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Atopic dermatitis (AD) is often characterized by chronic skin changes of dermal fibrosis, typically regulated by inflammatory and angiogenic factors. However, the significance of angiogenesis inhibitory factors in the development of AD is poorly understood. The present study investigated the potential role of an angiogenesis inhibitory factor, vasohibin‐1 (VASH1), in AD by evaluating serum and skin VASH1 levels and their correlation with clinical features. The results showed that VASH1 expression levels in both the serum and skin of patients with AD were significantly elevated compared to healthy controls. Immunohistochemical staining of AD skin showed increased VASH1 expression in dermal vascular endothelial cells. Notably, there was a significant correlation between serum VASH1 levels and disease duration as well as VASH1 and vascular endothelial growth factor A expression levels in the skin tissue of patients with AD. These results may suggest a pathogenesis of increased angiogenesis and associated elevated inhibitory processes accompanying inflammation in the chronic phase of AD. [ABSTRACT FROM AUTHOR]

ABSTRACT Background Vasohibin‐1 (VASH1), an angiogenic inhibitor, exhibits tubulin carboxypeptidase activity, which is involved in microtubule functions. Paclitaxel, the core chemotherapeutic agent for ovarian cancer chemotherapy, has a point of action on microtubules and may interact with VASH1. Aims To examine the influence of VASH1 on intracellular tubulin detyrosination status, cyclin B1 expression, and paclitaxel chemosensitivity using VASH1‐overexpressing ovarian cancer cell lines. Methods and Results Gene‐transfected human ovarian cancer cell lines were subjected to western blot analysis. Western blot analysis of VASH1‐overexpressing ovarian cancer cells revealed upregulated expression of detyrosinated tubulin and cyclin B1 compared with control cells. By WST‐1 assay, paclitaxel chemosensitivity of VASH1‐overexpressing ovarian cancer cells was markedly enhanced compared with that of control cells, whereas there was no significant difference in chemosensitivity to cisplatin. The forced expression of VASH1 enhanced tubulin carboxypeptidase activity and increased cyclin B1 expression, resulting in augmented paclitaxel chemosensitivity in ovarian cancer cells. Conclusion Ovarian cancer treatment strategies targeting VASH1 can potentiate the effects of conventional chemotherapy by inhibiting angiogenesis and regulating microtubule activity.

Renal fibrosis (RF) stands as a pivotal pathological process in the advanced stages of chronic kidney disease (CKD), and impeding its progression is paramount for delaying the advancement of CKD. The miR-10 family, inclusive of miR-10a and miR-10b, has been implicated in the development of various fibrotic diseases. Nevertheless, the precise role of miR-10 in the development of RF remains enigmatic. In this study, we utilized both an in vivo model involving unilateral ureteral obstruction (UUO) in mice and an in vitro model employing TGF-β1 stimulation in HK-2 cells to unravel the mechanism underlying the involvement of miR-10a/b in RF. The findings revealed heightened expression of miR-10a and miR-10b in the kidneys of UUO mice, accompanied by a substantial increase in p-Smad3 and renal fibrosis-related proteins. Conversely, the deletion of these two genes led to a notable reduction in p-Smad3 levels and the alleviation of RF in mouse kidneys. In the in vitro model of TGF-β1-stimulated HK-2 cells, the co-overexpression of miR-10a and miR-10b fostered the phosphorylation of Smad3 and RF, while the inhibition of miR-10a and miR-10b resulted in a decrease in p-Smad3 levels and RF. Further research revealed that miR-10a and miR-10b, through binding to the 3'UTR region of Vasohibin-1 (VASH-1), suppressed the expression of VASH-1, thereby promoting the elevation of p-Smad3 and exacerbating the progression of RF. The miR-10 family may play a pivotal role in RF. [ABSTRACT FROM AUTHOR]

Objective: Glomerular neoangiogenesis contributes to increased glomerular filtration rate in patients with diabetic kidney disease. Vasohibin-1 is a neoangiogenesis inhibitor. We aimed to evaluate serum vasohibin-1 levels of diabetic patients with and without diabetic kidney disease. Methods: A total of 105 diabetic patients and 35 healthy controls were included in the study. Diabetic patients with estimated glomerular filtration rate <60 mL/min/1.73 m2 and/or those who had persistent proteinuria (>200 mg/g) measured by urinary protein/creatinine ratio were diagnosed as diabetic kidney disease patients if they do not have any other known kidney diseases or findings suggesting another kidney disease. Serum creatinine, estimated glomerular filtration rate, protein/creatinine ratio, and vasohibin-1 levels were recorded. Results: Systolic blood pressure and protein/creatinine ratio were higher in diabetic patients than in healthy controls, and age, sex, and estimated glomerular filtration rate were similar. Diabetic patients have slightly lower but statistically nonsignificant serum vasohibin-1 levels than healthy controls. Patients with diabetic kidney disease had higher protein/creatinine ratio, lower estimated glomerular filtration rate, and long-standing diabetes compared to diabetic patients without kidney disease. Serum vasohibin-1 levels were similar between patients with and without diabetic kidney disease. There was no correlation between serum vasohibin-1 levels and estimated glomerular filtration rate or protein/creatinine ratio. In logistic regression analysis, vasohibin-1 was not associated with diabetic kidney disease. Conclusion: We showed that diabetic patients have slightly lower vasohibin-1 levels than healthy subjects but there was no difference between diabetic patients with and without kidney disease in terms of serum vasohibin levels. Because vasohibin-1 exhibits its antiangiogenic properties by acting via autocrine-paracrine pathways, local vasohibin activity at the tissue level may be more important than the circulating levels. [ABSTRACT FROM AUTHOR]

BACKGROUND: Alveolar echinococcosis and cystic echinococcosis grow in different ways in the body. Alveolar echinococcosis is infiltrating growth, which can invade tissues, blood vessels, and bile ducts. Cystic echinococcosis has fibrous outer cyst wall-wrapped lesions, which show compressive growth of tissues. The effect of the two types of hydatidosis on the invasion and formation of blood vessels is still unclear. OBJECTIVE: To explore the effects of two kinds of Echinococcus granulosus protoscolex on angiogenesis-related factors in endothelial progenitor cells. METHODS: After extraction, culture, and identification of endothelial progenitor cells from C57BL/6 mouse bone marrow, and extraction of two types of Echinococcus granulosus protoscolex, two kinds of Echinococcus granulosus protoscolex were co-cultured with endothelial progenitor cells for 24, 48, and 60 hours. ELISA was applied to detect the secretion of vascular endothelial growth factor A and stromal cell-derived factor-1α in the supernatant of cell co-culture. Western blot assay was utilized to detect the relative expression of vasohibin-1, vascular endothelial growth factor A, hypoxia-inducible factor 1α, and stromal cell-derived factor-1α protein in endothelial progenitor cells of each group. RESULTS AND CONCLUSION: (1) The levels of vascular endothelial growth factor A and stromal cell-derived factor-1α were significantly higher in the alveolar echinococcosis group than those in the cystic echinococcosis group at 60 hours of coculture (P < 0.05). (2) Relative expression levels of vasohibin-1, hypoxiainducible factor 1α, and stromal cell-derived factor-1α were higher in the alveolar echinococcosis group than those in the cystic echinococcosis group at 48 and 60 hours of coculture (P < 0.05). (3) The relative expression levels of vascular endothelial growth factor A were not significantly different in the alveolar echinococcosis and cystic echinococcosis groups at 48 and 60 hours of coculture (P > 0.05). (4) It is concluded that alveolar echinococcosis promotes angiogenesis, and cystic echinococcosis has little effect on angiogenesis. [ABSTRACT FROM AUTHOR]

Objective: Lung cancer constitutes 17% of all cancer cases and accounts for 23% of the deaths caused by cancer all over the world. Vasohibin-1 (VASH-1) is an angiogenesis-inhibiting factor synthesized by endothelial cells (ECs). This study aimed to examine the VASH-1 levels of the bronchoalveolar lavage (BAL) and serum in the patients with lung cancer. Methods: A total of 82 patients participated in this study. 39 and 43 of them had a benign lung disease and lung cancer, respectively. The VASH-1 levels of serum and BAL were measured using the Enzyme-Linked Immunosorbent Assay (ELISA). Results: The BAL VASH-1 levels of the patients in the lung cancer group were found to be statistically significantly lower than those of the patients in the benign lung disease group (p=0.032). No statistically significant difference was found between the individuals with lung cancer and benign lung disease in terms of the serum VASH-1 concentration (p=0.206). A statistically significantly moderate positive correlation was found between the serum and BAL VASH-1 levels in the benign and malignant cases (benign r=0.442, p=0.005; malignant r=0.364, p=0.016). When the lung cancer patients were categorized into pathological stages and histological types, no significant difference was found between the stages and histological types in terms of the serum and BAL fluid VASH-1 concentrations. Conclusions: BAL VASH-1 concentrations decreased in the lung cancer patients compared to the individuals having a benign lung disease. Considering the results reached in this study, it was thought that the BAL VASH-1 concentrations might be beneficial in distinguishing between the benign and malignant lung diseases. [ABSTRACT FROM AUTHOR]

Podocytes are highly specialized epithelial cells in glomeruli, with a complex morphology composed of a cell body, primary processes, and foot processes, which maintain barrier function in glomerular filtration. The microtubule-based cytoskeleton is necessary for podocyte morphology. Microtubule structure and function can be affected by post-translational modification of tubulin, including detyrosination. Recent studies have shown that vasohibin-1 (VASH1), an antiangiogenic factor, has tubulin carboxypeptidase activity that causes detyrosination of α-tubulin. We aimed to examine the role of VASH1 in regulating α-tubulin detyrosination in podocytes and the potential involvement of VASH1 deficiency in renal morphology. In normal mouse kidneys, detyrosinated α-tubulin was mainly identified in glomeruli, especially in podocytes; meanwhile, in cultured immortalized podocytes, α-tubulin detyrosination was promoted with cell differentiation. Notably, α-tubulin detyrosination in glomeruli was diminished in Vash1 homozygous knockout (Vash1 −/−) mice, and knockdown of VASH1 in cultured podocytes prevented α-tubulin detyrosination. Although VASH1 deficiency-induced downregulation of detyrosination caused no remarkable glomerular lesions, urinary albuminuria excretion and glomerular volume were significantly higher in Vash1 −/− mice than in wild-type mice. Furthermore, decreased glomerular nephrin expression and narrower slit diaphragms width were observed in Vash1 −/− mice. Taken together, we demonstrated that α-tubulin detyrosination in podocytes was mainly regulated by VASH1 and that VASH1 deficiency-mediated decreases in α-tubulin detyrosination led to minor alterations in podocyte morphology and predisposition to albuminuria. VASH1 expression and α-tubulin detyrosination may be novel targets for maintaining glomerular filtration barrier integrity. • In the kidney, detyrosinated α-tubulin, a component of stable microtubules, is mainly localized in glomerular podocytes. • Vash1 deficiency leads to diminished α-tubulin detyrosination in glomerular podocytes. • Defective glomerular α-tubulin detyrosination results in mild albuminuria and glomerular hypertrophy. • Decrease in glomerular α-tubulin detyrosination is associated with ultrastructural changes in podocyte slit diaphragms. [ABSTRACT FROM AUTHOR]

Vasohibin-1 (VASH1) is an angiogenesis inhibitor, while vasohibin-2 (VASH2) is a proangiogenic factor. The roles of VASH1 and VASH2 expression in gastroenterological cancers remain unclear. We searched for relevant literature, specifically studies on gastroenterological cancer, and evaluated the relationship between VASH expression and clinical outcomes. Nine studies on VASH1 involving 1,574 patients were included. VASH1 expression was associated with the TNM stage [OR (odds ratio) 2.05, 95% CI (confidence interval) 1.24-3.40], lymph node metastasis (OR 1.79, 95% CI 1.24-2.58), lymphatic invasion (OR 1.95, 95% CI 1.41-2.68), and venous invasion (OR 2.49, 95% CI 1.60-3.88); poor clinical outcomes were associated with high VASH1 expression. High VASH1 expression was associated with a significantly shorter overall survival (OS) [HR (hazard ratio) 1.69, 95% CI 1.25-2.29] and disease-free survival (DFS) (HR 2.01, 95% CI 1.28-3.15). Three studies on VASH2 involving 469 patients were analyzed. VASH2 expression was associated with the TNM stage (OR 4.21, 95% CI 1.89-9.51) and venous invasion (OR 2.10, 95% CI 1.15-3.84); poor clinical outcomes were associated with high VASH2 expression. High VASH2 expression was associated with a significantly lower OS (HR 1.61, 95% CI 1.09-2.37). In conclusion, high VASH1 and VASH2 expression levels were associated with poor clinical outcomes and prognosis in patients with gastroenterological cancers. [ABSTRACT FROM AUTHOR]

Vasohibin‐1 (VASH‐1) is a potent anti‐angiogenic factor mainly produced by endothelial cells. In addition, VASH‐1 prevents TGF‐β–dependent activation of renal fibroblasts. Since systemic sclerosis (SSc) is an autoimmune disease characterized by vasculopathy and fibrosis of multiple organs, VASH‐1 may be involved in the development of this disease. In this study, we investigated the potential role of VASH‐1 in SSc by evaluating the clinical correlation between serum VASH‐1 levels and the expression of VASH‐1 in SSc‐involved skin. Serum VASH‐1 levels were higher in SSc patients, especially those with diffuse cutaneous involvement, than in healthy controls and positively correlated with skin score. Furthermore, SSc patients with interstitial lung disease had significantly elevated levels of serum VASH‐1 as compared to those without. Importantly, serum VASH‐1 levels correlated inversely with both the percentage of predicted vital capacity and the percentage of predicted diffusion lung capacity for carbon monoxide and positively with serum KL‐6 levels, but not serum surfactant protein D levels. In SSc‐involved skin, VASH1 mRNA was remarkably upregulated compared with healthy control skin, but the major source of VASH‐1 was not clear. Fli1 deficiency, a predisposing factor inducing SSc‐like endothelial properties, did not affect VASH‐1 expression in human dermal microvascular endothelial cells. Collectively, these results suggest that VASH‐1 upregulation in the skin and sera is linked to dermal and pulmonary fibrotic changes in SSc, while the contribution of VASH‐1 to SSc vasculopathy seems to be limited. [ABSTRACT FROM AUTHOR]

Aims: To investigate the role of Vasohibin-1 (VASH-1), silence information adjustment factor 2-related enzyme 1 (SIRT1)/hypoxic-inducible factor 1α (HIF1α) and transforming growth factor-β1 (TGFβ1) /Smad3 signaling pathways in oxidative stress and fibrosis of diabetic kidney disease (DKD).Materials and Methods: A diabetic rat model was established in vivo and rat mesangial cells (RMCs) were cultured in vitro with high glucose via transfection with Vash1 small interfering RNA (siRNA), Hif1a siRNA, Sirt1 siRNA and TGFβ1/Smad3 pathway inhibitor (SB431542). Renal histology was used to detect renal changes. Real-time PCR and western blot were used to analyze the expression of VASH-1, SIRT1, HIF1α, TGFβ1, Smad3, vascular endothelial growth factor (VEGF), connective tissue growth factor (CTGF) and fibronectin (FN). Expression levels of tumor necrosis factor-α (TNFα), TGFβ1, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-PX), and malondialdehyde (MDA) in rat tissues and cell culture supernatant were detected by ELISA and chemiluminescence assay, while cell proliferation was detected by CCK-8.Results: The level of VASH-1 in renal tissues of diabetic rats was decreased, while both high glucose and Vash1 siRNA inhibited the expression of VASH-1 and SIRT1, increased the levels of HIF1α, TGFβ1, and Smad3 in RMCs, thus up-regulating oxidative stress and fibrosis factors, and abnormally increasing cell proliferation activity (P < 0.05). However, inhibition of SIRT1/HIF1α signaling pathway only reduced TGFβ1 and Smad3 (P < 0.05), while VASH-1 remained unchanged (P > 0.05).Conclusion: VASH-1 was under-expressed in renal tissues of diabetic rats and regulated the pathological process of oxidative stress and fibrosis in DKD via downstream SIRT1/HIF1α and TGFβ1/Smad3 signaling pathways.

Purpose: It was recently identified that the vasohibin family may regulate angiogenesis through suppression by the vasohibin-1 gene and promotion by the vasohibin-2 gene. We assessed vasohibin expression in gastric cancer patients and its effect on their prognosis. Methods: We evaluated vasohibin immunohistochemical expression in 210 patients with gastric cancer, who underwent radical surgery. The patients were divided first into a vasohibin-1-positive group and a vasohibin-1-negative group, and then into groups with high or low vasohibin-2 expression, to allow us to investigate the clinicopathological factors of prognosis retrospectively. Results: There were 139 patients in the vasohibin-1-positive group and 71 patients in the vasohibin-1-negative group, among which there were and 108 with high vasohibin-2 expression and 102 with low vasohibin-2 expression. Vasohibin-1 was associated with Ly (P = 0.003) and pT (P = 0.037), whereas vasohibin-2 was associated with Ly (P < 0.001), V (P < 0.001) and pStage (P < 0.001). Overall, cancer-specific and relapse-free survival rates were lower in the vasohibin-1-positive (P = 0.034, P < 0.001, P = 0.002, respectively) and high vasohibin-2 expression (P = 0.004, P = 0.003, P < 0.001, respectively) groups. Multivariate analysis revealed that vasohibin-1 expression was associated with cancer-specific (P = 0.014, hazard ratio [HR] 4.454) and relapse-free (P = 0.035, HR 2.557) survival and vasohibin-2 expression tended to influence relapse-free survival (P = 0.051, HR 2.061). Grouping patients by vasohibin expression status combinations showed correlation among their expressions (P = 0.005). Overall, cancer-specific and relapse-free survival rates were lowest in the vasohibin-1-positive and high vasohibin-2 expression group. Conclusion: Our findings demonstrate that vasohibin-1 and vasohibin-2 could be novel biomarkers for predicting gastric cancer prognosis. [ABSTRACT FROM AUTHOR]

Background: Endothelial dysfunction (ED) is associated with high cardiovascular disease burden in hemodialysis (HD) patients. Vasohibin-1, an endothelium-derived angiogenesis inhibitor, is essential for endothelial cell survival, therefore it may be a promising marker of ED. We aimed to investigate whether vasohibin-1 levels are associated with ED markers in HD patients.Methods: Fifty HD patients and 30 healthy controls were included in the study. As markers of ED, endothelium-dependent flow-mediated dilatation (FMD), carotid intima-media thickness (CIMT), and pulse wave velocity (PWV) were examined. Serum vasohibin-1 levels were measured with ELISA.Results: Serum vasohibin-1 levels were low (387.7 ± 115.7 vs 450.1 ± 140.1 P = .02), FMDs' were impaired (6.65 ± 2.50 vs 10.95 ± 2.86 P < .001), PWV (7.92 ± 1.964 vs 6.79 ± 0.96 P = .01) and CIMT (0.95 ± 0.20 vs 0.60 ± 0.11 P < .001) were increased in HD patients compared to healthy controls. In regression analysis, vasohibin-1 levels were not related with FMD, PWV, or CIMT.Conclusions: Hemodialysis patients have low serum vasohibin-1 levels but serum levels of vasohibin-1 did not show any significant relationship with FMD, PWV, and CIMT in HD patients. Since vasohibin-1 acts via paracrine pathways, serum levels may be insufficient to explain the relationship between vasohibin and ED. Local vasohibin-1 activity on tissue level may be more important instead of circulating levels. [ABSTRACT FROM AUTHOR]

Background: Vasohibins (VASH), which are angiogenesis regulators, consist of Vasohibin-1 (VASH1) and Vasohibin-2 (VASH2). VASH1 is an angiogenesis inhibitor, while VASH2 is a proangiogenic factor. Patients with esophageal squamous cell carcinoma (ESCC) with high tumor expression levels of VASH1 and VASH2 have been reported to show a poor prognosis. The clinical significance of VASH concentrations in the blood of patients with ESCC has not yet been investigated. Methods: Plasma samples from 89 patients with ESCC were analyzed, and the relationships between the plasma VASH concentrations and the clinicopathological factors of the patients were evaluated. Immunohistochemical examination (IHC) of the resected tumor specimens for VASH was performed in 56 patients, and the correlation between the plasma VASH concentrations and tumor expression levels of VASH was analyzed. Results: The patient group with high plasma concentrations of VASH1 showed a higher frequency of lymph node metastasis (P = 0.01) and an invasive growth pattern (P = 0.05). Furthermore, poorly differentiated cancer occurred at a higher frequency in the patient group with high plasma concentrations of VASH2 (P < 0.01). High tumor expression levels of VASH1 were encountered more frequently in the patient group with high plasma concentrations of VASH1 (P = 0.03), and high tumor expression levels of VASH2 were encountered more frequently in the patient group with high plasma concentrations of VASH2 (P = 0.04). Conclusions: In patients with ESCC, high plasma concentrations were associated with poor clinical outcomes for both VASH1 and VASH2. We propose that results indicate that plasma VASH1 and VASH2 are useful biomarkers in patients with ESCC. [ABSTRACT FROM AUTHOR]

Acute kidney injury (AKI) is frequently encountered in clinical practice, particularly secondarily to cardiovascular surgery and administration of nephrotoxic agents, and is increasingly recognized for initiating a transition to chronic kidney disease. Clarifying the pathogenesis of AKI could facilitate the development of novel preventive strategies, because the occurrence of hospital-acquired AKI is often anticipated. Vasohibin-1 (VASH1) was initially identified as an antiangiogenic factor derived from endothelial cells. VASH1 expression in endothelial cells has subsequently been reported to enhance cellular stress tolerance. Considering the importance of maintaining peritubular capillaries in preventing the progression of AKI, the present study aimed to examine whether VASH1 deletion is involved in the pathogenesis of cisplatin-induced AKI. For this, we injected male C57BL/6J wild-type (WT) and VASH1 heterozygous knockout (VASH1+/−) mice intraperitoneally with either 20 mg/kg cisplatin or vehicle solution. Seventy-two hours after cisplatin injection, increased serum creatinine concentrations and renal tubular injury accompanied by apoptosis and oxidative stress were more prominent in VASH1+/− mice than in WT mice. Cisplatin-induced peritubular capillary loss was also accelerated by VASH1 deficiency. Moreover, the increased expression of ICAM-1 in the peritubular capillaries of cisplatin-treated VASH1+/− mice was associated with a more marked infiltration of macrophages into the kidney. Taken together, VASH1 expression could have protective effects on cisplatin-induced AKI probably by maintaining the number and function of peritubular capillaries. [ABSTRACT FROM AUTHOR]

Aim: To determine the serum levels of vasohibin (VASH)-1 and other biomarkers in type 2 diabetes mellitus (T2DM) patients with different urinary albumin to creatinine ratios (UACR), and correlate VASH-1 expression with the inflammation and fibrosis in diabetic kidney disease (DKD).Methods: A total of 697 T2DM patients were stratified into four groups: N-UAlb (UACR <30 mg/g with normal blood pressure, n = 144), M-UAlb (UACR 30-300 mg/g with normal blood pressure, n = 143), L-UAlb (UACR >300 mg/g with normal blood pressure, n = 126), and L-UAlb+HP (UACR >300 mg/g with hypertension, n = 134). In addition, 150 healthy subjects were included as normal controls (NC). In addition to recording the age and duration of diabetes, the serum levels of VASH-1, silent information regulator factor 2-related enzyme 1 (sirtuin-1, SIRT1), hypoxia inducible factor 1α (HIF1α), vascular endothelial growth factor (VEGF), C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), transforming growth factor-β1 (TGF-β1), and the erythrocyte sedimentation rate (ESR) were measured. Clinical parameters related to UACR and VASH-1 were analyzed by one-way ANOVA, Pearson correlation and ridge regression analysis.Results: The UACR, VASH-1, glycosylated hemoglobin (HbA1c), ESR, CRP, VEGF, HIF1α, TNF-α and TGF-β1 levels in all patient groups were significantly higher, and SIRT1 levels were lower compared to the NC group. Pearson correlation analysis showed that UACR and VASH-1 levels were positively correlated with HbA1c, ESR, CRP, VEGF, HIF1α, TNF-α and TGF-β1, and negatively with SIRT1. Ridge regression analysis showed that every serological marker was an independent factor affecting UACR.Conclusion: Serum VASH-1 may be associated with the expression of renal inflammation and fibrosis-related factors, and have a potential connection with DKD. [ABSTRACT FROM AUTHOR]

Background/aim: Chronic kidney disease (CKD), which is one of the most important health problems worldwide, could be considered as an immune inflammatory disease. A prognostic biomarker may be helpful in determining the progression of CKD in children. We aimed to investigate the serum vasohibin-1 and soluble suppression of tumorigenicity-2 (sST2) levels as potential biomarkers in children with predialysis CKD. Materials and methods: Forty-seven children with stage 2–4 CKD and 20 healthy controls were included in this cross-sectional study. Glomerular filtration rate (GFR) and urinary excretion of protein were measured in 24-h urine samples. Serum vasohibin-1 levels and sST2 were measured. The results were expressed as pg/mL and ng/mL, respectively. Results: Serum vasohibin-1 levels were similar between the patients and the control group (P > 0.05), but serum vasohibin-1 levels were higher in patients with proteinuria than in nonproteinuric patients (2574.5 ± 701.60 vs. 1822.4 ± 300.32 pg/mL, P = 0.001). A positive correlation was found between serum vasohibin-1 levels and 24-h urine protein values in patients (P = 0.036). Serum sST2 levels were higher in patients than the control group (P = 0.013). The patients with hypertension had higher sST2 levels than normotensive patients (P = 0.015). Serum vasohibin-1 and sST2 levels were not correlated with age, GFR, albumin, hemoglobin, or PTH levels. Conclusion: Serum vasohibin-1 and sST2 levels were not associated with decline in renal function. Elevated serum vasohibin levels may be a compensatory response to proteinuria in patients with predialysis CKD. The measurement of serum sST2 levels might contribute to early detection of hypertension in patients. [ABSTRACT FROM AUTHOR]

TAp73 and p53 are involved in regulating tumor angiogenesis and vasohibin-1 (VASH1) is an anti-angiogenic factor. Whether TAp73 regulates angiogenesis positively or negatively is controversial. The status of P53 may determine the effect of TAp73 on angiogenesis. To the best of our knowledge it has not been previously reported whether TAp73, p53 and VASH1 are coexpressed in lung cancer. We profiled the association between TAp73 and p53 and VASH1 expression in lung adenocarcinoma (LAC) and investigated the function of TAp73 in regulating tumor angiogenesis. TAp73, p53 and VASH1 expression in 53 human LAC tissues and the adjacent normal tissues were evaluated using immunohistochemistry. The positive expression rates of p53, TAp73 and VASH1 were significantly higher (92.6, 97.7 and 67.4%, respectively) in LAC tissue compared with paraneoplastic lung tissue (7.4, 2.3 and 32.6%, respectively, P<0.01). Pearson's correlation coefficient showed a significant positive correlation between p53 and TAp73 (r=0.474, P<0.01) and TAp73a and VASH1 (r=0.367, P<0.01). The positive expression rate of p53 and VASH1 was almost significantly correlated (r=0.187, P=0.055). Similarly, p53 expression intensity had a significant positive correlation with TAp73a (r=0.517, P<0.01) and with VASH1 (r=0.277, P<0.01), as did TAp73a with VASH1 (r=0.351, P<0.01). TAp73, p53 (mutant) and VASH1 expression was significantly higher in LAC tissue compared with paraneoplastic lung tissue. The expression trends of the three proteins were significantly positively correlated with each other in LAC. These results suggest that TAp73 may suppress tumor angiogenesis in LAC. [ABSTRACT FROM AUTHOR]

Angiogenesis is important in the development of solid tumors. Vasohibin-1 (VASH-1) is an endothelium-derived protein that acts as an inhibitor of angiogenesis in many different types of cancer. However, the expression of VASH-1 and its clinical value in bladder cancer remain unknown. The current study analyzed the expression of VASH-1, as well as the expression of the angiogenesis-related factors vascular endothelial growth factor-A, hypoxia inducible factor-1a and cluster of differentiation 34 in bladder cancer tissues from 50 patients using immunohistochemistry. The associations between the expression of these factors and the clinicopathological characteristics of the patients were assessed. The current study demonstrated that VASH-1 is primarily expressed in the cytoplasm of bladder cancer cells and in a fraction of vascular endothelial cells. Furthermore, the expression of VASH-1 was positively associated with the tumor stage (P<0.01), pathological grade (P<0.01) and distant metastasis (P<0.05) but not with patient age or sex (P>0.05). Spearman rank correlation tests indicated that levels of those four factors were positively correlated with each other. Kaplan-Meier analysis indicated that high expression of these four factors was significantly associated with lower 5-year overall survival and progression-free survival rates. Collectively, the results of the current study suggest that VASH-1 is clinically significant in bladder cancer and its high expression may predict the progression and prognosis of patients with bladder cancer. The present study also implies that VASH-1 may be a novel target for vascular targeting therapy. [ABSTRACT FROM AUTHOR]

Vasohibin-1 (VASH1) is an identified negative feedback inhibitor of angiogenesis induced by vascular endothelial growth factor (VEGF) in vascular endothelial cells (ECs). Expression of VASH1 has been reported not only in ECs of normal tissue, but also in ECs surrounding malignant tumors. In malignant tumors, VASH1 is also gaining attention as a prognosis prediction marker. The aim of this study is to investigate the correlation between VASH1 expression and vascular-related factors and various clinicopathological outcomes in clinical cases of ovarian carcinoma. We retrospectively analyzed clinical records of 58 patients with ovarian carcinoma. The expression patterns of VASH1 and other vascularrelated factors (CD31 as markers of microvessel density (MVD), VEGF receptor type 2 (VEGFR2), D2-40 as markers of lymphovessel density), and Ki67 (as proliferation markers of cancer cells) were examined immunohistochemically. We studied the correlation between immunohistochemical expression and overall survival. VASH1 expression pattern significantly differed between Federation of Obstetrics and Gynecology (FIGO) Stages. Numbers of VASH1-positive vessels had a significant positive correlation with MVD (Speaman's correlation coefficient (ρ) was 0.51, p < 0.001), VEGFR2-positive vessels (ρ = 0.61, p < 0.001), and percentage of Ki67 (ρ = 0.28, p = 0.034). The Cox univariable analyses revealed that the group of high VASH1 expression (> 14.6 vessels per mm²) at Stages I-III is a prognostic factor (HR = 3.3, 95%CI = 0.4-8.4; p = 0.013). Our results indicate that VASH1 expression in ovarian carcinoma is significantly associated with vascular-related factors and Ki67 expression. We propose that VASH1 is a prognostic marker in ovarian carcinoma. [ABSTRACT FROM AUTHOR]

As one of the first-established negative feedback regulators of angiogenesis, mesenchymal vasohibin-1 (VASH1) serves important roles in the progression and prognosis of various types of tumor. However, the clinical implications of VASH1 in esophageal carcinoma (EC) cells have not been reported and the direct effects of VASH1 on EC cells remain unknown. In the present study, the expression of VASH1 in EC cells was observed using immunohistochemistry and western blotting; a χ² test was used to analyze the correlation of VASH1 with clinical parameters, and it was observed that VASH1 was negatively-correlated with tumor size (r=-0.399; P<0.01) and invasion depth (r=-0.318; P<0.01). Survival analysis demonstrated that VASH1 was positively-correlated with increased overall survival (P=0.039) and disease free survival (P=0.012). The direct effects of VASH1 on EC cells were analyzed by altering VASH1 expression, and it was observed that downregulation of VASH1 increased proliferation, clone formation and the migratory ability of EC9706 cells, whereas upregulation of VASH1 inhibited proliferation, clone formation and the migratory ability of EC1 cells. The results of the present study demonstrated that VASH1 in EC cells was negatively-correlated with progression and poor prognosis of patients with EC. VASH1 was able to directly inhibit the growth and migration of EC cells. [ABSTRACT FROM AUTHOR]

The results of our previous study revealed that microRNA (miRNA/miR)‑4530 was upregulated in the serum of patients with diabetic retinopathy. The TargetScan miRNA database was used to identify potential targets of miR‑4530 and vasohibin‑1 (VASH1) was predicted as one of the targets. The results of our previous study demonstrated that miR‑4530 was able to promote angiogenesis in human umbilical vein endothelial cells. Therefore, suppressing miR‑4530 may be a potentially novel approach towards inhibiting tumor angiogenesis. The present study aimed to investigate the function of miR‑4530 and determine whether miR‑4530 was able to regulate angiogenesis in breast carcinoma cells by targeting VASH1. MDA‑MB‑231 and MCF‑7 cells were transfected with miR‑4530 precursor, anti‑miR‑4530 and empty vector plasmids. The expression levels of miRNA and mRNA were detected using the reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR). The expression levels of protein were detected using western blotting. Dual‑luciferase reporter assays were used to identify the target of miR‑4530. Furthermore, cell proliferation, cell cycle, apoptosis and tube formation assays were used to investigate the function of miR‑4530 in vitro. Nude mice were used in a subcutaneous tumor model in vivo study. The results of the present study demonstrated that miR‑4530 significantly suppressed proliferation and promoted apoptosis of breast carcinoma cells. In addition, miR‑4530 expression promoted angiogenesis in vitro. Results from the western blotting and RT‑qPCR revealed that VASH1 was significantly downregulated by miR‑4530 in breast carcinoma cells. The results of the present study suggest that miR‑4530 promotes angiogenesis, inhibits proliferation and induces apoptosis in breast carcinoma cells by suppressing the expression of VASH1. [ABSTRACT FROM AUTHOR]

Vasohibin-1 (VASH1) is a key inhibitor of vascular endothelial growth factor-induced angiogenesis. Although the involvement of VASH1 in various pathological processes has been extensively studied, its role in periodontal disease (PD) remains unclear. We aimed to investigate the role of VASH1 in PD by focusing on osteoclastogenesis regulation. We investigated VASH1 expression in PD by analyzing data from the online Gene Expression Omnibus (GEO) database and using a mouse ligature-induced periodontitis model. The effects of VASH1 on osteoclast differentiation and osteoclastogenesis-supporting cells were assessed in mouse bone marrow-derived macrophages (BMMs) and human gingival fibroblasts (GFs). To identify the stimulant of VASH1, we used culture broth from Porphyromonas gingivalis (Pg), a periopathogen. The GEO database and mouse periodontitis model revealed that VASH1 expression was upregulated in periodontitis-affected gingival tissues, which was further supported by immunohistochemistry and qRT-PCR analyses. VASH1 expression was significantly stimulated in GFs after treatment with the Pg broth. Direct treatment with recombinant VASH1 protein did not stimulate osteoclast differentiation in BMMs but did contribute to osteoclast differentiation by inducing RANKL expression in GFs through a paracrine mechanism. Small interfering RNA-mediated silencing of VASH1 in GFs abrogated RANKL-mediated osteoclast differentiation in BMMs. Additionally, VASH1-activated RANKL expression in GFs was significantly suppressed by MK-2206, a selective inhibitor of AKT. These results suggest that Pg-induced VASH1 may be associated with RANKL expression in GFs in a paracrine manner, contributing to osteoclastogenesis via an AKT-dependent mechanism during PD progression. [Display omitted] • Periodontal disease stimulates VASH1 expression in gingiva. • VASH1 is responsible for Porphyromonas gingivalis -activated RANKL expression of gingival fibroblasts in osteoclastogenesis. • VASH1 stimulates RANKL expression through AKT-dependent mechanism. [ABSTRACT FROM AUTHOR]

Vasohibin-1 is an intrinsic inhibitor of angiogenesis induced by VEGF-A. However, there little is known about the relationship between Vasohibin-1 expression, angiogenesis, and tumor-associated macrophages (TAMs). Vasohibin-1 expression, VEGF-A expression, microvessel density (MVD) marked with CD34, and density of cells marked with CD68 were measured in 111 paraffin-embedded tissues of gastric cancer by immunohistochemistry. The length of tube forming structures of endothelial cells and mobility rate of gastric cancer cells in Matrigel were tested by three-dimensional live cell imaging system. The effect of TAMs on the tumor growth, MVD, and Vasohibin-1 expression was measured by nude mice tumor genesis assay in vivo. We found that high Vasohibin-1 protein expression correlated significantly with worse TNM stage ( P = 0.002), metastatic lymph node ( P = 0.014), distant metastasis ( P = 0.022), overall survival ( P < 0.001), and progression-free survival ( P < 0.001) compared to those with low Vasohibin-1 expression. Vasohibin-1 protein expression had statistical correlation with the MVD ( r = 0.860, P < 0.001), density of CD68 cells ( r = 0.882, P < 0.001), and VEGF-A expression ( r = 0.719, P < 0.001) in the gastric cancer tissues. Decreasing Vasohibin-1 expression with siRNA increased the length of tube forming structures of endothelial cells in co-culture with endothelial cells (EA-hy923), macrophages, and gastric cancers (Hs746T). Tumor volume ( P = 0.001), Vasohibin-1 ( P < 0.001), and VEGF-A ( P < 0.001) expression in mice inoculated with AGS and THP (10:1) was significantly higher than that with AGS alone ( P = 0.001). Vasohibin-1 protein expression had statistical correlation with VEGF expression ( r = 0.786, P < 0.001) and MVD ( r = 0.496, P = 0.014) in gastric xenografted tumor. Therefore, Vasohibin-1 might be a potential marker of worse prognosis and therapeutic target in gastric cancer. Vasohibin-1 might play an important role in the process of angiogenesis regulated by TAMs. [ABSTRACT FROM AUTHOR]

Vasohibin-1 ( VASH1) is a negative feedback regulator of angiogenesis, the first to be discovered, and was identified in vascular endothelial growth factor ( VEGF)-stimulated vascular endothelial cells. Vasohibin-1 inhibits abnormal vascularization induced by various angiogenic factors including fibroblast growth factor and platelet-derived growth factor ( PDGF), in addition to VEGF. By focusing on this characteristic of VASH1, we investigated the antitumor effects of VASH1 expression on ovarian cancer cells that produce different angiogenic factors. By using a high VEGF-producing ovarian cancer cell line, SHIN-3, and a high PDGF-producing ovarian cancer cell line, KOC-2S, the cells were transfected with either a VEGF antagonist, soluble VEGF receptor-1 ( sVEGFR-1, or sFlt-1), or VASH1 genes to establish their respective cellular expression. The characteristics of these transfectants were compared with controls. We previously reported that the expression of sFlt-1 inhibited tumor vascularization and growth of high VEGF-producing ovarian cancer cells, reduced peritoneal dissemination and ascites development, and prolonged the survival time of the host. However, in the current study, the expression of sFlt-1 had no such effect on the high PDGF-producing ovarian cancer cells used here, whereas VASH1 expression inhibited tumor vascularization and growth, not only in high VEGF-producing cells, but also in high PDGF-producing cells, reduced their peritoneal dissemination and ascites, and prolonged the survival time of the host. These results suggest that VASH1 is an effective treatment for ovarian cancer cells that produce different angiogenic factors. [ABSTRACT FROM AUTHOR]

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive disorder with poor prognosis. The treatment options for IPF are very limited. Gambogic acid (GA) has anticancer effect and anti-proliferative activity which is extracted from a dried yellow resin of the Garcinia hanburyi Hook.f. [Clusiaceae (Guttiferae)] in Southeast Asia. However, the anti-fibrotic activities of GA have not been previously investigated.Methods: In this study, the effects of GA on TGF-β1-mediated epithelial-mesenchymal transition (EMT) in A549 cells and endothelial-mesenchymal transition (EndoMT) in human pulmonary microvascular endothelial cells (HPMECs), on the proliferation of human lung fibroblasts (HLF-1) were investigated in vitro, and on bleomycin (BLM)-induced pulmonary fibrosis was investigated in vivo.Results: In TGF-β1 stimulated A549 cells, treatment with GA resulted in a reduction of EMT with a decrease in vimentin and p-Smad3 and an increase in E-cadherin instead. In TGF-β1 stimulated HPMECs, treatment with GA resulted in a reduction of EndoMT with a decrease in vimentin, and an increase in VE-cadherin instead. In the hypoxic HPMECs, treatment with GA reduced Vasohibin-2 (VASH-2), whereas increased VASH-1. In TGF-β1 stimulated HLF-1, treatment with GA reduced HLF-1 proliferation with a decrease in platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF-2) expressions. In vivo, treatment with GA for 2 weeks resulted in an amelioration of the BLM-induced pulmonary fibrosis in rats with a lower VASH-2. Instead, it was observed a higher VASH-1 expression at early stage of fibrosis at 1 mg/kg, with reductions of the pathological score, collagen deposition, α-SMA, PDGF and FGF-2 expressions at fibrotic stage at 0.5 mg/kg and 1 mg/kg.Conclusion: In summary, GA reversed EMT and EndoMT, as well as HLF-1 proliferation in vitro and prevented pulmonary fibrosis in vivo by modulating VASH-2/VASH-1 and suppressing the TGF-β1/Smad3 pathway. [ABSTRACT FROM AUTHOR]

Liver fibrosis is linked to VEGF-induced angiogenesis. Overexpression of exogenous vasohibin-1, a feedback inhibitor of angiogenesis, has been reported to reduce liver fibrosis after bile duct ligation (BDL). To uncover the function of endogenous vasohibin-1, we performed BDL using vasohibin-1-deficient mice and analyzed liver fibrosis, injury, and angiogenesis. Liver fibrosis was induced by 14-days of BDL in both wild-type and vasohibin-1-deficient mice. The liver sections were stained with anti-CD31 to visualize endothelial cells and with Sirius red to observe fibrotic regions. Total RNAs were purified from the livers and expression of collagen I α1 mRNA was measured by quantitative PCR. Plasma ALT activity was determined to assess liver injury. Surprisingly, the same extents of increases were seen in anti-CD31 and Sirius red stainings, collagen I α1 mRNA expressions, hepatic hydroxyproline contents, and ALT activity after 14-days of BDL in both wild-type and vasohibin-1-deficient mice. There was unexpectedly no difference between these mice, suggesting that anti-fibrogenic and angiogenic activities of the endogenous vasohibin-1 might be masked in the normal liver at early stage of hepatic fibrosis in mice. [ABSTRACT FROM AUTHOR]

Tubulointerstitial injuries are known to predict the deterioration of renal function in chronic kidney disease ( CKD). We recently reported the protective role of Vasohibin-1( VASH-1), a negative feedback regulator of angiogenesis, in diabetic nephropathy, but its impact on tubulointerstitial injuries remains to be elucidated. In the present study, we evaluated the role of endogenous VASH-1 in regulating the tubulointerstitial alterations induced by unilateral ureteral obstruction ( UUO), and assessed its role on fibrogenesis and the activation of Smad3 signaling in renal fibroblasts. UUO was induced in female Vasohibin-1 heterozygous knockout mice ( VASH-1+/−) or wild-type ( WT) ( VASH-1+/+) littermates. Mice were sacrificed on Day 7 after left ureter ligation, and the kidney tissue was obtained. Interstitial fibrosis, the accumulation of type I and type III collagen and monocytes/macrophages infiltration in the obstructed kidneys ( OBK) were significantly exacerbated in VASH-1+/− mice compared with WT mice (Day 7). The increases in the renal levels of TGF- β1, pSmad3, NF- κB pp65, CCL2 m RNA, and the number of interstitial fibroblast-specific protein-1 (FSP-1)+ fibroblasts in the OBK were significantly aggravated in VASH-1+/− mice. In addition, treatment with VASH-1 si RNA enhanced the TGF- β1-induced phosphorylation of Smad3, the transcriptional activation of the Smad3 pathway and the production of type I/type III collagen in fibroblasts, in vitro. Taken together, our findings demonstrate a protective role for endogenous VASH-1 on tubulointerstitial alterations via its regulation of inflammation and fibrosis and also show the direct anti-fibrotic effects of VASH-1 on renal fibroblasts through its modulation of TGF- β1 signaling. [ABSTRACT FROM AUTHOR]

Vasohibin-1 (VASH1) is a newly discovered angiogenesis inhibitor that is specifically expressed in human vascular endothelial cells in response to vascular endothelial growth factor and fibroblast growth factor-2. This study aimed to evaluate the expression of VASH1 in non-small cell lung cancer (NSCLC) and correlates its expression with the clinicopathological parameters and prognosis of the disease. Immunohistochemical analysis was used to determine the expression of VASH1 in NSCLC tissue and adjacent normal tissue from 84 patients. The relationship between VASH1 expression and clinicopathological indicators was examined with the chi-squared test. Moreover, the survival rate was calculated with the Kaplan-Meier survivor curve. Finally, the correlation between the indicators and patient survival was estimated with Cox analysis. VASH1 was high expressed in 63.1 % of NSCLC tissues versus 21.4 % of adjacent tissues ( P < 0.01). High VASH1 expression in NSCLC tissue was correlated with clinicopathological features including lymph node status ( P = 0.024) and TNM stage ( P = 0.036). The Kaplan-Meier curve indicated that the patients with high VASH1 expression had significantly shorter survival than those with low VASH1 expression. In the multivariate Cox regression model, high VASH1 expression was identified as an independent prognostic factor for patients with NSCLC. High VASH1 expression is predictive of poor prognosis of NSCLC, implying that VASH1 may be a promising new target for targeted therapies for NSCLC. [ABSTRACT FROM AUTHOR]

Vasohibin-1 has been recently detected in endothelial cells and identified as a negative feedback regulator of angiogenesis induced by VEGF-A. However, the expression of Vasohibin-1 in colorectal cancer and its correlations with VEGF-A, microvessel density (MVD), and the prognosis of the patients remain unclear. In this study, Vasohibin-1 and VEGF-A expression were measured in 132 paraffin-embedded tissues of colorectal cancer by immunohistochemistry and Western blot, as well as in colon cancer cell lines with different metastatic potential and in normal colon cell by Western blot and real-time PCR. MVD was measured by counting CD34 positive clusters in a single field of view with the most intensive neovascularization of colon cancer tissues. The correlation between the expression of Vasohibin-1, VEGF-A, MVD, clinicopathological features, and prognosis was analyzed. We found that Vasohibin-1 and VEGF-A proteins were expressed in 88.64 % (117/132) and 84.09 % (111/132) colorectal cancer tissues, respectively. Strongly positive correlations were found between Vasohibin-1, VEGF-A expression, and MVD in the colorectal cancer tissues (Vasohibin-1 vs. VEGF-A: r = 0.688, P < 0.001; Vasohibin-1 vs. MVD: r = 0.483, P < 0.001; VEGF-A vs. MVD: r = 0.491, P < 0.001). Vasohibin-1 expression has significant positive correlation with pathological TNM stage ( P = 0.001), tumor stromal invasion ( P = 0.004), lymph node status ( P = 0.003), and distant metastasis ( P = 0.033), but no correlation with tumor differentiation ( P = 0.756). The patients with high Vasohibin-1 expression had significantly worse overall survival (OS) and progression-free survival (PFS) than those with low Vasohibin-1 expression (OS: P = 0.001; PFS: P = 0.003). In addition, Vasohibin-1 protein expression is an independent risk factor affecting OS and PFS. Therefore, we conclude that Vasohibin-1 is a clinically relevant predictor of patient prognosis in colorectal cancer. Vasohibin-1 might become a new biomarker and provide additional prognostic information in patients with colorectal cancer. [ABSTRACT FROM AUTHOR]

Non-small cell lung carcinoma is one of the most common leading causes of cancer mortality, and studying the features of intratumoral vessels, especially their generation and maturation, has become more important because of the recent application of antiangiogenic therapy. Vasohibin-1 has been recently considered one of the immunohistochemical markers for identifying neovascularization in archival materials. In addition, the functional maturation of blood vessels is considered to be related to pericyte formation around endothelial cells. Therefore, in this study, we evaluated the status of angiogenesis and maturation of intratumoral blood vessels in 93 patients with non-small cell lung carcinoma (50 with adenocarcinoma and 43 with squamous cell carcinoma) using immunohistochemistry of vasohibin-1, endoglin, CD31, and nestin. The vasohibin-1/CD31-positive ratio was significantly (P = .03) correlated with the Ki-67/CD31 ratio, confirming that the vasohibin-1/CD31-positive ratio represented the status of neovascularization in lung cancer. There were no statistically significant differences in vasohibin-1/CD31 ratios between adenocarcinoma and squamous cell carcinoma in both inner (P = .39) and outer areas (P = .36) of the tumor. The vasohibin-1/nestin-positive ratio, which represents the degrees of vascular maturation in proliferative vessels, was significantly lower in inner areas of adenocarcinoma (0.4 ± 0.1) than those in squamous cell carcinoma (0.8 ± 0.1) (P = .02). These results demonstrated that the degrees of maturation in newly formed blood vessels were less developed in inner areas of squamous cell carcinoma than adenocarcinoma, which may account partly for the complications of antivascular endothelial growth factor therapy more frequently detected in patients with squamous cell carcinoma. [ABSTRACT FROM AUTHOR]

Clinical Relevance: To determine whether Vasohibin-1 which is a potential clinical biomarker is an independent risk factor in patients with diabetic retinopathy., Background: Diabetic retinopathy (DR) is a common chronic microangiopathy in type 2 diabetes mellitus (T2DM). Vasohibin-1 (VASH-1) is an angiogenesis regulator that is closely related to pathological vascularization in DM. This study aimed to determine whether the serum levels of VASH-1 were related to the occurrence of DR in T2DM patients., Methods: T2DM patients were divided into three groups: the nondiabetic retinopathy (NDR) group (n = 41), the nonproliferative diabetic retinopathy (NPRD) group (n = 40), and the proliferative diabetic retinopathy (PDR) group (n = 41). A control (CON) group consisting of 40 healthy subjects was also recruited. The serum levels of VASH-1 were measured by enzyme-linked immunosorbent assay kits., Results: The concentration of VASH-1 in the CON groups was less significantly than that of the NDR, NPDR and PDR groups. ( P < 0.05). Body mass index, fasting plasma glucose (FPG), hemoglobina1c (HbA1C), blood urea nitrogen (BUN) and diabetic durations were positively correlated with the serum concentration of VASH-1 (all P < 0.05). In univariate logistic regression analyses, the HbA1C, diabetic durations, HDL-c, eGFR and VASH1 were associated with the presence of diabetic retinopathy. Multivariate logistic regression analysis showed that duration of diabetes were significantly associated with diabetic retinopathy., Conclusion: We have shown that VASH-1 is associated with an increased risk of developing diabetic retinopathy. But the serum levels of VASH-1 are not independent risk factors for DR in T2DM.

Angiogenesis, a formation of neovessels, is regulated by the local balance between angiogenesis stimulators and inhibitors. A number of such endogenous regulators of angiogenesis have been found in the body. Recently, vasohibin-1 (VASH1) was isolated as a negative feedback regulator of angiogenesis produced by endothelial cells (ECs) and subsequently vasohibin-2 (VASH2) as a homologue of VASH1. It was then explored that VASH1 is expressed in ECs to terminate angiogenesis, whereas VASH2 is expressed in cells other than ECs to promote angiogenesis in the mouse model of angiogenesis. This review will focus on the vasohibin family members, which are novel regulators of angiogenesis. [ABSTRACT FROM AUTHOR]

Vasohibin-1(VASH1) has recently been isolated as a novel negative feedback inhibitor of angiogenesis. Several studies have demonstrated that VASH1 plays important roles in tumor angiogenesis but the role of this angiogenic inhibitor in renal cell carcinoma (RCC) has not been elucidated until now. In this study, we investigated the expression pattern of VASH1 and the association with clinicopathological features in RCC. Expression of VASH1, hypoxia-inducible factor-1α (HIF-1α), and microvessel density (MVD, labeled by CD34) was assessed by immunohistochemistry in 46 RCC specimens and 20 adjacent nontumorous renal tissues (ANRTs). Correlation between vasohibin-1 and HIF-1α, MVD, and clinicopathological features was then investigated. In RCC, VASH1 was expressed mainly in the cytoplasm and membrane of tumor cells and partly in vascular endothelial cells. In ANRT, it was mainly expressed in the cytoplasm and membrane of renal tubular epithelial cells and partly in vascular endothelial cells and glomerular mesangial cells. The expression level of VASH1 in RCC tissue was significantly lower than that in ANRT and was significantly reduced with the increased degree of malignancy in RCC tissues. In addition, a significantly negative correlation was noted between VASH1 expression and HIF-1α expression and a significantly negative correlation was noted between VASH1 expression and MVD in RCC. Therefore, VASH1 expression is reduced and it associates with clinicopathological features in RCC. Based on our findings and the knowledge of other angiogenesis inhibitors, we postulate that VASH1 would potentially be a biomarker and a candidate for molecular targeted therapy for patients with RCC in the future. [ABSTRACT FROM AUTHOR]

Vasohibin-1 has recently been found and is known as an endogenous angiogenesis inhibitor, but the role of vasohibin-1 in hepatocellular carcinoma (HCC) is unknown. This study investigated the expression pattern of vasohibin-1, its correlation with clinicopathological features, and its potential role in tumor angiogenesis and prognosis of HCC. Expression of vasohibin-1, vascular endothelial growth factor-A (VEGF-A), and intratumoral microvessel density (MVD, labeled by CD34) were assessed by immunohistochemistry in 117 HCC specimens and adjacent nontumor liver tissues (ANLT). Correlation between vasohibin-1 and VEGF-A, MVD, and clinicopathological features was then investigated. Prognostic value of these factors was determined using Kaplan-Meier analysis and a Cox proportional hazards regression model. Cytoplasm high expression of vasohibin-1 was detected in 38.5% (45/117) of the HCC tissues, which was significantly higher than that in 16.2% (19/117) of ANLT ( P < 0.001). Vasohibin-1 was statistically correlated with VEGF-A, MVD, and microvascular invasion in HCC ( P = 0.014, 0.035, and 0.002, respectively). Patients with vasohibin-1 high expression had significantly poor disease-free survival (DFS) and overall survival (OS) at 5 years after curative hepatectomy ( P < 0.001 for each). Multivariate analysis confirmed that vasohibin-1 high expression was an independent prognosticator for unfavorable DFS (HR = 2.554, P < 0.001) and OS (HR = 2.232, P = 0.002), along with VEGF-A and TNM stage. Upregulation of vasohibin-1 expression is associated with angiogenesis and poor prognosis of HCC. Vasohibin-1 and VEGF-A are the most important factors influencing the dismal prognosis based on the modulation of angiogenesis in HCC, which provides a rational approach for treatment in the future. [ABSTRACT FROM AUTHOR]

Accumulating evidence suggests that TAMs contribute to tumor progression. Recently, vasohibin-1 and vasohibin-2 were detected in endothelial cells and considered as intrinsic angiogenesis inhibitors. However, it is not known whether they are also expressed in cancer cells or tumor-associated macrophages (TAMs). Realtime RT-PCR was used to investigate the vasohibin-1 and vasohibin-2 expression in four gastric cancer cell lines, including a non-metastatic cell line AGS, and metastatic cell lines HGC-27, Hs-746T and NCI-N87, co-cultured with or without TAMs. The effect of hypoxic conditions on vasohibin expression was evaluated as well, and the correlation between vasohibin-1, vasohibin-2 and VEGF-A expression under different culture conditions was analyzed. We found that both vasohibin-1 and vasohibin-2 were expressed in the four gastric cancer cell lines and in TAMs. Under normal conditions, vasohibin-1 and vasohibin-2 expressions were significantly upregulated by TAMs in all the gastric cancer cell lines. Under hypoxia, both vasohibin-1 and vasohibin-2 expressions were significantly decreased in the distant metastasis cancer cell line Hs-746T, cultured with or without TAMs ( P < 0.001). After induction by TAMs or hypoxia, the vasohibin-1 and vasohibin-2 expressions correlated with that of VEGF-A. In addition, TAMs, when co-cultured with the metastatic cancer cell lines, showed hypoxia-induced vasohibin-1 upregulation ( P < 0.05). In conclusion, both vasohibin-1 and vasohibin-2 mRNA are expressed in gastric cancer cells and in TAMs, and their expressions are altered by hypoxia. [ABSTRACT FROM AUTHOR]

Lymphangioleiomyomatosis (LAM) is a rare pulmonary neoplasm, clinically associated with dyspnea and respiratory failure. Current therapeutic modalities do not necessarily reach satisfactory outcome and novel therapeutic approaches are currently warranted. Therefore, in this study, we focused on vasohibin-1 (VASH1) and -2 (VASH2); VASH1 terminated and VASH2 promoted angiogenesis. In addition, both VASH1/2 were reported to influence the progression of various human malignancies. We first performed hierarchical clustering analysis to attempt to classify 36 LAM cases into three different clusters according to immunoreactivity of VASH1/2 and other angiogenic and prognostic factors of LAM; VEGFR1/2/3, p-mTOR, p-S6, p-4EBP, ERα, PgR, MMP2, and MMP9. The cluster harboring higher angiogenic factors had higher VASH1/2 status. VASH1 was significantly positively correlated with VEGFR2, MMP9, and p-mTOR (p-value <0.05), and VASH2 with both angiogenic and prognostic factors including VEGFR1, PgR, MMP9, p-mTOR, p-S6, and p-4EBP (p-value <0.05). Subsequent PCR array of angiogenic genes demonstrated that high VASH1 mRNA was significantly positively associated with the status of SPHK1 and TYPM, lower EGF and EFNB2 (p-value <0.05), and high VASH2 mRNA negatively with MMP2 (p-value <0.05). VASH1 was considered to be up-regulated by activation of angiogenesis, whereas VASH2 could influence the angiogenesis and progression of LAM. • Vasohibin (VASH)1/2 are angiogenic inhibitor and promoter, respectively. • Both VASH1/2 were immunohistochemically expressed in LAM cells. • In immunohistochemistry and PCR array, VASH1 was associated with angiogenic factors. • VASH2 was associated with both angiogenic and prognostic factors of LAM. • VASH1/2 were associated with younger onset and lower P/F ratio, respectively. [ABSTRACT FROM AUTHOR]

Vasohibin-1 (VASH1) is an angiogenesis inhibitor, while vasohibin-2 (VASH2) is a proangiogenic factor. The roles of VASH1 and VASH2 expression in gastroenterological cancers remain unclear. We searched for relevant literature, specifically studies on gastroenterological cancer, and evaluated the relationship between VASH expression and clinical outcomes. Nine studies on VASH1 involving 1,574 patients were included. VASH1 expression was associated with the TNM stage [OR (odds ratio) 2.05, 95% CI (confidence interval) 1.24-3.40], lymph node metastasis (OR 1.79, 95% CI 1.24-2.58), lymphatic invasion (OR 1.95, 95% CI 1.41-2.68), and venous invasion (OR 2.49, 95% CI 1.60-3.88); poor clinical outcomes were associated with high VASH1 expression. High VASH1 expression was associated with a significantly shorter overall survival (OS) [HR (hazard ratio) 1.69, 95% CI 1.25-2.29] and disease-free survival (DFS) (HR 2.01, 95% CI 1.28-3.15). Three studies on VASH2 involving 469 patients were analyzed. VASH2 expression was associated with the TNM stage (OR 4.21, 95% CI 1.89-9.51) and venous invasion (OR 2.10, 95% CI 1.15-3.84); poor clinical outcomes were associated with high VASH2 expression. High VASH2 expression was associated with a significantly lower OS (HR 1.61, 95% CI 1.09-2.37). In conclusion, high VASH1 and VASH2 expression levels were associated with poor clinical outcomes and prognosis in patients with gastroenterological cancers.