Glutaminolysis and autophagy in cancer

The remarkable metabolic differences between cancer cells and normal cells result in the potential for targeted cancer therapy. The upregulation of glutaminolysis provides energetic advantages to cancer cells. The recently described link between glutaminolysis and autophagy, mediated by MTORC1, may constitute an attractive target for therapeutic strategies. A combination of therapies targeting simultane-ously cell signaling, cancer metabolism, and autophagy can solve therapy resistance and tumor relapse problems, commonly observed in patients treated with most of the current targeted therapies. In this review we summarize the mechanistic link between glutaminolysis and autophagy, and discuss the impacts of these processes on cancer progression and the potential for therapeutic intervention.     

Dapsone-Loaded Invasomes as a Potential Treatment of Acne: Preparation,Characterization, and <Emphasis Type="Italic">In Vivo</Emphasis> Skin Deposition Assay

Dapsone (DPS) is a unique sulfone with antibiotic and anti-inflammatory activity. Owing to its dual action, DPS has a great potential to treat acne. Topical DPS application is expected to be effective in treatment of mild to moderate acne conditions. Invasomes are novel vesicles composed of phosphatidylcholine, ethanol, and one or mixture of terpenes of enhanced percutaneous permeation. In this study, DPS-loaded invasomes were prepared using the thin film hydration technique. The effect of different terpenes (Limonene, Cineole, Fenchone, and Citral) in different concentrations on the properties of the prepared DPS-loaded invasomes was investigated using a full factorial experimental design, namely, the particle size, drug entrapment, and release efficiency. The optimized formulation was selected for morphological evaluation which showed spherical shaped vesicles. Further solid-state characterization using differential scanning calorimetry and X-ray diffractometry revealed that the drug was dispersed in an amorphous state within the prepared invasomes. Finally, the ability of the prepared DPS-loaded invasomes to deliver DPS through the skin was investigated in vivo using wistar rats. The maximum in vivo skin deposition amount of DPS was found to be 4.11 mcg/cm² for invasomes versus 1.71 mcg/cm² for the drug alcoholic solution, representing about 2.5-fold higher for the invasomes compared to the drug solution. The AUC0–10 calculated for DPS-loaded invasomes was nearly 2-fold greater than that of DPS solution (14.54 and 8.01 mcg.h/cm² for the optimized invasomes and DPS solution, respectively). These results reveal that the skin retention of DPS can be enhanced using invasomes.     

Chemical Composition and Activity of Essential Oils of Carissa macrocarpa (Eckl.) A.DC. Cultivated in Tunisia and Its Anatomical Features

This is the first study investigating the chemical composition of essential oils (EOs) isolated from different tissues of Carissa macrocarpa (Eckl .) A.DC., their antimicrobial activity and the anatomical characters of the aerial organs and the fruits. The main EO components were pentadecanal and tetradecan‐1‐ol (31.9 and 16.5% in fresh leaf EO, respectively), (E)‐nerolidol and caryophyllene oxide (27.3 and 15.0% in fruit EO, respectively), linalool and hexahydrofarnesyl acetone (30.9 and 24.9% in stem EO, respectively), benzyl benzoate (24.3% in flower EO). The fruit EO was more active against Candida albicans (MIC = 0.46 mg/mL) compared to the reference antibiotic (17.66 mg/mL). Furthermore, at this concentration it inhibited all the Gram‐positive bacteria. Concerning the anatomical features, it is noteworthy to mention the presence of a large cluster of calcium oxalate crystals inside some parenchymatous cells. Large ducts corresponding to non articulated laticifers were identified in the cortex of leaf, stem and fruit pericarp. The laticifers categories and their distribution are taxonomically important to discriminate this species from others acclimated in different countries. Considering the obtained results, EOs of C. macrocarpa can be a good source of antimicrobial compounds, contributing to solve the problem of microbial resistance to antibiotics.     

<Emphasis Type="Italic">Aureobasidium mangrovei</Emphasis> sp. nov., an ascomycetous species recovered from Hara protected forests in the Persian Gulf,Iran

A new ascomycetous black yeast-like species was recovered from healthy plant (Avicennia marina) of Hara protected mangrove forests at Qeshm Island, Iran. Morphological, physiological analysis as well as a molecular analysis of the internal transcribed spacer (ITS) and partial large ribosomal subunit (D1/D2 domains) confirmed the placement of this strain in the genus Aureobasidium and based on considerable sequence divergence, distinguishable cardinal growth temperatures and salt tolerance a new species Aureobasidium mangrovei sp. nov. is proposed. However, the type strain micro-morphologically is not clearly distinguishable from other members of the genus. The type strain, Aureobasidium mangrovei was preserved in a metabolically inactive state at the Iranian Biological Resource Centre, Tehran, Iran as IBRC-M 30265^T and the ex-type culture is deposited in the CBS yeast collection of the Westerdijk Fungal Biodiversity Institute, Utrecht, The Netherlands as CBS 142205^T. The GenBank accession numbers for the nucleotide sequences of the large subunit ribosomal DNA and ITS region are KY089084 and KY089085, respectively. The MycoBank number of the new species is MB 823444.     

Formulation and <Emphasis Type="Italic">In Vitro</Emphasis> and <Emphasis Type="Italic">In Vivo</Emphasis> Evaluation of Lipid-Based Terbutaline Sulphate Bi-layer Tablets for Once-Daily Administration

The objective of this study was to prepare and evaluate terbutaline sulphate (TBS) bi-layer tablets for once-daily administration. The bi-layer tablets consisted of an immediate-release layer and a sustained-release layer containing 5 and 10 mg TBS, respectively. The sustained-release layer was developed by using Compritol®888 ATO, Precirol® ATO 5, stearic acid, and tristearin, separately, as slowly eroding lipid matrices. A full 4?×?2² factorial design was employed for optimization of the sustained-release layer and to explore the effect of lipid type (X ₁), drug–lipid ratio (X ₂), and filler type (X ₃) on the percentage drug released at 8, 12, and 24 h (Y ₁, Y ₂, and Y ₃) as dependent variables. Sixteen TBS sustained-release matrices (F1–F16) were prepared by melt solid dispersion method. None of the prepared matrices achieved the targeted release profile. However, F2 that showed a relatively promising drug release was subjected to trial and error optimization for the filler composition to develop two optimized matrices (F17 and F18). F18 which consisted of drug–Compritol®888 ATO at ratio (1:6 w/w) and Avicel PH 101/dibasic calcium phosphate mixture of 2:1 (w/w) was selected as sustained-release layer. TBS bi-layer tablets were evaluated for their physical properties, in vitro drug release, effect of storage on drug content, and in vivo performance in rabbits. The bi-layer tablets showed acceptable physical properties and release characteristics. In vivo absorption in rabbits revealed initial high TBS plasma levels followed by sustained levels over 24 h compared to immediate-release tablets.     

Design,synthesis, antimicrobial evaluation and molecular docking studies of some new 2,3-dihydrothiazoles and 4-thiazolidinones containing sulfisoxazole

Microbial resistance to the available drugs poses a serious threat in modern medicine. We report the design, synthesis and in vitro antimicrobial evaluation of new functionalized 2,3-dihydrothiazoles and 4-thiazolidinones tagged with sulfisoxazole moiety. Compound 8d was most active against Bacillis subtilis (MIC, 0.007?µg/mL). Moreover, compounds 7c–d and 8c displayed significant activities against B. subtilis and Streptococcus pneumoniae (MIC, 0.03–0.06?µg/mL and 0.06–0.12?µg/mL versus ampicillin 0.24?µg/mL and 0.12?µg/mL; respectively). Compounds 7a and 7c–d were highly potent against Escherichia coli (MIC, 0.49–0.98?µg/mL versus gentamycin 1.95?µg/mL). On the other hand, compounds 7e and 9c were fourfolds more active than amphotericin B against Syncephalastrum racemosum. Molecular docking studies showed that the synthesized compounds could act as inhibitors for the dihydropteroate synthase enzyme (DHPS). This study is a platform for the future design of more potent antimicrobial agents.     

Association of IL‐37 gene polymorphisms with susceptibility to tuberculosis in Saudi subjects

Tuberculosis (TB) is one of the most common infectious diseases worldwide. IL‐37, a novel member of the IL‐1 family, has anti‐inflammatory activity. Various cytokine genes polymorphisms are reportedly associated with susceptibility to TB infection. However, an association between genetic variations in the IL‐37 gene and susceptibility to TB infection has not been investigated. The aim of this case‐control study was therefore to identify such an association in Saudi subjects, in which five single‐nucleotide polymorphisms (SNPs) in the IL‐37 gene were assessed. Serum concentrations of IL‐37 were evaluated using ELISA, and genetic variants genotyped by multiplex PCR and ligase detection reaction. It was found that the C/C genotype of rs2723176 (–6962 A/C) occurs significantly more frequently in patients with active TB and that the C allele of this SNP is associated with TB. In addition, the C allele of rs2723176 SNP was associated with high circulating concentrations of IL‐37. However, the genotype and allele frequency of the other four SNPs (rs3811046, rs3811047, rs2723186 and rs2723187) were not significantly associated with TB infection. In conclusion, the present data suggest that rs2723176 SNP of IL‐37 is involved in the development of TB infection. Furthermore, high circulating concentrations of IL‐37 may have a negative effect on protective immunity against TB infection.