Schistosomiasis caused by Schistosoma spp. is a serious public health concern, especially in subSaharan Africa. Praziquantel is the only drug currently administrated to treat this disease. However, praziquantel-resistant parasites have been identified in endemic areas and can be generated in the laboratory. Therefore, it is essential to find new therapeutics. Antioxidants are appealing drug targets. In order to survive in their hosts, schistosomes are challenged by reactive oxygen species from intrinsic and extrinsic sources. Schistosome antioxidant enzymes have been identified as essential proteins and novel drug targets and inhibition of the antioxidant response can lead to parasite death. Because the organization of the redox network in schistosomes is significantly different form that in humans, new drugs are being developed targeting schistosome antioxidants. In this paper the redox biology of schistosomes is discussed and their potential use as drug targets is reviewed. It is hoped that compounds targeting parasite antioxidant responses will become clinically relevant drugs in the near future. KeywordsSchistosoma; drug development; antioxidants; glutathione; thioredoxin; thioredoxin glutathione reductase Schistosomiasis (also known as bilharzia) is caused by blood-dwelling flatworms of the genus Schistosoma. Schistosomiasis is the second most important human parasitic disease after malaria, with an estimated 200 million people infected and greater than 200,000 deaths annually in tropical and subtropical areas [1][2][3]. Nearly 800 million people are at risk of infection in seventy-two counties [1]. In addition, schistosome infections lead to largely underreported chronic disabilities and morbidities, such as caloric malnutrition, growth stunting, anemia, and poor school performance, which lead to decreased quality of life and perpetuation of poverty [1][2][3]. The chronic morbidities associated with schistosomiasis can be exacerbated by co-infections with other helminths (parasitic worms, e.g., hookworms) [4] and schistosome infections can have significant impacts on the susceptibility and transmission of other infections, e.g., HIV [5,6] and malaria [7,8], and on immune responses to childhood vaccines [9]. Furthermore, S. haematobium is considered as a group 1 carcinogen leading to the development of urinary bladder cancer [10][11][12]. Intestinal schistosomiasis has been linked to hepatocellular carcinoma and colorectal cancer [13,14] NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptFive species of Schistosoma parasitize humans including S. mansoni, S. japonicum, S. haematobium, S. intercalatum, and S. mekongi; the first three species have the widest geographic distribution whereas infections with the last two species only occur locally [15]. The life cycle of Schistosoma ssp. is complex [16,17] and is divided into sexual and asexual cycles. In the asexual cycle, eggs are released into water with feces or urine of infected individuals. Miracidia hatch from the eggs and th...

Background There are two, largely autonomous antioxidant pathways in many organisms, one based on thioredoxin and one based on glutathione, with each pathway having a unique flavoprotein oxidoreductase to maintain them in a reduced state. A recently discovered protein, thioredoxin glutathione reductase (TGR) potentially connects these two pathways. In a large group of parasitic worms, responsible for hundreds of millions of infections in humans and animals, untold morbidity and significant mortality, TGR is the sole enzyme present to maintain redox balance. Scope of Review In this review, the current understanding of the biochemical properties of TGR enzymes is compared to the related enzymes thioredoxin reductase and glutathione reductase. The role of the rare amino acid selenocysteine is discussed. An overview of the potential to target TGR for drug development against a range of parasitic worms and preliminary results to identify TGR inhibitors for schistosomiasis treatment is presented. Major Conclusions TGR has properties that are both unique and common to other flavoprotein oxidoreductases. TGR plays a fundamentally different and essential role in the redox biology of parasitic flatworms. Therefore, TGR is a promising target for drug development for schistosomiasis and other trematode and cestodes infections. General Significance TGR may have differing functions in host organisms, but through analyses to understand its ability to reduce both glutathione and thioredoxin we can better understand the reaction mechanisms of an important class of enzymes. The unique properties of TGR in parasitic flatworms provide promising routes to develop new treatments for diseases.

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Summary Background Esophageal candidiasis (EC) often occurs in human immunodeficiency virus (HIV)‐infected patients, but is uncommon in non‐HIV‐infected patients. It is known that malignancy, diabetes mellitus, previous gastric surgery, and medications (antibiotics, proton pump inhibitors, and steroids) are risk factors for esophageal candidiasis in non‐HIV‐infected patients. However, the relationship between liver cirrhosis and esophageal candidiasis was unclear. This study aimed to elucidate the role of liver cirrhosis in esophageal candidiasis. Methods A retrospective chart review study was conducted on non‐HIV‐infected patients with esophageal candidiasis who presented to Tri‐Service General Hospital from January 2009 to December 2012. The diagnosis of EC was primarily based on endoscopic findings. The incidence of EC in cirrhotic and noncirrhotic patients was compared. Furthermore, differences in baseline characteristics, clinical variables, and mortality after antifungal treatment between the two groups were analyzed. Results In this study, 43,217 non‐HIV‐infected patients were enrolled, 3017 of whom had liver cirrhosis. The incidence of EC in cirrhotic patients was higher than that in noncirrhotic patients (0.8% vs. 0.36%; relative risk = 2.2; p < 0.001). Multivariate logistic regression analysis identified liver cirrhosis as an independent risk factor for EC (odds ratio, 1.74; 95% confidence interval, 1.06–2.87; p = 0.029). Moreover, cirrhotic patients tended to be asymptomatic compared with noncirrhotic patients (45.8% vs. 9%; p < 0.01). The most common coexisting endoscopic finding was reflux esophagitis (83.9%). However, antifungal treatment did not decrease the mortality of patients with EC during hospitalization. Conclusion Liver cirrhosis is an independent risk factor for EC. EC may be asymptomatic in cirrhotic patients. Although antifungal treatment did not improve the outcome in this study, a prospective study is still required to investigate this issue.

BackgroundUnsedated esophagogastroduodenoscopy (EGD) is simpler and safer than sedated EGD; however, approximately 40% of patients cannot tolerate it. Early identification of patients likely to poorly tolerate unsedated EGD is valuable for improving compliance. The modified Mallampati classification (MMC) has been used to evaluate difficult tracheal intubation and laryngoscope insertion. We tried to assess the efficacy of MMC to predict the tolerance of EGD in unsedated patients.MethodsTwo hundred patients who underwent an unsedated diagnostic EGD were recruited. They were stratified according to the view of the oropharynx as either MMC class I + II (good view) or class III + IV (poor view). EGD tolerance was assessed in three ways: gag reflex by endoscopist assessment, patient satisfaction by interview, and the degree of change in vital signs.ResultsMMC was significantly correlated to gag reflex (P < 0.001), patient satisfaction (P = 0.028), and a change of vital signs (P = 0.024). Patients in the poor view group had a 3.87-fold increased risk of gag reflex (P < 0.001), a 1.78-fold increased risk of unsatisfaction (P = 0.067), and a 1.96-fold increased risk of a change in vital signs (P = 0.025) compared to those in the good view group.ConclusionsMMC appears to be a clinically useful predictor of EGD tolerance. Patients with poor view of oropharynx by MMC criteria may be candidates for sedated or transnasal EGD.