Current Pharmaceutical Biotechnology - Volume 15, Issue 11, 2014

Proteins in the cell experience various stressful conditions that can affect their ability to attain and maintain the structural conformations they need to perform effectively. Protein chaperones are an important part of a cellular protein quality control system that protects the integrity of the proteome in the face of such challenges. Chaperones from different conserved families have multiple members that cooperate to regulate each other’s activity and produce machines that perform a variety of tasks. The large numbers of related chaperones with both functionally overlapping and distinct activities allows fine-tuning of the machinery for specific tasks, but presents a daunting degree of complexity. Yeast prions are misfolded forms of cellular proteins whose propagation depends on the action of protein chaperones. Studying how propagation of yeast prions is affected by alterations in functions of various chaperones provides an approach to understanding this complexity.

Presenilin (PS) was identified in screens for mutations causing the early onset forms of familial Alzheimer's disease (FAD) in 1995. As catalytic units of the γ-secretase complex, presenilins participate in the processing of amyloid beta protein (Aβ), the main component of deposits in brain of patients with AD. The more than 90 substrates of γ-secretase isolated so far demonstrate its contribution to wide range of cellular processes and signaling events. However, recent findings have revealed numerous γ-secretase-independent presenilin functions, including involvement in calcium homeostasis, endoplasmic reticulum (ER) stress and autophagy. This mini-review attempts to summarize the multiple physiological and pathological functions of presenilin.

Prion diseases which are serious neurodegenerative diseases that affect humans and animals occur in various of species. Unlike many other neurodegenerative diseases affected by amyloid, prion diseases can be highly infectious. Prion diseases occur in many species. In humans, prion diseases include the fatal human neurodegenerative diseases such as Creutzfeldt-Jakob Disease (CJD), Fatal Familial Insomnia (FFI), Gerstmann-Strussler-Scheinker syndrome (GSS) and Kuru etc. In animals, prion diseases are related to the bovine spongiform encephalopathy (BSE or ‘mad-cow’ disease) in cattle, the chronic wasting disease (CWD) found in deer and elk, and scrapie seen in sheep and goats, etc. More seriously, the fact that transmission of the prion diseases across the species barrier to other species such as humans has caused a major public health concern worldwide. For example, the BSE in Europe, the CWD in North America, and variant CJDs (vCJDs) in young people of UK. Fortunately, it is discovered that the hydrophobic region of prion proteins (PrP) controls the formation of diseased prions (PrPSc), which provide some clues in control of such diseases. This article provides a detailed survey of recent studies with respect to the PrP hydrophobic region of human PrP(110–136) using molecular dynamics studies.

Prion diseases are progressive neurodegenerative diseases that are associated with conformational changes that convert normal cellular prion protein (PrPC) into an abnormal pathogenic prion protein (PrPSc). It is widely recognized that prion diseases are forms of transmissible amyloidosis and are considered to be protein-misfolding diseases (conformational diseases), a category that also includes Alzheimer’s disease. Trace elements play crucial roles in the conformational change affecting PrPC, and increasing evidence suggests that PrPC is a metal-binding protein that is involved in the homeostasis of Cu, Zn, and Fe. In this article, we review the current understanding of links between trace elements and the conformational change to PrPSc, based on our studies using synthetic prion peptides, as well as other new findings. We also focus on PrPSc-induced disruption of Ca homeostasis as a molecular mechanism for neurodegeneration in prion diseases. Possible roles of carnosine (ß-alanyl histidine) as a candidate neuroprotective substance use in prion diseases are also discussed.

Recently the prevalence of obesity has increased dramatically across much of the world. Obesity, as a complex, multifactorial disease, and its health consequences probably result from the interplay of environmental, genetic, and behavioral factors. Several lines of evidence support the theory that obesity is programmed during early development and that environmental exposures can play a key role. We therefore hypothesize that the current epidemic might associated with the influence of chemical exposures upon genetically controlled developmental pathways, leading to metabolic disorders. Some environmental chemicals, such as PCBs and pesticide residues, are widespread in food, drinking water, soil, and they exert multiple effects including estrogenic on cellular processes; some have been shown to affect the development of obesity, insulin resistance, type 2 diabetes, and metabolic syndrome. To bring these lines of evidence together and address an important health problem, this narrative review has been primarily designed to address PCBs exposures that have linked with human disease, obesity in particular, and to assess the effects of PCBs on gene expression in a highlyexposed population. The results strongly suggest that further research into the specific mechanisms of PCBs-associated diseases is warranted.

Neoflavonoids comprise a group of natural compounds with varied chemical structures and promising pharmacological properties, including antioxidant capacity. This work describes an evaluation of the in vitro antioxidant capacity of a new coumarin derivative, i.e., 7-acetoxy-4-aryl-3,4-dihydrocoumarin, in terms of its ability to quench the 2,2- diphenyl-1-picrylhydrazyl (DPPH•), 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS•+), hydroxyl (OH•) and superoxide anion (O2•-) radicals, as well as its capacity to initiate electron transfer by reducing potential and inhibit lipid peroxidation by TBARS (thiobarbituric acid reactive substances) method. In addition, the antioxidant capacity of 7-acetoxy-4-aryl-3,4-dihydrocoumarin was evaluated against oxidative damage induced by hydrogen peroxide in erythrocyte suspensions and S. cerevisiae strains. In all methodologies investigated, high antioxidant capacities above 65% were demonstrated by 7-acetoxy-4-aryl-3,4-dihydrocoumarin against the DPPH•, ABTS•+, OH• and O2•- radicals. The ability of 7-acetoxy-4-aryl-3,4-dihydrocoumarin to inhibit oxidative damage induced by hydrogen peroxide in erythrocytes and S. cerevisiae strains demonstrates the importance of this compound in the protection against oxidative stress at the cellular level. Thus, the results obtained in this study suggest that 7-acetoxy-4-aryl-3,4-dihydrocoumarin can assist the development of new antioxidant products for possible use in the prevention or reduction of diseases related to oxidative stress.

Oridonin, an ent-kaurane diterpenoid mainly extracted from Chinese medical plant Rabdosia rubescens and some related species, has been reported its remarkable antitumor efficacy in various cancer cells. This review will be focused on the underlying molecular mechanisms for the treatments of oridonin in hematological malignancies, which include the regulation of oncoproteins (AML1-ETO, NPM1 mutants, PML-RARα, ABL kinase), accumulation of ROS, modulation of MAPKs and PI3K/Akt signaling pathways, and changes of abnormal expressions of MicroRNAs. And we get the conclusion that oridonin is a promising natural product with multiple targets against hematological malignancies.