Streptococcus thermophilus fermented milk reduces serum MDA-LDL and blood pressure in healthy and mildly hypercholesterolaemic adults.

Low-density lipoprotein (LDL)-cholesterol, malondialdehyde-modified low-density lipoprotein (MDA-LDL), MDA-LDL/LDL-cholesterol in serum, and blood pressure are considered useful risk markers of cardiovascular diseases. This study aimed to examine whether a fermented milk containing Streptococcus thermophilus YIT 2001 (ST), which has high anti-oxidative activity, would benefit healthy and mildly hyper-LDL-cholesterolaemic adults via a randomised, double-blind, placebo-controlled trial. ST-fermented milk or non-fermented placebo milk (PC) was consumed once a day for 12 weeks by 29 and 30 subjects, respectively, with average serum LDL-cholesterol levels of about 140 mg/dl. Serum levels of LDL-cholesterol and MDA-LDL and blood pressure were analysed before (baseline) and after consumption. Comparisons of the responses between both groups were assessed using analysis of covariance (ANCOVA, with the baseline value as the covariate). ANCOVA demonstrated that the ST group had significant reductions in MDA-LDL, MDA-LDL/LDL-cholesterol, systolic blood pressure (SBP), and diastolic blood pressure (DBP) compared with the PC group during the consumption period (P<0.05). Moreover, stratified analysis revealed that there were significant reductions in MDA-LDL, MDA-LDL/LDL-cholesterol, SBP, and DBP in the ST group compared with the PC group during the consumption period in subjects who had above median (65 U/l) levels of oxidative stress marker MDA-LDL at baseline (P<0.05), but not in subjects with levels below the median. These findings suggest that daily consumption of ST-fermented milk may be beneficial in healthy or mildly hyper-LDL cholesterolaemic subjects through reductions in risk marker values of oxidative stress and/or cardiovascular diseases. The benefits were particularly remarkable in subjects who had higher levels of MDA-LDL.

In-silico analyses of natural products on leishmania enzyme targets.

Natural products are compounds that are isolated from plants, provide a variety of lead structures for the development of new drugs by the pharmaceutical industry. The interest in these substances increases because of their beneficial effects on human health, which include antiviral, antiallergic, antiplatelet, anti-inflammatory, antitumor, antioxidant, and antiparasitic activities. Leishmaniasis is the infection caused by protozoa of the genus Leishmania, which affects mainly people who live in poor countries, and can cause chronic fever, liver problems, anemia, and other blood problems. Current chemotherapies against the disease cause side effects, and are ineffective. There are no vaccines, and new chemotherapeutic agents for the treatment of leishmaniasis are greatly needed. This work reports on some of the enzymatic targets studied in the development of new drugs using natural products as inhibitors for the treatment of leishmaniasis. We applied ligand-based-virtual screening using Random Forest, associated with structure-based-virtual screening (docking), of a small dataset of 683 flavonoids and derivatives from an in-house data bank to select structures with potential inhibitory activity against pyruvate kinase, an important enzyme in Leishmania mexicana's energy production chemistry. The computer-aided drug design studies revealed good results against Leishmaniasis for flavones.

Benzo- and thienobenzo- diazepines: multi-target drugs for CNS disorders.

Benzodiazepines (BZ or BZD) are a class of gabaminergic psychoactive chemicals used in hypnotics, sedation, in the treatment of anxiety, and in other CNS disorders. These drugs include alprazolam (Xanax), diazepam (Valium), clonazepam (Klonopin), and others. There are two distinct types of pharmacological binding sites for benzodiazepines in the brain (BZ1 and BZ2), these sites are on GABA-A receptors, and are classified as short, intermediate, or long-acting. From the thienobenzodiazepine class (TBZ), Olanzapine (2-methyl-4-(4-methyl-l-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine) (Zyprexa) was used as an example to demonstrate the antagonism of this class of compounds for multiples receptors including: dopamine D1-D5, α-adrenoreceptor, histamine H1, muscarinic M1-M5 and 5-HT2A, 5-HT2B, 5-HT2C, 5-HT3 and 5-HT6 receptors. Olanzapine is an atypical antipsychotic agent, structurally related to clozapine, and extensively used for the treatment of schizophrenia, bipolar disorder-associated mania, and the behavioral symptoms of Alzheimer's disease. The functional blockade of these multiple receptors contributes to the wide range of its pharmacologic and therapeutic activities, having relatively few side effects when compared to other antipsychotics agents. Thienobenzodiazepines (such as Olanzapine) are characterized as multi- receptor- targeted- acting- agents. This mini-review discusses these 2 drug classes that act on the central nervous system, the main active compounds used, and the various receptors with which they interact. In addition, we propose 12 olanzapine analogues, and generated Random Forest models, from a data set obtained from the ChEMBL database, to classify the structures as active or inactive against 5 dopamine receptors (D1, D2, D3, D4, D5 and D6), and dopamine transporter.

pH at the micellar interface: synthesis of pH probes derived from salicylic acid, acid-base dissociation in sodium dodecyl sulfate micelles, and Poisson-Boltzmann simulation.

The study of the H+ concentration at the micellar interface is a convenient system for modeling the distribution of H+ at interfaces. We have synthesized salicylic acid derivatives to analyze the proton dissociation of both the carboxylic and phenol groups of the probes, determining spectrophotometrically the apparent pK(a)'s (pK(ap)) in sodium dodecyl sulfate, SDS, micelles with and without added salt. The synthesized probes were 2-hydroxy-5-(2-trimethylammoniumacetyl)benzoate; 2-hydroxy-5-(2-dimethylhexadecylammoniumacetyl)benzoate; 2-hydroxy-5-(2-dimethylhexadecylammoniumhexanoyl)benzoate; 2-hydroxy-5-(2-dimethylhexadecylammoniumundecanoyl)benzoate; 2-hydroxy-5-acetylbenzoic acid; and 2-hydroxy-5-dodecanoylbenzoic acid. Upon incorporation into SDS micelles the pK(ap)'s of both carboxylic and phenol groups increased by ca. 3 pH units and NaCl addition caused a decrease in the probe-incorporated pK(ap). The experimental results were fitted with a cell model Poisson-Boltzmann (P-B) equation taking in consideration the effect of salt on the aggregation number of SDS and using the distance of the dissociating group as a parameter. The conformations of the probes were analyzed theoretically using two dielectric constants, e.g., 2 and 78. Both the P-B analysis and conformation calculations can be interpreted by assuming that the acid groups dissociate very close to, or at, the interface. Our results are consistent with the assumption that the intrinsic pK(a)'s of both carboxylic and phenol groups of the salicylic acid probes used here can be taken as those in water. Using this assumption the micellar and salt effects on the pK(ap)'s of the (trialkylammonium)benzoate probes were described accurately using a cell model P-B analysis.

Kinetic Analyses of Colloidal Crystallization in a Wide Range of Sphere Concentrations as Studied by Reflection Spectroscopy.

The nucleation and growth rates in the colloidal crystallization of silica spheres (103 nm in diameter) from 0.006 to 0.04 in volume fraction (straight phi) have been measured by reflection spectroscopy. Kinetics of the crystallization has been discussed in a wide sphere concentration range (from straight phi=0.0005 to straight phi=0.04) using the data of this work and the previous work (110 nm in diameter) in exhaustively deionized aqueous suspensions. The induction period for nucleation decreases sharply as the sphere concentration increases. The nucleation rate increases substantially from 1x10(-3) to 1x10(7) mm(-3) s(-1) when straight phi increases from 0.0005 to 0.04. The crystal growth process consists of the fast growing step toward metastable crystals (rate v(1)) and slow growth accompanied with the reorientation toward stable ones (rate v(2)). The v(1) values increase first from 5 to 20 µm/s and then turn back to 5 µm/s after passing a maximum. v(1) above straight phi=0.01 remains at 5 µm/s and is insensitive to sphere concentration. The slow step is observed in the high-sphere concentrations only, and v(2) decreases sharply from 3 µm/s to 0.7 nm/s when sphere concentration increases from 0.004 to 0.04 in volume fraction. Importance of the electrostatic intersphere repulsion by overlapping of the electrical double layers and the cooperative and synchronized fluctuation of colloidal spheres in the crystallization processes are supported strongly. Copyright 2000 Academic Press.

Kinetic Analyses of Colloidal Crystallization in a Sinusoidal Electric Field as Studied by Reflection Spectroscopy.

The effect of a sinusoidal electric field on crystal growth rates in the colloidal crystallization of silica spheres (110 nm in diameter) in exhaustively deionized aqueous suspensions has been studied by reflection spectroscopy. Sphere concentration is 0.0016 in volume fraction. Nucleation time is shorter than 1 s. The crystal growth rates, v, of the body-centered cubic lattices have been determined from the increase in the cube root of the intensity in the sharpened reflection peaks. The v value is 20 µm/s in the absence of an electric field. v decreases from 20 to 8 µm/s as the voltage applied increases from 0 to 10 V at 1 Hz. v decreases from 30 to 15 µm/s when frequency increases from 0.01 to 10 Hz at E = 6 V, and remains constant irrespective of frequencies higher than 10 Hz up to 10 kHz. Interestingly, the crystallization of bcc lattices is enhanced at low frequencies between 0.01 and 0.5 Hz. The main causes for the retardation of crystallization at high frequencies and voltages are (a) the additional translational fluctuation of the spheres and the surrounding electrical double layers by the electric field, and (b) the partial melting of the crystals by the shearing forces in an electric field. The importance of electrostatic intersphere repulsion resulting from overlap of the electrical double layers and cooperative and synchronized fluctuation of colloidal spheres in crystallization processes is strongly supported. Copyright 1999 Academic Press.