HIF Prolyl Hydroxylase Inhibitors for COVID-19 Treatment: Pros and Cons

The review analyzes the potential advantages and problems associated with using HIF prolyl hydroxylase inhibitors as a treatment for COVID-19. HIF prolyl hydroxylase inhibitors are known to boost endogenous erythropoietin (Epo) and activate erythropoiesis by stabilizing and activating the hypoxia inducible factor (HIF). Recombinant Epo treatment has anti-inflammatory and healing properties, and thus, very likely, will be beneficial for moderate to severe cases of COVID-19. However, HIF PHD inhibition may have a significantly broader effect, in addition to stimulating the endogenous Epo production. The analysis of HIF target genes reveals that some HIF-targets, such as furin, could play a negative role with respect to viral entry. On the other hand, HIF prolyl hydroxylase inhibitors counteract ferroptosis, the process recently implicated in vessel damage during the later stages of COVID-19. Therefore, HIF prolyl hydroxylase inhibitors may serve as a promising treatment of COVID-19 complications, but they are unlikely to aid in the prevention of the initial stages of infection. © Copyright © 2021 Poloznikov, Nersisyan, Hushpulian, Kazakov, Tonevitsky, Kazakov, Vechorko, Nikulin, Makarova and Gazaryan

Cervical cancer screening: What is new in global practice?

Objective. To carry out a systematic review of the data available in the modern literature on the role of different molecular genetic markers for cervical carcinogenesis along with traditional cervical cancer screening methods. Material and methods. The review included the data of foreign and Russian articles published over the past 5 years and found in the Pubmed on this topic. Results. The paper describes main methods used for cervical cancer screening, as well as new epigenetic biomarkers that enable proper management tactics to be chosen in difficult clinical situations. Conclusion. Diagnostic biomarkers (WIF1 gene methylation, the expression of mir-29b in the cervical epithelium, p16 and Ki67, etc.) play a pivotal role in interpreting the final diagnosis if there are controversial and ambiguous results of cytological examination and HPV testing, which emphasizes the need for their further investigation. © Bionika Media Ltd

Cervical cancer screening: What is new in global practice?

Objective. To carry out a systematic review of the data available in the modern literature on the role of different molecular genetic markers for cervical carcinogenesis along with traditional cervical cancer screening methods. Material and methods. The review included the data of foreign and Russian articles published over the past 5 years and found in the Pubmed on this topic. Results. The paper describes main methods used for cervical cancer screening, as well as new epigenetic biomarkers that enable proper management tactics to be chosen in difficult clinical situations. Conclusion. Diagnostic biomarkers (WIF1 gene methylation, the expression of mir-29b in the cervical epithelium, p16 and Ki67, etc.) play a pivotal role in interpreting the final diagnosis if there are controversial and ambiguous results of cytological examination and HPV testing, which emphasizes the need for their further investigation. © Bionika Media Ltd

WIF-1 gene methylation in cervical squamous intraepithelial lesions

Objective. To evaluate the diagnostic value of WIF-1 gene promoter region methylation in the development of cervical intraepithelial neoplasia. Subjects and methods. The investigation included 62 patients aged 18 to 55 years who had come to the Research Center of Obstetrics, Gynecology, and Perinatology, Ministry of Health of the Russian Federation, in the period February to August 2016 for examination and undergone liquid-based cytology, quantitative and qualitative tests for human papillomavirus (HPV), histological examination of cervical biopsy specimens, and extended colposcopy. Bisulfite sequencing was used to study the level of WIF-1 promoter methylation in 62 samples of cells taken from the cervical canal with a cervix brush. Results. The normal mean level of WIF-1 promoter region methylation was 2.3±5.4%. The women diagnosed with high-or low-grade squamous intraepithelial lesions were observed to have a more statistically significant than normal value (p < 0.0001), abnormal WIF-1 gene promoter region hypermethylation at mean frequencies of 29.2±17.2 and 54.8±18.7%, respectively. Conclusion. The findings suggest that the level of WIF-1 gene promoter region methylation significantly correlates with the stage of HPV-associated cervical disease. Thus, evaluation of the WIF-1 gene methylation status may be regarded as a potential diagnostic marker for cervical carcinogenesis and a predictive clinical marker during combination treatment for cervical cancer. © 2017, Bionika Media Ltd. All rights reserved

WIF-1 gene methylation in cervical squamous intraepithelial lesions

Objective. To evaluate the diagnostic value of WIF-1 gene promoter region methylation in the development of cervical intraepithelial neoplasia. Subjects and methods. The investigation included 62 patients aged 18 to 55 years who had come to the Research Center of Obstetrics, Gynecology, and Perinatology, Ministry of Health of the Russian Federation, in the period February to August 2016 for examination and undergone liquid-based cytology, quantitative and qualitative tests for human papillomavirus (HPV), histological examination of cervical biopsy specimens, and extended colposcopy. Bisulfite sequencing was used to study the level of WIF-1 promoter methylation in 62 samples of cells taken from the cervical canal with a cervix brush. Results. The normal mean level of WIF-1 promoter region methylation was 2.3±5.4%. The women diagnosed with high-or low-grade squamous intraepithelial lesions were observed to have a more statistically significant than normal value (p < 0.0001), abnormal WIF-1 gene promoter region hypermethylation at mean frequencies of 29.2±17.2 and 54.8±18.7%, respectively. Conclusion. The findings suggest that the level of WIF-1 gene promoter region methylation significantly correlates with the stage of HPV-associated cervical disease. Thus, evaluation of the WIF-1 gene methylation status may be regarded as a potential diagnostic marker for cervical carcinogenesis and a predictive clinical marker during combination treatment for cervical cancer. © 2017, Bionika Media Ltd. All rights reserved

Structure–Activity Relationships and Transcriptomic Analysis of Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors

To evaluate the differences in action of commercially available 2-oxoglutarate mimetics and “branched-tail” oxyquinoline inhibitors of hypoxia-inducible factor prolyl hydroxylase (HIF PHD), the inhibitors’ IC50 values in the activation of HIF1 ODD-luciferase reporter were selected for comparative transcriptomics. Structure–activity relationship and computer modeling for the oxyquinoline series of inhibitors led to the identification of novel inhibitors, which were an order of magnitude more active in the reporter assay than roxadustat and vadadustat. Unexpectedly, 2-methyl-substitution in the oxyquinoline core of the best HIF PHD inhibitor was found to be active in the reporter assay and almost equally effective in the pretreatment paradigm of the oxygen-glucose deprivation in vitro model. Comparative transcriptomic analysis of the signaling pathways induced by HIF PHD inhibitors showed high potency of the two novel oxyquinoline inhibitors (#4896-3249 and #5704-0720) at 2 µM concentrations matching the effect of 30 µM roxadustat and 500 µM dimethyl oxalyl glycine in inducing HIF1 and HIF2-linked pathways. The two oxyquinoline inhibitors exerted the same activation of HIF-triggered glycolytic pathways but opposite effects on signaling pathways linked to alternative substrates of HIF PHD 1 and 3, such as p53, NF-κB, and ATF4. This finding can be interpreted as the specificity of the 2-methyl-substitute variant for HIF PHD2. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]