Expanding therapeutic opportunities for neurodegenerative diseases: A perspective on the important role of phenotypic screening

Over the last 20 years, there have been remarkably few FDA-approved first-in-class drugs for neurodegenerative diseases. Debilitating conditions such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis have no effective disease-modifying therapeutics on the market, signifying an area of high unmet medical need where novel approaches are needed. Using a phenotypic screening approach, two separate groups discovered small molecule non-antisense oligonucleotide splice modulators for spinal muscular atrophy, a severe monogenetic disease that causes the degeneration of alpha motor neurons in the spinal cord. These compounds function by a novel mechanism: selective stabilization of the interaction of U1 small nuclear ribonucleic protein (snRNP), a core component of the spliceosome, with the 5′ splice site of a pre-mRNA. The ability of the phenotypic screening approach to uncover a previously unknown mechanism and reveal a new druggable target class has broader implications for other neurodegenerative diseases.     

Nrf2—a therapeutic target for the treatment of neurodegenerative diseases

The brain is very sensitive to changes in redox status; thus maintaining redox homeostasis in the brain is critical for the prevention of accumulating oxidative damage. Aging is the primary risk factor for developing neurodegenerative diseases. In addition to age, genetic and environmental risk factors have also been associated with disease development. The primary reactive insults associated with the aging process are a result of oxidative stress (OS) and nitrosative stress (NS). Markers of increased oxidative stress, protein and DNA modification, inflammation, and dysfunctional proteostasis have all been implicated in contributing to the progression of neurodegeneration. The ability of the cell to combat OS/NS and maintain a clearance mechanism for misfolded aggregating proteins determines whether or not it will survive. A critical pathway in this regard is the Nrf2 (nuclear factor erythroid 2-related factor 2)- antioxidant response element (ARE) pathway. Nrf2 activation has been shown to mitigate a number of pathologic mechanisms associated with Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, Huntington’s disease, and multiple sclerosis. This review will focus on the role of Nrf2 in these diseases and the potential for Nrf2 activation to attenuate disease progression.     

Place prioritization for biodiversity reserve network design: a comparison of the SITES and ResNet software packages for coverage and efficiency

Abstract. The place prioritization problem in conservation biology is that of establishing a sequentially prioritized list of places on the basis of biodiversity content. Such a list can then be used to select reserve networks that are designed to be fully representative of the biodiversity of an area as efficiently as possible (for instance, with minimum area or cost). The usual goal is the representation of all chosen biodiversity surrogates up to or beyond a required target, or to the greatest available extent. The purpose of this paper is to compare the respective performances of two place prioritization software packages, SITES and ResNet, on four datasets (distributions of termite genera in Namibia, breeding bird species in the Falkland Islands/Islas Malvinas, vertebrate species in Texas and flora and fauna species that are at risk in Québec), to determine their respective merits. The two software packages implement radically different algorithms: SITES is based on a simulated annealing procedure for finding (local) optima; ResNet uses an algorithm based on rarity and complementarity. This analysis indicates that the rarity‐complementarity based algorithm of ResNet surpasses the simulated annealing approach of SITES with respect to time and completeness. SITES, however, contains other features that are useful in conservation planning. Ways in which the two packages can be used together effectively are suggested.     

Relevance of protein nitration in brain injury: a key pathophysiological mechanism in neurodegenerative, autoimmune, or inflammatory CNS diseases and stroke

Summary. This review has focused on the evidence for the involvement of nitrative oxidation in certain neurodegenerative disorders (Parkinsons Disease, Alzheimers Disease, Amyotrophic Lateral Sclerosis), stroke, and inflammatory and autoimmune disorders (with particular attention devoted to multiple sclerosis).The relationship between protein peroxidation and pathological changes observed in the above disorders has been reported. Whereas many of the findings are from studies with animal models and autoptic specimens from human patients, few data are available from cerebrospinal fluid and blood samples of the patients at different times and disease stages.The participation of nitrative oxidation to the direct and indirect injury of neurons and other cells of the brain (i.e., oligodendrocytes, for multiple sclerosis) is clear; less evident is their relevance for the development and progression of these disorders.Further studies should be aimed to establish the clinical and prognostic value of peroxidative markers for the CNS diseases considered. This is fundamental for the development of therapeutic interventions antagonizing nitric oxide-related species damage.     

基于网络分析的生态建设评估指标体系定量选取——以福建省为例

科学有效的指标体系是开展区域生态建设评估以及规划、管理的重要技术手段。然而目前在生态指标体系构建中仍缺乏对指标内涵的系统研究,同时指标的选取过程不够透明,掺杂诸多主观臆断,损害了生态指标体系构建的科学性和有效性。针对福建省生态建设实践,将网络分析与量化指标选择过程相结合,(1)根据福建省生态建设规划和目标,建立主题导向的生态省建设评估网状指标体系;(2)从因果联系、生态过程和管理需求三方面分析各个备选指标之间的相互联系,形成基于主题导向的生态指标网络;(3)根据生态指标应用的科学性和实用性标准,基于网络分析原理,建立生态建设评估指标选择标准矩阵和备选指标矩阵;(4)构建面向经济社会成本和生态完整性的指标选取模型,定量化选取符合福建省实际发展特征的生态建设评估操作指标体系。将有助于深入理解生态建设评估指标体系的内涵,提高指标体系构建的科学性和系统性,提升生态指标体系在实际生态建设评估、规划和管理应用中的效用。     

Loss of 3-chlorotyrosine by inflammatory oxidants: implications for the use of 3-chlorotyrosine as a bio-marker in vivo

Activated neutrophils generate the potent oxidant hypochlorous acid (HOCl) from the enzyme myeloperoxidase (MPO). A proposed bio-marker for MPO-derived HOCl in vivo is 3-chlorotyrosine, elevated levels of which have been measured in several human inflammatory pathologies. However, it is unlikely that HOCl is produced as the sole oxidant at sites of chronic inflammation as other reactive species are also produced during the inflammatory response. The work presented shows that free and protein bound 3-chlorotyrosine is lost upon addition of the pro-inflammatory oxidants, HOCl, peroxynitrite, and acidified nitrite. Furthermore, incubation of 3-chlorotyrosine with activated RAW264.7 macrophages or neutrophil-like HL-60 cells resulted in significant loss of 3-chlorotyrosine. Therefore, at sites of chronic inflammation where there is concomitant ONOO⁻ and HOCl formation, it is possible measurement of 3-chlorotyrosine may represent an underestimate of the true extent of tyrosine chlorination. This finding could account for some of the discrepancies reported between 3-chlorotyrosine levels in tissues in the literature.