MOLECULAR DOCKING STUDIES OF BERBERINE DERIVATIVE AS NOVEL MULTITARGET PCSK9 AND HMGCR INHIBITORS

Hypercholesterolemia is a high risk for cardiovascular diseases, stroke, and mortality. Multitarget directed ligands (MTDLs) with dual inhibition of Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) and 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) are the potential targets for the treatment of hyperlipidemia. In this work, a novel series of Berberine (BBR) derivatives was designed based on molecular docking to serve as MTDLs for PCSK9 and HMGCR. The binding energy of BBR derivatives was investigated, which confirmed that all the designed compounds showed better binding energy than the parent BBR for both enzymes. The effect of different benzenesulfonyl ring substituents was explored to improve the binding affinity. The obtained results indicated that there are significant differences in their interactions and mode of binding. All 24 designed compounds were identified as the potent multitarget inhibitors because the increase of hydrogen bond, hydrophobic and electrostatic interactions were observed. Among them, 12 could be selected as the best candidate for further study as potential multitarget PCSK9 and HMGCR inhibitors for anti-hypercholesterolemia. The obtained result suggested that the introduction of the nitro- group plays a vital role in the binding pose of the BBR derivative. Finally, in silico study confirmed that most of the compounds pass the drug likeliness properties

Additive effects on cotton dyeing with dye extract from achiote seeds

Cotton yarns have been pretreated with the additives, such as chitosan, microcrystalline chitosan, quaternized chitosan &aqueous extract from the fruit of Diospyros mollis Griff, as well as with the commercial formaldehyde-free cationic fixingagent (Sera® Fast C-NC) & alum (post-mordanting), and their dyeing fastness properties are studied. These treated cottonyarns are then dyed with the annatto dye extract from Bixa orellana L. (Achiote) seeds and tested for different propertiesincluding K/S value, light fastness, and wash fastness. Pre-treatment of cotton yarn with chitosan or microcrystallinechitosan solution (together with glyoxal cross-linking) or quaternized chitosan, or Sera® Fast C-NC before dyeing, shows abetter color depth (K/S) and improved wash fastness properties in comparison to yarn with alum post-mordanting and theuntreated cotton yarn. Improved light fastness is also obtained on inclusion of the anti-oxidant ascorbic acid in the posttreatmentprotocol. These additive treatments thus offer considerable potential for the improved annatto dyeing of cotton

Additive effects on cotton dyeing with dye extract from achiote seeds

466-474Cotton yarns have been pretreated with the additives, such as chitosan, microcrystalline chitosan, quaternized chitosan & aqueous extract from the fruit of Diospyros mollis Griff, as well as with the commercial formaldehyde-free cationic fixing agent (Sera® Fast C-NC) & alum (post-mordanting), and their dyeing fastness properties are studied. These treated cotton yarns are then dyed with the annatto dye extract from Bixa orellana L. (Achiote) seeds and tested for different properties including K/S value, light fastness, and wash fastness. Pre-treatment of cotton yarn with chitosan or microcrystalline chitosan solution (together with glyoxal cross-linking) or quaternized chitosan, or Sera® Fast C-NC before dyeing, shows a better color depth (K/S) and improved wash fastness properties in comparison to yarn with alum post-mordanting and the untreated cotton yarn. Improved light fastness is also obtained on inclusion of the anti-oxidant ascorbic acid in the post-treatment protocol. These additive treatments thus offer considerable potential for the improved annatto dyeing of cotton

A Potential of Mutant Yeast Strain for Improvement Arabica Coffee Fermentation Process

Arabica coffee is a worldwide popular beverage. Coffee fermentation is important process to enhance the coffee flavor quality. Microorganisms involved in the process are the main factor affecting coffee quality. This study aims to apply the new starter culture of Wickerhamomyces anomalus UV22-3, a UV mutant strain, for coffee fermentation and to improve arabica coffee beverage quality. The results showed that W. anomalus UV22-3 as a starter culture for coffee fermentation could enhance the coffee flavor quality compared to the control experiment (without inoculum). Fermented arabica coffee by strain UV22-3 showed a higher cupping score than wild type and a control condition with unique cupping notes. According to the flavor profile evaluated by Q-graders, the result of this sensory evaluation is 82. Microbial population in the fermentation broth was evaluated. The total yeast number was stable, while the total bacteria was higher after 24 h of strain UV22-3 fermentation. The pH value slightly decreased when the total dissolved solid increased. This research is one alternative to improve the quality of coffee in Thailand by using a novel yeast strain

Chemical Profiling and in vitro Testing for PCSK9 Inhibition of Coffee Cascara Extract

Coffee cascara is a by-product generated from coffee processing. It has been discarded as an agricultural waste.  In order to reduce the environmental problems caused by coffee processing, this study aimed to investigate the effect of fresh coffee cascara extract (CCE) on the inhibition of PCSK9 which is an enzyme that can increase low-density plasma lipoprotein (LDL) cholesterol by destructing LDL receptor.  Moreover, the CCE chemical profile was identified by the thin-layer chromatography (TLC) technique together with diffusion-ordered NMR spectroscopy (DOSY). The chemical profile analysis results showed that trigonelline, caffeine, and chlorogenic acid were present in CCE, and its PCSK9 inhibitory activity screening showed that CCE at concentrations of 0.25 and 0.50 mg/mL reduced the amount of PCSK9 by 72 and 78%, respectively.  These results revealed that coffee cascara provides novel applications in the nutraceutical industry

A mechanism for the extension and unfolding of parallel telomeric G-quadruplexes by human telomerase at single-molecule resolution

30 pags., 10 figs., 1 tab.Telomeric G-quadruplexes (G4) were long believed to form a protective structure at telomeres, preventing their extension by the ribonucleoprotein telomerase. Contrary to this belief, we have previously demonstrated that parallel-stranded conformations of telomeric G4 can be extended by human and ciliate telomerase. However, a mechanistic understanding of the interaction of telomerase with structured DNA remained elusive. Here, we use single-molecule fluorescence resonance energy transfer (smFRET) microscopy and bulk-phase enzymology to propose a mechanism for the resolution and extension of parallel G4 by telomerase. Binding is initiated by the RNA template of telomerase interacting with the G-quadruplex; nucleotide addition then proceeds to the end of the RNA template. It is only through the large conformational change of translocation following synthesis that the G-quadruplex structure is completely unfolded to a linear product. Surprisingly, parallel G4 stabilization with either small molecule ligands or by chemical modification does not always inhibit G4 unfolding and extension by telomerase. These data reveal that telomerase is a parallel G-quadruplex resolvase.Cancer Council NSW RG 11-07 Tracy M Bryan, Cancer Institute NSW Aaron Lavel Moye, Australian Research Council FL140100027 Antoine M van Oijen, Ernest and Piroska Major Foundation Scott B Cohen, Natural Sciences and Engineering Research Council of Canada, Masad J Damha Centre of Excellence for Innovation in Chemistry PERCH-CIC Siritron Samosorn Research Unit of Natural Products and Organic Synthesis for Drug Discovery NPOS 405/2560 Siritron Samosorn Cancer Council NSW RG 16-10 Tracy M Brya

Development of berberine-based derivatives as novel antimicrobial agents

Multidrug resistance (MDR) mediated by a drug efflux mechanism is one of the major drug resistance problems not only in bacteria but also in other microorganisms. NorA MDR efflux protein is a well characterized and major efflux pump in the pathogenic Gram-positive bacterium, Staphylococcus aureus. It contributes to the resistance to berberine and ciprofloxacin antibiotics by extrusion of these drugs from the cells of S. aureus. In order to overcome this type of drug resistance by dual action agents incorporating efflux pump inhibitor properties and antibacterial activity, a variety of new, aryl group-substituted 2-aryl-5-nitro-1H-indole efflux pump inhibitors were synthesized. In the synthesis of these 2-aryl-5-nitro-1H-indoles, a new procedure for the N-acylation of indoles was developed based on DCC/DMAP coupling with carboxylic acids. This method was particularly effective with 5-nitro-1H-indole. The activity of these indole derivatives as inhibitors of the NorA MDR pump in S. aureus was assessed. It was found that some of the 2-aryl-5-nitro-1H-indole derivatives potentiated the activity of the antibacterial agents berberine and ciprofloxacin against the resistant strain, K2361, of S. aureus. The new 2-aryl-5-nitro-1H-indole inhibitors were particularly effective in potentiating the antibacterial activity of berberine. The compound [4-benzyloxy-2-(5-nitro-1H-2-yl)-phenyl]-methanol (43) was the most potent NorA pump inhibitor found in this work. A number of dual action antibacterial agents were designed and synthesized. These included dual action prodrugs, in which the MDR pump inhibitor and berberine were attached in the same molecule with enzymatically cleavable linkages (ester or amide groups), and dual action drugs with a non-cleavable linkage (methylene group). In the synthesis of the dual action agents, a direct new approach to 13-substituted berberine derivatives was found. This approach involved alkylation of 8-allyldihydroberberine followed by the elimination of propene. The antimicrobial activity of these indole-berberine compounds was assessed against a variety of pathogenic microorganisms. One of the dual action drugs, 9,10-dimethoxy-13-[2-(5-nitro-1H-indol-2-yl)benzyl]-5,6-dihydrobenzo[g]-1,3-benzodioxolo[5,6-a]quinolizinium bromide (64), was a potent antimicrobial agent at a clinically viable concentration against various bacteria in vitro, including Staphylococcus aureus K2361, Enterococcus faecalis V583, and Salmonella enterica Serovar Typhimurium SL1344R2. This compound also had good activity against the protozoan, Plasmodium falciparum K1 (in vitro). In the case of the dual action prodrugs, the amide prodrugs were more active than the ester prodrugs against the Gram-positive bacterium S. aureus and vice versa against the Gram-negative bacterium S. enterica Serovar Typhimurium. However, minimum inhibitory concentrations for all the dual action drugs and dual action prodrugs were near or at clinically useful concentrations (ca. 1��g/mL or less) as antibacterial agents against S. enterica Serovar Typhimurium SL1344R2, and they showed 400- to 1600-fold higher activity than the parent antibacterial agent berberine. The design principle of having in the one molecule an MDR inhibitor moiety and an antibacterial moiety was established as a viable one, which potentially could be extended to other types of antimicrobial agents