Aluminum oxide and zinc oxide induced nanotoxicity in rat brain, heart, and lung.

Nanomaterials or nanoparticles are commonly used in the cosmetics, medicine, and food industries. Many researchers studied the possible side effects of several nanoparticles including aluminum oxide (Al2O3-nps) and zinc oxide nanoparticles (ZnO-nps). Although, there is limited information available on their direct or side effects, especially on the brain, heart, and lung functions. This study aimed to investigate the neurotoxicity, cardiotoxicity, and lung toxicity induced by Al2O3-nps and ZnO-nps or in combination via studying changes in gene expression, alteration in cytokine production, tumor suppressor protein p53, neurotransmitters, oxidative stress, and the histological and morphological changes. Obtained results showed that Al2O3-nps, ZnO-nps and their combination cause an increase in 8-hydroxy-2´-deoxyguanosine (8-OHdG), cytokines, p53, oxidative stress, creatine kinase, norepinephrine, acetylcholine (ACh), and lipid profile. Moreover, significant changes in the gene expression of mitochondrial transcription factor-A (mtTFA) and peroxisome proliferator activator receptor-gamma-coactivator-1alpha (PGC-1alpha) were also noted. On the other hand, a significant decrease in the levels of antioxidant enzymes, total antioxidant capacity (TAC), reduced glutathione (GSH), paraoxonase 1 (PON1), neurotransmitters (dopamine - DA, and serotonin - SER), and the activity of acetylcholine esterase (AChE) in the brain, heart, and lung were found. Additionally, these results were confirmed by histological examinations. The present study revealed that the toxic effects were more when these nanoparticle doses are used in combination. Thus, Al2O3-nps and ZnO-nps may behave as neurotoxic, cardiotoxic, and lung toxic, especially upon exposure to rats in combination.

The translocator protein ligands as mitochondrial functional modulators for the potential anti-Alzheimer agents.

Small molecule modulators of mitochondrial function have been attracted much attention in recent years due to their potential therapeutic applications for neurodegenerative diseases. The mitochondrial translocator protein (TSPO) is a promising target for such compounds, given its involvement in the formation of the mitochondrial permeability transition pore in response to mitochondrial stress. In this study, we performed a ligand-based pharmacophore design and virtual screening, and identified a potent hit compound, 7 (VH34) as a TSPO ligand. After validating its biological activity against amyloid-ß (Aß) induced mitochondrial dysfunction and in acute and transgenic Alzheimer's disease (AD) model mice, we developed a library of analogs, and we found two most active compounds, 31 and 44, which restored the mitochondrial membrane potential, ATP production, and cell viability under Aß-induced mitochondrial toxicity. These compounds recovered learning and memory function in acute AD model mice with improved pharmacokinetic properties.

Development of tau-directed small molecule modulators for Alzheimer's disease: a recent patent review (2014-2018).

Alzheimer's disease (AD) is a progressive neurodegenerative disease that is characterized by memory loss and cognitive impairment. As this disease is becoming a serious global health issue, development of disease modifying therapeutics is urgently required. AD is characterized by deposits of two protein, amyloid ß and tau. Although amyloid ß-based therapeutics have been extensively investigated so far, tau has also received great attention as one of promising molecular targets for AD. In this review, a variety of tau-directed strategies to rescue tau-mediated neurotoxicity will be reviewed especially focusing on small molecules. Subsequently, recent patents published from 2014 to 2018 that integrate efforts to develop tau-directed small molecules for the treatment of AD will be reviewed.

Synthesis and in vitro antibacterial activity of novel 3-azabicyclo[3.3.0]octanyl oxazolidinones.

We synthesized a series of oxazolidinone-type antibacterials in which morpholine C-ring of linezolid has been modified by substituted 3-azabicyclo[3.3.0]octanyl rings. Acetamide or 1,2,3-triazole heterocycle was used as C-5 side chain of oxazolidinone. The resulting series of compounds was then screened in vitro against panel of susceptible and resistant Gram-positive, Gram-negative bacteria, and Mycobacterium tuberculosis (Mtb). Several analogs in this series exhibited potent in vitro antibacterial activity comparable or superior to linezolid against the tested bacteria. Compounds 10a, 10b, 11a, and 15a displayed highly potent activity against M. tuberculosis. Selected compound 10b showed good human microsomal stability and CYP-profile, and showed low activity against hERG channel.

Phytoextraction of cadmium by rice (Oryza sativa L.), soybean (Glycine max (L.) Merr.), and maize (Zea mays L.).

Selecting a phytoextraction plant with high Cd-accumulating ability based on the plant's compatibility with mechanized cultivation techniques may yield more immediately practical results than selection based on high tolerance to Cd. Rice (Oryza sativa L., cv. Nipponbare and Milyang 23), soybean (Glycine max [L.] Merr., cv. Enrei and Suzuyutaka), and maize (Zea mays L., cv. Gold Dent) were grown on one Andosol and two Fluvisols with low concentration of Cd contamination ranging from 0.83 to 4.29 mg Cd kg(-1), during 60 days in pots (550 mL) placed in a greenhouse. Shoot Cd uptake was as follows: Gold Dent

Substitution mapping of Pup1: a major QTL increasing phosphorus uptake of rice from a phosphorus-deficient soil.

A major QTL for P uptake had previously been mapped to a 13-cM marker interval on the long arm of chromosome 12. To map that major QTL with higher precision and certainty, a secondary mapping population was developed by backcrossing a near-isogenic line containing the QTL from the donor parent to the recurrent parent of low P uptake. Two different mapping strategies have been followed in this study. A conventional QTL mapping approach was based on individual F(2) RFLP data and the phenotypic evaluation of family means in the F(3). The second strategy employed a substitution-mapping approach. Phenotypic and marker data were obtained for 160 F(3) individuals of six highly informative families that differed in the size of donor chromosomal segments in the region of the putative QTL. QTL mapping showed that close to 80% of the variation between families was due to a single QTL, hereafter referred to as Pup1 (Phosphorus uptake 1). Pup1 was placed in a 3-cM interval flanked by markers S14025 and S13126, which is within 1 cM of the position identified in the original QTL mapping experiment. Other chromosomal regions and epistatic effects were not significant. Substitution mapping revealed that Pup1 co-segregated with marker S13126 and that the flanking markers, S14025 and S13752, were outside the interval containing Pup1. The two mapping strategies therefore yielded almost identical results and, in combining the advantages of both, Pup1 could be mapped with high certainty. The QTL mapping appoach showed that the phenotypic variation between families was due to only one QTL without any additional epistacic interactions, whereas the advantage of substitution mapping was to place clearly defined borders around the QTL.

Genotypic differences in the presence of hairs on roots and gynophores of peanuts (Arachis hypogaea L.) and their significance for phosphorus uptake.

Root hairs substantially increase the surface area of plant roots with positive effects for phosphorus (P) uptake, but the ability of peanuts to form root hairs has been questioned. The aim was to examine hair development on roots and gynophores of a variety of peanut genotypes and to relate genotypic differences in hair formation to differences in P uptake. Five out of eighteen genotypes completely lacked hairs on both organs whereas others consistently developed hairs on roots and gynophores, although with considerable variation in hair density. The ability to form root hairs as well as root hair density concurred with the presence and density of hairs on gynophores, suggesting a possible connection between both developmental processes. The contribution of root hairs to P uptake was studied in three genotypes differing in hair density. The final amount of P taken up by roots did not differ between genotypes but two distinct P uptake strategies could be identified. The genotype lacking root hairs maintained P uptake due to the development of a large root system whereas densely covered roots of genotype 'Wasedairyu' were three times as efficient in extracting P from a P-deficient soil. Furthermore P uptake through gynophores contributed about 20% to the total P uptake of Wasedairyu but only insignificant amounts to other genotypes. The ability to form hairs on roots and gynophores can therefore be seen as an adaptation to low P availability and if combined with a large root system, could substantially increase the tolerance of peanuts to P deficiency.

Synthesis of tricyclic indole-2-carboxylic [correction of caboxylic] acids as potent NMDA-glycine antagonists.

The practical synthesis of a series of tricyclic indole-2-carboxylic acids, 7-chloro-3-arylaminocarbonylmethyl-1,3,4,5-tetrahydrobenz[cd]indole-2-carboxylic acids, as a new class of potent NMDA-glycine antagonists is described. The synthetic route to the key intermediate 12a comprises a regioselective iodination of 4-chloro-2-nitrotoluene, modified Reissert indole synthesis, Jeffery's Heck-type reaction with allyl alcohol, Wittig-Horner-Emmons reaction, and iodination at the indole C-3 position. The key step in the route is an intramolecular cyclization of 12a to give the tricyclic indole structure. Two methods of cyclization, (1) an intramolecular radical cyclization of 12a and (2) a sequence of intramolecular Heck reaction of 12a followed by a 1,4-reduction, were performed. The resulting tricyclic indole diester 13a was selectively hydrolyzed to afford the desired tricyclic indole monocarboxylic acid 16 on a multihundred gram scale without any chromatographic purifications. Optical resolution of 16 to (-)-isomer 17 and (+)-isomer 18 was carried out, and the resulting isomers were derivatized, respectively. Evaluation of the optically active derivatives for affinity to the NMDA-glycine binding site using the radio ligand binding assay with [(3)H]-5,7-dichlorokynurenic acid revealed that the derivatives of (-)-isomer 17 were more potent than the others and that especially substituted anilide (-)-isomer 24 (K(i) = 0.8 nM) showed high affinity.

Tricyclic quinoxalinediones: 5,6-dihydro-1H-pyrrolo[1,2,3-de] quinoxaline-2,3-diones and 6,7-dihydro-1H,5H-pyrido[1,2,3-de] quinoxaline-2,3-diones as potent antagonists for the glycine binding site of the NMDA receptor.

A series of tricyclic quinoxalinediones, 5,6-dihydro-1H-pyrrolo[1,2,3-de]quinoxaline-2,3-diones and 6,7-dihydro-1H,5H-pyrido[1,2,3-de]quinoxaline-2,3-diones, were synthesized and was evaluated for their affinity for the glycine binding site of the NMDA receptor using a [3H]-5,7-dichlorokynurenic acid binding assay. The six-membered ring-fused tricyclic quinoxalinedione 18g (Ki = 9.9 nM) displayed high affinity for the glycine site. The anilide derivative 20g (Ki = 2.6 nM) was 4-fold more potent than 18g and as potent as L-689,560, one of the most potent glycine antagonists so far prepared. Although the carboxylic acid derivative of the corresponding five-membered ring-fused tricyclic quinoxalinedione 18e (Ki = 7.3 nM) had affinity comparable to that of 18g, the anilide derivative 20e largely decreased in the affinity in contrast to 20g. Enantiomers 23g, 24g, 25g, and 26g were prepared and tested. Only the S enantiomer 25g (Ki = 0.96 nM) retained the affinity among the anilide derivatives, whereas both enantiomers 23g (Ki = 2.3 nM) and 24g (Ki = 9.6 nM) were active among the carboxylic acid derivatives. The origin of the high affinity of carboxylic acid derivatives such as 18e and 18g would be a charge-charge interaction between the anionic carboxylate residues of the compounds and the cationic proton-donor site in the receptor.

Phosphorus uptake by pigeon pea and its role in cropping systems of the Indian subcontinent.

Pigeon pea was shown to be more efficient at utilizing iron-bound phosphorus (Fe-P) than several other crop species. This ability is attributed to root exudates, in particular piscidic acid and its p-O-methyl derivative, which release phosphorus from Fe-P by chelating Fe(3+). Pigeon pea is normally intercropped with cereals under low-input conditions in the Indian subcontinent. Although pigeon pea can utilize the relatively insoluble Fe-P, intercropped cereals must rely on the more soluble calcium-bound phosphorus. This finding suggests that cultivation of pigeon pea increases total phosphorus availability in cropping systems with low available phosphorus.