Sulfadiazine Sodium Ameliorates the Metabolomic Perturbation in Mice Infected with Toxoplasma gondii.

In this study, we analyzed the global metabolomic changes associated with Toxoplasma gondii infection in mice in the presence or absence of sulfadiazine sodium (SDZ) treatment. BALB/c mice were infected with T. gondii GT1 strain and treated orally with SDZ (250 µg/ml in water) for 12 consecutive days. Mice showed typical manifestations of illness at 20 days postinfection (dpi); by 30 dpi, 20% had survived and developed latent infection. We used ultraperformance liquid chromatography-mass spectrometry to profile the serum metabolomes in control (untreated and uninfected) mice, acutely infected mice, and SDZ-treated and infected mice. Infection induced significant perturbations in the metabolism of α-linolenic acid, purine, pyrimidine, arginine, tryptophan, valine, glycerophospholipids, and fatty acyls. However, treatment with SDZ seemed to alleviate the serum metabolic alterations caused by infection. The restoration of the serum metabolite levels in the treated mice was associated with better clinical outcomes. These data indicate that untargeted metabolomics can reveal biochemical pathways associated with restoration of the metabolic status of T. gondii-infected mice following SDZ treatment and could be used to monitor responses to SDZ treatment. This study provides a new systems approach to elucidate the metabolic and therapeutic effects of SDZ in the context of murine toxoplasmosis.

Synthesis, Biological Evaluation, and Docking Studies of a Novel Sulfonamido-Based Gallate as Pro-Chondrogenic Agent for the Treatment of Cartilage.

Gallic acid (GA) and its derivatives are anti-inflammatory agents and are reported to have potent effects on Osteoarthritis (OA) treatment. Nonetheless, it is generally accepted that the therapeutic effect and biocompatibility of GA is much weaker than its esters due to the high hydrophilicity. The therapeutic effect of GA on OA could be improved if certain structural modifications were made to increase its hydrophobicity. In this study, a novel sulfonamido-based gallate was synthesized by bonding sulfonamide with GA, and its biological evaluations on OA were investigated. Results show that 5-[4-(Pyrimidin-2-ylsulfamoylphenyl)]-carbamoyl-benzene-1,2,3-triyl triacetate (HAMDC) was able to reverse the effects induced by Interleukin-1 (IL-1) stimulation, and it also had a great effect on chondro-protection via promoting cell proliferation and maintaining the phenotype of articular chondrocytes, as well as enhancing synthesis of cartilage specific markers such as aggrecan, collagen II and Sox9. Furthermore, a docking study showed that HAMDC fits into the core of the active site of a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS-5), which provides an explanation for its activity and selectivity.

Anti-Toxoplasma gondii effect of tylosin in vitro and in vivo.

BACKGROUND: Toxoplasma gondii is an important protozoan pathogen with medical and veterinary importance worldwide. Drugs currently used for treatment of toxoplasmosis are less effective and sometimes cause serious side effects. There is an urgent need for the development of more effective drugs with relatively low toxicity. METHODS: The effect of tylosin on the viability of host cells was measured using CCK8 assays. To assess the inhibition of tylosin on T. gondii proliferation, a real-time PCR targeting the B1 gene was developed for T. gondii detection and quantification. Total RNA was extracted from parasites treated with tylosin and then subjected to transcriptome analysis by RNA sequencing (RNA-seq). Finally, murine infection models of toxoplasmosis were used to evaluate the protective efficacy of tylosin against T. gondii virulent RH strain or avirulent ME49 strain. RESULTS: We found that tylosin displayed low host toxicity, and its 50% inhibitory concentration was 175.3 µM. Tylsoin also inhibited intracellular T. gondii tachyzoite proliferation, with a 50% effective concentration of 9.759 µM. Transcriptome analysis showed that tylosin remarkably perturbed the gene expression of T. gondii, and genes involved in "ribosome biogenesis (GO:0042254)" and "ribosome (GO:0005840)" were significantly dys-regulated. In a murine model, tylosin treatment alone (100 mg/kg, i.p.) or in combination with sulfadiazine sodium (200 mg/kg, i.g.) significantly prolonged the survival time and raised the survival rate of animals infected with T. gondii virulent RH or avirulent ME49 strain. Meanwhile, treatment with tylosin significantly decreased the parasite burdens in multiple organs and decreased the spleen index of mice with acute toxoplasmosis. CONCLUSIONS: Our findings suggest that tylosin exhibited potency against T. gondii both in vitro and in vivo, which offers promise for treatment of human toxoplasmosis.

Molecular interaction of ctDNA and HSA with sulfadiazine sodium by multispectroscopic methods and molecular modeling.

Interactions of sulfadiazine sodium (SD-Na) with calf thymus DNA (ctDNA) and human serum albumin (HSA) were studied using fluorescence spectroscopy, UV absorption spectroscopy and molecular modeling. The fluorescence experiments showed that the processes were static quenching. The results of UV spectra and molecular modeling of the interaction between SD-Na and ctDNA indicated that the binding mode might be groove binding. In addition, the interaction of SD-Na with HSA under simulative physiological conditions was also investigated. The binding constants (K) and the number of binding sites (n) at different temperatures (292, 302, 312 K) were 5.23 × 10(3) L/mol, 2.18; 4.50 × 10(3) L/mol, 2.35; and 4.08 × 10(3) L/mol, 2.47, respectively. Thermodynamic parameters including enthalpy change (ΔH) and entropy change (ΔS) were calculated, the results suggesting that hydrophobic force played a very important role in SD-Na binding to HSA, which was in good agreement with the molecular modeling study. Moreover, the effect of SD-Na on the conformation of HSA was analyzed using three-dimensional fluorescence spectra.

Exploration of synthesizing fluorescent silicon nanoparticles and label-free detection of sulfadiazine sodium.

Herein, silica nanoparticles (SiNPs) with blue-fluorescence have been originally synthesized through one facile hydrothermal way, and this kind of SiNPs were water-soluble with the relative quantum yield of around 6%. Meanwhile, N-(triethoxysilylpropyl) urea severed as the silica source, while potassium hydrogen phthalate as the doping reagent. Also, SiNPs exhibited the acceptable stability and excitation-dependent fluorescence property. Moreover, their surfaces of the obtained SiNPs were equipped with multiple functional groups including -Si-O-Si-, -Si-H, -COOH, -NH2 and -OH. Importantly, the fluorescence of SiNPs could be specifically quenched by sulfadiazine sodium (SD-Na), thus achieving a label-free detection of SD-Na, which displayed a wide linear response in the range of 0.8 µM-800 µM with a detection limit of 1.02 µM. Additionally, we explored the mechanism of SiNPs sensing SD-Na on the basis of aggregation-induced quenching. To be specific, the particle size of SiNPs increased from 29.9 nm to 203.7 nm induced by the electrostatic interactions between SiNPs and SD-Na, which was further confirmed by high resolution transmission electron microscopy. Consequently, the proposed strategy here broadened the ways of assaying sulfadiazine sodium.

Niosomes containing hydroxyl additives as percutaneous penetration enhancers: effect on the transdermal delivery of sulfadiazine sodium salt.

The aim of this study was to improve the transdermal permeation of sulfadiazine sodium, employing synergistic combination of surfactants (in the form of niosomes) and additives with different number of hydroxylic groups, (following referred to as "alcohol"), as component of the bilayer. In particular the effect of different concentration of each alcohol (ethanol, propylene glycol or glycerol, from 5%, to 40% v/v) on niosomes size and distribution, drug entrapment efficiencies and ex vivo drug percutaneous permeation were evaluated, identifying formulations giving the best performances. The findings revealed that the presence of alcohol critically affect the physico-chemical properties of niosomes, with regards to dimensions, drug encapsulation and permeation. Vesicular size increased with the amount of alcohol and at the same alcohol concentration, follow the sequence ethanol>propylene glycol>glycerol. Loaded niosomes were larger than empty ones. Low E% values were found for ethanol, even less in propylene glycol and glycerol based samples, confirming that the chemical structure of the alcohol and its physico-chemical properties, affected the sulfadiazine entrapment efficiency. The comparative evaluation of percutaneous permeation profiles showed that the cumulative amount of permeated drug increases with alcohol concentration up to 20% v/v. Higher concentration (40% v/v) resulted in a strong decrease of the potential skin permeation. Best performances were obtained with glycerol. In all cases ex vivo sulfadiazine percutaneous permeations are controlled and improved respect to the corresponding free drug solutions and traditional niosomes used as controls.

Development and validation of a stability-indicating HPLC method for the simultaneous determination of sulfadiazine sodium and trimethoprim in injectable solution formulation.

A direct, precise, and stability-indicating HPLC method that is based on reversed-phase liquid chromatography (RP-HPLC) coupled with a photodiode array detector (PDA) was developed, optimized, and validated for the simultaneous determination of sulfadiazine sodium (SDZS) and Trimethoprim (TMP) in Bactizine® forte injectable solution. The separation was achieved using a C18 column (250 mm×4.6 mm i.d., 5 µm particle size) at room temperature, and an isocratic mobile phase that consisted of a trinary solvent mixture of water-acetonitrile-triethylamine (838:160:2, v/v) at pH 5.5 ± 0.05. The mobile phase was delivered at 1.4 ml/min and the analytes were monitored at 254 nm. The effects of the operational chromatographic conditions on the peak's USP tailing factor, column efficiency, and resolution were systematically optimized. Forced degradation experiments were carried out by exposing SDZS, TMP standards, and their formulation to thermal, photolytic, oxidative, and acid-base hydrolytic stress conditions. The method was successfully validated in accordance to International Conference on Harmonization (ICH) and United States Pharmacopoeia (USP34/NF29) guidelines and found to be suitable for the quantitative determination and stability of SDZS and TMP in Bactizine® forte injectable solution.