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The increasing incidence of hospital-acquired infections caused by drug-resistant pathogens, host toxicity, the poor efficacy of drugs and high treatment costs has drawn attention to the potential of natural products as antifungals in mucocutaneous infections and combinational therapies. Moreover, cellular and subcellular targets for these compounds may provide better options for the development of novel antifungal therapies. Eugenol, methyl eugenol and estragole are phenylpropanoids found in essential oil. They are known to possess pharmacological properties including antimicrobial activity. Induction of oxidative stress characterized by elevated levels of free radicals and an impaired antioxidant defence system is implicated as a possible mechanism of cell death. An insight into the mechanism of action was gained by propidium iodide cell sorting and oxidative stress response to test compounds in Candida albicans. The extent of lipid peroxidation (LPO) of cytoplasmic membranes was estimated to confirm a state of oxidative stress. Activity levels of primary defence enzymes and glutathione were thus further determined. Whereas these compounds cause fungal cell death by disrupting membrane integrity at minimum inhibitory concentrations (MIC), sub-MIC doses of these compounds significantly impair the defence system in C. albicans. The study has implications for understanding microbial cell death caused by essential oil components eliciting oxidative stress in Candida. The formation of membrane lesions by these phenylpropanoids thus appears to be the result of free radical cascade-mediated LPO. [ABSTRACT FROM AUTHOR]

We have recently reported that serum concentrations of α-carotene (AC) and β-carotene (BC) are under strong genetic influences and were correlated with obesity and other cardio-metabolic traits in Mexican American (MA) children. Our previously developed Pediatric Metabolic Index (PMI) correlates with insulin resistance (IR) after adjusting for age and sex using lipid and adiposity data from Mexican children. A PMI score > 2.0 predicts metabolic abnormalities including IR (i.e., HOMA-IR). Yet data on other MA children with PMI > 2 with normal IR and PMI < 2 with high IR, suggest a role for additional factors in determining insulin sensitivity (IS). In this study, we aimed to assess interactions between carotenoids and the PMI in predicting IS as measured by Matsuda index using the surface-response analysis (SRA). Four different carotenoids, namely, AC, BC, lycopene (Lyc), and β-cryptoxanthin (CX) from ∼590 children enrolled in the San Antonio Family Assessment of Metabolic Risk Indicators in Youth (SAFARI) study were measured by mass spectrometry. Glucose and insulin levels were measured after oral glucose tolerance test and IS index (ISI) was calculated using Matsuda method. SRA was used to determine two-way interactions of serum carotenoids and PMI on ISI. The computer programs SOLAR and STATISTICA 7.0 were used for statistical analysis. The SRA showed an increase in ISI in children with PMI scores between 2 to 4. This effect was modified in the presence of lower serum AC and BC levels; and, interactions between these two carotenoids and PMI had maximal effect on ISI. Conversely, MA children with moderate PMI scores can have substantial improvement in their IS with higher serum AC and BC levels. In contrast, there was a minimal surface response to Lyc and CX serum levels. Notably, despite an optimal PMI, children with lower concentrations of AC and BC showed less IS. In summary, we found that interactions between carotenoids with PMI may predict IS in MA children. Disclosure: S. Mummidi: None. J. Hernandez-Ruiz: None. V.S. Farook: None. L. Reddivari: None. A. Diaz-Badillo: None. S.P. Fowler: None. R.G. Resendez: None. F. Akhtar: None. D. Lehman: None. C. Jenkinson: None. R. Arya: None. J.L. Lynch: Board Member; Self; American Academy of Pediatrics. Consultant; Self; Novo Nordisk Inc. Research Support; Self; Daiichi Sankyo Company, Limited, National Institutes of Health, Novo Nordisk Inc., Pediatric Diabetes Consortium. R.A. DeFronzo: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Elcelyx Therapeutics, Inc., Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk Inc. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc. Speaker's Bureau; Self; AstraZeneca, Novo Nordisk Inc. D.E. Hale: None. J. Blangero: None. J.C. Lopez-Alvarenga: None. R. Duggirala: None. J.K. Vanamala: None. Funding: National Institutes of Health (R01HD049051, R01AI119131, HD049051-5S1, HD041111, DK053889, DK042273, DK047482, P01HL45522, MH59490, M01-RR-01346), U.S. Department of Veterans Affairs; Max and Minnie Tomerlin Voelcker Fund; National Institute of Food and Agriculture (2009-55200-05197) [ABSTRACT FROM AUTHOR]

CC-chemokine ligand 2 (CCL2) is involved in the pathogenesis of several diseases associated with monocyte/macrophage recruitment, such as HIV-associated neurocognitive disorder (HAND), tuberculosis, and atherosclerosis. The rs1024611 (alleles:A>G; G is the risk allele) polymorphism in the CCL2 cis -regulatory region is associated with increased CCL2 expression in vitro and ex vivo, leukocyte mobilization in vivo, and deleterious disease outcomes. However, the molecular basis for the rs1024611-associated differential CCL2 expression remains poorly characterized. It is conceivable that genetic variant(s) in linkage disequilibrium (LD) with rs1024611 could mediate such effects. Previously, we used rs13900 (alleles:&#95;C>T) in the CCL2 3' untranslated region (3' UTR) that is in perfect LD with rs1024611 to demonstrate allelic expression imbalance (AEI) of CCL2 in heterozygous individuals. Here we tested the hypothesis that the rs13900 could modulate CCL2 expression by altering mRNA turnover and/or translatability. The rs13900 T allele conferred greater stability to the CCL2 transcript when compared to the rs13900 C allele. The rs13900 T allele also had increased binding to Human Antigen R (HuR), an RNA-binding protein, in vitro and ex vivo. The rs13900 alleles imparted differential activity to reporter vectors and influenced the translatability of the reporter transcript. We further demonstrated a role for HuR in mediating allele-specific effects on CCL2 expression in overexpression and silencing studies. The presence of the rs1024611G-rs13900T conferred a distinct transcriptomic signature related to inflammation and immunity. Our studies suggest that the differential interactions of HuR with rs13900 could modulate CCL2 expression and explain the interindividual differences in CCL2-mediated disease susceptibility., Competing Interests: Declaration of interests The authors declare no competing interests.