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Scientific Reports Feb 2023Although several angiogenesis-related factors are reportedly involved in the pathogenesis of ulcerative colitis (UC), the mechanisms by which they contribute to disease...
Although several angiogenesis-related factors are reportedly involved in the pathogenesis of ulcerative colitis (UC), the mechanisms by which they contribute to disease are unclear. We first examined the expression of angiogenesis-related factors in inflamed colorectal tissue of UC patients using antibody array, and identified the 5 factors with highest expression, which included matrix metalloproteinase-8, urokinase-type plasminogen activator (uPA), angiostatin/plasminogen, hepatocyte growth factor and endoglin. Subsequent real-time PCR experiments using additional colorectal tissues revealed that uPA mRNA levels were significantly higher in inflamed tissues than in non-inflamed tissues, and significantly correlated with the severity of UC. Mirror section immunohistochemistry revealed that uPA was expressed in the neutrophils of inflamed colorectal tissues. We administered dextran sulfate sodium (DSS) in drinking water to uPA knockout (uPA) mice, and found that the disease activity index in uPA mice was marginally lower and the histological score in uPA mice was significantly lower than those in wild-type mice, suggesting the importance of uPA in colitis. When an uPA-selective inhibitor, UK122, was administered to DSS-treated C57BL6J mice, the disease activity index and histological score in those mice were significantly lower compared with control mice. Multiple cytokine/chemokine assay using colorectal tissues from uPA and UK122-treated mice revealed significantly lowered level of RANTES. In conclusion, uPA was highly expressed in neutrophils of the inflamed mucosa of UC patients, and the expression level correlated with the severity of UC. Genetic uPA deletion or pharmacological uPA blockade significantly ameliorated colitis in mice, concomitant with downregulation of RANTES.
Topics: Animals; Mice; Urokinase-Type Plasminogen Activator; Colitis; Colitis, Ulcerative; Serine Proteases; Colorectal Neoplasms
PubMed: 36806262
DOI: 10.1038/s41598-023-29824-1 -
Clinical and Experimental Rheumatology 2016To determine the concentrations of circulating endostatin and angiostatin in patients with systemic sclerosis (SSc) and to assess its relationship to disease subsets,... (Comparative Study)
Comparative Study
OBJECTIVES
To determine the concentrations of circulating endostatin and angiostatin in patients with systemic sclerosis (SSc) and to assess its relationship to disease subsets, evolution phase, organ involvement and nailfold capillaroscopic changes.
METHODS
Endostatin and angiostatin serum levels were measured by ELISA in a cohort of 57 patients with SSc, and correlated with disease subsets, evolution phase, organ involvement and nailfold capillaroscopic changes.
RESULTS
Endostatin and angiostatin serum levels were significantly higher in patients with SSc than in healthy controls. Also, angiostatin was elevated in diffuse cutaneous SSc (dcSSc) and limited cutaneous SSc (lcSSc), but not in pre-SSc, while endostatin was increased in all SSc subsets. Moreover, endostatin was augmented in lcSSc, with or without CREST syndrome, whereas angiostatin was increased exclusively in patients with CREST. Analysis according to disease evolution phase found that endostatin was elevated in all phases while angiostatin was only significantly higher in intermediate and late phases of disease. Analysis regarding organ involvement revealed that angiostatin was significantly higher in patients with osteoarticular involvement and with more serious lung affection; no significant differences were found for endostatin. Finally, endostatin was significantly increased in all nailfold capillaroscopy stages, while angiostatin was only elevated in active and late phases.
CONCLUSIONS
In accordance with previous studies, we found that endostatin and angiostatin concentrations are elevated in SSc patients. Additionally, we recognised the important role that endostatin might play as an early disease marker and realized that angiostatin is a marker of late disease and relates to lung disease severity.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Angiostatins; Biomarkers; CREST Syndrome; Case-Control Studies; Cohort Studies; Disease Progression; Early Diagnosis; Endostatins; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Microscopic Angioscopy; Middle Aged; Neovascularization, Pathologic; Predictive Value of Tests; Scleroderma, Diffuse; Scleroderma, Limited; Severity of Illness Index; Signal Transduction; Skin; Up-Regulation; Young Adult
PubMed: 26885625
DOI: No ID Found -
American Journal of Respiratory Cell... Dec 2014Macrophage elastase (MMP12) is a key mediator of cigarette smoke (CS)-induced emphysema, yet its role in other smoking related pathologies remains unclear. The weight...
Macrophage elastase (MMP12) is a key mediator of cigarette smoke (CS)-induced emphysema, yet its role in other smoking related pathologies remains unclear. The weight suppressing effects of smoking are a major hindrance to cessation efforts, and MMP12 is known to suppress the vascularization on which adipose tissue growth depends by catalyzing the formation of antiangiogenic peptides endostatin and angiostatin. The goal of this study was to determine the role of MMP12 in adipose tissue growth and smoking-related suppression of weight gain. Whole body weights and white adipose depots from wild-type and Mmp12-deficient mice were collected during early postnatal development and after chronic CS exposure. Adipose tissue specimens were analyzed for angiogenic and adipocytic markers and for content of the antiangiogenic peptides endostatin and angiostatin. Cultured 3T3-L1 adipocytes were treated with adipose tissue homogenate to examine its effects on vascular endothelial growth factor (VEGF) expression and secretion. MMP12 content and activity were increased in the adipose tissue of wild-type mice at 2 weeks of age, leading to elevated endostatin production, inhibition of VEGF secretion, and decreased adipose tissue vascularity. By 8 weeks of age, adipose MMP12 levels subsided, and the protein was no longer detectable. However, chronic CS exposure led to macrophage accumulation and restored adipose MMP12 activity, thereby suppressing adipose tissue mass and vascularity. Our results reveal a novel systemic role for MMP12 in postnatal adipose tissue expansion and smoking-associated weight loss by suppressing vascularity within the white adipose tissue depots.
Topics: 3T3-L1 Cells; Adipose Tissue, White; Adiposity; Animals; Body Weight; Endostatins; Macrophages; Matrix Metalloproteinase 12; Mice; Mice, Inbred C57BL; Mice, Knockout; Smoking; Vascular Endothelial Growth Factor A
PubMed: 24914890
DOI: 10.1165/rcmb.2014-0083OC -
Neoplasma Feb 2023Zerumbone had been verified as a potential anti-cancer agent. Our research aimed to investigate the effect of zerumbone combined with gefitinib in lung cancer. Human...
Zerumbone had been verified as a potential anti-cancer agent. Our research aimed to investigate the effect of zerumbone combined with gefitinib in lung cancer. Human pulmonary alveolar epithelial cells (HPAEpiC), A549, and H460 cell lines were used to detect the efficacy of zerumbone. BALB/c nude mice were randomly divided into five groups, including model, gefitinib (Gef, 10 mg/kg), low dose zerumbone (L-Zer, 20 mg/kg), high dose zerumbone (H-Zer, 40 mg/kg), and H-Zer + Gef groups, and the tumor growth in each group was monitored. TdT-mediated dUTP Nick-End Labeling (TUNEL) was used to detect cell apoptosis. Immunohistochemistry (IHC), immunofluorescence, and western blot were used to analyze the protein expressions in tumor tissues. Glutathione (GSH) and malondialdehyde (MAD) were detected by special kits. Zerumbone inhibited the proliferation of lung cancer cells in vitro. Tumor volume and weight were reduced after gefitinib or zerumbone treatment. Gefitinib and zerumbone treatment significantly promoted the apoptosis of tumor cells. The expression of Bcl-2, Bax, and P53 proteins confirmed cell apoptosis. IHC results indicated that zerumbone and gefitinib treatment decreased tumor angiogenesis. Consistent with this result, the expression of EGFR, VEGFR2, and Ki-67 proteins decreased, while the expression of angiostatin and endostatin proteins increased. Interestingly, zerumbone treatment increased the level of MDA while decreasing GSH. Next, the levels of glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11) decreased after zerumbone and gefitinib treatment. Our study suggested that zerumbone combined with gefitinib could effectively inhibit lung cancer for multi-model therapies, including the inhibition of tumor growth, angiogenesis, induce cell apoptosis, and ferroptosis.
Topics: Animals; Humans; Mice; Amino Acid Transport System y+; Apoptosis; Cell Line, Tumor; Cell Proliferation; Gefitinib; Lung Neoplasms; Mice, Nude; Proto-Oncogene Proteins c-akt; STAT3 Transcription Factor
PubMed: 36637083
DOI: 10.4149/neo_2022_220418N423 -
PloS One 2018Neoangiogenesis is a crucial event to promote the development of the hyperplasic proliferative pathologic synovium in Rheumatoid arthritis (RA). Ultrasound (US) is...
BACKGROUND
Neoangiogenesis is a crucial event to promote the development of the hyperplasic proliferative pathologic synovium in Rheumatoid arthritis (RA). Ultrasound (US) is sensitive for detection of power Doppler (PD) vascularization.
OBJECTIVE
To explore the associations between a set of complementary circulating angiogenic markers and a comprehensive US assessment in patients with RA.
PATIENTS AND METHODS
Serum levels of eight angiogenic markers were measured by quantitative ELISAs in a total of 125 patients with RA, who were all systematically assessed in parallel by PDUS, performed on 32 joints.
RESULTS
Serum levels of soluble Vascular Cell Adhesion Molecule-1 (sVCAM-1) and Tie-2 were more likely to be increased in patients with synovial hyperemia detected on at least one joint (Power Doppler grade ≥1). sVCAM-1, Tie-2 and Angiostatin concentrations gradually increased together with the grade of the semiquantitative PDUS scale and concentrations of these three markers were markedly increased in patients with moderate to marked hyperemia (Power Doppler grade 2 and 3). Levels of sVCAM-1, Tie-2, and Angiostatin correlated with a global arthritis sum score, defined by the sum of the semiquantitative PDUS scores for all joints examined. Levels of Tie-2 and Placenta Growth Factor (PlGF) were associated with PDUS features indicating residual disease activity.
CONCLUSION
Our results support the relevance of measuring serum levels of vascular markers to evaluate the intensity and extent of synovial vascularization. Angiogenic markers, and particularly Tie-2, could be a valuable surrogate of active synovitis and their place in relation to PDUS in clinical practice deserve further investigation.
Topics: Adult; Aged; Analysis of Variance; Antirheumatic Agents; Arthritis, Rheumatoid; Female; Humans; Male; Middle Aged; Neovascularization, Pathologic; Synovial Membrane; Synovitis; Ultrasonography, Doppler; Young Adult
PubMed: 30188942
DOI: 10.1371/journal.pone.0203607 -
Molecules (Basel, Switzerland) Sep 2019Diosmin is a natural compound with a wide range of biological activity, e.g., it improves lymphatic drainage, supports microcirculation, and increases venous tone, and... (Clinical Trial)
Clinical Trial
Diosmin is a natural compound with a wide range of biological activity, e.g., it improves lymphatic drainage, supports microcirculation, and increases venous tone, and venous elasticity, hence, it is applied in the pharmacotherapy of chronic venous disorders (CVD). The aim of this study was to assess the correlation between diosmin administration (2 × 600 mg daily) in patients suffering from CVD and the levels of selected factors influencing angiogenesis, which are involved in CVD pathophysiology. Thirty-five CVD patients were examined. Levels of plasma tumor necrosis factor alpha (TNF alpha), vascular endothelial growth factor (VEGF-A and VEGF-C); angiostatin, interleukin 6 (IL-6), fibroblast growth factor 2 (FGF2); and plasminogen (PLG) were measured with an Elisa assay before and after three months of diosmin administration. The clinical symptoms of CVD were monitored using ultrasound images, echo Doppler assay, visual analogue scale (VAS), and measurement of the leg circumference. The average content of TNF alpha, VEGF-C, VEGF-A IL-6, and FGF2 decreased after the therapy with diosmin in a significant manner; with < 0.001, < 0.05, < 0.05, < 0.01, and < 0.01, respectively, and a significant ( < 0.05) increase in the plasma angiostatin level after the three-month treatment was found. A significant ( < 0.05) decrease in edema and the average leg circumference of the patients was observed after the therapy. Diosmin influences the angiogenic and inflammatory mechanisms involved in the pathophysiology of edema presented in patients with a different class of CVD.
Topics: Adult; Angiostatins; Chronic Disease; Diosmin; Female; Fibroblast Growth Factor 2; Humans; Interleukin-6; Male; Middle Aged; Neovascularization, Physiologic; Treatment Outcome; Tumor Necrosis Factor-alpha; Ultrasonography, Doppler; Varicose Veins; Vascular Diseases; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor C; Veins
PubMed: 31547271
DOI: 10.3390/molecules24183316 -
Gastroenterology Report Aug 2020Neoadjuvant chemoradiotherapy (nCRT) is associated with post-operative anastomotic complications in rectal-cancer patients. Anastomosis involving at least one...
BACKGROUND
Neoadjuvant chemoradiotherapy (nCRT) is associated with post-operative anastomotic complications in rectal-cancer patients. Anastomosis involving at least one non-irradiated margin reportedly significantly reduces the risk of post-operative anastomotic complications in radiation enteritis. However, the exact scope of radiotherapy on the remaining sigmoid colon remains unknown.
METHODS
We evaluated the radiation damage of proximally resected colorectal segments in 44 patients with rectal cancer, who received nCRT followed by conventional resection (nCRT-C, = 21) or proximally extended resection (nCRT-E, = 23). The segments from another 13 patients undergoing neoadjuvant chemotherapy (nCT) were used as control. We dissected these samples at a distance of 2 cm between the two adjacent sections. Radiation damage in proximally resected colorectal segments was evaluated using the radiation injury score (RIS) and the concentration and distribution patterns of angiostatin.
RESULTS
Compared to those in the nCT group, the nCRT group showed higher RIS, levels of angiostatin, and proportion of diffuse pattern of angiostatin. With increasing distance from the tumor site, these parameters all gradually decreased; and the differences came to be not significant at the site that is over 20 cm from the tumor. The nCRT-E group showed lower RIS (median: 2 vs 4, = 0.002) and a greater proportion of non-diffuse angiostatin (87% vs 55%, = 0.039) at the proximal margins compared with the nCRT-C group.
CONCLUSIONS
The severity of the radiation damage of the proximal colon is inversely proportional to the proximal-resection margin length. Little damage was left on the proximal margin that was over 20 cm from the tumor. Removal of an initial length of ≥20 cm from the tumor may be beneficial for rectal-cancer patients after nCRT.
PubMed: 32843974
DOI: 10.1093/gastro/goz047 -
Journal of Cancer 2022Tranexamic acid (TA) has been reported to exhibit antitumor effects in various mouse models of cancer. However, the mechanism underlying its antitumor effects against...
Tranexamic acid (TA) has been reported to exhibit antitumor effects in various mouse models of cancer. However, the mechanism underlying its antitumor effects against endometrial cancer remains to be elucidated. This study was aimed at investigating the efficacy of TA against chronic inflammation-associated endometrial cancer induced by -methyl--nitrosourea (MNU) and estradiol in a mouse model. After cancer induction, the mice were administered TA (12 mg/kg) three times weekly during the experimental period. The endometrial cancer development induced by MNU and estradiol was ameliorated by TA administration. Furthermore, TA treatment suppressed the levels of carbohydrate antigen 125, interleukin-6, and tumor necrosis factor-α in the plasma. The level of plasminogen, known as a TA target, increased in endometrial cancer and was further increased by TA treatment. On the other hand, plasmin levels increased in the model mice but decreased after TA treatment. Furthermore, the macrophage counts and the levels of matrix metalloproteinase (MMP)-12 and angiostatin in tumor cells in the uterus increased compared to the corresponding values in the control group and further increased upon TA treatment. The results of our study indicate that TA ameliorated the endometrial cancer induced by MNU and estradiol by regulating the macrophage/MMP-12/plasminogen/angiostatin signal transmission pathway.
PubMed: 35371322
DOI: 10.7150/jca.68169 -
Journal of Physiology and Biochemistry Sep 2016Arteriogenesis is a main defense mechanism to prevent heart and local tissues dysfunction in occlusive artery disease. TGF-β and angiostatin have a pivotal role in... (Comparative Study)
Comparative Study
Arteriogenesis is a main defense mechanism to prevent heart and local tissues dysfunction in occlusive artery disease. TGF-β and angiostatin have a pivotal role in arteriogenesis. We tested the hypothesis that aerobic training and l-arginine supplementation promotes cardiac and skeletal muscles arteriogenesis after myocardial infarction (MI) parallel to upregulation of TGF-β and downregulation of angiostatin. For this purpose, 4 weeks after LAD occlusion, 50 male Wistar rats were randomly distributed into five groups: (1) sham surgery without MI (sham, n = 10), (2) control-MI (Con-MI, n = 10), (3) l-arginine-MI (La-MI, n = 10), (4) exercise training-MI (Ex-MI, n = 10), and (5) exercise and l-arginine-MI (Ex + La-MI). Exercise training groups running on a treadmill for 10 weeks with moderate intensity. Rats in the l-arginine-treated groups drank water containing 4 % l-arginine. Arteriolar density with different diameters (11-25, 26-50, 51-75, and 76-150 μm), TGF-β, and angiostatin gene expression were measured in cardiac (area at risk) and skeletal (soleus and gastrocnemius) muscles. Smaller arterioles decreased in cardiac after MI. Aerobic training and l-arginine increased the number of cardiac arterioles with 11-25 and 26-50 μm diameters parallel to TGF-β overexpression. In gastrocnemius muscle, the number of arterioles/mm(2) was only increased in the 11 to 25 μm in response to training with and without l-arginine parallel to angiostatin downregulation. Soleus arteriolar density with different size was not different between experimental groups. Results showed that 10 weeks aerobic exercise training and l-arginine supplementation promotes arteriogenesis of heart and gastrocnemius muscles parallel to overexpression of TGF-β and downregulation of angiostatin in MI rats.
Topics: Angiogenesis Inducing Agents; Angiostatins; Animals; Arginine; Arterioles; Arteriolosclerosis; Combined Modality Therapy; Coronary Vessels; Dietary Supplements; Gene Expression Regulation; Heart; Hindlimb; Male; Motor Activity; Muscle, Skeletal; Myocardial Infarction; Myocardium; Neovascularization, Physiologic; Physical Conditioning, Animal; Random Allocation; Rats, Wistar; Transforming Growth Factor beta
PubMed: 27121159
DOI: 10.1007/s13105-016-0480-x -
Animals : An Open Access Journal From... Dec 2023Precise coupling of two fundamental mechanisms, chondrogenesis and osteogenesis via angiogenesis, plays a crucial role during rapid proliferation of growth plates, and... (Review)
Review
Precise coupling of two fundamental mechanisms, chondrogenesis and osteogenesis via angiogenesis, plays a crucial role during rapid proliferation of growth plates, and alteration in their balance might lead to pathogenic conditions. Tibial dyschondroplasia (TD) is characterized by an avascular, non-mineralized, jade-white "cartilaginous wedge" with impaired endochondral ossification and chondrocyte proliferation at the proximal end of a tibial bone in rapidly growing poultry birds. Developing vascular structures are dynamic with cartilage growth and are regulated through homeostatic balance among pro and anti-angiogenic proteins and cytokines. Pro-angiogenic factors involves a wide spectrum of multifactorial mitogens, such as vascular endothelial growth factors (VEGF), platelet-derived growth factors (PDGF), basic fibroblast growth factor (bFGF), placental growth factors, transforming growth factor-β (TGF-β), and TNF-α. Considering their regulatory role via the sonic hedgehog, notch-gridlock, and ephrin-B2/EphB4 pathways and inhibition through anti-angiogenic proteins like angiostatin, endostatin, decoy receptors, vasoinhibin, thrombospondin, PEX, and troponin, their possible role in persisting inflammatory conditions like TD was studied in the current literature review. Balanced apoptosis and angiogenesis are vital for physiological bone growth. Any homeostatic imbalance among apoptotic, angiogenetic, pro-angiogenic, or anti-angiogenic proteins ultimately leads to pathological bone conditions like TD and osteoarthritis. The current review might substantiate solid grounds for developing innovative therapeutics for diseases governed by the disproportion of angiogenesis and anti-angiogenesis proteins.
PubMed: 38136788
DOI: 10.3390/ani13243750