G6pd-Deficient Mice Are Protected From Experimental Cerebral Malaria and Liver Injury by Suppressing Proinflammatory Response in the Early Stage of Plasmodium berghei Infection.

Epidemiological studies provide compelling evidence that glucose-6-phosphate dehydrogenase (G6PD) deficiency individuals are relatively protected against Plasmodium parasite infection. However, the animal model studies on this subject are lacking. Plus, the underlying mechanism in vivo is poorly known. In this study, we used a G6pd-deficient mice infected with the rodent parasite Plasmodium berghei (P.berghei) to set up a malaria model in mice. We analyzed the pathological progression of experimental cerebral malaria (ECM) and acute liver injury in mice with different G6pd activity infected with P.berghei. We performed dual RNA-seq for host-parasite transcriptomics and validated the changes of proinflammatory response in the murine model. G6pd-deficient mice exhibited a survival advantage, less severe ECM and mild liver injury compared to the wild type mice. Analysis based on dual RNA-seq suggests that G6pd-deficient mice are protected from ECM and acute liver injury were related to proinflammatory responses. Th1 differentiation and dendritic cell maturation in the liver and spleen were inhibited in G6pd-deficient mice. The levels of proinflammatory cytokines were reduced, chemokines and vascular adhesion molecules in the brain were significantly down-regulated, these led to decreased cerebral microvascular obstruction in G6pd-deficient mice. We generated the result that G6pd-deficiency mediated protection against ECM and acute liver injury were driven by the regulatory proinflammatory responses. Furthermore, bioinformatics analyses showed that P.berghei might occur ribosome loss in G6pd-deficient mice. Our findings provide a novel perspective of the underlying mechanism of G6PD deficiency mediated protection against malaria in vivo.

The Elderly with Glucose-6-Phosphate Dehydrogenase Deficiency are More Susceptible to Cardiovascular Disease.

AIM: Recent studies suggest that glucose-6-phosphate dehydrogenase (G6PD) deficiency, a genetically inherited condition causing hemolytic anemia, may be a risk factor for cardiovascular disease (CVD). We aimed to perform a retrospective case-control study in Sardinia taking advantage from clinical records of patients undergoing upper digestive endoscopy and screened for H. pylori infection. METHODS: A total of 9,604 patients with a known G6PD status and a complete clinical history, encompassing CVD, and leading CVD risk factors, including H. pylori infection, undergoing upper endoscopy between 2002 and 2017 were enrolled in this study. RESULTS: Multivariate logistic regression analysis confirmed an increased CVD risk in subjects with G6PD deficiency [odd ratio (OR), 3.24; 95% confidence interval (CI) 2.44-4.30] after adjusting for potential confounders and effect modifiers, including H. pylori infection. Cardiovascular risk was similar in subjects with and without G6PD deficiency before age 60 (OR, 1.26; 95% CI 0.78-2.04, P=0.562), whereas it increased after age 60 in the former group (OR, 3.05; 95% CI 2.22-4.19, P＜0.0001) especially in males (OR 3.67; 95% CI 2.19-6.14) compared with females (OR, 2.96; 95% CI 1.89-4.64) by sex-specific logistic regression analysis. CONCLUSION: The risk of CVD was greater in G6PD-deficient subjects after age 60, both in males and females, than those with normal enzyme activity, after adjusting for conventional CVD risk factors and H. pylori infection. The reduction of important protective mechanisms against oxidative stress in the elderly might explain the study findings.

Glucose-6-Phosphate Dehydrogenase Deficiency Activates Endothelial Cell and Leukocyte Adhesion Mediated via the TGFß/NADPH Oxidases/ROS Signaling Pathway.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency, the most common genetic inherited trait among humans, affects ~7% of the global population, and is associated with excess risk of cardiovascular disease (CVD). Transforming growth factor-ß (TGF-ß) regulates immune function, proliferation, epithelial-mesenchymal transition, fibrosis, cancer, and vascular dysfunction. This study examined whether G6PD deficiencies can alter TGF-ß-mediated NADPH oxidases (NOX) and cell adhesion molecules (CAM) in human aortic endothelial cells (HAEC). Results show that treatment with high glucose and the saturated free fatty acid palmitate significantly downregulated G6PD; in contrast, mRNA levels of TGF-ß components, NOX and its activity, and reactive oxygen species (ROS) were significantly upregulated in HAEC. The expression levels of TGF-ß and its receptors, NOX and its activity, and ROS were significantly higher in HG-exposed G6PD-deficient cells (G6PD siRNA) compared to G6PD-normal cells. The protein levels of adhesion molecules (ICAM-1 and VCAM-1) and inflammatory cytokines (MCP-1 and TNF) were significantly increased in HG-exposed G6PD-deficient cells compared to G6PD-normal cells. The adherence of monocytes (SC cells) to HAEC was significantly elevated in HG-treated G6PD-deficient cells compared to control cells. Pharmacological inhibition of G6PD enhances ROS, NOX and its activity, and endothelial monocyte adhesion; these effects were impeded by NOX inhibitors. The inhibition of TGF-ß prevents NOX2 and NOX4 mRNA expression and activity, ROS, and adhesion of monocytes to HAEC. L-Cysteine ethyl ester (cell-permeable) suppresses the mRNA levels of TGF-ß and its receptors, along with NOX2 and NOX4, and decreases NOX activity, ROS, and adhesion of monocytes to HAEC. This suggests that G6PD deficiency promotes TGF-ß/NADPH oxidases/ROS signaling, the expression of ICAM-1 and VCAM-1, and the adhesion of leukocytes to the endothelial monolayer, which can contribute to a higher risk for CVD.

The potential link between inherited G6PD deficiency, oxidative stress, and vitamin D deficiency and the racial inequities in mortality associated with COVID-19.

There is a marked variation in mortality risk associated with COVID-19 infection in the general population. Low socioeconomic status and other social determinants have been discussed as possible causes for the higher burden in African American communities compared with white communities. Beyond the social determinants, the biochemical mechanism that predisposes individual subjects or communities to the development of excess and serious complications associated with COVID-19 infection is not clear. Virus infection triggers massive ROS production and oxidative damage. Glutathione (GSH) is essential and protects the body from the harmful effects of oxidative damage from excess reactive oxygen radicals. GSH is also required to maintain the VD-metabolism genes and circulating levels of 25-hydroxyvitamin D (25(OH)VD). Glucose-6-phosphate dehydrogenase (G6PD) is necessary to prevent the exhaustion and depletion of cellular GSH. X-linked genetic G6PD deficiency is common in the AA population and predominantly in males. Acquired deficiency of G6PD has been widely reported in subjects with conditions of obesity and diabetes. This suggests that individuals with G6PD deficiency are vulnerable to excess oxidative stress and at a higher risk for inadequacy or deficiency of 25(OH)VD, leaving the body unable to protect its 'oxidative immune-metabolic' physiological functions from the insults of COVID-19. An association between subclinical interstitial lung disease with 25(OH)VD deficiencies and GSH deficiencies has been previously reported. We hypothesize that the overproduction of ROS and excess oxidative damage is responsible for the impaired immunity, secretion of the cytokine storm, and onset of pulmonary dysfunction in response to the COVID-19 infection. The co-optimization of impaired glutathione redox status and excess 25(OH)VD deficiencies has the potential to reduce oxidative stress, boost immunity, and reduce the adverse clinical effects of COVID-19 infection in the AA population.

L-Cysteine in vitro can restore cellular glutathione and inhibits the expression of cell adhesion molecules in G6PD-deficient monocytes.

L-Cysteine is a precursor of glutathione (GSH), a potent physiological antioxidant. Excess glucose-6-phosphate dehydrogenase (G6PD) deficiency in African Americans and low levels of L-cysteine diet in Hispanics can contributes to GSH deficiency and oxidative stress. Oxidative stress and monocyte adhesion was considered to be an initial event in the progression of vascular dysfunction and atherosclerosis. However, no previous study has investigated the contribution of GSH/G6PD deficiency to the expression of monocyte adhesion molecules. Using human U937 monocytes, this study examined the effect of GSH/G6PD deficiency and L-cysteine supplementation on monocyte adhesion molecules. G6PD/GSH deficiency induced by either siRNA or inhibitors (6AN/BSO, respectively) significantly (p < 0.005) increased the levels of cell adhesion molecules (ICAM-1, VCAM-1, SELL, ITGB1 and 2); NADPH oxidase (NOX), reactive oxygen species (ROS) and MCP-1 were upregulated, and decreases in levels of GSH, and nitric oxide were observed. The expression of ICAM-1 and VCAM-1 mRNA levels increased in high glucose, MCP-1 or TNF-α-treated G6PD-deficient compared to G6PD-normal cells. L-Cysteine treatment significantly (p < 0.005) increased G6PD activity and levels of GSH, and decreased NOX, ROS, and adhesion molecules. Thus, GSH/G6PD deficiency increases susceptibility to monocyte adhesion processes, whereas L-cysteine supplementation can restore cellular GSH/G6PD and attenuates NOX activity and expression of cell adhesion molecules.

Inverse Association between Glucose‒6‒Phosphate Dehydrogenase Deficiency and Hepatocellular Carcinoma

Background: Studies in experimental models and humans suggest that glucose‒6‒phosphate dehydrogenase (G6PD) deficiency, an inherited condition, may be inversely related to hepatocellular carcinoma (HCC). We tested this hypothesis in a large cohort of Sardinian patients. Methods: A case-control study was performed using data from 11,143 records of patients who underwent upper endoscopy between 2002 and 2017. Gender, age, G6PD status and information regarding the presence of HCC, were recorded. Cases (HCC positive) and controls (HCC negative) were compared for the presence of G6PD deficiency adjusting for major HCC risk factors using logistic regression. Results: Overall, 114 HCC cases and 11,029 controls were identified. G6PD deficiency was detected in 11.5% of study participants, and was associated with a reduced risk of HCC [odds ratio (OR); 0.451; 95% confidence interval (CI), 0.207−0.982] after adjusting for all covariates. Factors significantly associated with HCC were cirrhosis (OR, 23.30; 95% CI, 11.48−47.25), diabetes (OR, 2.396; 95% CI, 1.449−3.963), among infection hepatitis HBV with an OR of 2.326, age ≥65 years (OR, 1.941; 95% CI, 1.234−2.581) and male gender (OR, 1.611; 95% CI, 1.006−3.081). Conclusions: Our study revealed a significant inverse association between G6PD deficiency and risk of HCC. These findings need to be confirmed in further studies.

Inhibition of glucose-6-phosphate dehydrogenase protects hepatocytes from aluminum phosphide-induced toxicity.

Aluminum phosphide (AlP) poisoning is a severe toxicity with 30-70% mortality rate. However, several case reports presented AlP-poisoned patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency and extensive hemolysis who survived the toxicity. This brought to our mind that maybe G6PD deficiency could protect the patients from severe fatal poisoning by this pesticide. In this research, we investigated the protective effect of 6-aminonicotinamide (6-AN)- as a well-established inhibitor of the NADP+- dependent enzyme 6-phosphogluconate dehydrogenase- on isolated rat hepatocytes in AlP poisoning. Hepatocytes were isolated by collagenase perfusion method and incubated into three different flasks: control, AlP, and 6-AN+ALP. Cellar parameters such as cell viability, reactive oxygen species (ROS) formation, mitochondria membrane potential collapse (MMP), lysosomal integrity, content of reduced (GSH) and oxidized glutathione (GSSG) and lipid peroxidation were assayed at intervals. All analyzed cellular parameters significantly decreased in the third group (6-AN+AlP) compared to the second group (AlP), showing the fact that G6PD deficiency induced by 6-AN had a significant protective effect on the hepatocytes. It was concluded that G6PD deficiency significantly reduced the hepatotoxicity of AlP. Future drugs with the power to induce such deficiency may be promising in treatment of AlP poisoning.

Dietary alterations modulate susceptibility to Plasmodium infection.

The relevance of genetic factors in conferring protection to severe malaria has been demonstrated, as in the case of sickle cell trait and G6PD deficiency 1 . However, it remains unknown whether environmental components, such as dietary or metabolic variations, can contribute to the outcome of infection 2 . Here, we show that administration of a high-fat diet to mice for a period as short as 4 days impairs Plasmodium liver infection by over 90%. Plasmodium sporozoites can successfully invade and initiate replication but die inside hepatocytes, thereby are unable to cause severe disease. Transcriptional analyses combined with genetic and chemical approaches reveal that this impairment of infection is mediated by oxidative stress. We show that reactive oxygen species, probably spawned from fatty acid ß-oxidation, directly impact Plasmodium survival inside hepatocytes, and parasite load can be rescued by exogenous administration of the antioxidant N-acetylcysteine or the ß-oxidation inhibitor etomoxir. Together, these data reveal that acute and transient dietary alterations markedly impact the establishment of a Plasmodium infection and disease outcome.

Data mining and pathway analysis of glucose-6-phosphate dehydrogenase with natural language processing.

Human glucose-6-phosphate dehydrogenase (G6PD) is a crucial enzyme in the pentose phosphate pathway, and serves an important role in biosynthesis and the redox balance. G6PD deficiency is a major cause of neonatal jaundice and acute hemolyticanemia, and recently, G6PD has been associated with diseases including inflammation and cancer. The aim of the present study was to conduct a search of the National Center for Biotechnology Information PubMed library for articles discussing G6PD. Genes that were identified to be associated with G6PD were recorded, and the frequency at which each gene appeared was calculated. Gene ontology (GO), pathway and network analyses were then performed. A total of 98 G6PD­associated genes and 33 microRNAs (miRNAs) that potentially regulate G6PD were identified. The 98 G6PD­associated genes were then sub­classified into three functional groups by GO analysis, followed by analysis of function, pathway, network, and disease association. Out of the 47 signaling pathways identified, seven were significantly correlated with G6PD­associated genes. At least two out of four independent programs identified the 33 miRNAs that were predicted to target G6PD. miR­1207­5P, miR­1 and miR­125a­5p were predicted by all four software programs to target G6PD. The results of the present study revealed that dysregulation of G6PD was associated with cancer, autoimmune diseases, and oxidative stress­induced disorders. These results revealed the potential roles of G6PD­regulated signaling and metabolic pathways in the etiology of these diseases.

Severe glucose-6-phosphate dehydrogenase deficiency leads to susceptibility to infection and absent NETosis.

BACKGROUND: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common enzymatic disorder of red blood cells in human subjects, causing hemolytic anemia linked to impaired nicotinamide adenine dinucleotide phosphate (NADPH) production and imbalanced redox homeostasis in erythrocytes. Because G6PD is expressed by a variety of hematologic and nonhematologic cells, a broader clinical phenotype could be postulated in G6PD-deficient patients. We describe 3 brothers with severe G6PD deficiency and susceptibility to bacterial infection. OBJECTIVE: We sought to study the molecular pathophysiology leading to susceptibility to infection in 3 siblings with severe G6PD deficiency. METHODS: Blood samples of 3 patients with severe G6PD deficiency were analyzed for G6PD enzyme activity, cellular oxidized nicotinamide adenine dinucleotide phosphate/NADPH levels, phagocytic reactive oxygen species production, neutrophil extracellular trap (NET) formation, and neutrophil elastase translocation. RESULTS: In these 3 brothers strongly reduced NADPH oxidase function was found in granulocytes, leading to impaired NET formation. Defective NET formation has thus far been only observed in patients with the NADPH oxidase deficiency chronic granulomatous disease, who require antibiotic and antimycotic prophylaxis to prevent life-threatening bacterial and fungal infections. CONCLUSION: Because severe G6PD deficiency can be a phenocopy of chronic granulomatous disease with regard to the cellular and clinical phenotype, careful evaluation of neutrophil function seems mandatory in these patients to decide on appropriate anti-infective preventive measures. Determining the level of G6PD enzyme activity should be followed by analysis of reactive oxygen species production and NET formation to decide on required antibiotic and antimycotic prophylaxis.

Glucose-6-Phosphate Dehydrogenase Deficiency Improves Insulin Resistance With Reduced Adipose Tissue Inflammation in Obesity.

Glucose-6-phosphate dehydrogenase (G6PD), a rate-limiting enzyme of the pentose phosphate pathway, plays important roles in redox regulation and de novo lipogenesis. It was recently demonstrated that aberrant upregulation of G6PD in obese adipose tissue mediates insulin resistance as a result of imbalanced energy metabolism and oxidative stress. It remains elusive, however, whether inhibition of G6PD in vivo may relieve obesity-induced insulin resistance. In this study we showed that a hematopoietic G6PD defect alleviates insulin resistance in obesity, accompanied by reduced adipose tissue inflammation. Compared with wild-type littermates, G6PD-deficient mutant (G6PD(mut)) mice were glucose tolerant upon high-fat-diet (HFD) feeding. Intriguingly, the expression of NADPH oxidase genes to produce reactive oxygen species was alleviated, whereas that of antioxidant genes was enhanced in the adipose tissue of HFD-fed G6PD(mut) mice. In diet-induced obesity (DIO), the adipose tissue of G6PD(mut) mice decreased the expression of inflammatory cytokines, accompanied by downregulated proinflammatory macrophages. Accordingly, macrophages from G6PD(mut) mice greatly suppressed lipopolysaccharide-induced proinflammatory signaling cascades, leading to enhanced insulin sensitivity in adipocytes and hepatocytes. Furthermore, adoptive transfer of G6PD(mut) bone marrow to wild-type mice attenuated adipose tissue inflammation and improved glucose tolerance in DIO. Collectively, these data suggest that inhibition of macrophage G6PD would ameliorate insulin resistance in obesity through suppression of proinflammatory responses.

Inability to maintain GSH pool in G6PD-deficient red cells causes futile AMPK activation and irreversible metabolic disturbance.

AIMS: Glucose 6-phosphate dehydrogenase (G6PD) is essential for maintenance of nicotinamide dinucleotide hydrogen phosphate (NADPH) levels and redox homeostasis. A number of drugs, such as antimalarial drugs, act to induce reactive oxygen species and hemolytic crisis in G6PD-deficient patients. We used diamide (DIA) to mimic drug-induced oxidative stress and studied how these drugs affect cellular metabolism using a metabolomic approach. RESULTS: There are a few differences in metabolome between red blood cells (RBCs) from normal and G6PD-deficient individuals. DIA causes modest changes in normal RBC metabolism. In contrast, there are significant changes in various biochemical pathways, namely glutathione (GSH) metabolism, purine metabolism, and glycolysis, in G6PD-deficient cells. GSH depletion is concomitant with a shift in energy metabolism. Adenosine monophosphate (AMP) and adenosine diphosphate (ADP) accumulation activates AMP protein kinase (AMPK) and increases entry of glucose into glycolysis. However, inhibition of pyruvate kinase (PK) reduces the efficacy of energy production. Metabolic changes and protein oxidation occurs to a greater extent in G6PD-deficient RBCs than in normal cells, leading to severe irreversible loss of deformability of the former. INNOVATION AND CONCLUSION: Normal and G6PD-deficient RBCs differ in their responses to oxidants. Normal cells have adequate NADPH regeneration for maintenance of GSH pool. In contrast, G6PD-deficient cells are unable to regenerate enough NADPH under a stressful situation, and switch to biosynthetic pathway for GSH supply. Rapid GSH exhaustion causes energy crisis and futile AMPK activation. Our findings suggest that drug-induced oxidative stress differentially affects metabolism and metabolite signaling in normal and G6PD-deficient cells. It also provides an insight into the pathophysiology of acute hemolytic anemia in G6PD-deficient patients.

Inborn defects in the antioxidant systems of human red blood cells.

Red blood cells (RBCs) contain large amounts of iron and operate in highly oxygenated tissues. As a result, these cells encounter a continuous oxidative stress. Protective mechanisms against oxidation include prevention of formation of reactive oxygen species (ROS), scavenging of various forms of ROS, and repair of oxidized cellular contents. In general, a partial defect in any of these systems can harm RBCs and promote senescence, but is without chronic hemolytic complaints. In this review we summarize the often rare inborn defects that interfere with the various protective mechanisms present in RBCs. NADPH is the main source of reduction equivalents in RBCs, used by most of the protective systems. When NADPH becomes limiting, red cells are prone to being damaged. In many of the severe RBC enzyme deficiencies, a lack of protective enzyme activity is frustrating erythropoiesis or is not restricted to RBCs. Common hereditary RBC disorders, such as thalassemia, sickle-cell trait, and unstable hemoglobins, give rise to increased oxidative stress caused by free heme and iron generated from hemoglobin. The beneficial effect of thalassemia minor, sickle-cell trait, and glucose-6-phosphate dehydrogenase deficiency on survival of malaria infection may well be due to the shared feature of enhanced oxidative stress. This may inhibit parasite growth, enhance uptake of infected RBCs by spleen macrophages, and/or cause less cytoadherence of the infected cells to capillary endothelium.

Identifying term breast-fed infants at risk of significant hyperbilirubinemia.

BACKGROUND: The aim of this study was to establish a model to identify term breast-fed infants who are at risk of developing significant neonatal hyperbilirubinemia. METHODS: A prospective study was designed to investigate the effects of birth weight, mode of delivery, cephalohematoma, glucose-6-phosphate dehydrogenase (G6PD) deficiency, predischarge total serum bilirubin, variant uridine 5'diphospho-glucuronosyltransferase 1A1 (UGT1A1) gene, and hepatic solute carrier organic anion transporter 1B1 (SLCO1B1) gene on significant hyperbilirubinemia in term breast-fed neonates. Significant hyperbilirubinemia was defined as a bilirubin level exceeding the hour-specific phototherapy treatment threshold recommended by the American Academy of Pediatrics in 2004. RESULTS: Of 240 exclusively breast-fed term neonates, 26 (10.8%) had significant hyperbilirubinemia. The predischarge total serum bilirubin on the third day (odds ratio (OR) = 2.63; 95% confidence interval (CI): 1.87-3.70; P < 0.001) and the variant UGT1A1 gene at nucleotide 211 (OR = 5.00; 95% CI: 1.08-23.03; P < 0.05) were significant risk factors. The area under the receiver operating characteristic (ROC) curve of the predictive probability was 0.964 (95% CI: 0.932-0.984; P < 0.0001). CONCLUSION: Combining the total serum bilirubin on the third day and the variant UGT1A1 gene at nucleotide 211 can predict hyperbilirubinemia well in term breast-fed infants.

Glucose 6-phosphate dehydrogenase deficiency enhances germ cell apoptosis and causes defective embryogenesis in Caenorhabditis elegans.

Glucose 6-phosphate dehydrogenase (G6PD) deficiency, known as favism, is classically manifested by hemolytic anemia in human. More recently, it has been shown that mild G6PD deficiency moderately affects cardiac function, whereas severe G6PD deficiency leads to embryonic lethality in mice. How G6PD deficiency affects organisms has not been fully elucidated due to the lack of a suitable animal model. In this study, G6PD-deficient Caenorhabditis elegans was established by RNA interference (RNAi) knockdown to delineate the role of G6PD in animal physiology. Upon G6PD RNAi knockdown, G6PD activity was significantly hampered in C. elegans in parallel with increased oxidative stress and DNA oxidative damage. Phenotypically, G6PD-knockdown enhanced germ cell apoptosis (2-fold increase), reduced egg production (65% of mock), and hatching (10% of mock). To determine whether oxidative stress is associated with G6PD knockdown-induced reproduction defects, C. elegans was challenged with a short-term hydrogen peroxide (H2O2). The early phase egg production of both mock and G6PD-knockdown C. elegans were significantly affected by H2O2. However, H2O2-induced germ cell apoptosis was more dramatic in mock than that in G6PD-deficient C. elegans. To investigate the signaling pathways involved in defective oogenesis and embryogenesis caused by G6PD knockdown, mutants of p53 and mitogen-activated protein kinase (MAPK) pathways were examined. Despite the upregulation of CEP-1 (p53), cep-1 mutation did not affect egg production and hatching in G6PD-deficient C. elegans. Neither pmk-1 nor mek-1 mutation significantly affected egg production, whereas sek-1 mutation further decreased egg production in G6PD-deficient C. elegans. Intriguingly, loss of function of sek-1 or mek-1 dramatically rescued defective hatching (8.3- and 9.6-fold increase, respectively) induced by G6PD knockdown. Taken together, these findings show that G6PD knockdown reduces egg production and hatching in C. elegans, which are possibly associated with enhanced oxidative stress and altered MAPK pathways, respectively.

An in vivo drug screening model using glucose-6-phosphate dehydrogenase deficient mice to predict the hemolytic toxicity of 8-aminoquinolines.

Anti-malarial 8-aminoquinolines drugs cause acute hemolytic anemia in individuals with glucose-6-phosphate dehydrogenase deficiency (G6PDD). Efforts to develop non-hemolytic 8-aminoquinolines have been severely limited caused by the lack of a predictive in vivo animal model of hemolytic potential that would allow screening of candidate compounds. This report describes a G6PDD mouse model with a phenotype closely resembling the G6PDD phenotype found in the African A-type G6PDD human. These G6PDD mice, given different doses of primaquine, which used as a reference hemolytic drug, display a full array of hemolytic anemia parameters, consistently and reproducibly. The hemolytic and therapeutic indexes were generated for evaluation of hemotoxicity of drugs. This model demonstrated a complete hemolytic toxicity response to another known hemolytic antimalarial drug, pamaquine, but no response to non-hemolytic drugs, chloroquine and mefloquine. These results suggest that this model is suitable for evaluation of selected 8-AQ type candidate antimalarial drugs for their hemolytic potential.

Glucose-6-phosphate dehydrogenase deficiency: disadvantages and possible benefits.

We review here some recent data about Glucose-6-phosphate dehydrogenase (G6PD), the housekeeping X-linked gene encoding the first enzyme of the pentose phosphate pathway (PPP), a NADPH-producing dehydrogenase. This enzyme has been popular among clinicians, biochemists, geneticists and molecular biologists because it is the most common form of red blood cell enzymopathy. G6PD deficient erythrocytes do not generate NADPH in any other way than through the PPP and for this reason they are more susceptible than any other cells to oxidative damage. Moreover, this enzyme has also been of crucial importance in many significant discoveries; indeed, G6PD polymorphisms have been instrumental in studying X-inactivation in the human species, as well as in establishing the clonal nature of certain tumors. G6PD deficiency, generally considered as a mild and benign condition, is significantly disadvantageous in certain environmental conditions like in presence of certain drugs. Nevertheless, G6PD deficiency has been positively selected by malaria, and recent knowledge seems to show that it also confers an advantage against the development of cancer, reduces the risk of coronary diseases and has a beneficial effect in terms of longevity.

Α-lipoic acid supplementation up-regulates antioxidant capacity in adults with G6PD deficiency.

The purpose of this study was to examine the effect of α-lipoic acid (LA) supplementation on blood redox status in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Eight adults with G6PD deficiency (D group) and eight controls with normal G6PD levels (N group) participated in this study. Participants received LA (600 mg/day) for 28 days. At baseline, 2 and 4 weeks after supplementation, venous blood was collected for analysis of reduced glutathione (GSH), catalase, protein carbonyls (PC), thiobarbituric acid reactive substances (TBARS), total antioxidant capacity (TAC), bilirubin, uric acid (UA) and hemoglobin (Hb) levels. Baseline GSH was lower (P<0.05) in D compared to N group whereas LA supplementation for 2 and 4 weeks increased significantly (P<0.05) GSH levels in both groups. Catalase and TAC increased (P<0.05) in both groups following 2 and 4 weeks of supplementation. Baseline TBARS values were higher (P<0.05) in D compared to N group while LA supplementation reduced (P<0.05) TBARS and PC in both groups. There were no differences for UA at baseline between the two groups but LA supplementation increased significantly UA levels only in the D group. Bilirubin and Hb were unchanged. These results indicate that LA supplementation may modulate redox status regardless G6PD deficiency.

Safety of hematopoietic stem cell donation in glucose 6 phosphate dehydrogenase-deficient donors.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common RBC enzymatic disorder in humans capable of producing hemolytic events. Recently, concern has been raised about using G6PD-deficienct subjects as hemopoietic stem cell (HSC) donors. In a 10-year period, 101 consecutive HSC donors were submitted to donation procedures for transplantation inside their families in our Center. All donors were tested for G6PD and 19 (19%) turned out to be G6PD-deficient. The donors' safety and the effectiveness of these transplant outcomes were compared with those of the remaining 82 donors. No difference could be observed in any safety parameter between the two groups. No difference was recorded in donors' complications rates, in HSC production, in quantity of growth factor required, in Hb early drop or in Hb recovery. No difference was found in transplant outcome. From this retrospective analysis, we conclude that a G6PD-deficient but otherwise healthy volunteer can be selected as a HSC donor.