Effects of curcumin on hypoxia-inducible factor as a new therapeutic target.

The photodynamic activity and toxicity evaluation of 5,10,15-tris(ethoxylcarbonyl)corrole phosphorus(V) in vivo and in vitro

Renal tubulointerstitial fibrosis (TIF) is a common pathological feature of aristolochic acid (AA) nephropathy (AAN). G2/M arrest of proximal tubular cells (PTCs) is implicated in renal fibrosis of AAN, but the upstream regulatory molecule remains unknown. Hypoxia inducible factor-1α (HIF-1α) promotes renal fibrosis in kidney disease, but the role of HIF-1α in AAN is unclear. Evidence shows that HIF-1α and p21, a known inducer of cellular G2/M arrest, are closely related to each other. To investigate the role of HIF-1α in renal fibrosis of AAN and its effects on p21 expression and PTCs G2/M arrest, mice with HIF-1α gene knockout PTCs (PT-HIF-1α-KO) were generated, and AAN was induced by AA. In vitro tests were conducted on the human PTCs line HK-2 and primary mouse PTCs. HIF-1α and p21 expression, fibrogenesis, and G2/M arrest of PTCs were determined. Results showed that HIF-1α was upregulated in the kidneys of wild-type (WT) AAN mice, accompanied by p21 upregulation, PTCs G2/M arrest and renal fibrosis, and these alterations were reversed in PT-HIF-1α-KO AAN mice. Similar results were observed in HK-2 cells and were further confirmed in primary PTCs from PT-HIF-1α-KO and WT mice. Inhibiting p21 in HK-2 cells and primary PTCs did not change the expression of HIF-1α, but G2/M arrest and fibrogenesis were reduced. These data indicate that HIF-1α plays a key role in renal fibrosis in AAN by inducing PTCs G2/M arrest modulated through p21. HIF-1α may serve as a potential therapeutic target for AAN.

Aristolochic acid induces renal fibrosis by arresting proximal tubular cells in G2/M phase mediated by HIF-1α.

The objectives of this present work were to review recent developments on the role of hypoxia-inducible factor (HIF) in the survival of cells under normoxic versus hypoxic and inflammatory brain conditions. The dual nature of HIF effects appears well established, based on the accumulated evidence of HIF playing both the role of adaptive factor and mediator of cell demise. Cellular HIF responses depend on pathophysiological conditions, developmental phase, comorbidities, and administered medications. In addition, HIF-1α and HIF-2α actions may vary in the same tissues. The multiple roles of HIF in stem cells are emerging. HIF not only regulates expression of target genes and thereby influences resultant protein levels but also contributes to epigenetic changes that may reciprocally provide feedback regulations loops. These HIF-dependent alterations in neurological diseases and its responses to treatments in vivo need to be examined alongside with a functional status of subjects involved in such studies. The knowledge of HIF pathways might be helpful in devising HIF-mimetics and modulating drugs, acting on the molecular level to improve clinical outcomes, as exemplified here by clinical and experimental data of selected brain diseases, occasionally corroborated by the data from disorders of other organs. Because of complex role of HIF in brain injuries, prospective therapeutic interventions need to differentially target HIF responses depending on their roles in the molecular mechanisms of neurologic diseases.

The insights into molecular pathways of hypoxia‐inducible factor in the brain

In this article, we present a novel nitrocellulose-based microfluidic chip with 3-dimensional (3D) printing technology to study the effect of oxygen gradient on cells. Compared with conventional polydimethylsiloxane (PDMS) chips of oxygen gradient for cell cultures that can only rely on fluorescence microscope analysis, this hybrid nitrocellulose-based microfluidic platform can provide a variety of analysis methods for cells, including flow cytometry, western blot and RT-PCR, because the nitrocellulose-based chips with cells can be taken out from the growth chambers of 3D printed microfluidic chip and then used for cell collection or lysis. These advantages allow researchers to acquire more information and data on the basic biochemical and physiological processes of cell life. The effect of oxygen gradient on the zebrafish cells (ZF4) was used as a model to show the performance and application of our platform. Hypoxia caused the increase of intercellular reactive oxygen species (ROS) and accumulation of hypoxia-inducible factor 1α (HIF-1α). Hypoxia stimulated the transcription of hypoxia-responsive genes vascular endothelial growth factor (VEGF) and induced cell cycle arrest of ZF4 cells. The established platform is able to obtain more information from cells in response to different oxygen concentration, which has potential for analyzing the cells under a variety of pathological conditions.

Wooyoung Jeong

Papers

Hypoxia-dependent accumulation of hypoxia-inducible factor-1 alpha induces transient cell cycle arrest in porcine trophectoderm cells.