AIM To assess the use of serum levels of angiopoietin-1(Ang1), Ang2 and tumor necrosis factor-α(TNFα) as predictive factors for small bowel angiodysplasia(SBA).METHODS Serum samples were collected from patients unde...AIM To assess the use of serum levels of angiopoietin-1(Ang1), Ang2 and tumor necrosis factor-α(TNFα) as predictive factors for small bowel angiodysplasia(SBA).METHODS Serum samples were collected from patients undergoing capsule endoscopy for any cause of obscure gastrointestinal bleeding(OGIB) or anaemia. Based on small bowel findings patients were divided into 3 groups:(1) SBA;(2) other bleeding causes; and(3) normal, according to diagnosis. Using ELISA technique we measured serum levels of Ang1, Ang2 and TNFα and compared mean and median levels between the groups based on small bowel diagnosis. Using receiver operator curve analysis we determined whether any of the factors were predictive of SBA.RESULTS Serum samples were collected from a total of 120 patients undergoing capsule endoscopy for OGIB or anaemia: 40 with SBA, 40 with other causes of small bowel bleeding, and 40 with normal small bowel findings. Mean and median serum levels were measured and compared between groups; patients with SBA had significantly higher median serum levels of Ang2(3759 pg/mL) compared to both other groups, with no significant differences in levels of Ang1 or TNFα based on diagnosis. There were no differences in Ang2 levels between the other bleeding causes(2261 pg/mL) and normal(2620pg/mL) groups. Using Receiver Operator Curve analysis, an Ang2 level of > 2600 pg/mL was found to be predictive of SBA, with an area under the curve of 0.7. Neither Ang1 or TNFα were useful as predictive markers.CONCLUSION Elevations in serum Ang2 are specific for SBA and not driven by other causes of bleeding and anaemia. Further work will determine whether Ang2 is useful as a diagnostic or prognostic marker for SBA.展开更多
Existing literature supports the role of signaling protein vascular endothelial growth factor (VEGF) in tumor growth and metastasis and furthers its involvement in recurrence. In both experimental and clinical studies...Existing literature supports the role of signaling protein vascular endothelial growth factor (VEGF) in tumor growth and metastasis and furthers its involvement in recurrence. In both experimental and clinical studies, VEGF has been shown to be a significant factor involved for aberrant blood vessel growth, and in fact is the target of several classes of antineoplastic drugs [1] [2] [3] [4]. That said, the current standard of care for estrogen receptor positive breast cancer (although improved over the last decade), has not provided a “meaningful preventive shift” since the discovery of angiogenesis and its role in induction of recurrence. In this article, we discuss an anti angiogenic therapy implementing natural compounds to inhibit the production of VEGF. We applied our preclinical data to justify the predicted effect on VEGF. We used liquid biopsy to monitor patients response to therapy as a surrogate for recurrence. We hypothesize that by inhibition of angiogenesis through this protocol, we are able to positively impact tumor recurrence. It is our experience that patients in our sample even with high recurrence scores (based on Oncotype Dx testing) had a major reduction in recurrence when estrogen blockers were combined with this protocol. We also propose longitudinal studies to compare outcomes with combinational therapies with estrogen blockers in highly expected to recur disease.展开更多
A major portion of the beneficial effect of mesenchymal stem cells (MSC) is due to the production of trophic and angiogenic factors by these cells, and one of the efforts to improve the therapeutic efficacy of these c...A major portion of the beneficial effect of mesenchymal stem cells (MSC) is due to the production of trophic and angiogenic factors by these cells, and one of the efforts to improve the therapeutic efficacy of these cells lies in enhancing this capacity. Since there is complement activation in all areas of tissue injury, and both C3a and C5a activate MSC, it was asked whether stimulation with C3a or C5a would upregulate the production of trophic factors by MSC. C3a caused significant up-regulation of various angiogenic factors, including VEGF, CXCL8/IL-8 and IL-6. In contrast there was no detectable production of the pro-inflammatory cytokines TNF-α and IL-1β in spite of nuclear translocation of NFκB. Although C5a also caused moderate up-regulation of angiogenic factors, the effect was borderline significant. Furthermore the production of angiogenic factors induced by C3a was of physiological relevance: Supernatants of MSCs cultured under serum-free conditions induced minimal tube formation of HUVECs as an in vitro measure of angiogenesis;tube formation was considerably enhanced, when supernatants from C3a-stimulated MSC were used, while C3a itself had no direct angiogenic effect on HUVECs. The signaling cascade responsible for the production of angiogenic factors by C3a or C5a could be defined as activation of the rho cascade which was necessary for nuclear translocation of NFκB p65 and of phospho-ERK1/2. Although rho was only transiently activated, inhibition of the rho or “downstream of it” of the NFκB pathway, prevented C3a-and C5a-induced up-regulation of angiogenic factors.展开更多
BACKGROUND Neovascularisation is common to a variety of gastrointestinal(GI)disorders with differing aetiologies and presentations;usually affecting adults above 60 years.Shared angiogenic factors modulated by disease...BACKGROUND Neovascularisation is common to a variety of gastrointestinal(GI)disorders with differing aetiologies and presentations;usually affecting adults above 60 years.Shared angiogenic factors modulated by disease specific elements could be a common denominator and represent novel diagnostic and therapeutic targets.As yet,assessment of angiogenic factors across several GI vascular disorders associated with recurrent bleeding and anaemia has not been reported.AIM To assess serum levels of angiogenic factors in several intestinal vascular disorders.METHODS A case control study was performed in Tallaght University Hospital in patients with endoscopically proven small bowel angiodysplasia(SBA),portal hypertensive gastropathy(PHG),gastric antral vascular ectasia(GAVE)and nonbleeding,non-anaemic controls.Using enzyme-linked immunosorbent assay,concentrations of Angiopoietin 1(Ang-1),Ang-2 and vascular endothelial growth factor(VEGF)were measured from 2 serum tubes of blood following informed consent.The relative expression of Ang-1 and Ang-2 and Ang-1/2 ratio was calculated and compared between groups.Statistical analysis was applied using a t-test,and a P value of<0.05 was considered significant.RESULTS To date 44 samples were tested:10 SBA,11 PHG,8 GAVE and 15 controls.Mean age 60(range 20-85)years and 20(45%)were males.Controls were significantly younger(49 years vs 66 years,P=0.0005).There was no difference in VEGF levels between the groups(P=0.6).SBA,PHG and GAVE Ang-1 levels were similar and were significantly lower than controls,(P=0.0002,95%CI:241 to 701).Ang-2 levels were statistically higher in PHG and GAVE groups compared to controls(P= 0.01, 95%CI: 77.8 to 668) and as a result, also had a lower Ang-1/2 ratioscompared to controls. While SBA Ang-2 levels were higher than controls, this didnot reach statistical significance. Neither age nor haemoglobin level, which wassimilar between disease groups, could explain the difference. In addition, themedian Ang-1/Ang-2 ratio for all patients was found to be significantly lowercompared to controls, 8 vs 28 respectively, P = 0.001, 95%CI: -27.55 to -7.12.CONCLUSIONOur novel pilot study suggests common alterations in Ang-1 and Ang-2 levelsacross several GI vascular disorders. Differences in Ang-1/Ang-2 ratios amongvascular disorders compared to controls suggest disease-specific modulation.展开更多
Natural bone is a composite tissue made of organic and inorganic components,showing piezoelectricity.Whitlockite(WH),which is a natural magnesium-containing calcium phosphate,has attracted great attention in bone form...Natural bone is a composite tissue made of organic and inorganic components,showing piezoelectricity.Whitlockite(WH),which is a natural magnesium-containing calcium phosphate,has attracted great attention in bone formation recently due to its unique piezoelectric property after sintering treatment and sustained release of magnesium ion(Mg^(2+)).Herein,a composite scaffold(denoted as PWH scaffold)composed of piezoelectric WH(PWH)and poly(ε-caprolactone)(PCL)was 3D printed to meet the physiological demands for the regeneration of neuro-vascularized bone tissue,namely,providing endogenous electric field at the defect site.The sustained release of Mg^(2+)from the PWH scaffold,displaying multiple biological activities,and thus exhibits a strong synergistic effect with the piezoelectricity on inhibiting osteoclast activation,promoting the neurogenic,angiogenic,and osteogenic differentiation of bone marrow mesenchymal stromal cells(BMSCs)in vitro.In a rat calvarial defect model,this PWH scaffold is remarkably conducive to efficient neo-bone formation with rich neurogenic and angiogenic expressions.Overall,this study presents the first example of biomimetic piezoelectric scaffold with sustained Mg^(2+)release for promoting the regeneration of neuro-vascularized bone tissue in vivo,which offers new insights for regenerative medicine.展开更多
Angiogenesis is a process in which newborn vessels sprout from preexisting blood vessels(Isogai et al.,2003;Geudens and Gerhardt,2011;Herbert and Stainier,2011;Chen et al.,2019,2021),and the dynamic changes of the cyt...Angiogenesis is a process in which newborn vessels sprout from preexisting blood vessels(Isogai et al.,2003;Geudens and Gerhardt,2011;Herbert and Stainier,2011;Chen et al.,2019,2021),and the dynamic changes of the cytoskeleton system are important for angiogenesis.A previous study revealed that although F-actin polymerization is required for filopodia formation,impairing filopodia formation by disturbing F-actin polymerization only resulted in the slow growth of angiogenic sprouts in zebrafish(Phng et al.,2013).Therefore,F-actin may not be essential for angiogenic sprout elongation.Many studies have shown that microtubules also participate in angiogenesis(Myers et al.,2011;Ganguly et al.,2013;Martin et al.,2018).Due to the lack of in vivo real-time imaging,the role of microtubules in angiogenic sprout elongation remains unclear.展开更多
Hailed as the cancer treatment to end all the resistance to treatment,anti-angiogenic therapy turned out to be not quite what was promised.The hope that this therapeutic approach would not have suffered by the phenome...Hailed as the cancer treatment to end all the resistance to treatment,anti-angiogenic therapy turned out to be not quite what was promised.The hope that this therapeutic approach would not have suffered by the phenomenon of resistance was based on the fact that was targeting normal vessels rather than tumour cells prone to mutation and subject to drug induced selection.However,reality turned out to be more complex and since 1997,several mechanisms of resistance have been described to the point that the study of resistance to these drugs is now a very large field.Far from being exhaustive,this paper presents the main mechanisms discovered trough some examples.展开更多
Cancer is a group of diseases with significant morbidity and mortality.In cancer cells,where energy requirements are exceptionally high,angiogenesis,which is the sprouting of new blood vessels from pre-existing ones,i...Cancer is a group of diseases with significant morbidity and mortality.In cancer cells,where energy requirements are exceptionally high,angiogenesis,which is the sprouting of new blood vessels from pre-existing ones,is an important process for tumour survival and progression.Hence,extensive research in recent years focuses on the discovery of new anticancer drugs that target angiogenesis.Several methodologies have been developed preclinically,including the inhibition of pro-angiogenic factors and their receptors via micromolecular agents or monoclonal antibodies and the inhibition of other compensatory pathways beyond the traditional angiogenic ones.The purpose of the literature review is to present new anticancer drugs that target the process of angiogenesis and have been under preclinical or clinical investigation during the last five years.Many new anticancer drugs targeting angiogenesis are identified in the literature.The results of the in vitro and in vivo evaluation of these drugs show that,apart from inhibiting angiogenesis,they also affect cancer cell proliferation and tumour growth.Recent clinical studies show that these drugs increase the overall or disease-free survival of patients,even those with persistent,chemotherapy-resistant and metastatic types of cancer,although treatment-related side effects are not uncommon.Drugs that target the process of angiogenesis are likely to be the future of anticancer therapy,especially in cases where more traditional treatments do not produce the desired results and where combination regimens of anti-angiogenic agents with standard chemotherapeutics increase patient survival.展开更多
Progression of chronic lymphocytic leukemia(CLL)is determined by the localization of malignant cells in lymphoid tissues,where they receive growth and survival signals.CLL cells produce angiogenic factors that are reg...Progression of chronic lymphocytic leukemia(CLL)is determined by the localization of malignant cells in lymphoid tissues,where they receive growth and survival signals.CLL cells produce angiogenic factors that are regulated by internal and external stimuli and whose levels vary according to the clinical stage of the disease.Stromal cellular and molecular components in CLL niches disturb the balance of pro-and antiangiogenic molecules in CLL cells and induce an angiogenic switch.Additionally,CLL cells also influence the behavior of microenvironmental cells,inducing endothelial cell proliferation and increasing the angiogenic capacity of macrophages,neutrophils,and other cells present in CLL niches.As a result of these reciprocal functional interactions,bone marrow angiogenesis is frequently increased in CLL and has been proposed as a prognostic marker in early disease.Besides their role in regulating angiogenesis,angiogenic factors are also involved in CLL cell migration and survival,all contributing to disease progression.Angiogenic factors,particularly vascular endothelial growth factor,have therefore been attractive therapeutic targets in CLL and many clinical trials were established in the past years.However,the results of these trials reveal that anti-angiogenic therapies alone are not as efficient as expected and should rather be used in combination with other treatments.展开更多
The dental pulp has irreplaceable roles in maintaining healthy teeth and its regeneration is a primary aim of regenerative endodontics.This study aimed to replicate the characteristics of dental pulp tissue by using c...The dental pulp has irreplaceable roles in maintaining healthy teeth and its regeneration is a primary aim of regenerative endodontics.This study aimed to replicate the characteristics of dental pulp tissue by using cranial neural crest(CNC)-like cells(CNCLCs);these cells were generated by modifying several steps of a previously established method for deriving NC-like cells from induced pluripotent stem cells(iPSCs).CNC is the anterior region of the neural crest in vertebrate embryos,which contains the primordium of dental pulp cells or odontoblasts.The produced CNCLCs showed approximately 2.5-12,000-fold upregulations of major CNC marker genes.Furthermore,the CNCLCs exhibited remarkable odontoblastic differentiation ability,especially when treated with a combination of the fibroblast growth factors(FGFs)FGF4 and FGF9.The FGFs induced odontoblast marker genes by 1.7-5.0-fold,as compared to bone morphogenetic protein 4(BMP4)treatment.In a mouse subcutaneous implant model,the CNCLCs briefly fated with FGF4+FGF9 replicated dental pulp tissue characteristics,such as harboring odontoblast-like cells,a dentin-like layer,and vast neovascularization,induced by the angiogenic self-assembling peptide hydrogel(SAPH),SLan.SLan acts as a versatile biocompatible scaffold in the canal space.This study demonstrated a successful collaboration between regenerative medicine and SAPH technology.展开更多
Angiogenesis plays a crucial role in wound healing by forming new blood vessels from preexisting vessels by invading the wound clot and organizing into a microvascular network throughout the granulation tissue.This dy...Angiogenesis plays a crucial role in wound healing by forming new blood vessels from preexisting vessels by invading the wound clot and organizing into a microvascular network throughout the granulation tissue.This dynamic process is highly regulated by signals from both serum and the surrounding extracellular matrix environment.Vascular endothelial growth factor,angiopoietin,fibroblast growth factor and transforming growth factor-beta are among the potent angiogenic cytokines in wound angiogenesis.Specific endothelial cell ECM receptors are critical for morphogenetic changes in blood vessels during wound repair.In particular integrin(αvβ3)receptors for fibrin and fibronectin,appear to be required for wound angiogenesis:αvβ3 is focally expressed at the tips of angiogenic capillary sprouts invading the wound clot,and any functional inhibitors ofαvβ3 such as monoclonal antibodies,cyclic RGD peptide antagonists,and peptidomimetics rapidly inhibit granulation tissue formation.In spite of clear knowledge about influence of many angiogenic factors on wound healing,little progress has been made in defining the source of these factors,the regulatory events involved in wound angiogenesis and in the clinical use of angiogenic stimulants to promote repair.展开更多
Prolyl oligopeptidase (POP) is a cytosolic enzyme involved in the metabolism of many peptide hormones and neuropeptides (1). It was recently reported that POP is responsible
Gastric cancer(GC)is the second leading cause of cancer-related death.The poor survival rate may reflect the relatively aggressive tumor biology of GC.Recently,the importance of the tumor microenvironment in carcinoge...Gastric cancer(GC)is the second leading cause of cancer-related death.The poor survival rate may reflect the relatively aggressive tumor biology of GC.Recently,the importance of the tumor microenvironment in carcinogenesis has emerged.In the tumor microenvironment,tumor cells and the surrounding stromal cells aberrantly secrete matricellular proteins capable of modulating carcinogenesis and regulating metastasis.The Cyr61/CTGF/Nov(CCN)proteins are a family of matricellular proteins with variable roles in many physiological and pathological processes.The evidence suggests that CCN family proteins contribute to GC carcinogenic processes.Here,we briefly review recent research on the effects of CCN family proteins in GC carcinogenesis and the development of new targeted agents in this field.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
Sphingosine-1-phosphate (S1P) is a blood-borne lipid mediator with pleiotropic biological activities. S1P acts via the specific cell surface G-protein-coupled receptors, S1P1-5. S1P1 and S1P2 were originally identifie...Sphingosine-1-phosphate (S1P) is a blood-borne lipid mediator with pleiotropic biological activities. S1P acts via the specific cell surface G-protein-coupled receptors, S1P1-5. S1P1 and S1P2 were originally identified from vascular endothelial cells (ECs) and smooth muscle cells, respectively. Emerging evidence shows that S1P plays crucial roles in the regulation of vascular functions, including vascular formation, barrier protection and vascular tone via S1P1, S1P2 and S1P3. In particular, S1P regulates vascular formation through multiple mechanisms; S1P exerts both positive and negative effects on angiogenesis and vascular maturation. The positive and negative effects of S1P are mediated by S1P1 and S1P2, respectively. These effects of S1P1 and S1P2 are probably mediated by the S1P receptors expressed in multiple cell types including ECs and bone-marrow-derived cells. The receptor-subtype-specific, distinct effects ofS1P favor the development of novel therapeutic tactics for antitumor angiogenesis in cancer and therapeutic angiogenesis in ischemic diseases.展开更多
Purpose: To examine the effect of an intravitreal injection of angiostatin on vascular leakage in retina and iris of the diabetes and study its possible mechanism. Methods: Experimental diabetes was induced in 24 rats...Purpose: To examine the effect of an intravitreal injection of angiostatin on vascular leakage in retina and iris of the diabetes and study its possible mechanism. Methods: Experimental diabetes was induced in 24 rats by an intravenous injection of streptozotocin (STZ) during 48 adult rats. Three groups were randomization distributed of them. There were 8 of both normal and diabetic rats in each group. STZ-diabetic rats and age-matched normal rats received an intravitreal injection of 5 μl of sterile PBS (Phosphate Buffered Saline) into the right eye, and the left eye was non-injected in the group A; Angiostatin was injected into the vitreous of the right eye (7.5 μg / 5 μl / eye), and the left eye received the same volume of sterile PBS as the control in the group B and C. The vascular permeability of retina and iris was measured using the Evans blue method at 2 days following the injection in the group A and B. Expression of VEGF in retina was evaluated using western blot analysis 24 hours following the injection in the group C. Results: Diabetic rats showed significant increases of vascular permeability in the retina ( P < 0.01) and iris ( P < 0.05). Angiostatin-injected eyes showed significant decreases in vascular permeability in the retina ( P < 0.01) and iris ( P < 0.05) comparing with the PBS-injected eyes in STZ-diabetic rats. In contrast, intravitreal injection of the same dose of angiostatin into the age-matched normal rats did not result in any significant reduction in vascular permeability in the retina and iris, when compared with the contralateral eye with PBS injection ( P > 0.05). Angiostatin injection significantly reduced VEGF level in the retinas of STZ-diabetic rats but did not affect retinal VEGF level in normal rats. Conclusions: Angiostatin significantly reduce pathological vascular permeability in the retina and iris of STZ-diabetic rats but not in normal rats. Angiostatin down-regulates VEGF expression and thus, blocks the major cause of vascular leakage in the diabetic retina. Therefore, angiostatin may have a therapeutic potential in the treatment of diabetic macular edema, cystoid macular edema, uvietis and other diseases with vascular leakage.展开更多
Objective: To investigate the expression ofangiogenic factors, basic fibroblast growth factor (bFGF)and transforming growth factor (TGF)-β1 inosteosarcoma, its association with neovascularizationand prognosis. Method...Objective: To investigate the expression ofangiogenic factors, basic fibroblast growth factor (bFGF)and transforming growth factor (TGF)-β1 inosteosarcoma, its association with neovascularizationand prognosis. Methods: The expression of bFGF, TGFβ1 and their receptors, as well as intratumoralmicrovcssel count (MVD) were studied in 80osteosarcomas by immunohistochemical staining andmorphometry. The relationship between the angiogenicfactors expression and prognosis was evaluated by amultivariate analysis using Cox proportion hazardmodel. Results: Among 80 cases of osteosarcoma, 46cases were positive for bFGFlbFGFr (57.5%), and 31cases for TGF-β1/ TGF-β (RI)(38.8%) respectively. TheMVD and bFGF, TGF-β1, were important indicators topredict the prognosis of patients with osteosarconla bythe Cox proportion hazard model analysis. Conclusioll:The angiogenic factors bFGF and TGF-β1 are involvedin the angiogenesis of osteosarcoma, and theangiogenesis inf’luences the prognosis. Also they may beuseful in the evaluation of the prognosis of patients withosteosarcoma.展开更多
Objective:Primary biliary cholangitis(PBC)is a chronic progressive cholestatic liver disease.In recent years,researchers have found that cysteine-rich angiogenic inducer 61(Cyr61,also known as CCN1)has a potential rol...Objective:Primary biliary cholangitis(PBC)is a chronic progressive cholestatic liver disease.In recent years,researchers have found that cysteine-rich angiogenic inducer 61(Cyr61,also known as CCN1)has a potential role in reducing portal inflammation in patients with PBC.This study aimed to explore the relationship between Cyr61 and PBC to provide new ideas and an experimental basis for the clinical treatment of PBC.Methods:After induction of the overexpression of Cyr61 in a mouse model of PBC using recombinant adenovirus,hematoxylin and eosin staining and pathological scores were used to indicate intrahepatic inflammation and bile duct damage.Real-time PCR was used to detect changes in inflammation-related cytokines in the liver.To further study the mechanism,we assessed whether Cyr61 protects bile duct epithelial cells from cytotoxic effects.Results:Serum and hepatic Cyr61 levels were increased in the murine model of PBC.Overexpression of Cyr61 alleviated hepatic inflammation and bile duct injury in vivo.Cyr61 inhibited the cytotoxic effects of CD8^(+)T cells by acting on biliary epithelial cells(BECs)in vitro.Conclusion:Our results provide novel insight into the pathogenesis of PBC and suggest that Cyr61 plays a dominant role in the cytotoxic effects on BECs in PBC.Consequently,therapeutic strategies targeting Cyr61 could be a potent therapy for PBC.展开更多
文摘AIM To assess the use of serum levels of angiopoietin-1(Ang1), Ang2 and tumor necrosis factor-α(TNFα) as predictive factors for small bowel angiodysplasia(SBA).METHODS Serum samples were collected from patients undergoing capsule endoscopy for any cause of obscure gastrointestinal bleeding(OGIB) or anaemia. Based on small bowel findings patients were divided into 3 groups:(1) SBA;(2) other bleeding causes; and(3) normal, according to diagnosis. Using ELISA technique we measured serum levels of Ang1, Ang2 and TNFα and compared mean and median levels between the groups based on small bowel diagnosis. Using receiver operator curve analysis we determined whether any of the factors were predictive of SBA.RESULTS Serum samples were collected from a total of 120 patients undergoing capsule endoscopy for OGIB or anaemia: 40 with SBA, 40 with other causes of small bowel bleeding, and 40 with normal small bowel findings. Mean and median serum levels were measured and compared between groups; patients with SBA had significantly higher median serum levels of Ang2(3759 pg/mL) compared to both other groups, with no significant differences in levels of Ang1 or TNFα based on diagnosis. There were no differences in Ang2 levels between the other bleeding causes(2261 pg/mL) and normal(2620pg/mL) groups. Using Receiver Operator Curve analysis, an Ang2 level of > 2600 pg/mL was found to be predictive of SBA, with an area under the curve of 0.7. Neither Ang1 or TNFα were useful as predictive markers.CONCLUSION Elevations in serum Ang2 are specific for SBA and not driven by other causes of bleeding and anaemia. Further work will determine whether Ang2 is useful as a diagnostic or prognostic marker for SBA.
文摘Existing literature supports the role of signaling protein vascular endothelial growth factor (VEGF) in tumor growth and metastasis and furthers its involvement in recurrence. In both experimental and clinical studies, VEGF has been shown to be a significant factor involved for aberrant blood vessel growth, and in fact is the target of several classes of antineoplastic drugs [1] [2] [3] [4]. That said, the current standard of care for estrogen receptor positive breast cancer (although improved over the last decade), has not provided a “meaningful preventive shift” since the discovery of angiogenesis and its role in induction of recurrence. In this article, we discuss an anti angiogenic therapy implementing natural compounds to inhibit the production of VEGF. We applied our preclinical data to justify the predicted effect on VEGF. We used liquid biopsy to monitor patients response to therapy as a surrogate for recurrence. We hypothesize that by inhibition of angiogenesis through this protocol, we are able to positively impact tumor recurrence. It is our experience that patients in our sample even with high recurrence scores (based on Oncotype Dx testing) had a major reduction in recurrence when estrogen blockers were combined with this protocol. We also propose longitudinal studies to compare outcomes with combinational therapies with estrogen blockers in highly expected to recur disease.
文摘A major portion of the beneficial effect of mesenchymal stem cells (MSC) is due to the production of trophic and angiogenic factors by these cells, and one of the efforts to improve the therapeutic efficacy of these cells lies in enhancing this capacity. Since there is complement activation in all areas of tissue injury, and both C3a and C5a activate MSC, it was asked whether stimulation with C3a or C5a would upregulate the production of trophic factors by MSC. C3a caused significant up-regulation of various angiogenic factors, including VEGF, CXCL8/IL-8 and IL-6. In contrast there was no detectable production of the pro-inflammatory cytokines TNF-α and IL-1β in spite of nuclear translocation of NFκB. Although C5a also caused moderate up-regulation of angiogenic factors, the effect was borderline significant. Furthermore the production of angiogenic factors induced by C3a was of physiological relevance: Supernatants of MSCs cultured under serum-free conditions induced minimal tube formation of HUVECs as an in vitro measure of angiogenesis;tube formation was considerably enhanced, when supernatants from C3a-stimulated MSC were used, while C3a itself had no direct angiogenic effect on HUVECs. The signaling cascade responsible for the production of angiogenic factors by C3a or C5a could be defined as activation of the rho cascade which was necessary for nuclear translocation of NFκB p65 and of phospho-ERK1/2. Although rho was only transiently activated, inhibition of the rho or “downstream of it” of the NFκB pathway, prevented C3a-and C5a-induced up-regulation of angiogenic factors.
基金We thank all the volunteers and medical staff who agreed to participate in this study.
文摘BACKGROUND Neovascularisation is common to a variety of gastrointestinal(GI)disorders with differing aetiologies and presentations;usually affecting adults above 60 years.Shared angiogenic factors modulated by disease specific elements could be a common denominator and represent novel diagnostic and therapeutic targets.As yet,assessment of angiogenic factors across several GI vascular disorders associated with recurrent bleeding and anaemia has not been reported.AIM To assess serum levels of angiogenic factors in several intestinal vascular disorders.METHODS A case control study was performed in Tallaght University Hospital in patients with endoscopically proven small bowel angiodysplasia(SBA),portal hypertensive gastropathy(PHG),gastric antral vascular ectasia(GAVE)and nonbleeding,non-anaemic controls.Using enzyme-linked immunosorbent assay,concentrations of Angiopoietin 1(Ang-1),Ang-2 and vascular endothelial growth factor(VEGF)were measured from 2 serum tubes of blood following informed consent.The relative expression of Ang-1 and Ang-2 and Ang-1/2 ratio was calculated and compared between groups.Statistical analysis was applied using a t-test,and a P value of<0.05 was considered significant.RESULTS To date 44 samples were tested:10 SBA,11 PHG,8 GAVE and 15 controls.Mean age 60(range 20-85)years and 20(45%)were males.Controls were significantly younger(49 years vs 66 years,P=0.0005).There was no difference in VEGF levels between the groups(P=0.6).SBA,PHG and GAVE Ang-1 levels were similar and were significantly lower than controls,(P=0.0002,95%CI:241 to 701).Ang-2 levels were statistically higher in PHG and GAVE groups compared to controls(P= 0.01, 95%CI: 77.8 to 668) and as a result, also had a lower Ang-1/2 ratioscompared to controls. While SBA Ang-2 levels were higher than controls, this didnot reach statistical significance. Neither age nor haemoglobin level, which wassimilar between disease groups, could explain the difference. In addition, themedian Ang-1/Ang-2 ratio for all patients was found to be significantly lowercompared to controls, 8 vs 28 respectively, P = 0.001, 95%CI: -27.55 to -7.12.CONCLUSIONOur novel pilot study suggests common alterations in Ang-1 and Ang-2 levelsacross several GI vascular disorders. Differences in Ang-1/Ang-2 ratios amongvascular disorders compared to controls suggest disease-specific modulation.
基金This work was supported by the National Natural Science Foundation of China(U22A20159,52003161)the Central Universities(buctrc202220),and the SINOPEC project(421029).
文摘Natural bone is a composite tissue made of organic and inorganic components,showing piezoelectricity.Whitlockite(WH),which is a natural magnesium-containing calcium phosphate,has attracted great attention in bone formation recently due to its unique piezoelectric property after sintering treatment and sustained release of magnesium ion(Mg^(2+)).Herein,a composite scaffold(denoted as PWH scaffold)composed of piezoelectric WH(PWH)and poly(ε-caprolactone)(PCL)was 3D printed to meet the physiological demands for the regeneration of neuro-vascularized bone tissue,namely,providing endogenous electric field at the defect site.The sustained release of Mg^(2+)from the PWH scaffold,displaying multiple biological activities,and thus exhibits a strong synergistic effect with the piezoelectricity on inhibiting osteoclast activation,promoting the neurogenic,angiogenic,and osteogenic differentiation of bone marrow mesenchymal stromal cells(BMSCs)in vitro.In a rat calvarial defect model,this PWH scaffold is remarkably conducive to efficient neo-bone formation with rich neurogenic and angiogenic expressions.Overall,this study presents the first example of biomimetic piezoelectric scaffold with sustained Mg^(2+)release for promoting the regeneration of neuro-vascularized bone tissue in vivo,which offers new insights for regenerative medicine.
基金supported by the National Natural Science Foundation of China,China(32000576)the Natural Science Foundation of Chongqing,China(cstc2020jcyj-msxmX0882).
文摘Angiogenesis is a process in which newborn vessels sprout from preexisting blood vessels(Isogai et al.,2003;Geudens and Gerhardt,2011;Herbert and Stainier,2011;Chen et al.,2019,2021),and the dynamic changes of the cytoskeleton system are important for angiogenesis.A previous study revealed that although F-actin polymerization is required for filopodia formation,impairing filopodia formation by disturbing F-actin polymerization only resulted in the slow growth of angiogenic sprouts in zebrafish(Phng et al.,2013).Therefore,F-actin may not be essential for angiogenic sprout elongation.Many studies have shown that microtubules also participate in angiogenesis(Myers et al.,2011;Ganguly et al.,2013;Martin et al.,2018).Due to the lack of in vivo real-time imaging,the role of microtubules in angiogenic sprout elongation remains unclear.
文摘Hailed as the cancer treatment to end all the resistance to treatment,anti-angiogenic therapy turned out to be not quite what was promised.The hope that this therapeutic approach would not have suffered by the phenomenon of resistance was based on the fact that was targeting normal vessels rather than tumour cells prone to mutation and subject to drug induced selection.However,reality turned out to be more complex and since 1997,several mechanisms of resistance have been described to the point that the study of resistance to these drugs is now a very large field.Far from being exhaustive,this paper presents the main mechanisms discovered trough some examples.
文摘Cancer is a group of diseases with significant morbidity and mortality.In cancer cells,where energy requirements are exceptionally high,angiogenesis,which is the sprouting of new blood vessels from pre-existing ones,is an important process for tumour survival and progression.Hence,extensive research in recent years focuses on the discovery of new anticancer drugs that target angiogenesis.Several methodologies have been developed preclinically,including the inhibition of pro-angiogenic factors and their receptors via micromolecular agents or monoclonal antibodies and the inhibition of other compensatory pathways beyond the traditional angiogenic ones.The purpose of the literature review is to present new anticancer drugs that target the process of angiogenesis and have been under preclinical or clinical investigation during the last five years.Many new anticancer drugs targeting angiogenesis are identified in the literature.The results of the in vitro and in vivo evaluation of these drugs show that,apart from inhibiting angiogenesis,they also affect cancer cell proliferation and tumour growth.Recent clinical studies show that these drugs increase the overall or disease-free survival of patients,even those with persistent,chemotherapy-resistant and metastatic types of cancer,although treatment-related side effects are not uncommon.Drugs that target the process of angiogenesis are likely to be the future of anticancer therapy,especially in cases where more traditional treatments do not produce the desired results and where combination regimens of anti-angiogenic agents with standard chemotherapeutics increase patient survival.
基金supported by grants SAF2009-07035,SAF2012-31613,SAF2015-69180-R,PI060400,RD06/0020/0011,RD12/0036/0061(to García-Pardo A)and SAF2017-86327-R(to Redondo-Muñoz J)from the Ministerio de Ciencia e Innovacion-Fondo Europeo de Desarrollo Regional(FEDER),MadridP2010/BMD-2314 from the Comunidad de Madrid/European Union(to García-Pardo A)+1 种基金the Fundación de Investigación Mutua Madrileña(to García-Pardo A)the 2020 Leonardo Grant for Researchers and Cultural Creators(BBVA Foundation)(to Redondo-Muñoz J).
文摘Progression of chronic lymphocytic leukemia(CLL)is determined by the localization of malignant cells in lymphoid tissues,where they receive growth and survival signals.CLL cells produce angiogenic factors that are regulated by internal and external stimuli and whose levels vary according to the clinical stage of the disease.Stromal cellular and molecular components in CLL niches disturb the balance of pro-and antiangiogenic molecules in CLL cells and induce an angiogenic switch.Additionally,CLL cells also influence the behavior of microenvironmental cells,inducing endothelial cell proliferation and increasing the angiogenic capacity of macrophages,neutrophils,and other cells present in CLL niches.As a result of these reciprocal functional interactions,bone marrow angiogenesis is frequently increased in CLL and has been proposed as a prognostic marker in early disease.Besides their role in regulating angiogenesis,angiogenic factors are also involved in CLL cell migration and survival,all contributing to disease progression.Angiogenic factors,particularly vascular endothelial growth factor,have therefore been attractive therapeutic targets in CLL and many clinical trials were established in the past years.However,the results of these trials reveal that anti-angiogenic therapies alone are not as efficient as expected and should rather be used in combination with other treatments.
基金supported by NIH grants,R01DE025885(E.S),R15EY029504(VAK)National Science Foundation NSF IIP 1903617(VAK).
文摘The dental pulp has irreplaceable roles in maintaining healthy teeth and its regeneration is a primary aim of regenerative endodontics.This study aimed to replicate the characteristics of dental pulp tissue by using cranial neural crest(CNC)-like cells(CNCLCs);these cells were generated by modifying several steps of a previously established method for deriving NC-like cells from induced pluripotent stem cells(iPSCs).CNC is the anterior region of the neural crest in vertebrate embryos,which contains the primordium of dental pulp cells or odontoblasts.The produced CNCLCs showed approximately 2.5-12,000-fold upregulations of major CNC marker genes.Furthermore,the CNCLCs exhibited remarkable odontoblastic differentiation ability,especially when treated with a combination of the fibroblast growth factors(FGFs)FGF4 and FGF9.The FGFs induced odontoblast marker genes by 1.7-5.0-fold,as compared to bone morphogenetic protein 4(BMP4)treatment.In a mouse subcutaneous implant model,the CNCLCs briefly fated with FGF4+FGF9 replicated dental pulp tissue characteristics,such as harboring odontoblast-like cells,a dentin-like layer,and vast neovascularization,induced by the angiogenic self-assembling peptide hydrogel(SAPH),SLan.SLan acts as a versatile biocompatible scaffold in the canal space.This study demonstrated a successful collaboration between regenerative medicine and SAPH technology.
文摘Angiogenesis plays a crucial role in wound healing by forming new blood vessels from preexisting vessels by invading the wound clot and organizing into a microvascular network throughout the granulation tissue.This dynamic process is highly regulated by signals from both serum and the surrounding extracellular matrix environment.Vascular endothelial growth factor,angiopoietin,fibroblast growth factor and transforming growth factor-beta are among the potent angiogenic cytokines in wound angiogenesis.Specific endothelial cell ECM receptors are critical for morphogenetic changes in blood vessels during wound repair.In particular integrin(αvβ3)receptors for fibrin and fibronectin,appear to be required for wound angiogenesis:αvβ3 is focally expressed at the tips of angiogenic capillary sprouts invading the wound clot,and any functional inhibitors ofαvβ3 such as monoclonal antibodies,cyclic RGD peptide antagonists,and peptidomimetics rapidly inhibit granulation tissue formation.In spite of clear knowledge about influence of many angiogenic factors on wound healing,little progress has been made in defining the source of these factors,the regulatory events involved in wound angiogenesis and in the clinical use of angiogenic stimulants to promote repair.
文摘Prolyl oligopeptidase (POP) is a cytosolic enzyme involved in the metabolism of many peptide hormones and neuropeptides (1). It was recently reported that POP is responsible
文摘Gastric cancer(GC)is the second leading cause of cancer-related death.The poor survival rate may reflect the relatively aggressive tumor biology of GC.Recently,the importance of the tumor microenvironment in carcinogenesis has emerged.In the tumor microenvironment,tumor cells and the surrounding stromal cells aberrantly secrete matricellular proteins capable of modulating carcinogenesis and regulating metastasis.The Cyr61/CTGF/Nov(CCN)proteins are a family of matricellular proteins with variable roles in many physiological and pathological processes.The evidence suggests that CCN family proteins contribute to GC carcinogenic processes.Here,we briefly review recent research on the effects of CCN family proteins in GC carcinogenesis and the development of new targeted agents in this field.
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.
基金Supported by Grants from the Ministry of Education, Science, Sports and Culture of Japan and the Japan Society for the Promotion of Sciencethe Practical Application Research program of Japan Science and Technology Agency Innovation plaza Ishi-kawa
文摘Sphingosine-1-phosphate (S1P) is a blood-borne lipid mediator with pleiotropic biological activities. S1P acts via the specific cell surface G-protein-coupled receptors, S1P1-5. S1P1 and S1P2 were originally identified from vascular endothelial cells (ECs) and smooth muscle cells, respectively. Emerging evidence shows that S1P plays crucial roles in the regulation of vascular functions, including vascular formation, barrier protection and vascular tone via S1P1, S1P2 and S1P3. In particular, S1P regulates vascular formation through multiple mechanisms; S1P exerts both positive and negative effects on angiogenesis and vascular maturation. The positive and negative effects of S1P are mediated by S1P1 and S1P2, respectively. These effects of S1P1 and S1P2 are probably mediated by the S1P receptors expressed in multiple cell types including ECs and bone-marrow-derived cells. The receptor-subtype-specific, distinct effects ofS1P favor the development of novel therapeutic tactics for antitumor angiogenesis in cancer and therapeutic angiogenesis in ischemic diseases.
基金Supported by a grant from 2004 Shenzhen Technological Plan( code:200405097)
文摘Purpose: To examine the effect of an intravitreal injection of angiostatin on vascular leakage in retina and iris of the diabetes and study its possible mechanism. Methods: Experimental diabetes was induced in 24 rats by an intravenous injection of streptozotocin (STZ) during 48 adult rats. Three groups were randomization distributed of them. There were 8 of both normal and diabetic rats in each group. STZ-diabetic rats and age-matched normal rats received an intravitreal injection of 5 μl of sterile PBS (Phosphate Buffered Saline) into the right eye, and the left eye was non-injected in the group A; Angiostatin was injected into the vitreous of the right eye (7.5 μg / 5 μl / eye), and the left eye received the same volume of sterile PBS as the control in the group B and C. The vascular permeability of retina and iris was measured using the Evans blue method at 2 days following the injection in the group A and B. Expression of VEGF in retina was evaluated using western blot analysis 24 hours following the injection in the group C. Results: Diabetic rats showed significant increases of vascular permeability in the retina ( P < 0.01) and iris ( P < 0.05). Angiostatin-injected eyes showed significant decreases in vascular permeability in the retina ( P < 0.01) and iris ( P < 0.05) comparing with the PBS-injected eyes in STZ-diabetic rats. In contrast, intravitreal injection of the same dose of angiostatin into the age-matched normal rats did not result in any significant reduction in vascular permeability in the retina and iris, when compared with the contralateral eye with PBS injection ( P > 0.05). Angiostatin injection significantly reduced VEGF level in the retinas of STZ-diabetic rats but did not affect retinal VEGF level in normal rats. Conclusions: Angiostatin significantly reduce pathological vascular permeability in the retina and iris of STZ-diabetic rats but not in normal rats. Angiostatin down-regulates VEGF expression and thus, blocks the major cause of vascular leakage in the diabetic retina. Therefore, angiostatin may have a therapeutic potential in the treatment of diabetic macular edema, cystoid macular edema, uvietis and other diseases with vascular leakage.
文摘Objective: To investigate the expression ofangiogenic factors, basic fibroblast growth factor (bFGF)and transforming growth factor (TGF)-β1 inosteosarcoma, its association with neovascularizationand prognosis. Methods: The expression of bFGF, TGFβ1 and their receptors, as well as intratumoralmicrovcssel count (MVD) were studied in 80osteosarcomas by immunohistochemical staining andmorphometry. The relationship between the angiogenicfactors expression and prognosis was evaluated by amultivariate analysis using Cox proportion hazardmodel. Results: Among 80 cases of osteosarcoma, 46cases were positive for bFGFlbFGFr (57.5%), and 31cases for TGF-β1/ TGF-β (RI)(38.8%) respectively. TheMVD and bFGF, TGF-β1, were important indicators topredict the prognosis of patients with osteosarconla bythe Cox proportion hazard model analysis. Conclusioll:The angiogenic factors bFGF and TGF-β1 are involvedin the angiogenesis of osteosarcoma, and theangiogenesis inf’luences the prognosis. Also they may beuseful in the evaluation of the prognosis of patients withosteosarcoma.
基金supported by grants from the National Natural Science Foundation of China(No.81600449)the Nantong Science and Technology Bureau(No.MS22018007 and No.MSZ18130)+2 种基金Six Peak Talents in Jiangsu Province(No.YY-177)the Project of Jiangsu Province Youth Medical Talent Development(No.QNRC2016400)the Project of Nantong Youth Medical Talent Development(No.05).
文摘Objective:Primary biliary cholangitis(PBC)is a chronic progressive cholestatic liver disease.In recent years,researchers have found that cysteine-rich angiogenic inducer 61(Cyr61,also known as CCN1)has a potential role in reducing portal inflammation in patients with PBC.This study aimed to explore the relationship between Cyr61 and PBC to provide new ideas and an experimental basis for the clinical treatment of PBC.Methods:After induction of the overexpression of Cyr61 in a mouse model of PBC using recombinant adenovirus,hematoxylin and eosin staining and pathological scores were used to indicate intrahepatic inflammation and bile duct damage.Real-time PCR was used to detect changes in inflammation-related cytokines in the liver.To further study the mechanism,we assessed whether Cyr61 protects bile duct epithelial cells from cytotoxic effects.Results:Serum and hepatic Cyr61 levels were increased in the murine model of PBC.Overexpression of Cyr61 alleviated hepatic inflammation and bile duct injury in vivo.Cyr61 inhibited the cytotoxic effects of CD8^(+)T cells by acting on biliary epithelial cells(BECs)in vitro.Conclusion:Our results provide novel insight into the pathogenesis of PBC and suggest that Cyr61 plays a dominant role in the cytotoxic effects on BECs in PBC.Consequently,therapeutic strategies targeting Cyr61 could be a potent therapy for PBC.
