STAT3 Promotes Schistosome-Induced Liver Injury by Inflammation, Oxidative Stress, Proliferation, and Apoptosis Signal Pathway.

Schistosomiasis is a parasitic helminth disease that can cause organ lesions leading to health damage. During a schistosome infection, schistosome eggs can flow into the liver along the portal vein. Numerous inflammatory cells gather around the eggs, causing granulomas and fibrosis in the liver. In this process, many molecules are involved in the initiation and regulation of the fibrous scar formation. However, the precise molecular mechanisms responsible for the progression of granuloma formation and fibrosis initiation caused by schistosome infection have not been extensively studied. In this study, C57BL/6 wild-type mice and Stat3flox/flox Alb-Cre mice were infected with cercariae of Schistosoma japonicum Liver injury, effector molecule levels, and RNA transcriptome resequencing of liver tissue were detected at 4, 5, and 6 weeks postinfection. We investigated the role of STAT3 (signal transducer and activator of transcription 3) in Schistosoma-induced liver injury in mice. After 6 weeks postinfection, there was obvious liver fibrosis. A sustained pathological process (inflammation, oxidative stress, proliferation, and apoptosis) occurred in S. japonicum-induced liver fibrosis initiation. Meanwhile, we observed activation of the STAT3 pathway in hepatic injury during S. japonicum infection by RNA transcriptome resequencing. Liver deficiency of phospho-STAT3 alleviated infection-induced liver dysfunction, hepatic granuloma formation, and fibrosis initiation. It also promoted STAT3-dependent apoptosis and reduced liver inflammation, oxidative stress, and proliferation. Our results suggest that STAT3 signal pathway and its mediating inflammation, oxidative stress, proliferation, and apoptosis are involved in S. japonicum-induced liver injury and may be a new potential guideline for the treatment of schistosomiasis.

Taurine Alleviates Schistosoma-Induced Liver Injury by Inhibiting the TXNIP/NLRP3 Inflammasome Signal Pathway and Pyroptosis.

Schistosomiasis is a parasitic helminth disease that can cause severe inflammatory pathology, leading to organ damage, in humans. During a schistosomal infection, the eggs are trapped in the host liver, and products derived from eggs induce a polarized Th2 cell response, resulting in granuloma formation and eventually fibrosis. Previous studies indicated that the nucleotide-binding oligomerization domain-, leucine-rich repeat-, and pyrin domain-containing protein 3 (NLRP3) inflammasome is involved in schistosomiasis-associated liver fibrosis and that taurine could ameliorate hepatic granulomas and fibrosis caused by Schistosoma japonicum infection. Nevertheless, the precise role and molecular mechanism of the NLRP3 inflammasome and the protective effects of taurine in S. japonicum infection have not been extensively studied. In this study, we investigated the role of the NLRP3 inflammasome and the hepatoprotective mechanism of taurine in schistosoma-induced liver injury in mice. NLRP3 deficiency ameliorated S. japonicum-infection-induced hepatosplenomegaly, liver dysfunction, and hepatic granulomas and fibrosis; it also reduced NLRP3-dependent liver pyroptosis. Furthermore, taurine suppressed hepatic thioredoxin-interacting protein (TXNIP)/NLRP3 inflammasome activation in mice with S. japonicum infections, thereby inhibiting the activation of downstream inflammatory mediators such as interleukin-1ß and subsequent pyroptosis. Our results suggest that the TXNIP/NLRP3 inflammasome pathway and mediating pyroptosis are involved in S. japonicum-induced liver injury and may be a potential therapeutic target for schistosomiasis treatment. In addition, taurine may be useful to alleviate or to prevent the occurrence of schistosomiasis-associated liver fibrosis.

Antinuclear antibodies and interleukin responses in patients with Schistosoma japonicum infection.

Schistosomiasis poses a serious threat to public health, and the infection will develop into chronic and advanced late-stage disease if not treated. Apart from the clinical signs due to immune reactions to schistosome eggs trapped in host tissues, it also increases the risk for the development of autoimmunity reflected by dysfunctional, auto-reactive antibodies. Antinuclear antibodies (ANA) have been reported in schistosomiasis due to S. mansoni and S. haematobium. We demonstrate ANA in schistosomiasis japonica and explore the relationship between this infection and autoimmune disease by measuring ANA and interleukin (IL)-10, IL-12 and IL-17 responses in the sera of 125 Chinese patients with different stages of schistosomiasis japonica. The incidence rates of ANA in the patients with acute, chronic and late stages of schistosomiasis infection were 6.7%, 23.3% and 70.0%, respectively, with statistically significant differences between each stage (P = 0.000). IL-17 concentrations were high at the acute stage of schistosomiasis compared to the other stages of the disease (P = 0.000). This pattern was also seen for IL-10 and IL-12 concentrations (P = 0.01). IL concentrations in patients in the chronic and late stages of the disease were low and showed no difference compared to the healthy adults.

Utilization of real time PCR for the assessment of egg burden in the organs of Schistosoma japonicum experimentally infected mice.

Schistosoma japonicum, causing zoonotic intestinal schistosomiasis, is found in China, the Philippines and parts of Indonesia. Severe disease manifestations are basically due to the deposition of eggs in some vital organs such as the liver, spleen and brain. Traditionally, histopathological microscopic examination of the egg burden was used to evaluate the intensity of infection in the affected organs. However, this technique is laborious, time-consuming and requires trained personnel. In this study, real time PCR targeting the mitochondrial NADH dehydrogenase I gene was used to compare with microscopic examination of tissue sections in evaluating the egg burdens in different affected organs. Livers, spleens and brains of the S. japonicum infected mice after 8 and 18 weeks post-infection (p.i) were harvested and examined. Results showed that there were statistically significant correlations between the egg burden evaluated by tissue section examination, and the Ct values of the real time PCR of livers with heavy egg burden at 8 (r = -0.81) and 18 (r = -0.80) weeks p.i. Furthermore, a correlation (r = -0.56) between the egg burden assessed by the microscopic examination and Ct value of the real time PCR of spleens with moderate egg burden after 18 weeks p.i and not 8 weeks p.i was also observed. Brains with low egg burden showed no schistosome eggs in the microscopic examination, however one sample tested positive by real time PCR. These results suggested that real time PCR is useful in evaluating schistosome egg burden in the organs of the experimentally infected mice model that will give further insights into the pathology of schistosomiasis.

Immune modulation of Th1, Th2, and T-reg transcriptional factors differing from cytokine levels in Schistosoma japonicum infection.

In spite of long-term integrated control programs for Schistosoma japonicum infection in China, the infection is still persistent due to its zoonotic transmission and disease severity which further complicate its control. Th1, Th2, and T-reg cells are involved in S. japonicum immunity; however, their exact roles in immunopathology of this infection are still questionable. Therefore, the monitoring of these T cell subsets' immune responses during a primary infection of S. japonicum at both transcriptional (mRNA) and protein (cytokines) levels would be essential to point out. In experimentally infected white New Zealand rabbits, mRNA expression levels of TBX2, IRF8, GATA3, STAT6, FoxP3, and MAFF were evaluated using qPCR, whereas Th1 (IFN-γ and TNF-α), Th2 (IL4 and IL13), and T-reg (IL10 and TGF-ß1) cytokines were measured by ELISA test. Those parameters were estimated at two phases: the first being 4 and 8 weeks post-infection and the second phase at 12 weeks post-infection. The infected rabbits were categorized into group1 which was treated with praziquantel after the 8th week of infection and group 2 which was left untreated. In the first stage of infection, Th1 was superior to the other types at both mRNA (TBX2 and IRF8) and protein (IFN-γ and TNF-α) levels, but at the late stage, Th2 cytokines (IL4 and IL13) were surprisingly dominated without comparable change in Th2 transcriptional level in group 1. Concisely, the evaluation of T cell transcriptional factors provided clearer evidence about T cellular roles which would be a valuable supplement to control this disease in terms of protective and therapeutic vaccinations.

Cloning, expression and enzymatic characterization of 3-phosphoglycerate kinase from Schistosoma japonicum.

In the present study, a full-length cDNA encoding the Schistosoma japonicum 3-phosphoglycerate kinase (SjPGK) with an open reading frame of 1251 bp was isolated from 42-day-old (42-d) schistosome cDNAs. Real-time quantitative reverse transcription PCR analysis revealed that SjPGK was expressed in all investigated developmental stages and at a higher transcript levels in 21- and 42-d worms. Moreover, the SjPGK mRNA level was significantly downregulated in 10-d schistosomula from Wistar rats (non-susceptible host). SjPGK was subcloned into pET28a(+) and expressed as both supernatant and inclusion bodies in Escherichia coli BL21 cells. The enzymatic activity of recombinant SjPGK protein (rSjPGK) was 125 U/mg. Kinetic analyses with respect to 3-phosphoglycerate (3-PGA) as substrate gave a Km of 2.69 mmol/L and a Vmax of 748 µmol/min/mg protein. rSjPGK was highly stable over a range of pH 8.0-9.0 and temperature of 30°C-40 °C under physiological conditions. Immunolocalization analysis showed that SjPGK was mainly distributed in the tegument and parenchyma of schistosomes. Western blotting showed that rSjPGK had good immunogenicity. We vaccinated BALB/c mice with rSjPGK combined with Seppic 206 adjuvant. However, there were no significant reductions in the numbers of worms of eggs in the liver, as compared to adjuvant or blank control groups in two independent vaccination tests. This study provides the basis for further investigations into the biological function of SjPGK, although it might not be suitable as a potential vaccine candidate against schistosomiasis.

Schistosomiasis japonica during pregnancy is associated with elevated endotoxin levels in maternal and placental compartments.

Schistosomiasis affects approximately 40 million women of reproductive age and has been linked to elevated levels of circulating endotoxin in nonpregnant individuals. We have evaluated endotoxin levels in maternal, placental, and newborn blood collected from women residing in Leyte, Philippines. Endotoxin levels in both maternal and placental compartments in pregnant women with schistosomiasis were 1.3- and 2.4-fold higher, respectively, than in uninfected women. In addition, higher concentrations of endotoxin in placental blood were associated with premature birth, acute chorioamnionitis, and elevated proinflammatory cytokines. By promoting endotoxemia, schistosomiasis may exert additional, maladaptive influences on pregnancy outcomes.

Effects of different postharvest drying processes on flavonoid content and enzymatic activity of Styphnolobium japonicum (L.) Schott flowers for industrial and medicinal use.

Traditionally, fresh S. japonicum flowers (SJF) and S. japonicum flowers buds (SJFB) are dried prior to further processing and use. Here, we investigated the ways in which drying techniques, including sun drying (SD), steam drying (STD), microwave drying (MD), hot air drying (HAD, 40 °C, 60 °C, 80 °C, 100 °C), and freeze drying (FD), alter the flavonoid composition of freshly-harvested SJF and SJFB. The flavonoid content of dried samples was determined by Ultra High Performance Liquid Chromatography-Diode Array Detector (UPLC-DAD). Overall, different drying techniques had significantly different effects on the RU content, ranging from 10.63 % (HAD-80 °C) to 34.13 % (HAD-100 °C) in SJF and from 18.91 % (HAD-100 °C) to 29.16 % (HAD-40 °C) and 30.53 % (SD) in SJFB. To clarify the mechanism by which drying affects the RU content of S. japonicum flowers, we studied the activity of a rutin-hydrolyzing enzyme (RHE) isolated from SJF and SJFB using multiple separation and assay methods. According to the Sodium Dodecyl Sulfate-Polyacrylamide Gel Electrophoresis (SDS-PAGE) results, the apparent molecular weight of the purified RHE was approximately 38 kDa. According to UPLC-DAD, RHE catalyzes the production of quercetin (QU) from rutin (RU), but not from other flavonoid glycosides. Drying fresh SJF and SJFB at low and high temperatures can inhibit RHE activity and prevent RU hydrolysis. Therefore, subjecting freshly-harvest SJF to HAD-100 °C, and freshly-harvest SJFB to SD or HAD-40 °C, can greatly increase the RU content. In particular, HAD is viable for large-scale application due to its simplicity and industrial feasibility.

Inhibition of signal peptidase complex expression affects the development and survival of Schistosoma japonicum.

Background: Schistosomiasis, the second most neglected tropical disease defined by the WHO, is a significant zoonotic parasitic disease infecting approximately 250 million people globally. This debilitating disease has seriously threatened public health, while only one drug, praziquantel, is used to control it. Because of this, it highlights the significance of identifying more satisfactory target genes for drug development. Protein translocation into the endoplasmic reticulum (ER) is vital to the subsequent localization of secretory and transmembrane proteins. The signal peptidase complex (SPC) is an essential component of the translocation machinery and functions to cleave the signal peptide sequence (SP) of secretory and membrane proteins entering the ER. Inhibiting the expression of SPC can lead to the abolishment or weaker cleavage of the signal peptide, and the accumulation of uncleaved protein in the ER would affect the survival of organisms. Despite the evident importance of SPC, in vivo studies exploring its function have yet to be reported in S. japonicum. Methods: The S. japonicum SPC consists of four proteins: SPC12, SPC18, SPC22 and SPC25. RNA interference was used to investigate the impact of SPC components on schistosome growth and development in vivo. qPCR and in situ hybridization were applied to localize the SPC25 expression. Mayer's carmalum and Fast Blue B staining were used to observe morphological changes in the reproductive organs of dsRNA-treated worms. The effect of inhibitor treatment on the worm's viability and pairing was also examined in vitro. Results: Our results showed that RNAi-SPC delayed the worm's normal development and was even lethal for schistosomula in vivo. Among them, the expression of SPC25 was significantly higher in the developmental stages of the reproductive organs in schistosomes. Moreover, SPC25 possessed high expression in the worm tegument, testes of male worms and the ovaries and vitellarium of female worms. The SPC25 knockdown led to the degeneration of reproductive organs, such as the ovaries and vitellarium of female worms. The SPC25 exhaustion also reduced egg production while reducing the pathological damage of the eggs to the host. Additionally, the SPC-related inhibitor AEBSF or suppressing the expression of SPC25 also impacted cultured worms' pairing and viability in vitro. Conclusions: These data demonstrate that SPC is necessary to maintain the development and reproduction of S. japonicum. This research provides a promising anti-schistosomiasis drug target and discovers a new perspective on preventing worm fecundity and maturation.

Metabolic reprogramming of hepatocytes by Schistosoma mansoni eggs.

Background & Aims: Schistosomiasis is a parasitic infection which affects more than 200 million people globally. Schistosome eggs, but not the adult worms, are mainly responsible for schistosomiasis-specific morbidity in the liver. It is unclear if S. mansoni eggs consume host metabolites, and how this compromises the host parenchyma. Methods: Metabolic reprogramming was analyzed by matrix-assisted laser desorption/ionization mass spectrometry imaging, liquid chromatography with high-resolution mass spectrometry, metabolite quantification, confocal laser scanning microscopy, live cell imaging, quantitative real-time PCR, western blotting, assessment of DNA damage, and immunohistology in hamster models and functional experiments in human cell lines. Major results were validated in human biopsies. Results: The infection with S. mansoni provokes hepatic exhaustion of neutral lipids and glycogen. Furthermore, the distribution of distinct lipid species and the regulation of rate-limiting metabolic enzymes is disrupted in the liver of S. mansoni infected animals. Notably, eggs mobilize, incorporate, and store host lipids, while the associated metabolic reprogramming causes oxidative stress-induced DNA damage in hepatocytes. Administration of reactive oxygen species scavengers ameliorates these deleterious effects. Conclusions: Our findings indicate that S. mansoni eggs completely reprogram lipid and carbohydrate metabolism via soluble factors, which results in oxidative stress-induced cell damage in the host parenchyma. Impact and implications: The authors demonstrate that soluble egg products of the parasite S. mansoni induce hepatocellular reprogramming, causing metabolic exhaustion and a strong redox imbalance. Notably, eggs mobilize, incorporate, and store host lipids, while the metabolic reprogramming causes oxidative stress-induced DNA damage in hepatocytes, independent of the host's immune response. S. mansoni eggs take advantage of the host environment through metabolic reprogramming of hepatocytes and enterocytes. By inducing DNA damage, this neglected tropical disease might promote hepatocellular damage and thus influence international health efforts.

Comparison of intestinal flora between patients with chronic and advanced Schistosoma japonicum infection.

BACKGROUND: Schistosoma japonicum infection is an important public health problem, imposing heavy social and economic burdens in 78 countries worldwide. However, the mechanism of transition from chronic to advanced S. japonicum infection remains largely unknown. Evidences suggested that gut microbiota plays a role in the pathogenesis of S. japonicum infection. However, the composition of the gut microbiota in patients with chronic and advanced S. japonicum infection is not well defined. In this study, we compared the composition of the intestinal flora in patients with chronic and advanced S. japonicum infection. METHODS: The feces of 24 patients with chronic S. japonicum infection and five patients with advanced S. japonicum infection from the same area were collected according to standard procedures, and 16S rRNA sequencing technology was used to analyze the intestinal microbial composition of the two groups of patients. RESULTS: We found that alteration occurs in the gut microbiota between the groups of patients with chronic and advanced S. japonicum infections. Analysis of alpha and beta diversity indicated that the diversity and abundance of intestinal flora in patients with advanced S. japonicum infection were lower than those in patients with chronic S. japonicum infection. Furthermore, Prevotella 9, Subdoligranulum, Ruminococcus torques, Megamonas and Fusicatenibacter seemed to have potential to discriminate different stages of S. japonicum infection and to act as biomarkers for diagnosis. Function prediction analysis revealed that microbiota function in the chronic group was focused on translation and cell growth and death, while that in the advanced group was concentrated on elevating metabolism-related functions. CONCLUSIONS: Our study demonstrated that alteration in gut microbiota in different stages of S. japonicum infection plays a potential role in the pathogenesis of transition from chronic to advanced S. japonicum infection. However, further validation in the clinic is needed, and the underlying mechanism requires further study.

In vivo efficiency of praziquantel treatment of single-sex Schistosoma japonicum aged three months old in mice.

Schistosomiasis is a major neglected tropical disease mainly caused by Schistosoma haematobium, S. japonicum and S. mansoni, and results in the greatest disease burden. Mass drug administration (MDA) with praziquantel (PZQ), a single drug only available for the disease, has played a vital role in schistosomiasis control. Therefore, any possibility of selection of the parasites for PZQ resistance or low sensitivity may hamper the 2030's target of global disease elimination. We had experimentally demonstrated the long-term survival and reproductive potential of single-sex (of either sex) S. japonicum infections in definitive hosts mice. What has not yet been adequately addressed is whether the long live single-sex schistosomes remain sensitive to PZQ, and what reproduction potential for those schistosomes surviving treatment may have. We therefore performed experimental mice studies to explore the treatment effectiveness of PZQ (at total doses of 200 or 400 mg/kg, corresponding to the sub-standard or standard treatment doses in humans) for single-sex S. japonicum aged three months old. The results showed that no treatment efficiency was observed on female schistosomes, whereas on male schistosomes only at PZQ 400 mg/kg a significant higher efficiency in reducing worm burdens was observed. Moreover, either schistosome males or females surviving PZQ treatment remained their reproduction potential as normal. The results indicate that long (i.e., three months) live single-sex S. japonicum can easily survive the current treatment strategy, and moreover, any schistosomes, if with PZQ resistance or low sensitivity, could be easily transmitted in nature. Therefore, in order to realize the target for the national and the global schistosomiasis elimination, there is undoubtedly a great need for refining PZQ administration and dosage, looking for alternative therapies, and/or developing vaccines against schistosome.

Schistosome Sulfotransferases: Mode of Action, Expression and Localization.

Oxamniquine (OXA) is a prodrug activated by a sulfotransferase (SULT) that was only active against Schistosoma mansoni. We have reengineered OXA to be effective against S. haematobium and S. japonicum. Three derivatives stand out, CIDD-0066790, CIDD-0072229, and CIDD-0149830 as they kill all three major human schistosome species. However, questions remain. Is the OXA mode of action conserved in derivatives? RNA-interference experiments demonstrate that knockdown of the SmSULT, ShSULT, and SjSULT results in resistance to CIDD-0066790. Confirming that the OXA-derivative mode of action is conserved. Next is the level of expression of the schistosome SULTs in each species, as well as changes in SULT expression throughout development in S. mansoni. Using multiple tools, our data show that SmSULT has higher expression compared to ShSULT and SjSULT. Third, is the localization of SULT in the adult, multicellular eucaryotic schistosome species. We utilized fluorescence in situ hybridization and uptake of radiolabeled OXA to determine that multiple cell types throughout the adult schistosome worm express SULT. Thus, we hypothesize the ability of many cells to express the sulfotransferase accounts for the ability of the OXA derivatives to kill adult worms. Our studies demonstrate that the OXA derivatives are able to kill all three human schistosome species and thus will be a useful complement to PZQ.

Comparative proteomics analysis of Schistosoma japonicum developed in different Oncomelania snails as intermediate hosts.

Schistosomiasis is a tropical parasitic disease that seriously endangers humans and animals. In this study, two Oncomelania snails, Oncomelania hupensis (O. hupensis) and Oncomelania weishan (O. weishan), were infected with Schistosoma japonicum (S. japonicum) cercariae during the early period, and ICR mice were subsequently infected with two kinds of miracidia that developed in male and female adult worms. In this study, isobaric tags for relative and absolute quantification (iTRAQ) were used to identify four channels: 113, 115, 117, and 119. A total of 2364 adult schistosome proteins were identified, and 1901 proteins were quantitative. Our results revealed 68 differentially expressed proteins (DEPs) in female adult worms, including 24 upregulated proteins and 44 downregulated proteins, and 55 DEPs in male adult worms, including 25 upregulated proteins and 30 downregulated proteins. LC-MS/MS and bioinformatics analysis indicated that these DEPs are mainly concentrated in cellular composition, molecular function, biological function and catabolism pathways. In summary, this proteomics analysis of adult schistosomes that hatched in two intermediate hosts helps to improve our understanding of the growth and developmental mechanisms of S. japonicum.

Corrigendum: Comparative proteomics analysis of Schistosoma japonicum developed in different Oncomelania snails as intermediate hosts.

[This corrects the article DOI: 10.3389/fcimb.2022.959766.].

Roles of TLR7 in Schistosoma japonicum Infection-Induced Hepatic Pathological Changes in C57BL/6 Mice.

S. japonicum infection can induce granulomatous inflammation in the liver of the host. Granulomatous inflammation limits the spread of infection and plays a role in host protection. Toll-like receptor 7 (TLR7) is an endosomal TLR that recognizes single-stranded RNA (ssRNA). In this study, the role of TLR7 in S. japonicum infection-induced hepatitis was investigated in both normal and TLR7 knockout (KO) C57BL/6 mice. The results indicated that TLR7 KO could aggravate S. japonicum infection-induced damage in the body, with less granuloma formation in the tissue, lower WBCs in blood, and decreased ALT and AST in the serum. Then, the expression of TLR7 was detected in isolated hepatic lymphocytes. The results indicated that the percentage of TLR7+ cells was increased in the infected mice. Hepatic macrophages, DCs, and B cells could express TLR7, and most of the TLR7-expressing cells in the liver of infected mice were macrophages. The percentage of TLR7-expressing macrophages was also increased after infection. Moreover, macrophages, T cells, and B cells showed significant changes in the counts, activation-associated molecule expression, and cytokine secretion between S. japonicum-infected WT and TLR7 KO mice. Altogether, this study indicated that TLR7 could delay the progression of S. japonicum infection-induced hepatitis mainly through macrophages. DCs, B cells, and T cells were involved in the TLR7-mediated immune response.

Gallbladder schistosomiasis - a rare presentation as gallbladder polyp: a case report.

Background: Schistosomiasis is a neglected tropical disease second to malaria in prevalence with significant morbidity and mortality. Although, Schistosomiasis can affect multiple organs, gallbladder involvement is very rarely reported. We present a case of isolated gallbladder schistosomiasis in a 20-year-old female presenting as gallbladder polyp radiologically and also correlated the histopathological findings which to our knowledge has never been reported in the English literature. A high index of suspicion should be made for considering Schistosomiasis when an individual hailing from endemic region presents with gallbladder pathologies.

Schistosomiasis in the Philippines: Innovative Control Approach is Needed if Elimination is the Goal.

In 1996, schistosomiasis due to Schistosoma japonicum was declared eradicated in Japan. In the People's Republic of China, S. japonicum transmission has been interrupted in the major endemic areas in the coastal plains but the disease persists in the lake and marshland regions south of the Yangtze River. The disease remains a public health problem in endemic areas in the Philippines and in isolated areas in Indonesia. Comprehensive multidisciplinary campaigns had led to eradication of schistosomiasis in Japan and have been successful in the interruption of disease transmission in the major endemic regions of the People's Republic of China. Unfortunately, the integrated measures cannot be duplicated in schistosomiasis endemic areas in the Philippines because of limited resources. The problem is also more complicated due to the topography in the Philippines and transmission is not seasonal as in China. An innovative approach is needed in the Philippines if schistosomiasis elimination is the goal.

Improvement of Mitochondrial Activity and Fibrosis by Resveratrol Treatment in Mice with Schistosoma japonicum Infection.

Schistosomiasis caused by Schistosoma japonicum is a major parasitic disease in the People's Republic of China. Liver fibrosis is the main pathological mechanism of schistosomiasis, and it is also the major lesion. The common drug used for its treatment, praziquantel (PZQ), does not have a marked effect on liver fibrosis. Resveratrol (RSV), which is an antioxidant, improves mitochondrial function and also attenuates liver fibrosis. The combination of PZQ and RSV has been found to have a synergistic antischistosomal effect on Schistosoma mansoni; additionally, the activity of PZQ is enhanced in the presence of RSV. Here, we examine the therapeutic effects of RSV on the S. japonicum infection in a mouse model, and we investigate RSV as a novel therapeutic agent for mitochondrial function and schistosomiasis-associated liver fibrosis (SSLF). Mitochondrial membrane potential was examined using flow cytometry analysis. The expression of the mitochondrial biogenesis genes PGC-α and fibrosis-associated genes collagen I, collagen III and α-SMA were examined using western blot analysis. Fibrosis-associated histological changes were examined using Masson trichrome staining. Additionally, the effects of RSV on S. japonicum adult worms were examined using scanning electron microscopy and transmission electron microscopy. RSV treatment improved mitochondrial function by increasing membrane potential and increasing PGC-α expression (mitochondrial biogenesis). Further, RSV attenuated liver injury, including liver scarring, by decreasing collagen deposition and the extent of fibrosis, based on the decrease in expression of the fibrosis-related genes. RSV also decreased the adult worm count and caused considerable physical damage to the worm. These results indicate that RSV upregulates mitochondrial biogenesis and inhibits fibrosis. RSV may have potential as a therapeutic target for the treatment of fibrosis in schistosomiasis.

A perspective for improving the sensitivity of detection: The application of multi-epitope recombinant antigen in serological analysis of buffalo schistosomiasis.

The sensitivity and specificity are two crucial aspects of addressing the efficacy of diagnostic antigens. Achilles' heel of low sensitivity rate exists in current diagnostic recombinant antigens for schistosomiasis detection. This study focused on the diagnosis of water buffalo schistosomiasis japonica and a perspective of improving recombinant antigens' sensitivity was assessed using archived 220 water buffalo sera (114 positive sera, 92 negative sera and 14 Paramphistomum-infected sera) and the method of enzyme-linked immunosorbent assay (ELISA). The subjects included two trivalent recombinant proteins, one bivalent antigen and two single-molecular antigens. The crude antigen SEA (soluble egg antigen) was employed as reference antigen. The highest sensitivity rate in the five recombinant antigens assigned to the trivalent multi-epitope antigen PA4 (95.61%, 109/114), no significant difference with SEA (100%, 114/114, p = .836), and showing remarkable differences with the two single-molecular antigens (p < 0.01). In term of specificity, two trivalent multi-epitope antigens PA4 (97.83%, 90/92), PA5 (100%, 92/92) and the bivalent antigen PA3 (98.91%, 91/92) had few differences with one monovalent antigens PA1 (97.83%, 90/92, p = .304/0.103/0.640), significant differences with another monovalent antigens PA2 (92.39%, 85/92, p < 0.01) and SEA (82.61%, 76/92, p < 0.01). Additional, all the recombinant antigens had low cross-reactivity (7.14%, 1/14, 0% for PA5) with serum samples of paramphistomiasis, contrast with that of SEA (50%, 7/14, p < 0.01). The results indicated that multi-epitope antigens have the possibility to improve diagnostic sensitivity and the trivalent multi-epitope antigen PA4 possesses greater likelihood to be a diagnostic antigen for water buffalo schistosomiasis.