Tehran University Medical Journal

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Background: Uterine environment and fetal period can profoundly affect health of the neonat. Hypoxia-inducible factor-1α (HIF-1α) is a transcription factor that regulates cellular stress responses and its activity is essential in both embryogenesis and postnatal life. The aim of the present study was to investigate the effects of maternal swimming on rat pups' HIF-1α levels as a key regulator of oxygen in lungs.

Methods: Sixteen female Wistar rats weighing 180- 200 grams were acclimated to a new environment consisting of equal light-darkness cycle and ad lib access to chow and adapted to the stress caused by water for two weeks. The rats were divided into two swimming and control groups. Swimming training began on the first day of pregnancy in a pool and continued for 3 weeks (1 h/day, 5 days/wk). Pups' lungs were removed two days after birth and their HIF-1α concentration was determined with enzyme-linked immunosorbent assay (ELISA). Statistical analysis of the data was done using independent t-test. A p-value smaller than 0.05 was considered statistically significant.

Results: Swimming lead to a significant (P<0.001) increase in the pups' lung HIF-1α levels compared with the control group. Although 3-wk period of swimming training, showed no significant increase in weight and also lung weight of newborns. Thus it can be concluded that swimming endurance training in pregnancy, can be considered as appropriate alternative in order to embryos development.

Conclusion: Our research suggests that HIF-1α level is an essential element for the development of the lungs of embryos. Moreover, further studies on the lung HIF-1α levels at post-natal period with different modes of exercise will provide more clear insight into the mechanisms of the findings resulting from this study.

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Background: Colorectal cancer is a major cause of morbidity and mortality throughout the world, and its treatments include surgery, chemo-radiotherapy. Despite improvements in clinical outcomes of patients with this tumor over the past decades, prognosis remains poor with a 5-year survival rate of <10%. Angiogenesis inhibitor agents have been recently added to the treatment regimen of this disease. In the past two decades, it has been recognized that selective inhibitors of the cyclooxygenase -2 (Cox-2) enzyme result in the regression in the size of colorectal tumor, and one of its reasons is attributed to angiogenesis inhibition. The present study aimed at identifying the molecular pathways of angiogenesis inhibition by celecoxib. Methods: HCT-116, which is one of the cell lines of Colorectal cancer (separated from human colorectal adenocarcinoma) was provided by the National Cell bank of Iran (NCBI) affiliated to Pasteur Institute. It was then cultured in DMEM (high glucose) culture medium containing 10% FBS, and then treated in the active substance of celecoxib at pharmacological concentrations of 50 mM (C50) and 100 mM (C100). Afterwards, RNA was extracted and cDNA was prepared. The oligonucleotide of HIF-1 Alpha gene (angiogenesis initiator) was prepared and the level of HIF-1 alpha gene expression was assessed with a real-time PCR device in three control, C50 and C100 groups. Results: HIF-1 alpha gene expression significantly decreased in the celecoxib treatment group (compared with control group) with the concentration of C100 (P< 0.001), but no change was observed in the concentration of C50. Conclusion: Angiogenesis is a key factor in the carcinogenesis process and FDA today approved bevacizumab as a first-line treatment for patients with metastatic colorectal cancer. The results of this study showed one of the causes of angiogenesis reduction in celecoxib-treated colorectal cancer. According to clinical findings and basic studies, celecoxib will be hopefully used as a first-line therapy along with chemotherapy in the near future in colorectal cancer. The advantages of this treatment method include its low cost and low side effects.

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Angiogenesis, as the process of new vessel formation from pre-existing vessels is dependent on a delicate equilibrium between endogenous angiogenic and antiangiogenic factors. However, under pathological conditions, this tight regulation becomes lost which can result in the formation of the different diseases such as cancer. Angiogenesis is a complex process that includes many gene products that are produced by different cells. Each of the processes influenced by specific genes that their expression can be regulated by hypoxi inducible factor-1 (HIF-1). Hypoxia, the imbalance between the oxygen in need and the oxygen available, usually occurs in tumors and ischemic cardiovascular diseases. In order to overcome this challenge, tumors regulate and control the expression of genes related to angiogenesis, cell cycle and metabolism using hypoxia-inducible factor 1 (HIF-1). HIF-1 was first recognized as a transcription factor involved in hypoxia-induced erythropoietin expression. As angiogenesis pathway molecules are being described, this factor has been characterized as a key transcription regulator for these molecules. In this review article, after discussing HIF-1 structure and characterization, the role of this important factor in angiogenesis and cancer as a pathological case and finally, the clinical applications has been evaluated. Articles related to the key words of hypoxia, HIF-1 and angiogenesis were searched from valid databases such as Springer Link, google scholar, Pubmed and Sciencedirect. Then, the articles related to the role of hypoxia and HIF-1 in activation of genes that are involved in angiogenesis and cancer were searched and selected for this study. Studies show that, HIF-1 activation of genes including vascular endothelial growth factor (VEGF), angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2), etc., induced angiogenesis in the tumor cells. Furthermore, the activation of genes such as insulin-like growth factor 2 (IGF2), transforming growth factor &alpha; (TGF-&alpha;) and MAPK and PI3K signaling pathway will also enable the survival and proliferation of tumor cells. HIF-1 by activating genes involved in angiogenesis and also activates signaling pathways associated with cell survival and proliferation plays an important role in the stability and growth of tumors. Therefore, better understanding of molecular mechanisms associated with this factor can be effective in the treatment of cancer.