The Landscape of Interactions between Hypoxia-Inducible Factors and Reactive Oxygen Species in the Gastrointestinal Tract

Abstract

The gastrointestinal tract (GT) is the major organ involved in digestion, absorption, and immunity, which is prone to oxidative destruction by high levels of reactive oxygen species (ROS) from luminal oxidants, such as food, drugs, and pathogens. Excessive ROS will lead to oxidative stresses and disrupt essential biomolecules, which also act as cellular signaling molecules in response to growth factors, hormones, and oxygen tension changes. Hypoxia-inducible factors (HIFs) are critical regulators mediating responses to cellular oxygen tension changes, which are also involved in energy metabolism, immunity, renewal, and microbial homeostasis in the GT. This review discusses interactions between HIF (mainly HIF-1α) and ROS and relevant diseases in the GT combined with our lab’s work. It might help to develop new therapies for gastrointestinal diseases associated with ROS and HIF-1α.

Gene Profiling of SEC13, SMAD7, GHRL, Long Non-Coding RNA GHRLOS, HIF-1α In Gastric Cancer Patients

“…Reactive nitrogen species (RNS) induce S-nitrosation of prolyl 4-hydroxylase 2 (PHD2) to elevate HIF-1α stability and activity [12], [33]. In addition to oxygen, HIF-1 may be regulated by other stimuli involving hormones (insulin), growth factors (platelet-derived growth factor) and vasoactive peptide (angiotensin-2) [34].…”

“…Hypoxia-inducible factors (HIF-1α, -2α, -3α, -1β) are critical transcriptional regulator of cell response to hypoxia [11] where they involved in immunity, energy metabolism, microbial homeostasis and renewal [12]. HIF-1α is a prospective target gene implicated in bioenergetic metabolism including upregulate glucose transporters (GLUT1, GLUT4 and GLUT8), the genes expression of glycolysis enzyme [13], and lactate dehydrogenase-5 (LDH-5).…”

The Mechanism of the Neuroprotective Effect of Kynurenic Acid in the Experimental Model of Neonatal Hypoxia–Ischemia: The Link to Oxidative Stress

“…It is difficult to determine whether this decrease in HIF-1α is the result of a reduction in ROS production or an inhibition of NMDA receptors. ROS act as an important signal molecule on MAPK, PI3K/Act/mTOR, and NF-κB pathways, which regulate the expression of HIF-1α [ 42 ]. In hypoxic conditions, increased ROS activates NF-κB, which plays a key role in the transcription of HIF-1α.…”

“…In hypoxic conditions, increased ROS activates NF-κB, which plays a key role in the transcription of HIF-1α. Moreover, it was shown that reactive nitrogen species (RNS) formed by endogenous ROS and NO inactivate HIF prolyl 4-hydroxylases (PHDs) that degrade HIF-1α [ 42 ]. On the other hand, the inhibition of NMDA receptors by MK-801 was shown to inhibit HIF-1α expression, suggesting that this mechanism may also be involved in the operation of KYNA [ 43 ].…”

Gene profiling of SEC13, SMAD7, GHRL, long non-coding RNA GHRLOS, HIF-1α in gastric cancer patients

“…Hypoxia-inducible factors (HIF-1α, -2α, -3α, -1β) are critical transcriptional regulator of cell response to hypoxia 13 where they involved in immunity, energy metabolism, microbial homeostasis and renewal 14 . HIF-1α is a prospective target gene implicated in bioenergetic metabolism including upregulate glucose transporters (GLUT1, GLUT4 and GLUT8), the genes expression of glycolysis enzyme 15 , and lactate dehydrogenase-5 (LDH-5).…”