Targeting hypoxia-inducible factor-1 alpha suppresses Helicobacter pylori -induced gastric injury via attenuation of both cag -mediated microbial virulence and proinflammatory host responses

Abstract

Helicobacter pylori -induced inflammation is the strongest known risk factor for gastric adenocarcinoma. Hypoxia-inducible factor-1 (HIF-1α) is a key transcriptional regulator of immunity and carcinogenesis. To examine the role of this mediator within the context of H. pylori -induced injury, we first demonstrated that HIF-1α levels were significantly increased in parallel with the severity of gastric lesions in humans. In interventional studies targeting HIF-1α, H. pylori -infected mice were treated ± dimethyloxalylglycine (DMOG), a prolyl hydroxylase inhibitor that stabilizes HIF-1α. H. pylori significantly increased proinflammatory chemokines/cytokines and inflammation in vehicle-treated mice; however, this was significantly attenuated in DMOG-treated mice. DMOG treatment also significantly decreased function of the H. pylori type IV secretion system (T4SS) in vivo and significantly reduced T4SS-mediated NF-κB activation and IL-8 induction in vitro . These results suggest that prolyl hydroxylase inhibition protects against H. pylori -mediated pathologic responses, and is mediated, in part, via attenuation of H. pylori cag -mediated virulence and suppression of host proinflammatory responses.

Research Progress on the Pharmacological Effects and Molecular Mechanisms of Pinostrobin

“…Helicobacter pylori is a critical bacterium that infects the stomach and is a inducer of gastritis, stomach ulcers, and gastric cancer. 63,64 As mentioned previously, pinostrobin can significantly act against Helicobacter pylori activity, suggesting that pinostrobin is promising for many stomach diseases. 24 In addition, a study reported that pinostrobin protected against ethanol-induced gastric injury, as evidenced by reductions in the ulcer area, mucosal contents, submucosal edema, leukocyte infiltration, and TBARS levels in gastric homogenate.…”

Mitochondrial dysfunction induced by HIF‐1α under hypoxia contributes to the development of gastric mucosal lesions

“…Hypoxia is an important characteristic of gastric mucosal diseases, ranging from mucosal inflammatory reactions to GC. 29 , 30 PHT is indicated by a portal pressure gradient greater than 5 mmHg, namely, the difference in pressure between the portal vein and the hepatic veins, which mainly results from liver cirrhosis, 31 and PHT‐related gastric mucosal lesions are commonly defined as complications in patients with PHT. 3 And PHG and GC are the most representative benign and malignant gastric mucosal diseases characterised by hypoxia.…”

N6-methyladenosine modification of hypoxia-inducible factor-1α regulates Helicobacter pylori-associated gastric cancer via the PI3K/AKT pathway

“…Thus, HIF-1α is a crucial regulator in the hypoxic microenvironment of tumors, including GC. However, two studies have shown that HIF-1α can be induced by H. pylori under normoxic conditions through reactive oxygen species or the PI3K/AKT/mTOR pathway[ 5 - 7 ], and H. pylori strains isolated from high-risk patients exert strong effects[ 8 ]. In addition, the mechanisms underlying H. pylori -induced HIF-1α expression remains unclear.…”