMO4 in endothelial cells differentiation and angiogenesis from murine embryonic stem cells / 安徽医科大学学报

Objective @#To examine the role of LMO4 in the regulation of endothelial cell differentiation and angio- genesis in murine embryonic stem cells (mESC) ．@*Methods @#Mouse Lmo4 cDNA was obtained from MEL cells by using the reverse transcription-polymerase chain reaction (RT-PCR) and subcloned into the expression vector pFG to generate the pFLG ，in which contained Flk-1 promoter to drive Lmo4 expresses in only FLK-1 + cells．The mESC were transfected with pFG or pFLG plasmids and subsequently screened with geneticin ( G418) to produce cell clones． These cell clones were named mESC /pFG and mESC /pFLG ，respectively． The mESC /pFG and mESC /pFLG were cultured in the differentiation medium for either 4 days or 10 days to generate embryoid bodies (EB) ．The 10-day embryoid bodies ( 10 d-EBs) carrying the pFG and pFLG vectors were subsequently stimulated to generate the blast-colony forming cells (BL-CFC) ，which indicated the presence of hemangioblasts．The endo- thelial cell sprouting analysis was performed by using 10 d-EBs．The expression of the interest genes was detected by using qualitative RT-PCR or Western blot analysis. @*Results @#The pFLG expression vector was successfully con- structed through PCR identification．The mESC /pFG and mESC /pFLG cells were obtained after transfected with the pFG or pFLG vectors and selected by G418．The cells spontaneously differentiate to generate EBs，in which some green fluoresce cells were present．Western blot analysis showed that a significant increase in LMO4 expression in both 4 d-EB and 10 d-EB when compared to mESC．BL-CFC analysis showed that the 4 d-EB/ pFLG had a higher cloning efficiency ( 7. 70% ± 1. 27% ) ，comparing with that of the 4 d-EB/ pFG ( 1. 15% ± 0. 48% ) ( P = 0. 021) ．Quantitative RT-PCR results showed that the expression of Flk-1，C-kit，Tie-2 and Ve-cad genes in 10 d- EBs /pFLG increased more than 2-fold compared to 10 d-EBs /pFG．The endothelial cell sprouting analysis result showed a significant increase in the number and length of new blood vessels in 10 d-EB/ pFLG compared to 10 d- EB/ pFG (P＜0. 05) ．@*Conclusion @#Overexpression of LMO4 promotes hemangioblast differentiation from mESC， and benefits for endothelial cell differentiation and angiogenesis.

Effects of low temperature plasma-activated medium on proliferation and angiogenic capacity of vascular endothelial cells / 西安交通大学学报(医学版)

【Objective】 To explore the plasma-activated medium (PAM) produced by low temperature plasma (LTP) on the proliferation and angiogenesis of human umbilical vein endothelial cells (HUVECs) so as to provide theoretical basis for the future use of PAM to promote wound healing and inhibit tumor angiogenesis. 【Methods】 HUVECs were selected as the in vitro research model. The PAM-containing medium after LTP treatment for different time points (0 s, 15 s, 30 s, 45 s, 60 s, and 75 s) was used for intervention. The influence of PAM on HUVECs viability was assessed using the MTT assay and cell cycle analysis. The effects of PAM on angiogenesis were examined through angiogenesis experiments. Intracellular levels of reactive oxygen species (ROS) were measured using fluorescence probes. A melanoma mouse model was established, and CD31 expression was detected by immunohistochemistry. 【Results】 As the treatment time increased, the intracellular levels of ROS also elevated. PAM derived from LTP exhibited a bidirectional effect on angiogenesis in HUVECs. Compared to the control group (0 s), low-dose treatments (15 s and 30 s) enhanced HUVECs viability, while high-dose treatments (45 s, 60 s, and 75 s) significantly decreased cell viability (P<0.05). The proportion of HUVECs in the S phase was significantly increased in the PAM-15 s and PAM-30 s groups, but markedly decreased in the PAM-45 s, PAM-60 s, and PAM-75 s groups, with statistically significant differences (P<0.05). The HUVECs tube formation ability was enhanced in the 15 s and 30 s PAM groups, but diminished in the PAM-45 s, PAM-60 s, and PAM-75 s groups, characterized by the decreased numbers of vascular nodes, intersections, meshes, and branching points (P<0.05). After PAM treatment in the melanoma mouse model, the control group exhibited widespread distribution of CD31 in tumor tissue, while the PAM-5 min and PAM-10 min groups displayed reduced distribution of CD31. 【Conclusion】 Short-term exposure to PAM enhances HUVECs proliferation and angiogenesis, whereas prolonged exposure suppresses cell viability and inhibits angiogenesis.

Role of MAPK Signaling Pathway in Prevention and Treatment of Rheumatoid Arthritis and Chinese Medicine Intervention： A Review / 中国实验方剂学杂志

Rheumatoid arthritis （RA） is an autoimmune disease involving symmetrical small joints， with clinical manifestations such as small joint swelling， morning stiffness， progressive pain， and even joint deformity and loss of function. Due to the complex immune mechanism， the pathogenesis of RA remains unclear. However， studies have shown that the pathogenesis of RA is related to abnormal immune mechanism， increased synovial inflammatory response， abnormal biological behavior of RA fibroblast-like synoviocytes （RA-FLSs）， and abnormal degradation of extracellular matrix. Mitogen-activated protein kinase （MAPK） plays a key role in the regulation of cell growth， proliferation， differentiation， and apoptosis. It is involved in the abnormal release and activation of inflammatory mediators in RA， the abnormal proliferation， migration， and invasion of RA-FLSs， synovial angiogenesis， bone erosion， and cartilage destruction. The thousands of years of practical experience show that Chinese medicine can effectively mitigate the clinical symptoms such as joint swelling， morning stiffness， and pain and delay the occurrence of joint deformity in RA patients. Moreover， the Chinese medicine treatment has the advantages of overall regulation， personalized treatment， multiple pathways and targets， high safety， few adverse reactions， and stable quality. Modern studies have confirmed that Chinese medicine can play a role in the prevention and treatment of RA by interfering in the MAPK signaling pathway， reducing pro-inflammatory cytokines， inhibiting the abnormal proliferation， migration， and invasion of RA-FLSs， regulating the apoptosis of RA-FLSs， and protecting extracellular matrix. This article elaborates on the key role of MAPK signaling pathway in the development of RA and reviews the latest research results of Chinese medicine intervention in MAPK signaling pathway for the prevention and treatment RA， aiming to provide a basis for the development of new drugs and the clinical application of Chinese medicine in the prevention and treatment of RA.

The research of transcription factor CEBPB activates FJX1 to promote the proliferation,invasion,migration and angiogenesis of colon cancer cells / 中国现代医生

Objective To explore the regulatory relationship between CCAAT enhancer binding protein beta(CEBPB)and four-jointed box kinase 1(FJX1)in colon cancer and their effect on colon cancer(CC)malignant progression and angiogenesis.Methods Bioinformatics was used to analyze the expression of FJX1 and CEBPB in CC and the regulatory relationship between them.Real-time quantitative reverse transcription polymerase chain reaction(qRT-PCR)was used to verify the expression of FJX1 and CEBPB in CC cells,and chromatin immunoprecipitation(CHIP)and dual luciferase assay were used to verify the binding relationship between FJX1 and CEBPB.The effects of FJX1 and CEBPB on the viability,migration,invasion and angiogenesis of CC cells were detected by cell counting kit-8(CCK-8),scratch test,Transwell and angiogenesis test.Results This study revealed that FJX1 was highly expressed in CC.Inhibiting the expression of FJX1 could significantly inhibit the cell viability,migration,invasion and angiogenesis of CC cells.Subsequently,we found that CEBPB was an upstream regulatory gene of FJX1,and CEBPB was highly expressed in CC.CHIP and dual luciferase experiments showed that CEBPB could bind to FJX1.The results of cell experiments showed that the transcription factor CEBPB could promote the proliferation,migration,invasion and angiogenesis of CC cells by activating FJX1.Conclusion CEBPB/FJX1 axis played a cancer-promoting role in the progression of CC,suggesting that CEBPB and FJX1 may be potential therapeutic targets for CC.