Evaluation of the inhibitory effects and the mechanism of terpenoids on Toxoplasma gondii tachyzoites.

BACKGROUND: Currently, symptomatic toxoplasmosis is treated with a combination of sulfadiazine and pyrimethamine. However, significant adverse effects and drug resistance have been reported. Terpenoids are widely found in nature, with numerous studies demonstrating that they have effective inhibitory effects on a variety of parasites. METHODS: In this study, we employed intermediates or derivatives of lindenane sesquiterpenoids to evaluate their intracellular and extracellular inhibitory effects on Toxoplasma gondii tachyzoites and their cytotoxicity on macrophages. RESULTS: We demonstrated that two of these target terpenoids could effectively reduce the number of extracellular tachyzoites, probably by inducing tachyzoite apoptosis through altering tachyzoites mitochondrial membrane potential and calcium homeostasis. In addition, the two target terpenoids were able to promote intracellular tachyzoites elimination, possibly by enhancing macrophage activities. CONCLUSIONS: Two derivatives of lindenane sesquiterpenoids with low cytotoxicity to macrophages demonstrated direct and indirect antitoxoplasma effects.

Estimating Causal Effects using a Multi-task Deep Ensemble.

A number of methods have been proposed for causal effect estimation, yet few have demonstrated efficacy in handling data with complex structures, such as images. To fill this gap, we propose Causal Multi-task Deep Ensemble (CMDE), a novel framework that learns both shared and group-specific information from the study population. We provide proofs demonstrating equivalency of CDME to a multi-task Gaussian process (GP) with a coregionalization kernel a priori. Compared to multi-task GP, CMDE efficiently handles high-dimensional and multi-modal covariates and provides pointwise uncertainty estimates of causal effects. We evaluate our method across various types of datasets and tasks and find that CMDE outperforms state-of-the-art methods on a majority of these tasks.

The role of SIRT1 in the process of Toxoplasma gondii infection of RAW 264.7 macrophages.

Toxoplasma gondii is an opportunistic pathogenic protozoan that can infect almost all kinds of warm-blooded animals, including humans. T. gondii can evade the host's immune response, a process known as immune evasion. Our main objective was to evaluate the role played by Sirtuin1 (SIRT1) [one of the sirtuins (SIRTs) that are a family of nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylases (HDACs)] in the T. gondii infection of RAW264.7 macrophages. In this study, we evaluated and observed alterations in the activity, expression, and localization of SIRT1 and assessed its involvement in the CD154/IFN-γ (CD40 ligand/interferon gamma) killing pathway and in autophagy during T. gondii infection. The inhibition of SIRT1 in host cells effectively reduced the number of intracellular tachyzoites, and the mechanism behind this effect might be the upregulation of IRGM1 [murine ortholog of IRGM (immunity-related GTPase family M)] and the initiation of autophagy. To the best of our knowledge, our study is the first to prove that T. gondii infection upregulates SIRT1 in RAW264.7 cells and that the inhibition of SIRT1 reduces the number of intracellular tachyzoites. Moreover, the upregulation of IRGM1 and the activation of autophagy may contribute to the intracellular inhibition of T. gondii caused by SIRT1 inhibition.

Bacillus coagulans in Combination with Chitooligosaccharides Regulates Gut Microbiota and Ameliorates the DSS-Induced Colitis in Mice.

Ulcerative colitis (UC) are chronic inflammatory disorders, which may be caused by intestinal barrier dysfunction, immune system disorders and intestinal microbiota dysbiosis. Synbiotic, the combination of probiotics and prebiotics, is thought to be a pragmatic approach in mitigating inflammation in UC. Bacillus coagulans has been recognized as a potential probiotic for treating intestinal diseases because of its favorable industrial and probiotic properties, including sporulation and lactic acid production. In this study, we evaluated the treatment effects of the B. coagulans FCYS01 spores with or without the chitooligosaccharides (COSs) on UC generated using dextran sulfate sodium (DSS) in mice. Supplementation of B. coagulans spores, prebiotic COSs or the synbiotic (the spores + COSs) had a significant positive effect on DSS-induced UC. The disease activity index and histological damage score were significantly reduced after these supplementations. Compared to DSS group, these supplementations also significantly modulated the cytokines IL-4, IL-6, IL-8, IL-10, and C-reactive protein (CRP) levels and significantly maintained expressions of tight junction proteins and mucin protein and promotes recovery of the intestinal barrier. In addition, these supplementations regulate the composition of gut microbiota and improve the production of short-chain fatty acids (SCFAs), through enrichment of SCFA-producing bacteria, such as Akkermansia and Ruminococcus species. In summary, the synbiotic ameliorated the overall inflammatory status of the experimental UC model and showed a better treatment effect than B. coagulans or COSs did alone as revealed by the markers such as, colon length, IL-4 and Occludin levels. IMPORTANCE Probiotic and prebiotic are believed to be useful in alleviating the inflammatory, thereby resolving or preventing the severity of UC. Spore-forming bacteria Bacillus coagulans show advantages of stability and probiotic effects, being suggested as the important probiotics for UC treatment. Here, we demonstrate that administration of B. coagulans spores, chitooligosaccharides (COSs), or the synbiotic attenuates DSS-induced colitis and significantly correlates with altered gut immune responses. The treatment effect of the synbiotic is inferred to be relied on the enrichment of probiotic bacteria, such as Akkermansia and Ruminococcaceae species, which are reported to be crucial important for gut health. Our findings facilitate the development of therapeutic and preventive strategies for UC using spore-forming lactic acid bacteria in combination with COSs.

Accumulation of nutrients and potentially toxic elements in plants and fishes in restored mangrove ecosystems in South China.

Mangroves are highly dynamic ecosystems that offer important services such as maintaining biodiversity, filtering pollutants, and providing habitats for fishes. We investigated the uptake and accumulation of nutrients and potentially toxic elements in mangrove plants and fish to better understand the role of mangrove restoration in maintaining mangrove biota quality. In mangrove plants, the average bioconcentration factors of nutrients and potentially toxic elements were in the order P > Pb > Mn > Mg > Se > Zn > Hg > Cu > Cd > As > Co > Cr > Ni > Fe > V > Sb, where only P (all plant species) and Pb (Sonneratia apetala Buchanan-Hamilton) had a BCF > 1.0 in mangrove plants. In general, Sonneratia spp. had better performances than Kandelia candel (Linn.) Druce, Aegiceras corniculatum (Linn.) Blanco and Acanthus ilicifolius L. Sp. in terms of nutrient uptake and toxic metal(loid)s accumulation, and the best uptake capacity was found in S. apetala. Fast growth and easy adaptation make S. apetala suitable for a restored mangrove ecosystem, but continual management is needed to prevent its suppression of mangrove species diversity. The concentration of As, Cd, Hg, Cu, Cr and Pb in the mangrove sediment were 30-220% higher than the Chinese National Standard of Marine Sediment Quality Class I limits, suggesting that the sediments were unsuitable for aquaculture and nature reserves. Although a higher toxic metal(loid)s concentration in the sediment was found, the target hazard quotient (THQ) of this toxic metal(loid)s in 5 mangrove habitat fishes was <1.0, except THQ of Pb in Boleophthalmus pectinirostris Linnaeus was 1.17, and THQ of Cr in Bostrychus sinensis Lacépède was 1.12. The low THQ (less than 1.0) of mangrove habitat fishes suggested that the restored mangrove system could alleviate the bioaccumulation of toxic metal(loid)s in mangrove fish.

Visualization and quantification of cadmium accumulation, chelation and antioxidation during the process of vacuolar compartmentalization in the hyperaccumulator plant Solanum nigrum L.

Hyperaccumulators store metals in the vacuoles of leaf cells. To investigate the role of vacuolar compartmentalization in Cd accumulation, chelation and induced antioxidation, we quantified the amounts of total cadmium (Cd), Cd2+, glutathione (GSH) and reactive oxygen species (ROS) in leaf cells of Solanum nigrum L. The results confirmed that vacuoles were, indeed, the main storage compartments for Cd. We then found that with increased Cd treatment concentration, the proportion of vacuolar Cd in protoplasts showed its ultimate storage capacity (82.24 %-83.40 %), and the Cd concentration stored in the protoplast maintained at a certain level (73.81-77.46 mg L-1). Besides, studies on different forms of Cd showed that the chelation state was dominant in the protoplast. The large level appearance of Cd2+ outside the vacuole revealed the limitations of vacuolar Cd2+ sequestration. The relationships between the combined forms of Cd and GSH outside the vacuole (R2 = 0.9906) showed GSH was mainly distributed to important compartments for chelation, not to vacuoles. We also demonstrated the presence of ROS-induced oxidative stress and detoxification mediated by the antioxidant GSH in vacuoles, suggesting that sequestration into vacuoles is an active process accompanied by chelation and antioxidant-mediated detoxification.

Iodine-catalyzed oxidative functionalization of purines with (thio)ethers or methylarenes for the synthesis of purin-8-one analogues.

An efficient oxidative functionalization of purine-like substrates with (thio)ethers or methylarenes under mild conditions is described. Using I2 as the catalyst, and TBHP as the oxidant, this protocol provides a valuable synthetic tool for the assembly of a wide range of 9-alkyl(benzyl)purin-8-one derivatives with high atom- and step-economy and exceptional functional group tolerance.

Optimization of preparation parameters for environmentally friendly attapulgite functionalized by chitosan and its adsorption properties for Cd2.

This work focused on using attapulgite and chitosan as raw materials to improve the adsorption capacity of Cd2+ from the aqueous phase by optimizing the preparation experimental parameters. The modification parameters (attapulgite-chitosan mass ratio, calcination temperature, and time) were specifically studied and optimized. The results indicated that the mass ratio of attapulgite to chitosan was 1:4, the calcination temperature was 300 °C, and the calcination time was 1 h. Both raw and functionalized attapulgite samples were characterized by nitrogen adsorption-desorption isotherms at 77 K, X-ray diffraction, Fourier transform infrared spectroscopy, scanning electron microscopy, and zeta potential analysis. A series of adsorption experiments showed that the pseudo-second-order kinetic model and Langmuir adsorption isotherm better corresponded with the adsorption characteristics of the newly prepared adsorbent, and the maximum adsorption amount of Cd2+ was 109.30 mg/g. Moreover, the effects of the pH value and coexisting cations on the Cd2+ adsorption in aqueous solution were investigated. Adsorption mechanism of Cd2+ on adsorbent might attribute to complexation, ion exchange reaction, and self-polarization.

Characterization of binding interaction of triclosan and trypsin.

Triclosan (TCS), a broad-spectrum antibacterial agent, exhibits a high exposure in the environment. However, the residual TCS in the environment poses a potential risk to human health. In this study, spectroscopic methods, molecular docking and animal experiment were conducted to completely understand the interaction between trypsin and TCS. The formation of the TCS-trypsin complex was spontaneously achieved through hydrogen bonds and Van der Waals forces with a binding constant (Ka) between 103 and 104 L mol-1. In addition, the trypsin activity in fish intestine was inhibited by TCS exposure, revealing the potentially negative effects of TCS on metabolism. The results might be explained by changes in the conformation of the trypsin, inducing the content of unordered coil increasing significantly (from 36.2% to over 80%). This work provides useful information for assessing the toxicity of TCS at the molecular level.

C-H Amination of Purine Derivatives via Radical Oxidative Coupling.

An oxidative coupling reaction between purines and alkyl ethers/benzyl compounds was developed to synthesize a series of N9 alkylated purine derivatives using n-Bu4NI as a catalyst and t-BuOOH as an oxidant. This protocol uses commercially available, inexpensive catalysts and oxidants and has a wide range of substrates with a simple operation.