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Background: Tumor cells that have the ability to express vascular endothelial growth factor (VEGF) are more competent to growth and metastasize by the adequate amount of blood and oxygen supply by the blood vessels to the growing mass of cells. Hypoxic tumors are known for its aggressiveness and resistance to the treatment. Targeting VEGF and hypoxia‑inducible factor‑1 alpha (HIF‑1α) is an attractive strategy to interrupt the multiple pathways crucial for tumor growth. In the present study, two thiazole acetamide derivative’s anticancer property, anti VEGF and HIF‑1α inhibitory property were investigated. Methodology: Two thiazole acetamide compounds were synthesized, TA1 and TA2 and its anticancer property was studied in Erlich’s ascites cancer cells. To evaluate the anticancer property the assays such as 3‑(4,5‑dimethylthiazol‑2‑yl)‑2,5‑diphenyltetrazolium bromide assay, DNA diffusion assay for apoptosis, and lactate dehydrogenase leakage assay were carried out. The cell culture media was used to assess the secreted VEGF level. Molecular docking studies were performed to analyze the binding efficiency of the study compounds to the kinase insert domain‑containing receptor (KDR) and fms‑like tyrosine kinase (FLT)‑binding domains of VEGF protein. HIF‑1α inhibitory study was performed by flow cytometry analysis using HUVEC cell line. Results: The study compounds inhibited HIF‑1α and VEGF secretion, these data shown positive prop up for the anticancer property of the derivatives. The docking studies showed moderate binding of study compounds to KDR and FLT‑binding domains of VEGF protein. Conclusion: These results conclude the anticancer and anti‑angiogenic property of the synthesized thiazole‑acetamide derivatives. [ABSTRACT FROM AUTHOR]

Background: Tumor cells that have the ability to express vascular endothelial growth factor (VEGF) are more competent to growth and metastasize by the adequate amount of blood and oxygen supply by the blood vessels to the growing mass of cells. Hypoxic tumors are known for its aggressiveness and resistance to the treatment. Targeting VEGF and hypoxia-inducible factor-1 alpha (HIF-1α) is an attractive strategy to interrupt the multiple pathways crucial for tumor growth. In the present study, two thiazole acetamide derivative's anticancer property, anti VEGF and HIF-1α inhibitory property were investigated.Methodology: Two thiazole acetamide compounds were synthesized, TA1 and TA2 and its anticancer property was studied in Erlich's ascites cancer cells. To evaluate the anticancer property the assays such as 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, DNA diffusion assay for apoptosis, and lactate dehydrogenase leakage assay were carried out. The cell culture media was used to assess the secreted VEGF level. Molecular docking studies were performed to analyze the binding efficiency of the study compounds to the kinase insert domain-containing receptor (KDR) and fms-like tyrosine kinase (FLT)-binding domains of VEGF protein. HIF-1α inhibitory study was performed by flow cytometry analysis using HUVEC cell line.Results: The study compounds inhibited HIF-1α and VEGF secretion, these data shown positive prop up for the anticancer property of the derivatives. The docking studies showed moderate binding of study compounds to KDR and FLT-binding domains of VEGF protein.Conclusion: These results conclude the anticancer and anti-angiogenic property of the synthesized thiazole-acetamide derivatives. [ABSTRACT FROM AUTHOR]

Objective: The goal of this research was to determine the influence of 4 weeks aerobic training on gene expression of tumor necrosis factor alpha (TNF-α), hypoxia-inducible factor-1 alpha (HIF-1a) and vascular endothelial growth factor (VEGF) in the cardiac tissue of diabetic rats. Materials and Methods: In an experimental study, 30 male wistar rats were partitioned into three groups (n=10), diabetic aerobic training, diabetic control and healthy control (n=10). Induction of type 2diabetes (T2DM) was done by intraperitoneal infusion of streptozotocin. The progressive aerobic training protocol entailed 4 weeks, 5 sessions per week running on treadmill at velocity of 20 m/min for 60 min. The gene expression of TNF-α, VEGF and HIF-1α were measured by real time & PCR. One way analysis of variance and bonferroni test were applied to analysis the data. The significant level was set at P-value< 0.05. Results: The results indicated that the aerobic training induced significant decrease in TNF-α mRNA (P-value< 0.001) and significant increase in HIF-1α mRNA (P-value< 0.001) and VEGF mRNA (P-value< 0.001) compared to diabetic control group. Conclusion: It appears that aerobic training with reduction of TNF-α issues an affirmative effect on angiogenesis, as a result, it improves diabetic cardiac. [ABSTRACT FROM AUTHOR]

CONTEXT: Glioblastoma is a malignant brain tumor with limited treatment modalities due to its nature. SB365, Pulsatilla saponin D, is known to induce apoptosis and inhibit the growth of many cancer cells. AIM: We elucidated the anticancer effects of SB365 in glioblastoma cells. METHODS: We examined the antiproliferative activity of SB365 in human glioblastoma cell lines. Apoptosis was evaluated using the Hoechst assay, TUNEL assay, DAPI nuclear staining, and Western blotting analysis. To test the antimetastatic capacity of SB365, cell migration assay was conducted, and hypoxia-inducible factor-1 alpha (HIF-1a) expression and vascular endothelial growth factor (VEGF) level were determined under hypoxic conditions. STATICAL ANALYSIS: Significance of the results was confirmed by a one-way analysis of variance analysis. RESULTS: SB365 treatment suppressed the growth of glioblastoma cells and resulted in apoptotic morphological features such as nuclear condensation and fragmentation, enhancing the expression of cleaved poly (ADP-ribose) polymerase and caspase-3. It also significantly delayed cell migration and decreased the HIF-1a expression and VEGF secretion. CONCLUSION: Our findings thus demonstrate that SB365 induced apoptosis and delayed the growth and migration of human glioblastoma cells. It is considered that SB365 would be a promising therapeutic option for glioblastoma. [ABSTRACT FROM AUTHOR]

Background The prognostic predict biomarkers are important in oral squamous cell carcinoma (OSCC). We investigated the expression patterns and quantitation of hypoxia-inducible factor-1 alpha (HIF-1α) and vascular endothelial growth factor (VEGF) in OSCC patients. Among OSCC patients with recurrence and metastasis, the expression percentages of HIF-1α and VEGF also were analyzed. Methods Thirty-eight patients (8 hyperkeratosis, 30 oral squamous cell carcinoma) were included in this study. In the follow-up period, 5 OSCC patients had metastasis and 12 OSCC patients had local recurrence. We used computer-assisted image processing to analyze immunohistochemistry (IHC). The quantitative analysis of IHC slides, including upper-layer epithelium (U) and lower-layer epithelium (L), was calculated. Results We found homogeneous expression of VEGF in the epithelium. However, two patterns of HIF-1α expression were observed: homogeneous and heterogeneous. The highest U + L layer percentage in HIF-1α and VEF expression had significant association in tumor metastasis and recurrence ( p < 0.001 in HIF-1α and p < 0.001 in VEGF). U + L layer HIF-1α expression percentage was >156.4%, and the survival rate was poor ( p < 0.001). Conclusion HIF-1α expression was not only influenced by tumor hypoxia, it also reflected tumor cell characteristics. High concentrations of VEGF and HIF-1α may have value as prognostic markers of tumor metastasis and recurrence. [ABSTRACT FROM AUTHOR]

The histopathological growth pattern (HGP) is a morphological reflection of interactions between cancer cells and the surrounding tissue, and has been identified with a remarkably predictive value in liver metastases. However, there is still a lack of studies on HGP of primary liver cancer even furtherly on HGP evolution. We employed VX2 tumor-bearing rabbits as the primary liver cancer model of which tumor size and distant metastasis were investigated. HGP assessment and computed tomography scanning was performed in four cohorts of different time points to map the HGP evolution. Additionally, Fibrin deposition and neovascularization were evaluated by Masson staining and immunohistochemical analysis of CD31, hypoxia-inducible factor-1 alpha (HIF1A) and vascular endothelial growth factor (VEGF). Tumors displayed exponential growth in the VX2 liver cancer model, but these tumor-bearing animals did not show any visible metastasis until they reached a specific stage of development. Correspondingly, the components of HGPs changed along with the tumor growth. The proportion of desmoplastic HGP (dHGP) decreased initially and then grew, but in contrast, the level of replacement HGP (rHGP) rose from the 7th day, reached a peak at around the 21st day, and then appeared drop. Importantly, the collagen deposition and expression of HIF1A and VEGF correlated with dHGP, while CD31 did not. HGP evolution presents a two-way switch including dHGP to rHGP and rHGP to dHGP, in which the emergence of rHGP may be linked to metastases. HIF1A-VEGF partially participates in the HGP evolution and presumably plays a key role in the formation of dHGP. [ABSTRACT FROM AUTHOR]

Vascular endothelial growth factor (VEGF)-dependent angiogenesis has a crucial role in the corpus luteum formation and their functional maintenances in mammalian ovaries. A previous study by our group reported that activation of hypoxia-inducible factor (HIF)-1α signaling contributes to the regulation of VEGF expression in the luteal cells (LCs) in response to hypoxia and human chorionic gonadotropin. The present study was designed to test the hypothesis that HIF prolyl-hydroxylases (PHDs) are expressed in LCs and overexpression of PHD2 attenuates the expression of VEGF induced by hypoxia in LCs. PHD2-overexpressing plasmid was transfected into LC2 cells, and successful plasmid transfection and expression was confirmed by reverse transcription quantitative polymerase chain reaction and western blot analysis. In addition, the present study investigated changes of HIF-1α and VEGF expression after incubation under hypoxic conditions and PHD2 transfection. PHD2 expression was significantly higher expressed than the other two PHD isoforms, indicating its major role in LCs. Moreover, a significant increase of VEGF mRNA expression was identified after incubation under hypoxic conditions, which was, however, attenuated by PHD2 overexpression in LCs. Further analysis also indicated that this hypoxia-induced increase in the mRNA expression of VEGF was consistent with increases in the protein levels of HIF-1α, which is regulated by PHD-mediated degradation. In conclusion, the results of the present study indicated that PHD2 is the main PHD expressed in LCs and hypoxia-induced VEGF expression can be attenuated by PHD2 overexpression through HIF-1α-mediated mechanisms in LCs. This PHD2-mediated transcriptional activation may be one of the mechanisms regulating VEGF expression in LCs during mammalian corpus luteum development. [ABSTRACT FROM AUTHOR]

Aim To assess the pro-angiogenic and pro-inflammatory capacity of the dentine-pulp complex in response to the prolyl hydroxylase inhibitor L-mimosine in a tooth slice organ culture model. Methodology Human teeth were sectioned transversely into 600-μm-thick slices and cultured in medium supplemented with serum and antibiotics. Then, pulps were stimulated for 48 h with L-mimosine. Pulps were subjected to viability measurements based on formazan formation in MTT assays. In addition, histological evaluation of pulps was performed based on haematoxylin and eosin staining. Culture supernatants were subjected to immunoassays for vascular endothelial growth factor ( VEGF) to determine the pro-angiogenic capacity and to immunoassays for interleukin ( IL)-6 and IL-8 to assess the pro-inflammatory response. Interleukin-1 served as pro-inflammatory control. Echinomycin was used to inhibit hypoxia-inducible factor-1 ( HIF-1) alpha activity. Data were analysed using Student's t-test and Mann-Whitney U test. Results Pulps within tooth slices remained vital upon L-mimosine stimulation as indicated by formazan formation and histological evaluation. L-mimosine increased VEGF production when normalized to formazan formation in the pulp tissue of the tooth slices ( P < 0.05). This effect on VEGF was reduced by echinomycin ( P < 0.01). Changes in normalized IL-6 and IL-8 levels upon treatment with L-mimosine did not reach the level of significance ( P > 0.05), whilst treatment with IL-1, which served as positive control, increased IL-6 ( P < 0.05) and IL-8 levels ( P < 0.05). Conclusions The prolyl hydroxylase inhibitor L-mimosine increased VEGF production via HIF-1 alpha in the tooth slice organ culture model whilst inducing no prominent increase in IL-6 and IL-8. Pre-clinical studies will reveal if these in vitro effects translate into dental pulp regeneration. [ABSTRACT FROM AUTHOR]

To evaluate the expression of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1 alpha (HIF-1α) during the periovulatory period, goat ovaries were collected at 0, 4, 8, 12, 24, and 48 h after treatment with 300 IU hCG. Total cellular RNA was isolated and VEGF and HIF-1α were quantified using real-time RT-PCR. The mRNA levels of VEGF in thecal tissue remained unchanged prior to ovulation. However, the mRNA levels of VEGF in thecal tissues at 48 h increased to 7.5-fold of the level at 0 h (P < 0.05). In granulosa tissue, the VEGF mRNA levels were not detected in granulosa cells at 48 h. In thecal tissue, the mRNA level of HIF-1 1α at 4 h was 1.5-fold of the level at 0 h and remained unchanged during 8-24 h; however the levels were significantly increased at 48 h. The mRNA levels of HIF-1α in granulosa at 4 h was not changed but levels were increased (P < 0.05) at 8 h and at 12 h and then decreased at 24 and 48 h, respectively. These data describe the relationships of VEGF- and HIF-1α-dependent angiogenesis during the periovulatory periods by which hypoxia during ovulation is crucial for establishing the thecal new vasculature. [ABSTRACT FROM AUTHOR]

Abstract: Hinokitiol, a natural iron-chelating agent, is known to have diverse biological and pharmacological activities in various cell types. However, the effect of hinokitiol on dental pulp cells has not yet been reported. In this study, hinokitiol increases hypoxia-inducible factor-1α (HIF-1α) protein levels and vascular endothelial growth factor (VEGF) secretion in human dental pulp cells. The extracellular-signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK) pathways are involved in hinokitiol-induced HIF-1α protein expression in dental pulp cells. Conditioned media from hinokitiol-treated pulp cells enhances angiogenesis in vitro and in vivo. Overall, these results show that hinokitiol promotes ERK and p38MAPK activation and HIF-1α-induced VEGF production, thus increasing the angiogenic potential of dental pulp cells. [Copyright &y& Elsevier]

Age-related macular degeneration (AMD) is a leading cause of irreversible vision loss among the elderly population. Vascular endothelial growth factor (VEGF) is essential for choroidal neovascularization (CNV) development in advanced, wet AMD. Chrysin (5,7-dihydroxyflavone) is a natural flavonoid with anti-inflammatory, anti-oxidative, and anti-angiogenic effects. We hypothesized that intravitreally injected chrysin may inhibit CNV due to its inhibitory effect on angiogenesis. To determine the effects of chrysin on an experimental CNV model, we induced CNV in Brown Norway rats with a diode laser. One week later, rats were injected intravitreally with chrysin in the right eye and vehicle in the left eye. The following week, we evaluated chrysin's effects via the CNV grade assessed with fluorescein angiography and histologic analyses. Hypoxia-inducible factor-1 alpha (HIF-1α) and VEGF expression in the retina/choroid complex were also measured in both eyes. The mean CNV grade was significantly lower in chrysin-treated vs. control eyes (2.34 ± 1.14 vs. 2.97 ± 1.05, p < 0.001), as was the mean CNV thickness (33.90 ± 4.89 vs. 38.50 ± 5.43 μm, p < 0.001) and mean HIF-1α and VEGF levels (both p < 0.001). Compared to chrysin-treated eyes, the relative risk of control eyes developing high-leakage lesions was 2.03 (95% confidence interval: 1.46–2.83). Since chrysin inhibited laser-induced CNV and downregulated HIF-1α and VEGF expression, it is a candidate for treating wet AMD and other CNV-associated conditions. [ABSTRACT FROM AUTHOR]