Virtual screening and molecular dynamic study of potential new binders to mTOR.

In the present work, a library of 239 frentizole derivatives formerly synthesized by our research group were virtually screened on the FRB domain of mTOR in a search of potential binders for further experimental evaluation. 39 compounds from this library were virtually selected and classified in 7 groups according to their structural features. 9 representative compounds of these 7 groups were further submitted to rounds of MD simulation and MM-PBSA calculations. Analysis of our results pointed to the most promising among these groups as binders to the FRB domain of mTOR. We believe that they structurally represent a priority portion of the original library for further experimental evaluation.

Alterations in Growth and Morphology of Ganoderma lucidum and Volvariella volvaceae in Response to Nanoparticle Supplementation

Use of nanoparticles (NPs) in several commercial products has led to emergence of novel contaminants of air, soil and water bodies. The NPs may exhibit greater ecotoxicity due to nano-scale dependent properties over their bulk counterparts. The present investigation explores the effect of in vitro supplementation of TiO2, silica and silver NPs on radial growth and ultrastructural changes in the hyphae and spores of two mushroom genera, Ganoderma lucidum and Volvariella volvaceae. A concentration dependent decrease in radial growth on NP amended potato dextrose agar medium was recorded. However, in comparison to control, there was decrease in radial diameter on supplementation with TiO2 NPs while an increase was recorded for silica and silver NPs amendments as compared to their bulk salts at same concentrations after 48 h of incubation. Optical microscopy studies showed decrease in the number of spores while increase in spore diameter and thinning of hyphal diameter on NPs supplementation. Scanning electron microscopy analysis of fungal growth showed presence of deflated and oblong spores in two fruiting strains of Ganoderma while Volvariella exhibited decreased sporulation. Further, hyphal thinning and branching was recorded in response to NP amendments in both the test mushrooms. Enhancement of protein content was observed on NP compared to bulk supplementation for all cultures, concentrations and hours of incubation except for TiO2 NPs. Likewise, bulk and NP supplementations (at 100 mg L−1) resulted in enhanced laccase activity with occurrence of laccase specific protein bands on SDS-PAGE analysis.

Toxic potential of palytoxin / 华中科技大学学报（医学）（英德文版）

This review briefly describes the origin, chemistry, molecular mechanism of action, pharmacology, toxicology, and ecotoxicology of palytoxin and its analogues. Palytoxin and its analogues are produced by marine dinoflagellates. Palytoxin is also produced by Zoanthids (i.e. Palythoa), and Cyanobacteria (Trichodesmium). Palytoxin is a very large, non-proteinaceous molecule with a complex chemical structure having both lipophilic and hydrophilic moieties. Palytoxin is one of the most potent marine toxins with an LD50 of 150 ng/kg body weight in mice exposed intravenously. Pharmacological and electrophysiological studies have demonstrated that palytoxin acts as a hemolysin and alters the function of excitable cells through multiple mechanisms of action. Palytoxin selectively binds to Na(+)/K(+)-ATPase with a Kd of 20 pM and transforms the pump into a channel permeable to monovalent cations with a single-channel conductance of 10 pS. This mechanism of action could have multiple effects on cells. Evaluation of palytoxin toxicity using various animal models revealed that palytoxin is an extremely potent neurotoxin following an intravenous, intraperitoneal, intramuscular, subcutaneous or intratracheal route of exposure. Palytoxin also causes non-lethal, yet serious toxic effects following dermal or ocular exposure. Most incidents of palytoxin poisoning have manifested after oral intake of contaminated seafood. Poisonings in humans have also been noted after inhalation, cutaneous/systemic exposures with direct contact of aerosolized seawater during Ostreopsis blooms and/or through maintaining aquaria containing Cnidarian zoanthids. Palytoxin has a strong potential for toxicity in humans and animals, and currently this toxin is of great concern worldwide.

Albumin and α1-acid glycoprotein: old acquaintances.

INTRODUCTION: Albumin and α1-acid glycoprotein (AGP) are two of the most abundant proteins found in plasma. Their effect on the pharmacokinetic profile of exogenous compounds has major implications to clinical practice. Recent exploration into their possible role as diagnostic markers underlines their significance, and provides highlights their potential in medicinal applications. AREAS COVERED: This review summarizes the current understanding behind albumin and AGP. Specifically, the review focuses on their structure, physiological function, and their potential use in diagnostics as biomarkers. The article lists and describes the most common methods, with a specific focus on their use in drug design and clinical practice. EXPERT OPINION: Human serum albumin and AGP play a significant role in clinical practice. Research on human serum albumin and AGP, as potential diagnostic biomarkers, has been so far successful, with the development of novel diagnostic methods for detecting ischemia-modified albumin in cardiac ischemia patients. While research into this particular aspect is still in its infancy, future research should make things somewhat clearer and provide a better insight into the true potential of plasma proteins as a whole.

[Gamma-secretase inhibitors in Alzheimer's disease therapy]. / Inhibítory gamma-sekretázy v terapii Alzheimerovej choroby.

Neuritic plaques, which are situated in the brain of Alzheimer's disease (AD) patients, are composed mainly of peptides containing 40 or 42 amino acid residues known as ß-amyloid plaques (Aß). The Aß peptide is the result of the enzymatic cleavage of the amyloid precursor protein (APP). In the so-called amyloidogenic pathway, the ß-secretase enzyme releases a protein fragment (C99), which is subsequently metabolized by the enzyme γ-secretase. Monomer forms of Aß are turned into oligomer forms, which are the main cause of cellular neuronal death in AD patients. The following study is focused on γ-secretase inhibitors that can slow down the production or accumulation of pathologic Aß deposits. γ secretase inhibitors that reached different phases of clinical trials are particularly reported as well as other promising groups of these analogues.

[Myasthenia gravis--current treatment standards and emerging drugs]. / Myasthenia gravis--soucasné terapeutické moznosti a nové trendy.

Myasthenia gravis is very rare autoimmune disease of neuromuscular junction, which presents as a weakness and increased fatiquability of striated muscles. Formerly, myasthenia was largely constraining disease and often ended by death. Recently, advanced diagnostic methods and variety of therapeutic options allow the full compensation of the disease and the quality of patient life is restored. In this review, the methods used during the myasthenia treatment along with the description of the disease itself were detailed.