Three Origanum essential oils, Origanum vulgare ssp. hirtum, Origanum dictamnus, and a commercially available Origanum oil, were analyzed by gas chromatography-mass spectrometry (GC-MS) and showed a high content of carvacrol, thymol, γ-terpinene, and p-cymene representing 73.7%, 92.8%, and 87.78% of the total oil, respectively. The three essential oils exhibited high levels of antimicrobial activity against eight strains of Gram-positive and Gram-negative bacteria. Among the major components of the three oils, carvacrol and thymol exhibited the highest levels of antimicrobial activity, while their biosynthetic precursors γ-terpinene and p-cymene were inactive. The essential oil of O. vulgare ssp. hirtum was extremely bactericidal at 1/4000 dilution and even at dilutions as high as 1/50000 caused considerable decrease in bacterial growth rates. The same essential oil also exhibited high levels of cytotoxicity against four permanent animal cell lines including two derived from human cancers.

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Salvia fructicosa essential oil analyzed by gas chromatography/mass spectrometry showed high contents of 1,8-cineole, α- and β-thujone, and camphor, representing 47.48%, 11.93%, and 9.04% of the total oil, respectively. The essential oil and its isolated components thujone and 1,8-cineole exhibited antimicrobial activity against eight bacterial strains, while camphor was almost inactive against all of the bacteria tested. The essential oil was bactericidal at 1/4000 dilution, and dilutions up to 1/10000 caused considerable decrease in bacterial growth rates. The essential oil of S. fructicosa and the three main components exhibited cytotoxic activity against African Green Monkey kidney (Vero) cells and high levels of virucidal activity against herpes simplex virus 1, a ubiquitous human virus. Keywords: Salvia fructicosa; essential oil; antimicrobial activity; cytotoxicity; antiviral activity (herpes simplex virus); camphor; 1,8-cineole; thujone

β-Thalassemia major results from severely reduced or absent expression of the β-chain of adult hemoglobin (α2β2;HbA). Increased levels of fetal hemoglobin (α2γ2;HbF), such as occurs with hereditary persistence of HbF, ameliorate the severity of β-thalassemia, raising the potential for genetic therapy directed at enhancing HbF. We used an in vitro model of human erythropoiesis to assay for enhanced production of HbF after gene delivery into CD34+ cells obtained from mobilized peripheral blood of normal adults or steady-state bone marrow from patients with β-thalassemia major. Lentiviral vectors encoding (1) a human γ-globin gene with or without an insulator, (2) a synthetic zinc-finger transcription factor designed to interact with the γ-globin gene promoters, or (3) a short-hairpin RNA targeting the γ-globin gene repressor, BCL11A, were tested. Erythroid progeny of normal CD34+ cells demonstrated levels of HbF up to 21% per vector copy. For β-thalassemic CD34+ cells, similar gene transfer efficiencies achieved HbF production ranging from 45% to 60%, resulting in up to a 3-fold increase in the total cellular Hb content. These observations suggest that both lentiviral-mediated γ-globin gene addition and genetic reactivation of endogenous γ-globin genes have potential to provide therapeutic HbF levels to patients with β-globin deficiency.

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Background and PurposeAsthma manifests as a heterogeneous syndrome characterized by airway obstruction, inflammation and hyperresponsiveness (AHR). Although the molecular mechanisms remain unclear, activation of specific PI3K isoforms mediate inflammation and AHR. We aimed to determine whether inhibition of PI3Kδ evokes dilation of airways and to elucidate potential mechanisms.Experimental ApproachHuman precision cut lung slices from non‐asthma donors and primary human airway smooth muscle (HASM) cells from both non‐asthma and asthma donors were utilized. Phosphorylation of Akt, myosin phosphatase target subunit 1 (MYPT1) and myosin light chain (MLC) were assessed in HASM cells following either PI3K inhibitor or siRNA treatment. HASM relaxation was assessed by micro‐pattern deformation. Reversal of constriction of airways was assessed following stimulation with PI3K or ROCK inhibitors.Key ResultsSoluble inhibitors or PI3Kδ knockdown reversed carbachol‐induced constriction of human airways, relaxed agonist‐contracted HASM and inhibited pAkt, pMYPT1 and pMLC in HASM. Similarly, inhibition of Rho kinase also dilated human PCLS airways and suppressed pMYPT1 and pMLC. Baseline pMYPT1 was significantly elevated in HASM cells derived from asthma donors in comparison with non‐asthma donors. After desensitization of the β2‐adrenoceptors, a PI3Kδ inhibitor remained an effective dilator. In the presence of IL‐13, dilation by a β agonist, but not PI3K inhibitor, was attenuated.Conclusion and ImplicationsPI3Kδ inhibitors act as dilators of human small airways. Taken together, these findings provide alternative approaches to the clinical management of airway obstruction in asthma.

Amid an increasing number of reports in the literature concerning epithelial barrier enhancement by various nutrient compounds, there has never been a study performing side-by-side comparisons of these agents in a single epithelial model. We compare five nutrient compounds (previously reported in various epithelial models to enhance barrier function) regarding their ability to increase transepithelial electrical resistance (Rt) and decrease transepithelial mannitol permeability (Jm) across LLC-PK1 renal epithelial cell layers. The effects of these nutrients on the abundance of various tight junctional proteins are also compared. In the overall group of nutrients tested - zinc, indole, quercetin, butyrate and nicotine - only nicotine failed to improve barrier function by either parameter. Nicotine also was without effect on tight junctional proteins. Quercetin simultaneously increased Rt and decreased Jm. Zinc, butyrate and indole only exhibited statistically significant enhancement of Rt. Each of these four effective nutrient compounds had unique patterns of effects on the panel of tight junctional proteins studied. No two compounds produced the same pattern of effects. This unique pattern of effects on tight junctional complex composition by each compound establishes the chance for additive or even synergistic improvement of barrier function by combinations of compounds. A synergistic effect of the combination of quercetin and zinc on Rt is shown.