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Journal of Ethnopharmacology Apr 2021Normalization of the tumor vasculature can enhance tumor perfusion and the microenvironment, leading to chemotherapy potentiation. Shenmai injection (SMI) is a widely... (Randomized Controlled Trial)
Randomized Controlled Trial
ETHNOPHARMACOLOGICAL RELEVANCE
Normalization of the tumor vasculature can enhance tumor perfusion and the microenvironment, leading to chemotherapy potentiation. Shenmai injection (SMI) is a widely used traditional Chinese herbal medicine for the combination treatment of cancer in China.
AIM OF THIS STUDY
This study aimed to investigate whether SMI can regulate tumor vasculature to improve chemotherapy efficacy and identify the underlying mechanism.
MATERIALS AND METHODS
The antitumor effect of SMI combined with 5-florouracil (5-FU) was investigated in xenograft tumor mice. Two-photon microscopy, laser speckle contrast imaging and immunofluorescence staining were used to investigate the effects of SMI on tumor vasculature in vivo. The mRNA and protein expression of pro- and anti-angiogenic factors were measured by Q-PCR and ELISA. Histone acetylation and transcriptional regulation were detected by Western blot and ChIP assay.
RESULTS
SMI promoted normalization of tumor microvessels within a certain time window, which was accompanied by enhanced blood perfusion and 5-FU distribution in tumors. SMI significantly increased the expression of antiangiogenic factor angiostatin and decreased the pro-angiogenic factors VEGF, FGF and PAI-1 by day 10. SMI combined with neoadjuvant chemotherapy in colorectal cancer patients also showed a significant increase in angiostatin and decrease in VEGF and FGF in surgically resected tumors when compared to the neoadjuvant chemotherapy group. Further in vitro and in vivo studies revealed that SMI downregulated VEGF, FGF and PAI-1 mRNA expression by inhibiting histone H3 acetylation at the promoter regions. The enhanced production of angiostatin was attributed to the regulation of the plasminogen proteolysis system via SMI-induced PAI-1 inhibition.
CONCLUSION
SMI can remodel the homeostasis of pro- and anti-angiogenic factors to promote tumor vessel normalization, and thus enhance drug delivery and anti-tumor effect. This study provides additional insights into the pharmacological mechanisms of SMI on tumors from the perspective of vascular regulation.
Topics: Angiogenesis Inhibitors; Angiostatins; Animals; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Combined Modality Therapy; Drug Combinations; Drugs, Chinese Herbal; Fluorouracil; Histones; Homeostasis; Human Umbilical Vein Endothelial Cells; Humans; Male; Mice, Inbred BALB C; Mice, Nude; Neovascularization, Pathologic; Plasminogen Activator Inhibitor 1; Receptors, Fibroblast Growth Factor; Treatment Outcome; Tumor Microenvironment; Vascular Endothelial Growth Factor A; Xenograft Model Antitumor Assays; Mice
PubMed: 33388426
DOI: 10.1016/j.jep.2020.113770 -
Turkish Journal of Medical Sciences Dec 2018The clinical effect of angiostatin in diabetes mellitus (DM) patients receiving insulin is a meaningful gap in the literature. In this study, we aimed to show the levels...
BACKGROUND/AIM
The clinical effect of angiostatin in diabetes mellitus (DM) patients receiving insulin is a meaningful gap in the literature. In this study, we aimed to show the levels and the clinical significance of angiostatin in DM patients receiving insulin.
MATERIALS AND METHODS
This is a case-control study. Serum angiostatin levels were determined by ELISA. A total of 83 people consisting of healthy subjects (n = 36) and patients with a diagnosis of DM receiving insulin therapy (n = 47) were included in this study.
RESULTS
The mean angiostatin levels of the DM group were significantly higher than those of the control group (86.0 ± 68.1 ng/mL and 58.0 ± 22.4 ng/mL, respectively; P = 0.011). Significantly lower angiostatin levels were determined in the DM patients receiving metformin with respect to those not receiving metformin (97.2 ± 74.4 ng/mL and 49.3 ± 7.0 ng/mL, respectively; P = 0.021). Significantly higher levels of angiostatin were observed among the DM patients using a beta-blocker (BB) than the DM patients not using a BB (115.5 ± 78.71 ng/mL and 73.44 ± 60.08 ng/mL, respectively; p = 0.029).
CONCLUSION
This is the first study evaluating and demonstrating the serum angiostatin levels in DM patients receiving insulin. Further studies are required to understand the effect of angiostatin in diabetics and the effect of medications on angiogenesis in these patients.
PubMed: 30541246
DOI: 10.3906/sag-1802-130 -
Journal of Nanobiotechnology Apr 2024Early-onset bone dysplasia is a common manifestation of hypophosphatasia (HPP), an autosomal inherited disease caused by ALPL mutation. ALPL ablation induces...
BACKGROUND
Early-onset bone dysplasia is a common manifestation of hypophosphatasia (HPP), an autosomal inherited disease caused by ALPL mutation. ALPL ablation induces prototypical premature bone ageing characteristics, resulting in impaired osteogenic differentiation capacity of human bone marrow mesenchymal stem cells (hBMMSCs). As angiogenesis is tightly coupled with osteogenesis, it also plays a necessary role in sustaining bone homeostasis. We have previously observed a decrease in expression of angiogenesis marker gene CD31 in the metaphysis of long bone in Alpl mice. However, the role of ALPL in regulation of angiogenesis in bone has remained largely unknown.
METHODS
Exosomes derived from Normal and HPP hBMMSCs were isolated and identified by ultracentrifugation, transmission electron microscopy, and nanoparticle size measurement. The effects of ALPL on the angiogenic capacity of hBMMSCs from HPP patients were assessed by immunofluorescence, tube formation, wound healing and migration assay. exo-ELISA and Western Blot were used to evaluate the exosomes secretion of hBMMSCs from HPP, and the protein expression of VEGF, PDGFBB, Angiostatin and Endostatin in exosomes respectively.
RESULTS
We verified that ALPL ablation resulted in impaired pro-angiogenic capacity of hBMMSCs, accounting for reduced migration and tube formation of human umbilical vein endothelial cells, as the quantities and proteins composition of exosomes varied with ALPL expression. Mechanistically, loss of function of ALPL enhanced ATP release. Additional ATP, in turn, led to markedly elevated level of ATP receptor P2X7, which consequently promoted exosomes secretion, resulting in a decreased capacity to promote angiogenesis. Conversely, inhibition of P2X7 increased the angiogenic induction capacity by preventing excessive release of anti-angiogenic exosomes in ALPL deficient-hBMMSCs.
CONCLUSION
The ALPL-ATP axis regulates the pro-angiogenic ability of hBMMSCs by controlling exosomes secretion through the P2X7 receptor. Thus, P2X7 may be proved as an effective therapeutic target for accelerating neovascularization in ALPL-deficient bone defects.
Topics: Humans; Animals; Mice; Endothelial Cells; Exosomes; Osteogenesis; Mesenchymal Stem Cells; Adenosine Triphosphate; Alkaline Phosphatase
PubMed: 38609899
DOI: 10.1186/s12951-024-02396-6 -
Urology Journal May 2019The novel biomarkers that would identify patients at risk for relapse and metastatic spread are needed. The aim of this study was the evaluation of serum levels of...
PURPOSE
The novel biomarkers that would identify patients at risk for relapse and metastatic spread are needed. The aim of this study was the evaluation of serum levels of osteopontin (OPN) and tumor endogenous angiogenic factors such as vascular-endothelial growth factor (VEGF), vascular-endothelial growth factor receptor 2 (VEGF R2), endostatin, angiostatin and thrombospondin 1, in prostate cancer (PC) patients.
MATERIAL AND METHODS
Blood concentrations of the analyzed parameters were determined in 40 prostate cancer patients eligible for radiotherapy as well as in the control group consisted of 25 volunteers. Commercial ELISA kits were used for the analysis.
RESULTS
Significantly higher levels of OPN (101.49 ng/mL vs 59.88 ng/mL; P<.001), endostatin (252.60 ng/mL vs. 223.55 ng/mL; P=.043), angiostatin (47 ng/mL vs. 13 ng/mL; P=.047), VEGF (262.1 pg/mL vs. 138.0 pg/mL; P=.056) and VEGF R2 (11188.81 pg/mL vs. 9377.50 pg/mL; P=.047) were detected in PC patients compared with the control group. In PC patients we showed a positive correlation between OPN level and TNM clinical stage(R=0.36; P=.02) and negative correlation between OPN level and hemoglobin concentration (R=-0.33; P=.04).
CONCLUSION
The study showed higher levels of the angiogenic factors in PC patients compared with the control group and identified OPN as an indicator of the PC clinical stage as well as a decreased hemoglobin level.
Topics: Aged; Aged, 80 and over; Angiogenic Proteins; Biomarkers, Tumor; Humans; Male; Middle Aged; Osteopontin; Prostatic Neoplasms
PubMed: 30178447
DOI: 10.22037/uj.v0i0.4282 -
The American Journal of Pathology Nov 2016Integrins are transmembrane receptors composed of one α subunit and one β subunit and are involved in cellular growth, differentiation, and apoptosis. The...
Integrins are transmembrane receptors composed of one α subunit and one β subunit and are involved in cellular growth, differentiation, and apoptosis. The collagen-binding integrins α1β1 and α2β1 have been shown to regulate wound and tumor vascularization by different mechanisms. In this study, we assessed wound and tumor vascularization in mice with genetic ablation of both integrin subunits α1 and α2, which resulted in loss of integrins α1β1 and α2β1. Wound angiogenesis was investigated in excisional wounds that were inflicted on the back skin of control and mice lacking integrin α1β1 and α2β1. Mutant mice displayed reduced wound angiogenesis, which correlated with decreased macrophage numbers at 3 and 7 days after injury, and showed significantly attenuated vascularization of sponge implants. Angiogenesis induced by tumors arising from intradermal injection of B16 F1 melanoma cells was also reduced in comparison to controls 7 days after injection. This reduction in angiogenesis correlated with increased levels and activity of circulating matrix metalloproteinase 9 and elevated angiostatin levels in plasma of mutant mice, which reduced endothelial cell proliferation. Ex vivo mutant aortic ring explants developed significantly fewer and thinner aortic sprouts with fewer branch points than controls because of impaired endothelial cell proliferation. In conclusion, the loss of integrins α1β1 and α2β1 in mice results in reduced wound and tumor angiogenesis by cell-autonomous and extrinsic mechanisms.
Topics: Animals; Disease Models, Animal; Female; Fibroblasts; Humans; Integrin alpha1beta1; Integrin alpha2beta1; Melanoma; Mice; Mice, Inbred C57BL; Mice, Knockout; Neoplasms; Neovascularization, Pathologic; Skin; Skin Neoplasms; Wound Healing; Wounds and Injuries
PubMed: 27639165
DOI: 10.1016/j.ajpath.2016.06.021 -
Metabolic Brain Disease Dec 2021Vascular endothelial growth factor (VEGF) regulates angio/neurogenesis and also tightly links to the pathogenesis of Alzheimer's disease (AD). Although exercise has a...
Vascular endothelial growth factor (VEGF) regulates angio/neurogenesis and also tightly links to the pathogenesis of Alzheimer's disease (AD). Although exercise has a beneficial effect on neurovascular function and cognitive function, the direct effect of exercise on VEGF-related signaling and cognitive deficit in AD is incompletely understood. Therefore, the purpose of this study was to investigate the protective effect of exercise on angiostatin/VEGF cascade and cognitive function in AD model rats. Wistar male rats were randomly divided into five groups: control (CON), injection of DMSO (Sham-CON), CON-exercise (sham-EX), intrahippocampal injection of Aβ (Aβ), and Aβ-exercise (Aβ-EX). Rats in EX groups underwent treadmill exercise for 4 weeks, then the cognitive function was measured by the Morris Water Maze (MWM) test. mRNA levels of hypoxia-induced factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor 2 (VEGFR2), and angiostatin were determined in hippocampus by RT-PCR. We found that spatial learning and memory were impaired in Aβ-injected rats, but exercise training improved it. Moreover, exercise training increased the reduced mRNA expression level of VEGF signaling, including HIF1α, VEGF, and VEGFR2 in the hippocampus from Aβ-injected rats. Also, the mRNA expression level of angiostatin was elevated in the hippocampus from Aβ-injected rats, and exercise training abrogated its expression. Our findings suggest that exercise training improves cognitive function in Aβ-injected rats, possibly through enhancing VEGF signaling and reducing angiostatin.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Angiostatins; Animals; Cognitive Dysfunction; Disease Models, Animal; Hippocampus; Male; Maze Learning; Rats; Rats, Wistar; Vascular Endothelial Growth Factor A
PubMed: 34003412
DOI: 10.1007/s11011-021-00751-2 -
Circulation Research Sep 2016
Review
Topics: Angiogenesis Inhibitors; Animals; Humans; Neoplasms; Neovascularization, Pathologic; Tumor Microenvironment
PubMed: 27587409
DOI: 10.1161/CIRCRESAHA.116.309411 -
BMC Nephrology Apr 2019This study aimed to evaluate the value of urinary angiostatin levels for assessing disease severity and progression of IgA nephropathy (IgAN).
BACKGROUND
This study aimed to evaluate the value of urinary angiostatin levels for assessing disease severity and progression of IgA nephropathy (IgAN).
METHODS
Urinary angiostatin was identified as one of the distinct proteins in samples of patients with IgAN analyzed by Raybiotech protein array, and further confirmed by enzyme-linked immunosorbent assay (ELISA).
RESULTS
Urinary angiostatin levels were significantly higher in IgAN patients than that in healthy controls (HC) subjects and lower than in disease controls (DC) patients. The concentrations of angiostatin in urine normalized to urinary creatinine (angiostatin/Cr) were positively associated with proteinuria level. With advancing chronic kidney disease (CKD) stage, urinary angiostatin/Cr levels were gradually increased. Urinary angiostatin/Cr levels in patients with Lee's grade IV-V were significantly higher than those in Lee's grade I-II and III. We further compared urinary angiostatin/Cr levels by using Oxford classification and found the expression in patients with mesangial proliferative score 1(M1) was significantly higher than that in M0 (P < 0.001). In addition, the levels of urinary angiostatin/Cr in patients with tubular atrophy/interstitial fibrosis score 1(T1) and T2 were significantly higher than those in T0 (P < 0.01, P < 0.001, respectively). After follow-up, renal survival was significantly worse in patients with higher levels of urinary angiostatin (P < 0.05).
CONCLUSIONS
Urinary angiostatin may be a useful novel noninvasive biomarker to evaluate disease severity and progression of IgAN.
Topics: Adult; Angiostatins; Biomarkers; Creatinine; Disease Progression; Female; Glomerulonephritis, IGA; Humans; Kidney Function Tests; Male; Proteinuria; Reproducibility of Results; Severity of Illness Index; Urinalysis
PubMed: 30943905
DOI: 10.1186/s12882-019-1305-2 -
Cancer Genomics & Proteomics 2024Transcriptional factor prospero homeobox-1 (PROX-1) is crucial for the embryonic development of various organs and cell fate specification. It exhibits either an...
BACKGROUND/AIM
Transcriptional factor prospero homeobox-1 (PROX-1) is crucial for the embryonic development of various organs and cell fate specification. It exhibits either an oncogenic or tumor suppressive activity depending on cancer types. However, the relationship between PROX-1 and hepatocellular carcinoma (HCC) remains obscure. This study was conducted to investigate the effect of PROX-1 on the invasive and oncogenic phenotypes of human HCC cells.
MATERIALS AND METHODS
The effect of PROX-1 on tumor cell behavior was investigated by using a pcDNA-myc vector and a small interfering RNA in HepG2 and Huh7 human HCC cell lines. Flow cytometry, migration, invasion, proliferation, and tube formation assays were performed. PROX-1 expression in human HCC cells was explored by western blotting.
RESULTS
PROX-1 overexpression enhanced tumor cell proliferation and inhibited apoptosis and cell cycle arrest by modulating the activities of caspase-3, PARP, and cyclin-dependent kinase inhibitors, including p21, p27, and p57 in HCC cells. After PROX-1 overexpression, the number of migrating and invading HCC cells significantly increased, and the expression levels of N-cadherin and Snail increased in HCC cells. PROX-1 overexpression enhanced angiogenesis through increased VEGF-A and VEGF-C expression and decreased angiostatin expression. PROX-1 overexpression also increased the phosphorylation of glycogen synthase kinase-3β (GSK-3β) and forkhead box O1 (FOXO1) in HCC cells. After PROX-1 knockdown, their phosphorylation was reversed.
CONCLUSION
PROX-1 overexpression is associated with the invasive and oncogenic phenotypes of human HCC cells via GSK-3β and FOXO1 phosphorylation.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Homeodomain Proteins; Cell Proliferation; Tumor Suppressor Proteins; Apoptosis; Phenotype; Cell Movement; Cell Line, Tumor; Gene Expression Regulation, Neoplastic
PubMed: 38670585
DOI: 10.21873/cgp.20448 -
Cancers Nov 2023The present study develops a numerical model, which is the most complex one, in comparison to previous research to investigate drug delivery accompanied by the...
The present study develops a numerical model, which is the most complex one, in comparison to previous research to investigate drug delivery accompanied by the anti-angiogenesis effect. This paper simulates intravascular blood flow and interstitial fluid flow using a dynamic model. The model accounts for the non-Newtonian behavior of blood and incorporates the adaptation of the diameter of a heterogeneous microvascular network derived from modeling the evolution of endothelial cells toward a circular tumor sprouting from two-parent vessels, with and without imposing the inhibitory effect of angiostatin on a modified discrete angiogenesis model. The average solute exposure and its uniformity in solid tumors of different sizes are studied by numerically solving the convection-diffusion equation. Three different methodologies are considered for simulating anti-angiogenesis: modifying the capillary network, updating the transport properties, and considering both microvasculature and transport properties modifications. It is shown that anti-angiogenic therapy decreases drug wash-out in the periphery of the tumor. Results show the decisive role of microvascular structure, particularly its distribution, and interstitial transport properties modifications induced via vascular normalization on the quality of drug delivery, such that it is improved by 39% in uniformity by the second approach in R = 0.2 cm.
PubMed: 38001724
DOI: 10.3390/cancers15225464