Terpenoid phenols, including carvacrol, are components of oregano and other plant essential oils that exhibit potent antifungal activity against a wide range of pathogens, including Candida albicans, Staphylococcus aureus, and Pseudomonas aeruginosa. To gain a mechanistic view of the cellular response to terpenoid phenols, we used Saccharomyces cerevisiae as a model organism and monitored temporal changes in metabolic activity, cytosolic and vacuolar pH, and Ca 2؉ transients. Using a panel of related compounds, we observed dosedependent Ca 2؉ bursts that correlated with antifungal efficacy. Changes in pH were long lasting and followed the Ca 2؉ transients. A vma mutant lacking functional vacuolar H ؉ -ATPase (V-ATPase) and defective in ion homeostasis was hypersensitive to carvacrol toxicity, consistent with a role for ionic disruptions in mediating cell death. Genomic profiling within 15 min of exposure revealed a robust transcriptional response to carvacrol, closely resembling that of calcium stress. Genes involved in alternate metabolic and energy pathways, stress response, autophagy, and drug efflux were prominently upregulated, whereas repressed genes mediated ribosome biogenesis and RNA metabolism. These responses were strongly reminiscent of the effects of rapamycin, the inhibitor of the TOR pathway of nutrient sensing. The results point to the activation of specific signaling pathways downstream of cellular interaction with carvacrol rather than a nonspecific lesion of membranes, as has been previously proposed.While the medicinal properties of herbs have been recognized since ancient times, there has been a resurgence of interest in the antimicrobial properties of botanical extracts. Essential oils have been amply documented to kill a wide range of pathogenic fungi and bacteria, such as Candida albicans, Staphylococcus aureus, and Pseudomonas aeruginosa, including their drug-resistant variants (6,10,21,22). Of the herbal extracts tested, essential oils derived from the genus Oreganum were among the most effective, with an in vitro MIC of 500 ppm against C. albicans (27). Major components of oregano extract, which include the terpenoid phenols carvacrol, thymol, and eugenol, have potent antifungal activity of their own (4, 23, 24). Terpenoid phenols have been shown to be efficacious not only on planktonic cells but also on biofilms of Candida albicans that are resistant to many antifungal drugs. Carvacrol demonstrated the strongest antifungal activity against Candida albicans biofilms, with a MIC of Ͻ0.03% (9). Furthermore, carvacrol was shown to be effective regardless of the maturity of the biofilm. The terpenoid phenols tested were able to inhibit biofilms of several strains of Candida, including C. albicans, C. glabrata, and C. parapsilosis. In addition to their antimycotic, antibacterial, insecticidal, and bioherbicidal properties, essential oils are also well known for their antioxidant characteristics and are used to inhibit lipid peroxidation in preventing food spoilage or as chemoprotective agen...

Background: Neuroinflammation is an important secondary injury mechanism that has dual beneficial and detrimental roles in the pathophysiology of traumatic brain injury (TBI). Compelling data indicate that statins, a group of lipid-lowering drugs, also have extensive immunomodulatory and anti-inflammatory properties. Among statins, atorvastatin has been demonstrated as a neuroprotective agent in experimental TBI; however, there is a lack of evidence regarding its effects on neuroinflammation during the acute phase of TBI. The current study aimed to evaluate the effects of atorvastatin therapy on modulating the immune reaction, and to explore the possible involvement of peripheral leukocyte invasion and microglia/macrophage polarization in the acute period post-TBI.

Protons, the smallest and most ubiquitous of ions, are central to physiological processes. Transmembrane proton gradients drive ATP synthesis, metabolite transport, receptor recycling and vesicle trafficking, while compartmental pH controls enzyme function. Despite this fundamental importance, the mechanisms underlying pH homeostasis are not entirely accounted for in any organelle or organism. We undertook a genome-wide survey of vacuole pH (pHv) in 4,606 single-gene deletion mutants of Saccharomyces cerevisiae under control, acid and alkali stress conditions to reveal the vacuolar pH-stat. Median pHv (5.27±0.13) was resistant to acid stress (5.28±0.14) but shifted significantly in response to alkali stress (5.83±0.13). Of 107 mutants that displayed aberrant pHv under more than one external pH condition, functional categories of transporters, membrane biogenesis and trafficking machinery were significantly enriched. Phospholipid flippases, encoded by the family of P4-type ATPases, emerged as pH regulators, as did the yeast ortholog of Niemann Pick Type C protein, implicated in sterol trafficking. An independent genetic screen revealed that correction of pHv dysregulation in a neo1ts mutant restored viability whereas cholesterol accumulation in human NPC1−/− fibroblasts diminished upon treatment with a proton ionophore. Furthermore, while it is established that lumenal pH affects trafficking, this study revealed a reciprocal link with many mutants defective in anterograde pathways being hyperacidic and retrograde pathway mutants with alkaline vacuoles. In these and other examples, pH perturbations emerge as a hitherto unrecognized phenotype that may contribute to the cellular basis of disease and offer potential therapeutic intervention through pH modulation.