Unravelling the Untapped Pharmacological Potential of Plant Molecules as Inhibitors of BACE1: In Silico Explorations for Alzheimer's Disease.

Alzheimer's disease (AD) is an extremely complex, heterogeneous, and multifactorial neurodegenerative disease clinically characterized by progressive memory loss and progressive decline in cognitive function. There is currently no effective treatment for the onset and/or progression of the pathophysiological diseases of AD. The global prevalence of this disease has increased in recent years due to modern lifestyle. Therefore, there is an urgent need to develop a drug with significant neuroprotective potential. Since plant metabolites, especially polyphenols, have important pharmacological properties acting against ß-amyloid (Aß), Tau, neuroinflammation, and oxidative stress, such phytochemicals were selected in the present research. Using the Schrödinger tool (Maestro V.13.6), the drug potency of these metabolites was studied after installation in the highly configured workstation. Among the 120 polyphenols docked, amygdalin showed notable docking values of - 11.2638, followed by eriocitrin (- 10.9569), keracyanin (- 10.7086), and amaroswerin (- 9.48126). The prominent MM-GBSA values of these molecules were - 62.8829, - 52.1914, - 68.6307, and - 63.1074, respectively. The MM-GBSA energy values demonstrated the drug stability of these molecules for ß-site amyloid precursor protein-cleaving enzyme 1 (BACE1)-causing AD. In the absorption and distribution assessment, these phytochemicals showed significantly better values than the inhibitors CNP520. The chosen phytochemicals have been demonstrated as non-hepatotoxic; however, the BACE1 inhibitor CNP520 is hepatotoxic. In both the molecular docking and ADMET assessments, these natural chemicals have shown optimism as potential drug candidates for Alzheimer's disease. However, in order to understand the detailed biological metabolism of these compounds in AD, they need to be evaluated in in vivo studies to validate its efficacy.

Anti-biofilm investigation of graphene/chitosan nanocomposites against biofilm producing P. aeruginosa and K. pneumoniae.

In this study graphene/chitosan nanoparticles (GR/CS NCs) were developed. The homogenous combination of GR and CS was confirmed by FTIR spectroscopy. The combination of CS with GR sheets reduced the XRD intensity of the GR peak in GR/CS NCs, while TEM images revealed the immobile CS coating of GR sheets. Further, the anti-biofilm activity of GR/CS NCs was tested. The tests showed that the formation of biofilm by Pseudomonas aeruginosa and Klebsiella pneumoniae was inhibited at 40□g/mL GR/CS NCs up to 94 and 92 %, respectively. The intracellular and cell surface damage of the bacteria was observed by CLSM and SEM. Also, GR/CS NCs produced a toxic effect of 90 % on Artemia franciscana at 70□g/mL upon 24 h incubation. The recorded properties of the synthesized GR/CS NCs qualify them as potential agents against multi-drug resistant bacteria.

Genome analysis of a Bacillus subtilis strain reveals genetic mutations determining biocontrol properties.

Several Bacillus strains are used as biocontrol agents, as they frequently have strong antagonistic effects against microbial plant pathogens. Bacillus strain SZMC 6179J, isolated from tomato rhizosphere, was previously shown to have excellent in vitro antagonistic properties against the most important fungal pathogens of tomato (Alternaria solani, Botrytis cinerea, Phytophthora infestans and Sclerotinia sclerotiorum) as well as several Fusarium species. Taxonomic investigations revealed that it is a member of the B. subtilis subsp. subtilis group and very closely related with the reference type strain B. subtilis subsp. subtilis 168. The sequenced genome of strain SZMC 6179J contains the genes responsible for the synthesis of the extracellular antibiotics surfactin, fengycin and bacilysin. Compared to strain 168, a prophage-like region is missing from the genome of SZMC 6179J, while there are 106 single nucleotide polymorphisms and 23 deletion-insertion polymorphisms. The high biocontrol potential of strain SZMC 6179J may results from a single base deletion in the sfp gene encoding the transcription factor of the surfactin and fengycin operons. Hypermutated regions reflecting short-time evolutionary processes could be detected in SZMC 6179J. The deletion-insertion polymorphism in the sfp gene and the detected hypermutations can be suggested as genetic determinants of biocontrol features in B. subtilis.

Influence of agro-environmental pollutants on a biocontrol strain of Bacillus velezensis.

Metal- and pesticide-tolerant biocontrol agents are preferred in integrated pest management, as such strains can be applied in combination with different pesticides. The Bacillus velezensis strain SZMC 6161J proved to be sensitive to copper, nickel, zinc, and cadmium, while manganese elevated its growth. At concentrations higher than 1 mmol L-1 , zinc and iron inhibited the chymotrypsin-like activity of this strain. In addition, trypsin-like protease and palmitoyl esterase activities were insensitive to all tested heavy metals in the applied concentration range. We studied the effects of some widely used herbicides and fungicides on the growth of this strain. The presence of sulfonylurea herbicides, like bensulfuron-methyl, cinosulfuron, chlorsulfuron, ethoxysulfuron, triasulfuron, and primisulfuron-methyl strongly inhibited the biomass production of the strain even at the concentration of 6.25 mg L-1 . Glyphosate also inhibited the growth above 30 mg L-1 . Similarly, contact fungicides like captan, maneb, mancozeb, and thiram resulted in total inhibition at the concentration as low as 6.25 mg L-1 . Interestingly, the sterol-biosynthesis-inhibiting fungicides imazalil, fenarimol, penconazole, and tebuconazole also proved to be potent inhibitors. Heavy metal- and fungicide-tolerant strains were isolated from the parental strain and their antagonistic abilities were evaluated. There was no substantial difference between the antagonism capability of wild-type strain and the resistant mutants.

High-Frequency Occurrence of Surfactin Monomethyl Isoforms in the Ferment Broth of a Bacillus subtilis Strain Revealed by Ion Trap Mass Spectrometry.

Surfactins are cyclic lipopeptides consisting of a ß-hydroxy fatty acid of various chain length and a peptide ring of seven amino acids linked together by a lactone bridge, forming the cyclic structure of the peptide chain. These compounds are produced mainly by Bacillus species and possess numerous biological effects such as antimicrobial (antiviral, antibacterial, and antifungal) activities. A mixture of surfactins extracted from Bacillus subtilis strain SZMC 6179J was examined by HPLC-ESI-IT-MS technique, enhancing their separation to reveal novel lipopeptide varieties with higher masses and to characterize their structures. During the MS² spectra analyses of their sodiated molecular ions [M + Na]⁺, a previously rarely encountered group of surfactins was detected and two novel types of the group were discovered containing methyl esterified aspartic acid residue in their fifth amino acid position. The relative amounts of these monomethyl isoforms exceeded 35% of the produced surfactin in total. In the m/z value of 1114, all the detected isoforms possessed aspartic acid 4-methyl ester residue in their fifth amino acid position (C17-[Lxx4, AME5], C18-[AME5]), offering an opportunity to separate a pure fraction of the compound and to study its biological activities in the future.