Effect of environmental factors on the relationship between concentrations of coprostanol and fecal indicator bacteria in tropical (Mekong Delta) and temperate (Tokyo) freshwaters

A reliable assessment of microbial indicators of fecal pollution (total coliform, Escherichia coli, and fecal streptococcus) is critical in tropical environments. Therefore, we investigated the relationship between concentrations of indicator bacteria and a chemical indicator, coprostanol (5beta-cholestan-3beta-ol), in tropical and temperate regions. Water samples were collected from the Mekong Delta, Vietnam, during wet and dry seasons, and from Tokyo, Japan, during summer, the aftermath of a typhoon, and winter. During the wet season in the Mekong Delta, higher bacterial densities were observed in rivers, probably due to the higher bacterial inputs from soil particles with runoff. In Tokyo, higher bacterial densities were usually observed during summer, followed by those in the typhoon aftermath and winter. A strong logarithmic correlation between the concentrations of E. coli and coprostanol was demonstrated in all surveys. Distinctive seasonal fluctuations were observed, as concentrations of coprostanol corresponding to 1,000 CFU of E. coli/100 ml were at their lowest during the wet season in the Mekong Delta and the typhoon aftermath in Tokyo (30 ng/liter), followed by the dry season in the Mekong Delta and the summer in Tokyo (100 ng/liter), and they were much higher during the winter in Tokyo (400 ng/liter). These results suggested that E. coli is a specific indicator of fecal contamination in both tropical and temperate regions but that the densities are affected by elevated water temperature and input from runoff of soil particles. The concurrent determination of E. coli and coprostanol concentrations could provide a possible approach to assessing the reliability of fecal pollution monitoring data.     

Suprafenacine,an Indazole-Hydrazide Agent,Targets Cancer Cells Through Microtubule Destabilization

Microtubules are a highly validated target in cancer therapy. However, the clinical development of tubulin binding agents (TBA) has been hampered by toxicity and chemoresistance issues and has necessitated the search for new TBAs. Here, we report the identification of a novel cell permeable, tubulin-destabilizing molecule - 4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid [1p-tolyl-meth-(E)-ylidene]-hydrazide (termed as Suprafenacine, SRF). SRF, identified by in silico screening of annotated chemical libraries, was shown to bind microtubules at the colchicine-binding site and inhibit polymerization. This led to G₂/M cell cycle arrest and cell death via a mitochondria-mediated apoptotic pathway. Cell death was preceded by loss of mitochondrial membrane potential, JNK - mediated phosphorylation of Bcl-2 and Bad, and activation of caspase-3. Intriguingly, SRF was found to selectively inhibit cancer cell proliferation and was effective against drug-resistant cancer cells by virtue of its ability to bypass the multidrug resistance transporter P-glycoprotein. Taken together, our results suggest that SRF has potential as a chemotherapeutic agent for cancer treatment and provides an alternate scaffold for the development of improved anti-cancer agents.     

Potent inhibitors of farnesyltransferase and geranylgeranyltransferase-I

Compound 1 has been shown to be a dual prenylation inhibitor with FPTase (IC50=2 nM) and GGPTase-I (IC50=95 nM). Analogues of 1, which replaced the cyanophenyl group with various biaryls, led to the discovery of highly potent dual FPTase/GGPTase-I inhibitors. 4-trifluoromethylphenyl, trifluoropentynyl, and trifluoropentyl were identified as good p-cyano replacements.     

Pyrrolopyrimidine inhibitors of DNA gyrase B (GyrB) and topoisomerase IV (ParE). Part I: Structure guided discovery and optimization of dual targeting agents with potent,broad-spectrum enzymatic activity

The bacterial topoisomerases DNA gyrase (GyrB) and topoisomerase IV (ParE) are essential enzymes that control the topological state of DNA during replication. The high degree of conservation in the ATP-binding pockets of these enzymes make them appealing targets for broad-spectrum inhibitor development. A pyrrolopyrimidine scaffold was identified from a pharmacophore-based fragment screen with optimization potential. Structural characterization of inhibitor complexes conducted using selected GyrB/ParE orthologs aided in the identification of important steric, dynamic and compositional differences in the ATP-binding pockets of the targets, enabling the design of highly potent pyrrolopyrimidine inhibitors with broad enzymatic spectrum and dual targeting activity.     

Novel 3-O-carbamoyl erythromycin A derivatives (carbamolides) with activity against resistant staphylococcal and streptococcal isolates

A novel series of 3-O-carbamoyl erythromycin A derived analogs, labeled carbamolides, with activity versus resistant bacterial isolates of staphylococci (including macrolide and oxazolidinone resistant strains) and streptococci are reported. An (R)-2-aryl substituent on a pyrrolidine carbamate appeared to be critical for achieving potency against resistant strains. Crystal structures showed a distinct aromatic interaction between the (R)-2-aryl (3-pyridyl for 4d) substituent on the pyrrolidine and G2484 (G2505, Escherichia coli) of the Deinococcus radiodurans 50S ribosome (3.2 Å resolution).     

Lipid-Based Nanocarriers via Nose-to-Brain Pathway for Central Nervous System Disorders

Neurochemical Research - Neurodegenerative disorders are distinguished by the gradual deterioration of the nervous system’s structure and function due to oxidative stress, mitochondrial...     

Classification of hybrid and altered Vibrio cholerae strains by CTX prophage and RS1 element structure

Analysis of the CTX prophage and RS1 element in hybrid and altered Vibrio cholera O1 strains showed two classifiable groups. Group I strains contain a tandem repeat of classical CTX prophage on the small chromosome. Strains in this group either contain no element(s) or an additional CTX prophage or RS1 element(s) on the large chromosome. Group II strains harbor RS1 and CTX prophage, which has an E1 Tor type rstR and classical ctxB on the large chromosome.