Parasitic Reduction Research Articles

In vitro and In vivo Biological Activity of Two Aryloxy-naphthoquinones in Mice Infected with Trypanosoma cruzi Strains.

Chagas disease, a condition caused by Trypanosoma cruzi, is an endemic disease in Latin American countries that affects approximately eight million people worldwide. It is a continuing public health problem. As nifurtimox and benznidazole are the two pharmacological treatments currently used to treat it, the present research proposes new therapeutic alternatives. Previous studies conducted on naphthoquinone derivatives have found interesting trypanocidal effects on epimastigotes, with the molecules 2-phenoxy-1,4-naphthoquinone (IC50= 50 nM and SI < 250) and 2-(3-nitrophenoxy)-naphthalene-1,4-dione (IC50= 20 nM and SI=625) presenting the best biological activity.. The present study evaluated the efficacy of in vitro, ex vivo and in vivo models of two aryloxyquinones, 2-phenoxy-1,4-naphthoquinone (1) and 2-(3-nitrophenoxy)-naphthalene-1,4- dione (2), against two Mexican T. cruzi strains in both their epimastigote and blood Trypomastigote stage. Both compounds were evaluated against T. cruzi using a mouse model (CD1) infected with Mexican isolates of T. cruzi, nifurtimox and benznidazole used as control drugs. Finally, the cytotoxicity of the two compounds against the J774.2 mouse macrophage cell line was also determined. The in vitro and in vivo results obtained indicated that both quinones were more active than the reference drugs. Compound 1 presents in vivo activity, showing up to 40% parasite reduction after 8 h of administration, a finding which is 1.25 times more effective than the results obtained using nifurtimox. These are encouraging results for proposing new naphthoquinone derivatives with potential anti-T. cruzi activity.

Triple artemisinin-based combination therapy (TACT): Efficacy of dihydroartemisinin-piperaquine plus chloroquine against Plasmodium berghei ANKA strains with different drug sensitivities in a murine malaria model

BackgroundEvident detection of artemisinin resistance markers in patient isolates of Plasmodium falciparum from East Africa threatens the efficacy of artemisinin-based combination therapies (ACTs) as first-line treatment of malaria in sub-Saharan Africa. Repositioning previously used antimalarials as complementary addition to ACTs has been suggested as a viable option to mitigating this threat. This study evaluated the potential benefit of chloroquine (CQ) as a complementary partner to dihydroartemisinin/piperaquine (DHA/PQ) in the treatment of malaria in a mice model. MethodsThe comparative efficacy of the combination of DHA/PQ/CQ and DHA/PQ against two strains of Plasmodium berghei ANKA (MRA 311 and 671) with different levels of sensitivities to chloroquine was evaluated in separate experiments. Parasitological activities including; parasite suppression time, parasite clearance time, recrudescence time, and parasite reduction ratio were evaluated in vivo. The mean survival time was also monitored throughout the duration of the study. ResultsIn both parasite lines, 99.99 % chemo-suppression was observed on day 4 in the drug treatment groups (CQ alone, DHA/PQ and DHA/PQ/CQ). In the curative test, there were significant differences between DHA/PQ/CQ and DHQ/PQ treatment, highlighted by reduced parasite clearance time (4.75 ± 0.3 Vs 5.5 ± 0.3 days, P < 0.05), significantly delayed recrudescence time (28.5 ± 1.04 Vs 13.3 ± 0.48 days, P < 0.01), a 1.5-fold change in parasite reduction ratio, and a prolonged mean survival time (34.5 ± 1.04 Vs 26.7 ± 0.48 days, P < 0.05). ConclusionThe addition of chloroquine to dihydroartemisinin-piperaquine may be beneficial in the treatment of malaria, especially in areas where malaria parasite sensitivity to chloroquine is predominant.

Cryptosporidium lysyl-tRNA synthetase inhibitors define the interplay between solubility and permeability required to achieve efficacy.

Cryptosporidiosis is a diarrheal disease caused by infection with Cryptosporidium spp. parasites and is a leading cause of death in malnourished children worldwide. The only approved treatment, nitazoxanide, has limited efficacy in this at-risk patient population. Additional safe therapeutics are urgently required to tackle this unmet medical need. However, the development of anti-cryptosporidial drugs is hindered by a lack of understanding of the optimal compound properties required to treat this gastrointestinal infection. To address this knowledge gap, a diverse set of potent lysyl-tRNA synthetase inhibitors was profiled to identify optimal physicochemical and pharmacokinetic properties required for efficacy in a chronic mouse model of infection. The results from this comprehensive study illustrated the importance of balancing solubility and permeability to achieve efficacy in vivo. Our results establish in vitro criteria for solubility and permeability that are predictive of compound efficacy in vivo to guide the optimization of anti-cryptosporidial drugs. Two compounds from chemically distinct series (DDD489 and DDD508) were identified as demonstrating superior efficacy and prioritized for further evaluation. Both compounds achieved marked parasite reduction in immunocompromised mouse models and a disease-relevant calf model of infection. On the basis of these promising data, these compounds have been selected for progression to preclinical safety studies, expanding the portfolio of potential treatments for this neglected infectious disease.

Fosfatriclaben: Effective dose determination and comparative efficacy assessment with closantel, triclabendazole+ivermectin, triclabendazole+albendazole in artificially infected cattle

Two controlled efficacy studies were conducted to determine the effective dose of fosfatriclaben (FTCB) and compare its fasciolicidal efficacy with that of three commercial products against eggs and adult stages of Fasciola hepatica in artificially infected cattle. In study 1, 20 trematode-free Holstein Friesian steers were infected on day 0 with 500 F. hepatica metacercariae. Ten weeks after infection and the steers were confirmed to be positive for trematode eggs through a modified sedimentation method. On day 75, they were divided into five groups of four animals each for treatment. Group 1 (G1) served as the untreated control; G2, G3, and G4 received FTCB at 4, 6, and 8 mg/kg/intramuscularly (IM), respectively. G5 received a combined treatment of triclabendazole (TCBZ) (12 mg/kg IM + ivermectin (0.2 mg/kg IM). Individual faecal analyses were performed on days −8, 0, 70, 75, and 105 to evaluate the reduction in trematode eggs. Four weeks after treatment, the steers were humanely slaughtered to harvest the livers and remove the parasites present in the bile ducts. Efficacy was evaluated by the reduction in fecal egg counts or in number of adult parasites, compared to the untreated control. The effective FTCB dose was 6 mg/kg. Once the effective dose was determined, study 2 was conducted on another 20 steers infected with 500 F. hepatica metacercariae, to compare the effectiveness of FTCB with three commercials fasciolicides. All procedures were performed as described in study 1, and treatments were as follows: Group 1 (G1), closantel (5 mg/kg subcutaneously (SC)); G2, TCBZ (12 mg/kg IM) + ivermectin (0.2 mg/kg IM); G3, FTCB (6 mg/kg IM); G4, triclabendazole (12 mg/kg) + albendazole (5 mg/kg/PO (orally); and G5 served as an untreated control. The results indicated that all tested compounds were highly effective in the reduction of faecal egg excretion (99.7–100%) and adult parasites (98.9–100%), except closantel, which exhibited low efficacy (74.4%) when tested against adult trematodes. We concluded that the effective dose of FTCB for cattle was 6 mg/kg IM, which is half the recommended clinical dose of the commercial combination of TCBZ and ivermectin. The fasciolicidal efficacy of FTCB was like the other three flukicides in reducing adult F. hepatica and Fasciola eggs; however, closantel was not sufficiently efficient against adult flukes.

A fast-acting inhibitor of blood-stage P. falciparum with mechanism distinct from artemisinin and chloroquine.

Artemisinins are first-line treatment for malaria, prized for their extremely fast reduction of parasite load in patients. New fast-acting antimalarial compounds are urgently needed to counter artemisinin resistance, but the fast parasite reduction observed with artemisinins is rare among antimalarial compounds. Here we show that MMV1580853 has a very fast in vitro killing rate, comparable to that of dihydroartemisinin. Near-complete parasite growth inhibition was observed within 1 hour of treatment with MMV1580853 and dihydroartemisinin, while chloroquine, another fast-acting antimalarial, showed partial growth inhibition after 1h. MMV1580853 was reported to inhibit prenyltransferases, but its fast killing rate is inconsistent with this mechanism-of-action and we were unable to validate any of 3 annotated P. falciparum prenyltransferases as MMV1580853 targets. MMV1580853 also did not phenocopy the inhibition phenotype of either chloroquine or dihydroartemisinin. These results indicate that MMV1580853 has a distinct mechanism-of-action leading to a very fast killing rate. MMV1580853 compound development and investigation of its mechanism-of-action will be critical avenues in the search for drugs matching the remarkable clinical efficacy of artemisinin.

Experimental manipulation of nest temperature and relative humidity reduces ectoparasites and affects body condition of Blue Tits (Cyanistes caeruleus)

Many models predict changes in the distribution and incidence of diseases associated with climate change. However, studies exploring the effect of microclimatic changes on host–parasite relationships are scarce. In this study, we increased temperature or humidity in Eurasian Blue Tit Cyanistes caeruleus nestboxes during the breeding season, to analyse the effect of each variable on the abundance of ectoparasites and, also, on the body condition of the hosts. Temperature and humidity were experimentally increased on average by about 2°C and 15%, respectively. The abundance of blowfly Protocalliphora azurea pupae was significantly reduced in nests with increased temperature compared with control nests and those with increased humidity, and was also significantly reduced in nests with increased humidity compared with control nests. The abundance of mites Dermanyssus spp. was significantly reduced in nests with increased humidity. However, there was no significant effect of the experiment on the abundance of flea Ceratophyllus gallinae larvae, biting midges (Culicoides spp.) and blackflies (Simuliidae). The body condition of nestlings was lower in nests with increased humidity and slightly lower in heated nests. However, the body condition of adults was not significantly affected by the experiment. In addition, blowfly pupae and biting midge abundance were negatively related to the body condition of the nestlings, and biting midge abundance was also negatively related to the body condition of the adults. Overall, an increase in temperature and humidity reduces the abundance of ectoparasites, which suggests that these parasites are sensitive to sudden changes in the microclimate in which they develop. Moreover, these fluctuations negatively affect the body condition of Blue Tit nestlings despite the concurrent decrease of parasites in nests. In other words, the expected benefit to the nestlings from the reduction in parasites does not occur because the microclimate also adversely affects nestlings, probably affecting their heat exchange with the nest environment.

Nicotinamide mitigates visceral leishmaniasis by regulating inflammatory response and enhancing lipid metabolism

BackgroundCurrently, treatment regimens for visceral leishmaniasis (VL) are limited because of the presence of numerous adverse effects. Nicotinamide, a readily available and cost-effective vitamin, has been widely acknowledged for its safety profile. Several studies have demonstrated the anti-leishmanial effects of nicotinamide in vitro. However, the potential role of nicotinamide in Leishmania infection in vivo remains elusive.MethodsIn this study, we assessed the efficacy of nicotinamide as a therapeutic intervention for VL caused by Leishmania infantum in an experimental mouse model and investigated its underlying molecular mechanisms. The potential molecular mechanism was explored through cytokine analysis, examination of spleen lymphocyte subsets, liver RNA-seq analysis, and pathway validation.ResultsCompared to the infection group, the group treated with nicotinamide demonstrated significant amelioration of hepatosplenomegaly and recovery from liver pathological damage. The NAM group exhibited parasite reduction rates of 79.7% in the liver and 86.7% in the spleen, respectively. Nicotinamide treatment significantly reduced the activation of excessive immune response in infected mice, thereby mitigating hepatosplenomegaly and injury. Furthermore, nicotinamide treatment enhanced fatty acid β-oxidation by upregulating key enzymes to maintain lipid homeostasis.ConclusionsOur findings provide initial evidence supporting the safety and therapeutic efficacy of nicotinamide in the treatment of Leishmania infection in BALB/c mice, suggesting its potential as a viable drug for VL.Graphical

Incomplete Plasmodium falciparum growth inhibition following piperaquine treatment translates into increased parasite viability in the in vitro parasite reduction ratio assay.

Antimalarial resistance to the first-line partner drug piperaquine (PPQ) threatens the effectiveness of artemisinin-based combination therapy. In vitro piperaquine resistance is characterized by incomplete growth inhibition, i.e. increased parasite growth at higher drug concentrations. However, the 50% inhibitory concentrations (IC50) remain relatively stable across parasite lines. Measuring parasite viability of a drug-resistant Cambodian Plasmodium falciparum isolate in a parasite reduction ratio (PRR) assay helped to better understand the resistance phenotype towards PPQ. In this parasite isolate, incomplete growth inhibition translated to only a 2.5-fold increase in IC50 but a dramatic decrease of parasite killing in the PRR assay. Hence, this pilot study reveals the potential of in vitro parasite viability assays as an important, additional tool when it comes to guiding decision-making in preclinical drug development and post approval. To the best of our knowledge, this is the first time that a compound was tested against a drug-resistant parasite in the in vitro PRR assay.

A Fast‐Charge Graphite Anode with a Li‐Ion‐Conductive, Electron/Solvent‐Repelling Interface

AbstractGraphite has been serving as the key anode material of rechargeable Li‐ion batteries, yet is difficultly charged within a quarter hour while maintaining stable electrochemistry. In addition to a defective edge structure that prevents fast Li‐ion entry, the high‐rate performance of graphite could be hampered by co‐intercalation and parasitic reduction of solvent molecules at anode/electrolyte interface. Conventional surface modification by pitch‐derived carbon barely isolates the solvent and electrons, and usually lead to inadequate rate capability to meet practical fast‐charge requirements. Here we show that, by applying a MoOx−MoNx layer onto graphite surface, the interface allows fast Li‐ion diffusion yet blocks solvent access and electron leakage. By regulating interfacial mass and charge transfer, the modified graphite anode delivers a reversible capacity of 340.3 mAh g−1 after 4000 cycles at 6 C, showing promises in building 10‐min‐rechargeable batteries with a long operation life.

A Fast-Charge Graphite Anode with a Li-Ion-Conductive, Electron/Solvent-Repelling Interface.

Graphite has been serving as the key anode material of rechargeable Li-ion batteries, yet is difficultly charged within a quarter hour while maintaining stable electrochemistry. In addition to a defective edge structure that prevents fast Li-ion entry, the high-rate performance of graphite could be hampered by co-intercalation and parasitic reduction of solvent molecules at anode/electrolyte interface. Conventional surface modification by pitch-derived carbon barely isolates the solvent and electrons, and usually lead to inadequate rate capability to meet practical fast-charge requirements. Here we show that, by applying a MoOx-MoNx layer onto graphite surface, the interface allows fast Li-ion diffusion yet blocks solvent access and electron leakage. By regulating interfacial mass and charge transfer, the modified graphite anode delivers a reversible capacity of 340.3 mAh g-1 after 4000 cycles at 6 C, showing promises in building 10-min-rechargeable batteries with a long operation life.

Differences in colostrum components of Katahdin ewes varies with post-weaning FEC EBV

Variation in post-weaning fecal egg count (PFEC) estimated breeding values (EBV) has revealed effects beyond the reduction of parasitism. Previous work demonstrated lambs with a PFEC of < −50 (Low-PFEC) have higher survivability to weaning than lambs with a PFEC of > +50 (High-PFEC). In response to clostridial vaccination, Low-PFEC lambs also generate a more robust and rapid antibody response. These findings prompted curiosity of the maternal influence underpinning differences observed in lamb survivability based upon PFEC genotype. Thus, this study aimed to assess the impact of dam PFEC EBV on IgG concentration, Brix values, and color within colostrum. For Year 1 (YR1), Katahdin ewes from the Virginia Tech SWAREC were selected based on the following criteria: age (3–6 years), have a Katahdin Hair Index EBV (>104, pre-genomic EBV), and be twin bearing. Ewes fitting those criteria were sorted by their PFEC EBV into two groups: Low-PFEC (PFEC < −50; n=20) and High-PFEC (PFEC > +50; n=18) and sampled at three distinct time points, early (within 24-hr post-partition), mid (30-d post-parturition) and late (60-d post-parturition) lactation. For Year 2 (YR2), all lactating ewes at the SWAREC were analyzed and were sorted into three groups: Low-PFEC (PFEC < −50; n=39), Mid-PFEC ( −49 < PFEC < +49; n=38), and High-PFEC (PFEC > +50; n=23) and colostrum samples were taken within 6-hrs post-partition. All colostrum and milk samples were collected by milking 10 mL from each half of the ewes' udder. Total IgG within colostrum and milk was measured using an ovine-specific enzyme-linked immunosorbent assay (ELISA). In YR1, main effects of ewe genotype revealed that Low-PFEC ewes had a greater concentration of IgG across all lactation time points (631 ng/mL vs 222 ng/mL; P < 0.0001). This was primarily driven by IgG differences within colostrum, where a 2.5 fold difference in IgG were observed between Low-PFEC and High-PFEC groups (937 ng/mL vs. 319 ng/mL, P < 0.0001). In YR2, a stepwise decrease in average colostrum IgG concentration from Low-PFEC to High-PFEC groups was observed (825 ng/mL, 513 ng/mL, and 258 ng/mL, respectively; P < 0.0429). Likewise, a stepwise decrease in yellow to blue hue or b* value occurs from Low-PFEC to High-PFEC groups (18.97, 16.91, and 15.22, respectively; P < 0.0459). No correlations were found between IgG and Brix values within the Low-PFEC and High-PFEC grouping; remarkably, Mid-PFEC ewes have a slightly positive correlation between IgG and Brix (r= 0.34, P = 0.0334). These data indicate that Low-PFEC Katahdin ewes generate colostrum with greater antibody concentration and more yellow color. Lambs born to these ewes would have a significant advantage in passive immunity from their dams, which may explain some component of the enhanced lamb survivability observed pre-weaning.

Intranasal delivery of LaAg vaccine improves immunity of aged mice against visceral Leishmaniasis

There are no approved vaccines yet for human visceral leishmaniasis (VL), the most severe form of the leishmaniasis clinical manifestations that is fatal in over 95 % of untreated cases. It is well-accepted that immunological changes during aging have deleterious impact on the efficacy of vaccines and response to infections. In this work, we compared the response of young and aged mice to intranasal vaccination with killed Leishmania amazonensis promastigote antigens (LaAg) that were then challenged with L. infantum infection, a species that causes visceral leishmaniasis. Intranasal vaccination with LaAg induced a similar reduction in parasitism and hepatosplenomegaly in both young and aged mice compared to their unvaccinated counterparts. Following infection, there was also a less prominent inflammatory profile particularly in the vaccinated aged group, with lower production of TNF-α and nitrite compared to the respective unvaccinated group. Interestingly, the LaAg intranasal vaccination promoted increased production of IFN-γ that was observed in both young- and aged vaccinated groups. Additionally, CD4+ and CD8+T cells from both vaccinated groups presented decreased expression of the inhibitory receptors PD-1 and KLRG1 compared to their unvaccinated controls. Interestingly, a strong positive correlation was observed between the expression of both inhibitory receptors PD-1 and KLRG1 and parasitism, which was more conspicuous in the unvaccinated-aged mice than in the others. Overall, this study helps define new strategies to improve vaccine effectiveness and provides a perspective for prophylactic alternatives against leishmaniasis.

The Prado Wetlands: 24 years of river diversion treatment wetlands reducing nitrate and phosphate while increasing an endangered bird

Nitrate pollution of surface water from farms and urban runoff is widespread – impairing drinking water supplies, recreation, and wildlife habitat. The scale of the problem in rivers has overwhelmed most watershed-based best management practices. A new paradigm is needed. In this paper we highlight the 119 ha (294 acres) Prado Wetlands in southern California, USA as an example of a gravity-enabled, free surface flow vegetated wetlands to treat a river – the nitrate-rich, effluent-dominated Santa Anna River. The wetland treats ∼1–2 m3/s of the 7.1 m3/s (250 cfs) flow of the river in 28 wetland cells in two parallel trains (residence time 2–4 d, hydraulic loading rate 10–20 cm/d). The cleaner water is returned to the river and infiltrated downstream into a managed groundwater basin supplying 2.4 million customers. Since 1998, ∼1200 t of nitrate-N have been permanently removed from the river and released as N2-gas into the air. Over 24 years, in the warm summers an average of 6.1 mg-N/L entered the wetland and 3.7 mg-N/L flowed out, a removal efficiency of 57%. In the cooler winters, an average of 6.4 mg NO3-N/L entered and 2.6 mg NO3-N/L flowed out, a removal efficiency of 45%. Individual months varied widely in concentration removal efficiency from 7% (winter) to 98% (high summer). Areal summer removal averaged 137 mg NO3-N/m2/d and the apparent “k” was around 46 m/y. All-year rates were 129 mg NO3-N/m2/d or 47 g/m2/y, a reasonable performance considering the size of the system and its configuration for both nitrate removal and duck hunting (i.e., more open water). Annual average nitrate removal efficiency increased substantially over time (45 to 72% for 1998–2004 versus 2016–22) and is attributed to an increase in hydraulic residence time, upgraded internal plumbing, and increased winter temperatures (+3C°). Prado Wetlands also removes phosphorus, though not as well as nitrate; average warm season removal efficiency was 23% (inflow 1.20 mg PO4-P/L, outflow 0.93 mg PO4-P/L). The aerial removal rate was high at 23 mg P/m2/d or 8.5 g/y, probably due to the high inflowing P-concentrations and the hard water. Wildlife was also enhanced. Least Bell's Vireo (Vireo belli pusillus), an endangered bird in the Prado Basin, increased from 19 pairs (1998) to a recent average of 444 pairs due to habitat improvement and reduction of cowbird parasitism. Results from the Prado Wetlands show that cleaning up rivers via diversion through wetlands benefits both water quality and wildlife.

The impact of cholesteryl ester transfer protein on the progression of cutaneous leishmaniasis.

Pathogenesis of cutaneous leishmaniases involves parasite growth, persistent inflammation, and likely participation of lipoproteins (LP). The cholesteryl ester transfer protein (CETP), involved in LP remodeling, has been shown to participate in the inflammatory response and the evolution of infectious conditions. We evaluated the impact of the presence of CETP on infection by Leishmania (L.) amazonensis in an experimental model of cutaneous leishmaniasis using C57BL6/J mice transgenic for human CETP (CETP), having as control their littermates that do not express the protein, wild-type (WT) mice. The progression of the lesion after infection in the footpad was monitored for 12 weeks. Two groups of animals were formed to collect the plantar pad in the 4th and 12th week post-infection. The lesion increased from the 3rd week onwards, in both groups, with a gradual decrease from the 10th week onwards in the CETP group compared to the WT group, showing a reduction in parasitism and an improvement in the healing process, a reduction in CD68+ cells, and an increase in CD163+ and CD206, characterizing a population of M2 macrophages. A reduction in ARG1+ cells and an increase in INOS+ cells were observed. During infection, the LP profile showed an increase in triglycerides in the VLDL fraction in the CETP group at 12 weeks. Gene expression revealed a decrease in the CD36 receptor in the CETP group at 12 weeks, correlating with healing and parasite reduction. In vitro, macrophages derived from bone marrow cells from CETP mice showed lower parasite load at 48 h and, a reduction in arginase activity at 4 h accompanied by increased NO production at 4 and 24 h compared to WT macrophages, corroborating the in vivo findings. The data indicate that the presence of CETP plays an important role in resolving Leishmania (L.) amazonensis infection, reducing parasitism, and modulating the inflammatory response in controlling infection and tissue repair.

A Fully-Integrated Flexible Dual-Ring Switched-Capacitor DC–DC Converter With Fractional VCRs and Parasitic Reduction

A Fully-Integrated Flexible Dual-Ring Switched-Capacitor DC–DC Converter With Fractional VCRs and Parasitic Reduction

Stabilization of lithium metal in concentrated electrolytes: effects of electrode potential and solid electrolyte interphase formation.

Lithium (Li) metal negative electrodes have attracted wide attention for high-energy-density batteries. However, their low coulombic efficiency (CE) due to parasitic electrolyte reduction has been an alarming concern. Concentrated electrolytes are one of the promising concepts that can stabilize the Li metal/electrolyte interface, thus increasing the CE; however, its mechanism has remained controversial. In this work, we used a combination of LiN(SO2F)2 (LiFSI) and weakly solvating 1,2-diethoxyethane (DEE) as a model electrolyte to study how its liquid structure changes upon increasing salt concentration and how it is linked to the Li plating/stripping CE. Based on previous works, we focused on the Li electrode potential (ELi with reference to the redox potential of ferrocene) and solid-electrolyte-interphase (SEI) formation. Although ELi shows a different trend with DEE compared to conventional 1,2-dimethoxyethane (DME), which is accounted for by different ion-pair states of Li+ and FSI-, the ELi-CE plots overlap for both electrolytes, suggesting that ELi is one of the dominant factors of the CE. On the other hand, the extensive ion pairing results in the upward shift of the FSI- reduction potential, as demonstrated both experimentally and theoretically, which promotes the FSI--derived inorganic SEI. Both ELi and SEI contribute to increasing the Li plating/stripping CE.

Subunit nanovaccine elicited T cell functional activation controls Trypanosoma cruzi mediated maternal and placental tissue damage and improves pregnancy outcomes in mice

This study investigated a candidate vaccine effect against maternal Trypanosoma cruzi (Tc) infection and improved pregnancy outcomes. For this, TcG2 and TcG4 were cloned in a nanoplasmid optimized for delivery, antigen expression, and regulatory compliance (nano2/4 vaccine). Female C57BL/6 mice were immunized with nano2/4, infected (Tc SylvioX10), and mated 7-days post-infection to enable fetal development during the maternal acute parasitemia phase. Females were euthanized at E12–E17 (gestation) days. Splenic and placental T-cell responses were monitored by flow cytometry. Maternal and placental/fetal tissues were examined for parasites by qPCR and inflammatory infiltrate by histology. Controls included age/immunization-matched non-pregnant females. Nano2/4 exhibited no toxicity and elicited protective IgG2a/IgG1 response in mice. Nano2/4 signaled a splenic expansion of functionally active CD4+ effector/effector memory (Tem) and central memory (Tcm) cells in pregnant mice. Upon challenge infection, nano2/4 increased the splenic CD4+ and CD8+T cells in all mice and increased the proliferation of CD4+Tem, CD4+Tcm, and CD8+Tcm subsets producing IFNγ and cytolytic molecules (PRF1, GZB) in pregnant mice. A balanced serum cytokines/chemokines response and placental immune characteristics indicated that pregnancy prevented the overwhelming damaging immune response in mice. Importantly, pregnancy itself resulted in a significant reduction of parasites in maternal and fetal tissues. Nano2/4 was effective in arresting the Tc-induced tissue inflammatory infiltrate, necrosis, and fibrosis in maternal and placental tissues and improving maternal fertility, placental efficiency, and fetal survival. In conclusion, we show that maternal nano2/4 vaccination is beneficial in controlling the adverse effects of Tc infection on maternal health, fetal survival, and pregnancy outcomes.

Green Synthesis, Characterization, and Antileishmanial Activity of the Silver Nanoparticles Alone and Along with Meglumine Antimoniate against Leishmania major Infection.

The most commonly available drugs for leishmaniasis are pentavalent antimony compounds; whereas the recent studies showed various complications and limitations of these drugs. We aimed to green synthesized silver nanoparticles (AgNPs) and study the promising antileishmanial and synergic effects of green synthesized silver nanoparticles alone and combined with glucantime. The precipitation technique was used to drop silver ions via an extract of Astragalus spinosus to AgNPs at Department of Biological Sciences, Faculty of Science and Humanities, Shaqra University, Saudi Arabia in 2022. Then, its anti-amastigotes, caspase-3-like activity, triggering the nitric oxide (NO) as well as its cytotoxicity effects on macrophage cells as well as effects on leishmaniasis in BALB/c mice infected by L. major were measured. The size of the AgNPs were ranging from 30-40 nm. The IC50 value for AgNPs, AgNPs+ meglumine antimoniate (MA), and MA was 59.3, 18.6, and 51.2 μg/mL, respectively. The determined FIC value for AgNPs and MA was found to be 0.31 and 0.36, respectively; demonstrating the synergistic potency of AgNPs when combined with MA. The diameter of CL lesions treated with various doses of AgNPs and AgNPs+MA notably (p<0.001) decreased. AgNPs, particularly at the concentrations of ½ IC50 and IC50, considerably triggered the caspase-3 activation. The calculated CC50 of AgNPs and MA was 612.5 and 789.8 μg/mL, respectively. Green synthesized AgNPs, especially in combination with MA had synergic antileishmanial effects and displayed a promising drug candidate for treating L. major CL. We found satisfactory findings in the parasite reduction in both in vitro and animal models. Still, more studies are expected to explain the precise action mechanisms of AgNPs and their efficacy in humans.

Efficiency of Vinasse Application on Root-Knot Nematodes in Soybean

Vinasse is not only effectively used in pest control but also creates a conducive environment for the growth of antagonistic microorganisms. Thus, this study aimed to evaluate the potential of vinasse applied via soil for the management of root-knot nematodes in soybean culture. The experimental design was entirely random, in a factorial scheme (2 × 6), consisting of two species of nematodes, Meloidogyne incognita and M. javanica, under vinasse application at five concentrations (20, 40, 60, 80, and 100%) and one control (water), with five repetitions. Soybean plants Intacta cv. M-Soy 8644 IPRO were inoculated with 4000 eggs/juveniles of each species separately. At 60 days after the first application of vinasse, evaluations of parasitism and agronomic characteristics in soybean were performed. Stillage resulted in the highest average values for root volume and root fresh mass in plants inoculated with M. incognita, showing respective increases of 24.33% and 14.92% compared to plants inoculated with M. javanica. However, concentrations exceeding 60% had a detrimental effect on all agronomic variables of soybean. For parasitism, an interaction among the factors was observed, with a significant effect (p &lt; 0.01) for most of the evaluated variables, except for the number of eggs in the soil. The concentration equivalent to 60% vinasse promoted a sharp reduction in parasitism for the two nematode species, making reproduction on plant roots unfeasible.

Efficacy and safety of ivermectin for the treatment of Plasmodium falciparum infections in asymptomatic male and female Gabonese adults – a pilot randomized, double-blind, placebo-controlled single-centre phase Ib/IIa clinical trial

Ivermectin's mosquitocidal effect and invitro activity against Plasmodium falciparum asexual stages are known. Its invivo blood-schizonticidal efficacy is unknown. Ivermectin's tolerability and efficacy against P.falciparum infections in Gabonese adults were assessed. The study consisted of a multiple dose stage and a randomized, double-blind, placebo-controlled stage. Adults with asymptomatic P.falciparum parasitaemia (200-5000 parasites/μl) were enrolled. First, three groups of five participants received 200μg/kg ivermectin once daily for one, two, and three days, respectively, and then 34 participants were randomized to 300μg/kg ivermectin or placebo once daily for 3 days. Primary efficacy outcome was time to 90% parasite reduction. Primary safety outcomes were drug-related serious and severe adverse events (Trial registration: PACTR201908520097051). Between June 2019 and October 2020, 49 participants were enrolled. Out of the 34 randomized participants, 29 (85%) completed the trial as per protocol. No severe or serious adverse events were observed. The median time to 90% parasite reduction was 24.1 vs. 32.0h in the ivermectin and placebo groups, respectively (HR 1.38 [95% CI 0.64 to 2.97]). Ivermectin was well tolerated in doses up to 300μg/kg once daily for three days and asymptomatic P.falciparum asexual parasitaemia was reduced similarly with this dose of ivermectin compared to placebo. Further studies are needed to evaluate plasmodicidal effect of ivermectin at higher doses and in larger samples. This study was funded by the Centre de Recherches Médicales de Lambaréné and the Centre for Tropical Medicine of the Bernhard Nocht Institute for Tropical Medicine.