Evidence for the progression through S-phase in the ectopic cell cycle re-entry of neurons in Alzheimer disease

Aberrant neuronal re-entry into the cell cycle is emerging as a potential pathological mechanism in Alzheimer disease (AD). However, while cyclins, cyclin dependent kinases (CDKs), and other mitotic factors are ectopically expressed in neurons, many of these proteins are also involved in other pathological and physiological processes, generating continued debate on whether such markers are truly indicative of a bona fide cell cycle process. To address this issue, here we analyzed one of the minichromosome maintenance (Mcm) proteins that plays a role in DNA replication and becomes phosphorylated by the S-phase promoting CDKs and Cdc7 during DNA synthesis. We found phosphorylated Mcm2 (pMcm2) markedly associated with neurofibrillary tangles, neuropil threads, and dystrophic neurites in AD but not in aged-matched controls. These data not only provide further evidence for cell cycle aberrations in AD, but the cytoplasmic, rather than nuclear, localization of pMcm2 suggests an abnormal cellular distribution of this important replication factor in AD that may explain resultant cell cycle stasis and consequent neuronal degeneration

Glutathione “Redox Homeostasis” and Its Relation to Cardiovascular Disease

More people die from cardiovascular diseases (CVD) than from any other cause. Cardiovascular complications are thought to arise from enhanced levels of free radicals causing impaired “redox homeostasis,” which represents the interplay between oxidative stress (OS) and reductive stress (RS). In this review, we compile several experimental research findings that show sustained shifts towards OS will alter the homeostatic redox mechanism to cause cardiovascular complications, as well as findings that show a prolonged antioxidant state or RS can similarly lead to such cardiovascular complications. This experimental evidence is specifically focused on the role of glutathione, the most abundant antioxidant in the heart, in a redox homeostatic mechanism that has been shifted towards OS or RS. This may lead to impairment of cellular signaling mechanisms and elevated pools of proteotoxicity associated with cardiac dysfunction

DES-ncRNA: A knowledgebase for exploring information about human micro and long noncoding RNAs based on literature-mining

Noncoding RNAs (ncRNAs), particularly microRNAs (miRNAs) and long ncRNAs (lncRNAs), are important players in diseases and emerge as novel drug targets. Thus, unraveling the relationships between ncRNAs and other biomedical entities in cells are critical for better understanding ncRNA roles that may eventually help develop their use in medicine. To support ncRNA research and facilitate retrieval of relevant information regarding miRNAs and lncRNAs from the plethora of published ncRNA-related research, we developed DES-ncRNA (www.cbrc.kaust.edu.sa/des_ncrna). DES-ncRNA is a knowledgebase containing text- and data-mined information from public scientific literature and other public resources. Exploration of mined information is enabled through terms and pairs of terms from 19 topic-specific dictionaries including, for example, antibiotics, toxins, drugs, enzymes, mutations, pathways, human genes and proteins, drug indications and side effects, mutations, diseases, etc. DES-ncRNA contains approximately 878,000 associations of terms from these dictionaries of which 36,222 (5,373) are with regards to miRNAs (lncRNAs). We provide several ways to explore information regarding ncRNAs to users including controlled generation of association networks as well as hypotheses generation. We show an example how DES-ncRNA can aid research on Alzheimer disease and suggest potential therapeutic role for Fasudil. DES-ncRNA is a powerful tool that can be used on its own or as a complement to the existing resources, to support research in human ncRNA. To our knowledge, this is the only knowledgebase dedicated to human miRNAs and lncRNAs derived primarily through literature-mining enabling exploration of a broad spectrum of associated biomedical entities, not paralleled by any other resource

DES-Amyloidoses “Amyloidoses through the looking-glass”: A knowledgebase developed for exploring and linking information related to human amyloid-related diseases

More than 30 types of amyloids are linked to close to 50 diseases in humans, the most prominent being Alzheimer’s disease (AD). AD is brain-related local amyloidosis, while another amyloidosis, such as AA amyloidosis, tends to be more systemic. Therefore, we need to know more about the biological entities’ influencing these amyloidosis processes. However, there is currently no support system developed specifically to handle this extraordinarily complex and demanding task. To acquire a systematic view of amyloidosis and how this may be relevant to the brain and other organs, we needed a means to explore "amyloid network systems" that may underly processes that leads to an amyloid-related disease. In this regard, we developed the DES-Amyloidoses knowledgebase (KB) to obtain fast and relevant information regarding the biological network related to amyloid proteins/peptides and amyloid-related diseases. This KB contains information obtained through text and data mining of available scientific literature and other public repositories. The information compiled into the DES-Amyloidoses system based on 19 topic-specific dictionaries resulted in 796,409 associations between terms from these dictionaries. Users can explore this information through various options, including enriched concepts, enriched pairs, and semantic similarity. We show the usefulness of the KB using an example focused on inflammasome-amyloid associations. To our knowledge, this is the only KB dedicated to human amyloid-related diseases derived primarily through literature text mining and complemented by data mining that provides a novel way of exploring information relevant to amyloidoses

DES-ROD: Exploring Literature to Develop New Links between RNA Oxidation and Human Diseases

Normal cellular physiology and biochemical processes require undamaged RNA molecules. However, RNAs are frequently subjected to oxidative damage. Overproduction of reactive oxygen species (ROS) leads to RNA oxidation and disturbs redox (oxidation-reduction reaction) homeostasis. When oxidation damage affects RNA carrying protein-coding information, this may result in the synthesis of aberrant proteins as well as a lower efficiency of translation. Both of these, as well as imbalanced redox homeostasis, may lead to numerous human diseases. The number of studies on the effects of RNA oxidative damage in mammals is increasing by year due to the understanding that this oxidation fundamentally leads to numerous human diseases. To enable researchers in this field to explore information relevant to RNA oxidation and effects on human diseases, we developed DES-ROD, an online knowledgebase that contains processed information from 298,603 relevant documents that consist of PubMed abstracts and PubMed Central full-text articles. The system utilizes concepts/terms from 38 curated thematic dictionaries mapped to the analyzed documents. Researchers can explore enriched concepts, as well as enriched pairs of putatively associated concepts. In this way, one can explore mutual relationships between any combinations of two concepts from used dictionaries. Dictionaries cover a wide range of biomedical topics, such as human genes and proteins, pathways, Gene Ontology categories, mutations, noncoding RNAs, enzymes, toxins, metabolites, and diseases. This makes insights into different facets of the effects of RNA oxidation and the control of this process possible. The usefulness of the DES-ROD system is demonstrated by case studies on some known information, as well as potentially novel information involving RNA oxidation and diseases. DES-ROD is the first knowledgebase based on text and data mining that focused on the exploration of RNA oxidation and human diseases

Evidence for the progression through s-phase in the ectopic cell cycle re-entry of neurons in alzheimer disease

Aberrant neuronal re-entry into the cell cycle is emerging as a potential pathological mechanism in Alzheimer disease (AD). However, while cyclins, cyclin dependent kinases (CDKs), and other mitotic factors are ectopically expressed in neurons, many of these proteins are also involved in other pathological and physiological processes, generating continued debate on whether such markers are truly indicative of a bona fide cell cycle process. To address this issue, here we analyzed one of the minichromosome maintenance (Mcm) proteins that plays a role in DNA replication and becomes phosphorylated by the S-phase promoting CDKs and Cdc7 during DNA synthesis. We found phosphorylated Mcm2 (pMcm2) markedly associated with neurofibrillary tangles, neuropil threads, and dystrophic neurites in AD but not in aged-matched controls. These data not only provide further evidence for cell cycle aberrations in AD, but the cytoplasmic, rather than nuclear, localization of pMcm2 suggests an abnormal cellular distribution of this important replication factor in AD that may explain resultant cell cycle stasis and consequent neuronal degeneration