Glucose-6-Phosphate Dehydrogenase, Redox Homeostasis and Embryogenesis.

Normal embryogenesis requires complex regulation and precision, which depends on multiple mechanistic details. Defective embryogenesis can occur by various mechanisms. Maintaining redox homeostasis is of importance during embryogenesis. NADPH, as produced from the action of glucose-6-phosphate dehydrogenase (G6PD), has an important role in redox homeostasis, serving as a cofactor for glutathione reductase in the recycling of glutathione from oxidized glutathione and for NADPH oxidases and nitric oxide synthases in the generation of reactive oxygen (ROS) and nitrogen species (RNS). Oxidative stress differentially influences cell fate and embryogenesis. While low levels of stress (eustress) by ROS and RNS promote cell growth and differentiation, supra-physiological concentrations of ROS and RNS can lead to cell demise and embryonic lethality. G6PD-deficient cells and organisms have been used as models in embryogenesis for determining the role of redox signaling in regulating cell proliferation, differentiation and migration. Embryogenesis is also modulated by anti-oxidant enzymes, transcription factors, microRNAs, growth factors and signaling pathways, which are dependent on redox regulation. Crosstalk among transcription factors, microRNAs and redox signaling is essential for embryogenesis.

The Redox Role of G6PD in Cell Growth, Cell Death, and Cancer.

The generation of reducing equivalent NADPH via glucose-6-phosphate dehydrogenase (G6PD) is critical for the maintenance of redox homeostasis and reductive biosynthesis in cells. NADPH also plays key roles in cellular processes mediated by redox signaling. Insufficient G6PD activity predisposes cells to growth retardation and demise. Severely lacking G6PD impairs embryonic development and delays organismal growth. Altered G6PD activity is associated with pathophysiology, such as autophagy, insulin resistance, infection, inflammation, as well as diabetes and hypertension. Aberrant activation of G6PD leads to enhanced cell proliferation and adaptation in many types of cancers. The present review aims to update the existing knowledge concerning G6PD and emphasizes how G6PD modulates redox signaling and affects cell survival and demise, particularly in diseases such as cancer. Exploiting G6PD as a potential drug target against cancer is also discussed.

What has passed is prolog: new cellular and physiological roles of G6PD.

G6PD deficiency has been the most pervasive inherited disorder in the world since having been discovered. G6PD has an antioxidant role by functioning as a major nicotinamide adenine dinucleotide phosphate (NADPH) provider to reduce excessive oxidative stress. NADPH can produce reactive oxygen species (ROS) and reactive nitrogen species (RNS) mediated by NADPH oxidase (NOX) and nitric oxide synthase (NOS), respectively. Hence, G6PD also has a pro-oxidant role. Research in the past has focused on the enhanced susceptibility of G6PD-deficient cells or individuals to oxidative challenge. The cytoregulatory role of G6PD has largely been overlooked. By using a metabolomic approach, it is noted that upon oxidant challenge, G6PD-deficient cells will reprogram the GSH metabolism from regeneration to synthesis with exhaustive energy consumption. Recently, new cellular/physiologic roles of G6PD have been discovered. By using a proteomic approach, it has been found that G6PD plays a regulatory role in xenobiotic metabolism possibly via NOX and the redox-sensitive Nrf2-signaling pathway to modulate the expression of xenobiotic-metabolizing enzymes. Since G6PD is a key regulator responsible for intracellular redox homeostasis, G6PD deficiency can alter redox balance leading to many abnormal cellular effects such as the cellular inflammatory and immune response against viral infection. G6PD may play an important role in embryogenesis as G6PD-knockdown mouse cannot produce offspring and G6PD-deficient C. elegans with defective egg production and hatching. This array of findings indicates that the cellular and physiologic roles of G6PD, other than the classical role as an antioxidant enzyme, deserve further attention.

Glucose 6-phosphate dehydrogenase knockdown enhances IL-8 expression in HepG2 cells via oxidative stress and NF-κB signaling pathway.

BACKGROUND: This study was designed to investigate the effect of glucose 6-phosphate dehydrogenase (G6PD) deficiency on pro-inflammatory cytokine secretion using a palmitate-induced inflammation HepG2 in vitro model. The modulation of cellular pro-inflammatory cytokine expression under G6PD deficiency during chronic hepatic inflammation has never been investigated before. METHODS: The culture medium of untreated and palmitate-treated G6PD-scramble (Sc) and G6PD-knockdown (Gi) HepG2 cells were subjected to cytokine array analysis, followed by validation with ELISA and qRT-PCR of the target cytokine. The mechanism of altered cytokine secretion in palmitate-treated Sc and Gi HepG2 cells was examined in the presence of anti-oxidative enzyme (glutathione peroxidase, GPX), anti-inflammatory agent (curcumin), NF-κB inhibitor (BAY11-7085) and specific SiRNA against NF-κB subunit p65. RESULTS: Cytokine array analysis indicated that IL-8 is most significantly increased in G6PD-knockdown HepG2 cells. The up-regulation of IL-8 caused by G6PD deficiency in HepG2 cells was confirmed in other G6PD-deficient cells by qRT-PCR. The partial reduction of G6PD deficiency-derived IL-8 due to GPX and NF-κB blockers indicated that G6PD deficiency up-regulates pro-inflammatory cytokine IL-8 through oxidative stress and NF-κB pathway. CONCLUSIONS: G6PD deficiency predisposes cells to enhanced production of pro-inflammatory cytokine IL-8. Mechanistically, G6PD deficiency up-regulates IL-8 through oxidative stress and NF-κB pathway. The palmitate-induced inflammation in G6PD-deficient HepG2 cells could serve as an in vitro model to study the role of altered redox homeostasis in chronic hepatic inflammation.

Analysis of the causes and clinical characteristics of jejunoileal hemorrhage in China: a multicenter 10 year retrospective survey.

BACKGROUND: A retrospective study was performed to assess the causes, diagnostic methods for, and clinical features of, jejunoileal hemorrhage in Shandong province, China and to derive recommendations for management of this condition from these data. METHODS: We performed a retrospective systematic collection of data from between January 1999 and December 2008 in seven cities in Shandong province, China, identified 72 patients with jejunoileal hemorrhage and analyzed the relevant clinical data. RESULTS: Overall, tumors were the most common cause of jejunoileal hemorrhage (42 patients, 58.3%). The causes of this condition were significantly different (P < 0.05) in male and female patients. In male patients, the commonest factors were tumor (52.2%), enteritis (17.4%) and angiopathy (15.2%). However, in female patients, tumors accounted for a greater proportion of cases (18/26, 69.2%). In 38 cases (52.8%) the diagnosis was made by intraoperative enteroscopy or laparotomy, in 14 by capsule endoscopy and in the remainder by radiological methods. The most frequent presentation was melena (62.7%), followed by maroon stools (26.9%) and hematochezia (9.0%). Of the 72 patients,laparotomy is the main treatment method. CONCLUSION: Tumor, enteritis and angiopathy and diverticular disease are the most common causes of jejunoileal hemorrhage in Shandong province, China. The main clinical manifestations are bloody stools, most commonly in the form of melena, with or without abdominal pain. We recommend that female patients over the age of 40 with jejunoileal hemorrhage accompanied by abdominal pain should undergo urgent further assessment because of the strong probability of jejunoileal tumor.