Prolyl hydroxylase domain protein 2 (PHD2) belongs to an evolutionarily conserved superfamily of 2-oxoglutarate and Fe(II)-dependent dioxygenases that mediates homeostatic responses to oxygen deprivation by mediating hypoxia-inducible factor-1α (HIF-1α) hydroxylation and degradation. Although oxidative stress contributes to the inactivation of PHD2, the precise molecular mechanism of PHD2 inactivation independent of the levels of co-factors is not understood. Here, we identified disulfide bond-mediated PHD2 homo-dimer formation in response to oxidative stress caused by oxidizing agents and oncogenic H-ras^V12 signalling. Cysteine residues in the double-stranded β-helix fold that constitutes the catalytic site of PHD isoforms appeared responsible for the oxidative dimerization. Furthermore, we demonstrated that disulfide bond-mediated PHD2 dimerization is associated with the stabilization and activation of HIF-1α under oxidative stress. Oncogenic H-ras^V12 signalling facilitates the accumulation of HIF-1α in the nucleus and promotes aerobic glycolysis and lactate production. Moreover, oncogenic H-ras^V12 does not trigger aerobic glycolysis in antioxidant-treated or PHD2 knocked-down cells, suggesting the participation of the ROS-mediated PHD2 inactivation in the oncogenic H-ras^V12-mediated metabolic reprogramming. We provide here a better understanding of the mechanism by which disulfide bond-mediated PHD2 dimerization and inactivation result in the activation of HIF-1α and aerobic glycolysis in response to oxidative stress.

Accumulating epidemiological and clinical study indicates that inflammation is a significant risk factor to develop various human diseases such as inflammatory bowel disease (IBD), chronic asthma, rheumatoid arthritis, multiple sclerosis, and psoriasis. Suppressing inflammation is therefore important to control or prevent various diseases. Among them, IBD is one of the major problems affecting people worldwide. IBD affects at least one in a thousand persons in many Western countries. Various natural products have been shown to safely suppress pro-inflammatory pathway and control IBD. In vivo and/or in vitro studies indicate that anti-IBD effects of natural products occur by inhibition of the expression of pro-inflammatory cytokines (for example, tumor necrosis factor-α (TNF-α), intercellular adhesion molecule expression and pro-inflammatory mediators (such as inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX2), master transcription factors (such as nuclear factor-κB (NF-κB)), reactive oxygen species (ROS) and by improving the antioxidant activity. In this review, we summarize recent research focused on IBD and the effects that natural products have on IBD factors.

To explore the immunological roles of dietary fiber, male 4-wk-old Sprague-Dawley rats were fed for 2 wk cellulose (water-insoluble), konjak mannan (water-soluble), pectin (water-soluble) or chitosan (acid-soluble) at 5 g/100 g diet. Serum IgE concentrations in rats fed konjak mannan, pectin and chitosan were significantly lower than in those fed cellulose (mean ± SEM: 5.0 ± 1.1, 3.6 ± 1.3, 3.0 ± 1.2 and 9.6 ± 1.9 μg/L, respectively). Rats fed pectin had significantly higher serum IgA and IgG concentrations (358 ± 38 and 424 ± 36 mg/L for IgA and IgG, respectively) than those fed cellulose (240 ± 31 and 337 ± 25 mg/L) or chitosan (176 ± 22 and 379 ± 23 mg/L), while the IgM concentration did not differ among the groups. Concentrations of IgA, IgG and IgM in mesenteric lymph node (MLN) lymphocytes generally were greater, while IgE concentration was lower, in rats fed pectin and chitosan than in those fed cellulose. The proportion of CD4⁺ T-cells in MLN lymphocytes was also dietary fiber-dependent, and the CD4⁺/CD8⁺ ratio was significantly higher in the pectin fed group than in all other groups. Under certain experimental conditions, MLN lymphocytes from rats fed pectin had markedly greater interferon-γ concentration than cells from other groups, while the effect on tumor necrosis factor-α concentration was less marked. Thus, dietary fiber may have an immunoregulatory effect on the intestinal immune system of rats.

Diets, functional foods, and nutraceuticals as alternative therapies for inflammatory bowel disease: Present status and future trends