The multi-target effects of CNI-1493: convergence of anti-amylodogenic and anti-inflammatory properties in animal models of Alzheimer's disease.

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The multi-target effects of CNI-1493: convergence of anti-amylodogenic and anti-inflammatory properties in animal models of Alzheimer's disease.

Mol Med. 2016 Nov 15;22:

Authors: Sankowski R, Herring A, Keyvani K, Frenzel K, Wu J, Röskam S, Noelker C, Bacher M, Al-Abed Y

Abstract
After several decades of Alzheimer's disease (AD) research and failed clinical trials, one can speculate that targeting a single pathway is not sufficient. However, a cocktail of novel therapeutics will constitute a challenging clinical trial. A more plausible approach will capitalize on a drug that has relevant and synergistic multiple-target effects in AD. We have previously demonstrated the efficacy of CNI-1493 in the CRND8 transgenic AD mouse model. Similar to many anti-inflammatory drugs that were tested in preclinical model of AD, it was speculated that the significant effect of CNI-1493 is due to its established anti-inflammatory properties in rodents and humans. In the present study, we set out to elucidate the protective mechanism of CNI-1493 as a drug simultaneously targeting several aspects of AD pathology. Using C1213, a highly similar analogue of CNI-1493 that lacks anti-inflammatory properties, we show that both compounds directly interact with soluble and insoluble Amyloid β (Aβ) aggregates and attenuate Aβ cytotoxicity in vitro. Additionally, CNI-1493 and C1213 ameliorated Aβ-induced behavioral deficits in nematodes. Finally, C1213 reduced Aβ plaque burden and cognitive deficits in transgenic CRND8 mice to a similar extent as previously shown with CNI-1493. Taken together, our findings suggest anti-amyloidogenic activity as a relevant component for the in-vivo efficacy of CNI-1493 and its analogue C1213. Thus, CNI-1493, a drug with proven safety in humans, is a viable candidate for novel multi-target therapeutic approaches to AD.

PMID: 27847962 [PubMed - as supplied by publisher]

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Herb medicines against osteoporosis: Active compounds & relevant biological mechanisms.

Herb medicines against osteoporosis: Active compounds & relevant biological mechanisms.

Curr Top Med Chem. 2016 Nov 16;

Authors: Wu L, Ling Z, Feng X, Mao C, Xu Z

Abstract
Osteoporosis is one of common bone disorders, affecting millions of people worldwide. Treatments of osteoporosis consist of pharmacotherapy and non-pharmacological interventions, such as mineral supplementation, lifestyle changes, and exercise programs. Due to the minimum side effects and favorable cost-effective therapeutic effects, herbal medicine has been widely applied in clinical practices for more than 2,000 years in China. Of the many traditional formulas reported for treating bone diseases, 4 single herbs namely (1) Herba Epimedii, (2) Rhizoma Drynariae, (3) Fructus Psoraleae, and (4) Cortex Eucommiae, are considered as the featured "Kidney-Yang" tonics, and frequently and effectively applied for preventing and treating osteoporosis. With the accruing development of modern chemistry, hundreds of active compounds have been identified and isolated for their anti-osteoporotic effects. This review would first sketch the phytochemistry of these featured "Kidney-Yang" tonics and present the pharmacological characteristics of the most abundant and bioactive compounds derived from the herb Herba Epimedii and Rhizoma Drynariae, including icariin and naringin. Then, the cellular and molecular underpinnings under anti-osteoporotic effects of icariin and naringin are discussed. The concerned structure-function relationships of the featured active herbal compounds would also be reviewed so as to pave the way for future drug design in treating osteoporosis.

PMID: 27848901 [PubMed - as supplied by publisher]

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Antioxidative Effects of Rhodiola genus: Phytochemistry and Pharmacological Mechanisms against the Diseases.

Antioxidative Effects of Rhodiola genus: Phytochemistry and Pharmacological Mechanisms against the Diseases.

Curr Top Med Chem. 2016 Nov 16;

Authors: Li Y, Wu J, Shi R, Li N, Xu Z, Sun M

Abstract
Rhodiola as one of traditional medicines has been used for clinical treatments due to their strong antioxidant properties. Phytochemical analysis revealed the presence of flavonoids, phenylpropanoids, phenylethanol/benzyl alcohol derivatives, cyanogenic glycosides and terpenoids. The bioactive compounds had been demonstrated to be effective at scavenging reactive oxygen species (ROS). The structures contain phenolic hydroxyl groups and unsaturated bonds. This article reviews antioxidant capacities of the extracts and bioactive components derived from Rhodiola plants. As the major pharmacological ingredient, salidroside is rigorously investigated and used in scientific researches and clinical practices. Accumulated evidences indicated that extracts of Rhodiola plants or salidroside could be able to reverse DNA damage and alter expression of cytokines and antioxidative enzymes induced by ROS. The underlying mechanisms for the antioxidative effects of the herb have been investigated in the last two decades. We summarize the possible effects and acting pathways for the herb involved in several chronic diseases in cardiovascular, respiratory, and nervous systems, as well as potential epigenetic influences. The information generated from experimental and clinical studies offered valuable insights for further investigations of medical potentials of Rhodiola plants.

PMID: 27848900 [PubMed - as supplied by publisher]

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Computational modeling approach in probing effects of cytosine methylation on the transcription factor binding to DNA.

Computational modeling approach in probing effects of cytosine methylation on the transcription factor binding to DNA.

Curr Top Med Chem. 2016 Nov 16;

Authors: Tenayuca J, Cousins K, Yang S, Zhang L

Abstract
Cytosine methylation at CpG dinucleotides is a chief mechanism in epigenetic modification of gene expression patterns. Previous studies demonstrated that increased CpG methylation of Sp1 sites at -268 and -346 of protein kinase C  promoter repressed the gene expression. The present study investigated the impact of CpG methylation on the Sp1 binding via molecular modeling and electrophoretic mobility shift assay. Each of the Sp1 sites contain two CpGs. Methylation of either CpG lowered the binding affinity of Sp1, whereas methylation of both CpGs produced a greater decrease in the binding affinity. Computation of van der Waals (VDW) energy of Sp1 in complex with the Sp1 sites demonstrated increased VDW values from one to two sites of CpG methylation. Molecular modeling indicated that single CpG methylation caused underwinding of the DNA fragment, with the phosphate groups at C1, C4 and C5 reoriented from their original positions. Methylation of both CpGs pinched the minor groove and increased the helical twist concomitant with a shallow, hydrophobic major groove. Additionally, double methylation eliminated hydrogen bonds on recognition helix residues located at positions -1 and 1, which were essential for interaction with O6/N7 of G-bases. Bonding from linker residues Arg565, Lys595 and Lys596 were also reduced. Methylation of single or both CpGs significantly affected hydrogen bonding from all three Sp1 DNA binding domains, demonstrating that the consequences of cytosine modification extend beyond the neighboring nucleotides. The results indicate that cytosine methylation causes subtle structural alterations in Sp1 binding sites consequently resulting in inhibition of side chain interactions critical for specific base recognition and reduction of the binding affinity of Sp1.

PMID: 27848899 [PubMed - as supplied by publisher]

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Proteomic analysis of endothelin-1 targets in the regulation of cardiomyocyte proliferation.

Proteomic analysis of endothelin-1 targets in the regulation of cardiomyocyte proliferation.

Curr Top Med Chem. 2016 Nov 16;

Authors: Shin AN, Dasgupta C, Zhang L, Zhang G, Seal K

Abstract
Hypoxia is a fetal stressor that leads to the production of endothelin-1 (ET-1). Previous work has shown that ET-1 treatment leads to the premature terminal differentiation of fetal cardiomyocytes. However, the precise mechanism is unknown. We tested the hypothesis that the fetal cardiomyocyte proteome will be greatly altered due to ET-1-treatment, which reveals a potential molecular mechanism of ET-1-induced terminal differentiation. Over a thousand proteins were detected in the fetal cardiomyocytes and among them 75 proteins were significantly altered due to ET-1 treatment. Using IPA pathway analysis, the merged network depicted several key proteins that appeared to be involved in regulating proliferation, including: EED, UBC, ERK1/2, MAPK, Akt, and EGFR. EED protein, which is associated with regulating proliferation via epigenetic mechanisms, is of particular interest. Herein we propose a model of the molecular mechanism by which ET-1 induced cardiomyocyte terminal differentiation occurs.

PMID: 27848898 [PubMed - as supplied by publisher]

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Bioinformatics and Drug Discovery.

Bioinformatics and Drug Discovery.

Curr Top Med Chem. 2016 Nov 16;

Authors: Xia X

Abstract
Bioinformatic analysis can not only accelerate drug target identification and drug candidate screening and refinement, but also facilitate characterization of side effects and predict drug resistance. High-throughput data such as genomic, epigenetic, genome architecture, cistromic, transcriptomic, proteomic, and ribosome profiling data have all made significant contribution to mechanism-based drug discovery and drug repurposing. Accumulation of protein and RNA structures, as well as development of homology modeling and protein structure simulation, coupled with large structure databases of small molecules and metabolites, paved the way for more realistic protein-ligand docking experiments and more informative virtual screening. I present the conceptual framework that drives the collection of these high-throughput data, summarize the utility and potential of mining these data in drug discovery, outline a few inherent limitations in data and software mining these data, point out news ways to refine analysis of these diverse types of data, and highlight commonly used software and databases relevant to drug discovery.

PMID: 27848897 [PubMed - as supplied by publisher]

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Probes and targets of DNA methylation and demethylation in drug development.

Probes and targets of DNA methylation and demethylation in drug development.

Curr Top Med Chem. 2016 Nov 16;

Authors: Mirfattah B, Herring J, Tang H, Zhang K

Abstract
DNA methylation and demethylation is part of the essential biological processes regulating gene expression in normal cell development. Abnormal methylation status of specific genes and their irregularly translated proteins are normally associated with certain kinds of diseases or cancer. The rapid development of innovative DNA methylation mapping techniques provides a better understanding of DNA methylation pattern and its mechanisms in the human genome and its correlation with numerous diseases. These new techniques can lead us to develop new epigenetic medications, such as DNA methyltransferase inhibitors. As part of the approaches to probe DNA methylation and evaluate the effects of epigenetic therapy, mass spectrometry has been taking an important role in the identification, validation, and quantification of DNA methylation and demethylation. In this review, we will briefly summarize the current breadth of knowledge on the topic of DNA methylation and its occurrence in diseases, DNA methylation drugs, and mass spectrometry based approaches used to study DNA methylation.

PMID: 27848896 [PubMed - as supplied by publisher]

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