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Herein we demonstrate the expanded utility of a recently described N-trifluoromethylthiolation protocol to sulfonimidamide containing substances. The novel Ntrifluoromethylthio sulfonimidamide derivatives thus obtained were evaluated for antibacterial activity against Mycobacterium tuberculosis (M. tb.) and Mycobacterium abscessus and Gram + Ve (Streptococcus aureus, Bacillus subtilis), and Gram − Ve (Escherichia coli, Pseudomonas aeruginosa) bacteria. Two compounds, 13 and 15 showed high antimycobacterial activity with MIC value of 4−8 μg/mL; i.e. comparable to WHO recommended first line antibiotic for TB infection ethambutol. The same compounds were also found to be cytotoxic in HepG2 cells (compound 13 IC 50 = 15 μg/mL; compound 15 IC 50 = 65 μg/mL). A structure activity relationship, using matched pair analysis, gave the unexpected conclusion that the trifluoromethylthio moiety was responsible for the cellular and bacterial toxicity. Given the increasing use of the trifluoromethylthio group in contemporary medicinal chemistry, this observation calls for considerations before implementation of the functionality in drug design.

Fumonisins are a family of potentially carcinogenic mycotoxins produced by Fusarium verticillioides. Several fumonisins have been identified with fumonisin B1 (FB1) being the most toxic. The canonical mechanism of FB1 toxicity is centered on its structural resemblance with sphinganine and consequent competitive inhibition of ceramide synthase and disruption of lipidomic profiles. Recent and emerging evidence at the molecular level has identified the disruption of mitochondria and excessive generation of toxic reactive oxygen species (ROS) as alternative/additional mechanisms of toxicity. The understanding of how these pathways contribute to FB1 toxicity can lead to the identification of novel, effective approaches to protecting vulnerable populations. Natural compounds with antioxidant properties seem to protect against the induced toxic effects of FB1. Rooibos (Aspalathus linearis), endemic to South Africa, has traditionally been used as a medicinal herbal tea with strong scientific evidence supporting its anecdotal claims. The unique composition of phytochemicals and combination of metabolic activators, adaptogens and antioxidants make rooibos an attractive yet underappreciated intervention for FB1 toxicoses. In the search for a means to address FB1 toxicoses as a food safety problem in developing countries, phytomedicine and traditional knowledge systems must play an integral part. This review aims to summarize the growing body of evidence succinctly, which highlights mitochondrial dysfunction as a secondary toxic effect responsible for the FB1‐induced generation of ROS. We further propose the potential of rooibos to combat this induced toxicity based on its integrated bioactive properties, as a socio‐economically viable strategy to prevent and/or repair cellular damage caused by FB1.

BackgroundPsoriasis and psoriatic arthritis (PsA) are inflammatory associated autoimmune disorders. MicroRNA (miR)-146a plays a crucial role in regulating inflammation. A single nucleotide polymorphism in the miR-146a gene (rs2910164), aberrantly alters its gene expression and linked with the pathogenesis of several disorders, including psoriasis and PsA. In South Africa, psoriasis and PsA are extremely rare in the indigenous African population and most common in both the Indian and Caucasian population. The aim of this study was to investigate whether the miR-146a rs2910164 contributes towards psoriasis and PsA development in South African Indian and Caucasian patients.MethodsSouth African Indian (n = 84) and Caucasian (n = 32) PsA patients (total n = 116) and healthy control subjects (Indian: n = 62 and Caucasian: n = 38; total n = 100) were recruited in the study. DNA was extracted from whole blood taken from all subjects, and genotyped for the miR-146a rs2910164 using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Data for laboratory parameters were obtained from pathology reports. The consulting rheumatologist collected all other clinical data.ResultsUnstratified data (Caucasians + Indians): A significant decrease in C-reactive protein (CRP) levels in PsA patients was observed (CRP monitored at inclusion vs. after 6 months of treatment) (18.95 ± 2.81 mg/L vs. 9.68 ± 1.32 mg/L, p = 0.0011). The miR-146a rs2910164 variant C-allele frequency in PsA patients was significantly higher vs. healthy controls (35.78% vs. 26% respectively, p = 0.0295, OR = 1.59 95% CI 1.05–2.40). Stratified data (Indians): The variant C-allele frequency in Indian PsA patients was significantly higher vs. healthy Indian controls (35.71% vs. 22.58%, p = 0.0200, OR = 1.91 95% CI 1.13–3.22). Stratified data (Caucasians): The variant C-allele frequency distribution between Caucasian PsA patients and healthy Caucasian controls was similar.ConclusionThe rs2910164 variant C-allele may play a role in the progression of PsA in the South African Indian population. The main limitation in this study was the small sample size in the case-control cohorts, with a low overall statistical power (post-hoc power analysis = 19%).

Fusaric acid (FA), a common fungal contaminant of maize, is known to mediate toxicity in plants and animals; however, its mechanism of action is unclear. p53 is a tumor suppressor protein that is activated in response to cellular stress. The function of p53 is regulated by post-translational modifications-ubiquitination, phosphorylation, and acetylation. This study investigated a possible mechanism of FA induced toxicity in the human hepatocellular carcinoma (HepG ) cell line. The effect of FA on DNA integrity and post-translational modifications of p53 were investigated. Methods included: (a) culture and treatment of HepG cells with FA (IC : 580.32 μM, 24 h); (b) comet assay (DNA damage); (c) Western blots (protein expression of p53, MDM2, p-Ser-15-p53, a-K382-p53, a-CBP (K1535)/p300 (K1499), HDAC1 and p-Ser-47-Sirt1); and (d) Hoechst 33342 assay (apoptosis analysis). FA caused DNA damage in HepG cells relative to the control (P < 0.0001). FA decreased the protein expression of p53 (0.24-fold, P = 0.0004) and increased the expression of p-Ser-15-p53 (12.74-fold, P = 0.0126) and a-K382-p53 (2.24-fold, P = 0.0096). This occurred despite the significant decrease in the histone acetyltransferase, a-CBP (K1535)/p300 (K1499) (0.42-fold, P = 0.0023) and increase in the histone deacetylase, p-Ser-47-Sirt1 (1.22-fold, P = 0.0020). The expression of MDM2, a negative regulator of p53, was elevated in the FA treatment compared to the control (1.83-fold, P < 0.0001). FA also inhibited cell proliferation and induced apoptosis in HepG cells as evidenced by the Hoechst assay. Together, these results indicate that FA is genotoxic and post-translationally modified p53 leading to HepG cell death. J. Cell. Biochem. 118: 3866-3874, 2017. © 2017 Wiley Periodicals, Inc.