Asymmetric Total Synthesis of ent-Sandaracopimaradiene,a Biosynthetic Intermediate of Oryzalexins

An asymmetric total synthesis of ent-sandaracopimaradiene, a biosynthetic intermediate of oryzalexins, via B-alkyl Suzuki-Miyaura coupling and Lewis acid-mediated B-ring formation as key steps was achieved.     

Rutin as promising drug for the treatment of Parkinson’s disease: an assessment of MAO-B inhibitory potential by docking,molecular dynamics and DFT studies

ABSTRACT

Inhibitors of monoamine oxidase (MAO)-B have been used for many years in the therapy of Parkinson’s disease (PD). Owing to the safety concerns of the currently used agents, the discovery of novel scaffolds is of considerable interest. MAO-B inhibitory potential of rutin, a flavonoid derived from natural sources, has been established in experimental findings. Hence, the current study seeks to examine the interactions between rutin and crystal structure of human MAO-B enzyme. Molecular docking calculations, as well as molecular dynamics simulations, were employed to investigate the binding mode and the stability of the rutin/MAO-B complex. Energies of highest occupied/lowest unoccupied molecular orbitals were computed through DFT studies and used to calculate electron affinity, hardness, chemical potential, electronegativity, and electrophilicity index in order to investigate the capability of these parameters to influence the ligand–receptor interactions. It was found that rutin traverses both the entrance cavity and the substrate cavity, forcing the Ile-199 ‘gate’ to rotate into its open conformation. It results in the fusion of the two cavities of the MAO-B binding site and directly leads to better binding interactions. Results of the current study can be used for lead modification and development of novel drugs for the treatment of PD.     

The thiol proteinase inhibitor E-64-d ameliorates amyloid-β-induced reduction of sAPPα secretion by reversing ceramide-induced protein kinase C down-regulation in SH-SY5Y neuroblastoma cells

In Alzheimer’s disease (AD), enhancing α-secretase processing of amyloid precursor protein (APP) is an important pathway to decrease neurotoxic amyloid β (Aβ) secretion. The α-secretase is reported to be regulated by protein kinase C (PKC) and various endogenous proteins or cell surface receptors. In this report, we first examined whether Aβ reduces α-secretase activity, and showed that Aβ peptide 1–40 (0.001 and 0.01 μM) reduced the secretion of soluble amyloid precursor protein α (sAPPα) in carbachol-stimulated SH-SY5Y neuroblastoma cells. E-64-d (3 μM), which is a potent calpain inhibitor that prevents PKC degradation, ameliorated the Aβ-induced reduction of sAPPα secretion. In addition, we observed that Aβ significantly enhanced ceramide production by activating neutral sphingomyelinase. The cell-permeable ceramide analog, C₂-ceramide (1 μg/mL), also reduced sAPPα secretion, and in addition, E-64-d eliminated the observed decrease of sAPPα secretion. C₂-ceramide induced down-regulation of PKC-α, -β₁, and -β₂ isozymes in SH-SY5Y cells. These findings suggest that ceramide may play an important role in sAPPα processing by modulating PKC activity.     

Sortilin,a novel APOE receptor implicated in Alzheimer disease

In the brain, apolipoprotein E (APOE) delivers cholesterol-rich lipoproteins to neurons to support synaptogenesis and maintenance of synaptic connections. Three APOE alleles exist in the human population with ε4 being an Alzheimer disease (AD) risk gene and ε2 being protective relative to the common ε3 variant. Many hypotheses have been advanced concerning allele-specific effects of APOE on neurodegeneration including effects on Aβ clearance, synaptic transmission, or neurotoxicity. Central to most proposed APOE functions is its interaction with receptors that mediate cellular uptake of this ligand. Several members of the LDL receptor gene family have been implicated as APOE receptors in the (patho)physiology of APOE in the brain, yet their specific modes of action in AD remain controversial. Recently, the pro-neurotrophin receptor sortilin has been identified as a novel APOE receptor in neurons. Ablation of sortilin expression in mice results in accumulation of APOE and Aβ in the brain. Moreover, primary neurons lacking sortilin exhibit significantly impaired uptake of APOE/Aβ complexes. Despite increased brain APOE levels, sortilin-deficient animals recapitulate anomalies in brain lipid homeostasis seen in APOE null mice, indicating functional deficiency in APOE uptake pathways. Taken together, these findings suggest a link between Aβ catabolism and pro-neurotrophin signaling converging on this receptor pathway.     

In utero Measurement of Heart Rate in Mouse by Noninvasive M-mode Echocardiography

Congenital heart disease (CHD) is the most frequent noninfectious cause of death at birth. The incidence of CHD ranges from 4 to 50/1,000 births (Disease and injury regional estimates, World Health Organization, 2004). Surgeries that often compromise the quality of life are required to correct heart defects, reminding us of the importance of finding the causes of CHD. Mutant mouse models and live imaging technology have become essential tools to study the etiology of this disease. Although advanced methods allow live imaging of abnormal hearts in embryos, the physiological and hemodynamic states of the latter are often compromised due to surgical and/or lengthy procedures. Noninvasive ultrasound imaging, however, can be used without surgically exposing the embryos, thereby maintaining their physiology. Herein, we use simple M-mode ultrasound to assess heart rates of embryos at E18.5 in utero. The detection of abnormal heart rates is indeed a good indicator of dysfunction of the heart and thus constitutes a first step in the identification of developmental defects that may lead to heart failure.     

Uric Acid: The Oxidant-Antioxidant Paradox

Uric acid, despite being a major antioxidant in the human plasma, both correlates and predicts development of obesity, hypertension, and cardiovascular disease, conditions associated with oxidative stress. While one explanation for this paradox could be that a rise in uric acid represents an attempted protective response by the host, we review the evidence that uric acid may function either as an antioxidant (primarily in plasma) or pro-oxidant (primarily within the cell). We suggest that it is the pro-oxidative effects of uric acid that occur in cardiovascular disease and may have a contributory role in the pathogenesis of these conditions.     

Polymorphisms in GSTT1 and p53 and urinary transitional cell carcinoma in south-western Taiwan: A preliminary study

Little is known about the relevance of genetic polymorphisms to arsenic-related bladder cancer. A preliminary case-control study was conducted to explore the association between genetic polymorphisms of GSTT1, p53 codon 72 and bladder cancer in southern Taiwan, a former high arsenic exposure area. Fifty-nine urinary transitional cell carcinoma (TCC) patients from a referral centre in south-western Taiwan and 81 community controls matched on residence were recruited from 1996 to 1999. A questionnaire was administered to obtain arsenic exposure and general health information. Genotypes of p53 codon 72 and GSTT1 were analysed by polymerase chain reaction-restriction fragment length polymerase. The combined variant genotypes (heterozygous or homozygous variant) of p53 codon 72 and GSTT1 null were observed in 29% of cases and in 44% of controls, respectively. In this preliminary study, bladder cancer risk was slightly elevated for subjects carrying the variant genotype of p53 codon 72 or in subjects carrying the GSTT1 null genotype. Variants in p53 codon 72 increased the risk of bladder cancer among smokers. However, the results were not statistically significant and larger confirmatory studies are needed to clarify the role of candidate gene polymorphisms and bladder cancer risk in arsenic exposed populations.     

Inhibition of Ache: Structure-Activity Relationship Among Conformational Transition of Trp84 and Bimolecular Rate Constant

Abstract

In this study the authors attempt to correlate kinetic constants for carbamylation of AChE, by a series of carbamate inhibitors, with the conformational positioning of Trp84 in transition state complexes of the same carbamates with Torpedo AChE, as obtained by computerized molecular modelling. They present evidence for changes in the distance of the carbamates from the center of the indole ring which can be correlated with the bimolecular rate constants for inhibition. As a result the greater the distance from Trp84, the smaller the bimolecular inhibition constant value, k₁ (= k₂/K_a), becomes. In conclusion, the value of the biinolecular rate constant for selected AChE inhibitors (structural changes that have been hypothesised or natural alkaloids of unknown activity) which possess similar size and rigidity, can be obtained. Under these conditions energy minimization alone seems to be sufficient even to accurately predict protein-substrate interactions that actually occur. Modelling studies also suggest that conformational re-orientation of Trp84 in the transition state could produce an overall movement of the Cys67-Cys94 loop.