Anti-cholinesterase hybrids as multi-target-directed ligands against Alzheimer’s disease (1998–2018)

Alzheimer’s disease (AD) is a genetically complex, progressive and irreversible neurodegenerative disorder of the brain which involves multiple associated etiological targets. The complex pathogenesis of AD gave rise to multi-target-directed ligands (MTDLs) principle to combat this dreaded disease. Within this approach, the design and synthesis of hybrids prevailed greatly because of their capability to simultaneously target the intertwined pathogenesis components of the disease. The hybrids include pharmacophoric hybridization of two or more established chemical scaffolds endowed with the desired pharmacological properties into a single moiety. In AD, the primary foundation of medication therapy and drug design strategies includes the inhibition of cholinesterase (ChE) enzymes. Hence the development of ChE inhibition based hybrids is the central choice of AD medicinal chemistry research. To illustrate the progress of ChE inhibition based hybrids and novel targets, we reviewed the medicinal chemistry and pharmacological properties of the multi-target molecules published since 1998-December 2018. We hope that this article will allow the readers to easily follow the evolution of this prominent medicinal chemistry approach to develop a more efficient inhibitor.     

A life cycle sustainability assessment (LCSA) of oxymethylene ether as a diesel additive produced from forest biomass

The International Journal of Life Cycle Assessment - Due to efforts to reduce dependence on limited fossil energy reserves and increasing GHG emissions related to fossil fuel extraction and use in...     

Metabolic coupling in the co-cultured fungal-yeast suite of Trametes ljubarskyi and Rhodotorula mucilaginosa leads to hypersecretion of laccase isozymes

Trametes ljubarskyi produces multiple laccase isozymes under various physicochemical conditions. During co-cultivation condition Rhodotorula mucilaginosa showed inter-specific interactions with T. ljubarskyi and hypersecretion of laccases; however, the underlying molecular mechanism is less-known. The analysis of proteomics data of co-cultivated cultures revealed the mechanism of metabolic coupling during fungal-yeast interactions. The results suggested high score GO terms related to stimulus-response, protein binding, membrane components, transport channels, oxidoreductases, and antioxidants. The SEM studies confirmed the cellular communication and their inter-specific interactions. This study allows us to deepen and refine our understanding of fungal-yeast symbiotic interaction; further, it also establishes a mutual relation by metabolic coupling for 10-fold higher laccase isozyme secretion (6532 U/ml). The purified laccase isozymes showed acidic pH optima (pH 3–4), higher thermo-stability (60 °C), and broad enzyme kinetics (K_m) values. Our study also provides an in-depth understanding of laccase isozymes and their potential to degrade synthetic dyes, which may help the fungi to survive in an adverse environment.     

Extracting kinetics from single-molecule force spectroscopy: nanopore unzipping of DNA hairpins

Single-molecule force experiments provide powerful new tools to explore biomolecular interactions. Here, we describe a systematic procedure for extracting kinetic information from force-spectroscopy experiments, and apply it to nanopore unzipping of individual DNA hairpins. Two types of measurements are considered: unzipping at constant voltage, and unzipping at constant voltage-ramp speeds. We perform a global maximum-likelihood analysis of the experimental data at low-to-intermediate ramp speeds. To validate the theoretical models, we compare their predictions with two independent sets of data, collected at high ramp speeds and at constant voltage, by using a quantitative relation between the two types of measurements. Microscopic approaches based on Kramers theory of diffusive barrier crossing allow us to estimate not only intrinsic rates and transition state locations, as in the widely used phenomenological approach based on Bell's formula, but also free energies of activation. The problem of extracting unique and accurate kinetic parameters of a molecular transition is discussed in light of the apparent success of the microscopic theories in reproducing the experimental data.     

Directed evolution of glucose oxidase from Aspergillus niger for ferrocenemethanol-mediated electron transfer

A directed evolution protocol was developed for glucose oxidase (GOx) from Aspergillus niger that mimics applications conditions and employs a well-known mediator, oxidized ferrocenemethanol, in a medium throughput screen (96-well plate format). Upon reduction, oxidized ferrocenemethanol shows a color change from blue to pale yellow that can be recorded at 625 nm. Under optimized screening conditions, a CV of less than 20% was achieved in 96-well microtiter plates. For validating the screening system, two mutant libraries of GOx were generated by standard error-prone PCR conditions (0.04 mM MnCl(2)) and Saccharomyces cerevisiae was employed as host for secreted GOx expression. Two screening of approximately 2000 GOx mutants yielded a double mutant (T30S I94V) with improved pH and thermal resistance. Thermal resistance at a residual activity of 50% was increased from 58 degrees C (wild type, WT) to 62 degrees C (T30S I94V) and pH stability was improved at basic pH (pH 8-11). K(m) for glucose remained nearly unchanged (20.8 mM WT; 21.3 mM T30S I94V) and k(cat) increased (69.5/s WT; 137.7/s T30S I94V).     

Anthropometry and body composition in soccer and volleyball players in West Bengal, India

50 sedentary males and 128 sports persons (volleyball=82, soccer=46) of 20-24 years were selected from West Bengal, India, to evaluate and compare their anthropometry and body composition. Skinfolds, girth measurements, body fat percentage (%fat), and endomorphy were significantly higher among sedentary individuals, but lean body mass (LBM) and mesomorphy were significantly (p<0.001) higher among the sports persons. Soccer and volleyball players were found to be ectomorphic mesomorph, whereas sedentary subjects were endomorphic mesomorph. The soccer and volleyball players had higher %fat with lower body height and body mass than their overseas counterparts. %fat exhibited a significant correlation with body mass index (BMI) and thus prediction equations for %fat from BMI were computed in each group. The present data will serve as a reference standard for the anthropometry and body composition of Indian soccer and volleyball players and the prediction norms for %fat will help to provide a first-hand impression of body composition in the studied population.     

Effects of a reimbursement incentive on enrollment in a weight control program

Objective: The objective was to examine the effect of offering a reimbursement incentive on the percentage of inquirers who enrolled in a weight control program and on weight loss and program attendance among enrollees. Research Methods and Procedures: We used a sequential control‐intervention design to observe how inquirers of the University of Alabama at Birmingham EatRight Lifestyle Program responded to an enrollment incentive for potential 50% ($150) reimbursement of the total program fee if they attended 10 of 12 classes and lost at least 6% of their current body weight. Inquirers had to be adults with a BMI ≥30 kg/m², seeking information about a weight control program, and informed of the program cost. Outcomes included proportion of inquirers enrolled, overall number of classes attended, and weight loss. Results: Of the 401 people who inquired during the study periods, 24.5% and 25.0% enrolled in the intervention and control periods, respectively. There was a trend toward higher attendance in the intervention group, compared with the control group; there were no differences in percentage of weight loss. The odds of attending ≥10 classes were 2.4 times as high, and both losing >6% body weight and attending ≥10 classes were three times as high in the intervention subjects compared with controls, although non‐significant. Discussion: The potential of earning a performance‐based reimbursement incentive did not affect enrollment in the EatRight Lifestyle Program. Performance‐based incentives may be an ideal mechanism for extending coverage of weight‐loss interventions by insurers because of limited financial risk and improved adherence.     

Continuous delivery of IFN-beta promotes sustained maturation of intratumoral vasculature

IFNs have pleiotropic antitumor mechanisms of action. The purpose of this study was to further investigate the effects of IFN-beta on the vasculature of human xenografts in immunodeficient mice. We found that continuous, systemic IFN-beta delivery, established with liver-targeted adeno-associated virus vectors, led to sustained morphologic and functional changes of the tumor vasculature that were consistent with vessel maturation. These changes included increased smooth muscle cell coverage of tumor vessels, improved intratumoral blood flow, and decreased vessel permeability, tumor interstitial pressure, and intratumoral hypoxia. Although these changes in the tumor vasculature resulted in more efficient tumor perfusion, further tumor growth was restricted, as the mature vasculature seemed to be unable to expand to support further tumor growth. In addition, maturation of the intratumoral vasculature resulted in increased intratumoral penetration of systemically administered chemotherapy. Finally, molecular analysis revealed increased expression by treated tumors of angiopoietin-1, a cytokine known to promote vessel stabilization. Induction of angiopoietin-1 expression in response to IFN-beta was broadly observed in different tumor lines but not in those with defects in IFN signaling. In addition, IFN-beta-mediated vascular changes were prevented when angiopoietin signaling was blocked with a decoy receptor. Thus, we have identified an alternative approach for achieving sustained vascular remodeling-continuous delivery of IFN-beta. In addition to restricting tumor growth by inhibiting further angiogenesis, maturation of the tumor vasculature also improved the efficiency of delivery of adjuvant therapy. These results have significant implications for the planning of combination anticancer therapy.