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1.
Enhancing Antioxidant Effect against Peroxyl Radical-Induced Oxidation of DNA: Linking with Ferrocene Moiety!
Liu, ZQ
Chemical record (New York, N.Y.). 2019;(12):2385-2397
Abstract
As a major member in the family of reactive oxygen species, peroxyl radical is able to abstract hydrogen atom from 4-position of ribose, leading to the collapse of DNA strand. Thus, inhibiting oxidative stress with exogenous antioxidants acts as a promising strategy to protect the integrity of DNA structure and is thereby suggested to be a pathway against developments of related diseases. Ferrocene as an organometallic scaffold is widely applied in the design of organometallic drugs, and redox of Fe(II)/Fe(III) in ferrocene offers advantage for providing electron to radicals. Presented herein are our ongoing studies on ferrocene-appended antioxidants, including McMurry reaction applied to construct ferrocifen; Aldol condensation used to prepare ferrocenyl curcumin; Povarov reaction employed to prepare ferrocenyl quinoline; Biginelli reaction used to construct ferrocenyl dihydropyrimidine; Groebke reaction used to synthesize ferrocenyl imidazo[1,2-a]pyridine; and Passerini three-component reaction as well as Ugi four-component reaction applied to synthesize α-acyloxycarboxamide and bisamide, respectively. It is found that ferrocene moiety is able to enhance antioxidative effect of the aforementioned scaffolds even without the aid of phenolic hydroxyl group. The role of ferrocene in enhancing antioxidative effect can be attributable to trapping radicals, decreasing oxidative potential, and increasing the affinity toward DNA strand. Therefore, ferrocene is worthy to be taken into consideration in the design of drugs in relation to DNA oxidation.
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2.
Autoimmune and inflammatory K+ channelopathies in cardiac arrhythmias: Clinical evidence and molecular mechanisms.
Capecchi, PL, Laghi-Pasini, F, El-Sherif, N, Qu, Y, Boutjdir, M, Lazzerini, PE
Heart rhythm. 2019;(8):1273-1280
Abstract
Cardiac K+ channelopathies account for a significant proportion of arrhythmias and sudden cardiac death (SCD) in subjects without structural heart disease. It is well recognized that genetic defects are key factors in many cases, and in practice, the term cardiac channelopathies currently coincides with inherited cardiac channelopathies. However, mounting evidence demonstrate that not only genetic alterations but also autoimmune and inflammatory factors can cause cardiac K+-channel dysfunction and arrhythmias in the setting of a structurally normal heart. In particular, it has been demonstrated that specific autoantibodies as well as inflammatory cytokines can modulate expression and/or function of different K+ channels in the heart, resulting in a disruption of the cardiac action potential and arrhythmias/sudden cardiac death. Awareness about the existence of these newly recognized forms is essential to identify and adequately manage affected patients. In the present review, we focus on autoimmune and inflammatory K+ channelopathies as a novel mechanism for cardiac arrhythmias and analyze the recent advancements in this topic, providing complementary basic, clinical, and population health perspectives.
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3.
APOE Alleles and Extreme Human Longevity.
Sebastiani, P, Gurinovich, A, Nygaard, M, Sasaki, T, Sweigart, B, Bae, H, Andersen, SL, Villa, F, Atzmon, G, Christensen, K, et al
The journals of gerontology. Series A, Biological sciences and medical sciences. 2019;(1):44-51
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Abstract
We assembled a collection of 28,297 participants from seven studies of longevity and healthy aging comprising New England Centenarian, Long Life Family, Longevity Gene Population, Southern Italian Centenarian, Japanese Centenarian, the Danish Longevity, and the Health and Retirement Studies to investigate the association between the APOE alleles ε2ε3 and ε4 and extreme human longevity and age at death. By using three different genetic models and two definitions of extreme longevity based on either a threshold model or age at death, we show that ε4 is associated with a substantially decreased odds for extreme longevity, and increased risk for death that persists even beyond ages reached by less than 1% of the population. We also show that carrying the ε2ε2 or ε2ε3 genotype is associated with significantly increased odds to reach extreme longevity, with decreased risk for death compared with carrying the genotype ε3ε3 but with only a modest reduction in risk for death beyond an age reached by less than 1% of the population.
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Atomistic mechanisms of the double proton transfer in the H-bonded nucleobase pairs: QM/QTAIM computational lessons.
Brovarets', OO, Hovorun, DM
Journal of biomolecular structure & dynamics. 2019;(7):1880-1907
Abstract
In this Review, we have summarized and generalized the results of the investigation of the microstructural mechanisms of the tautomerization by the counter movement of the protons along the neighboring intermolecular H-bonds in 22 biologically important pairs of nucleotide bases in the framework of the original method, which allows to trace the evolution of the physicochemical parameters, that characterize these processes along the intrinsic reaction coordinate (IRC). It was demonstrated the performance of the introduction of the conception of the key points (KPs) (from nine to five, depending on the symmetry and nature of system), which exhaustively characterize the flow of the tautomerization processes. It was proved that for all tautomerizing base pairs the extrema of the first derivative of the electron energy of the complex by IRC coincide with the second and penultimate KPs, in which the Laplacian of the electron density equals zero at the corresponding (3,-1) bond critical points of the H-bonds. It was established the linear dependence of the width of the transition state zone of the DPT tautomerization on the degree of its asynchrony. Authors emphasize that the tautomerization reaction through the DPT of the H-bonded pairs of nucleotide bases can be considered successful in those and only in those case if the tautomerized complex is a dynamically stable system, during lifetime of which low-frequency intermolecular vibrations could develop. Perspectives of the application of the obtained approaches to the thorough study of the proton transfer processes in the biologically important objects have been briefly discussed.
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Heterozygous familial hypercholesterolaemia in a pair of identical twins: a case report and updated review.
Mohd Nor, NS, Al-Khateeb, AM, Chua, YA, Mohd Kasim, NA, Mohd Nawawi, H
BMC pediatrics. 2019;(1):106
Abstract
BACKGROUND Familial hypercholesterolaemia (FH) is the most common inherited metabolic disease with an autosomal dominant mode of inheritance. It is characterised by raised serum levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-c), leading to premature coronary artery disease. Children with FH are subjected to early and enhanced atherosclerosis, leading to greater risk of coronary events, including premature coronary artery disease. To the best of our knowledge, this is the first report of a pair of monochorionic diamniotic identical twins with a diagnosis of heterozygous FH, resulting from mutations in both LDLR and ABCG8 genes. CASE PRESENTATION This is a rare case of a pair of 8-year-old monochorionic diamniotic identical twin, who on family cascade screening were diagnosed as definite FH, according to the Dutch Lipid Clinic Criteria (DLCC) with a score of 10. There were no lipid stigmata noted. Baseline lipid profiles revealed severe hypercholesterolaemia, (TC = 10.5 mmol/L, 10.6 mmol/L; LDL-c = 8.8 mmol/L, 8.6 mmol/L respectively). Their father is the index case who initially presented with premature CAD, and subsequently diagnosed as FH. Family cascade screening identified clinical FH in other family members including their paternal grandfather who also had premature CAD, and another elder brother, aged 10 years. Genetic analysis by targeted next-generation sequencing using MiSeq platform (Illumina) was performed to detect mutations in LDLR, APOB100, PCSK9, ABCG5, ABCG8, APOE and LDLRAP1 genes. Results revealed that the twin, their elder brother, father and grandfather are heterozygous for a missense mutation (c.530C > T) in LDLR that was previously reported as a pathogenic mutation. In addition, the twin has heterozygous ABCG8 gene mutation (c.55G > C). Their eldest brother aged 12 years and their mother both had normal lipid profiles with absence of LDLR gene mutation. CONCLUSION A rare case of Asian monochorionic diamniotic identical twin, with clinically diagnosed and molecularly confirmed heterozygous FH, due to LDLR and ABCG8 gene mutations have been reported. Childhood FH may not present with the classical physical manifestations including the pathognomonic lipid stigmata as in adults. Therefore, childhood FH can be diagnosed early using a combination of clinical criteria and molecular analyses.
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6.
Structure and function of archaeal histones.
Henneman, B, van Emmerik, C, van Ingen, H, Dame, RT
PLoS genetics. 2018;(9):e1007582
Abstract
The genomes of all organisms throughout the tree of life are compacted and organized in chromatin by association of chromatin proteins. Eukaryotic genomes encode histones, which are assembled on the genome into octamers, yielding nucleosomes. Post-translational modifications of the histones, which occur mostly on their N-terminal tails, define the functional state of chromatin. Like eukaryotes, most archaeal genomes encode histones, which are believed to be involved in the compaction and organization of their genomes. Instead of discrete multimers, in vivo data suggest assembly of "nucleosomes" of variable size, consisting of multiples of dimers, which are able to induce repression of transcription. Based on these data and a model derived from X-ray crystallography, it was recently proposed that archaeal histones assemble on DNA into "endless" hypernucleosomes. In this review, we discuss the amino acid determinants of hypernucleosome formation and highlight differences with the canonical eukaryotic octamer. We identify archaeal histones differing from the consensus, which are expected to be unable to assemble into hypernucleosomes. Finally, we identify atypical archaeal histones with short N- or C-terminal extensions and C-terminal tails similar to the tails of eukaryotic histones, which are subject to post-translational modification. Based on the expected characteristics of these archaeal histones, we discuss possibilities of involvement of histones in archaeal transcription regulation.
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The past and presence of gene targeting: from chemicals and DNA via proteins to RNA.
Geel, TM, Ruiters, MHJ, Cool, RH, Halby, L, Voshart, DC, Andrade Ruiz, L, Niezen-Koning, KE, Arimondo, PB, Rots, MG
Philosophical transactions of the Royal Society of London. Series B, Biological sciences. 2018;(1748)
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Abstract
The ability to target DNA specifically at any given position within the genome allows many intriguing possibilities and has inspired scientists for decades. Early gene-targeting efforts exploited chemicals or DNA oligonucleotides to interfere with the DNA at a given location in order to inactivate a gene or to correct mutations. We here describe an example towards correcting a genetic mutation underlying Pompe's disease using a nucleotide-fused nuclease (TFO-MunI). In addition to the promise of gene correction, scientists soon realized that genes could be inactivated or even re-activated without inducing potentially harmful DNA damage by targeting transcriptional modulators to a particular gene. However, it proved difficult to fuse protein effector domains to the first generation of programmable DNA-binding agents. The engineering of gene-targeting proteins (zinc finger proteins (ZFPs), transcription activator-like effectors (TALEs)) circumvented this problem. The disadvantage of protein-based gene targeting is that a fusion protein needs to be engineered for every locus. The recent introduction of CRISPR/Cas offers a flexible approach to target a (fusion) protein to the locus of interest using cheap designer RNA molecules. Many research groups now exploit this platform and the first human clinical trials have been initiated: CRISPR/Cas has kicked off a new era of gene targeting and is revolutionizing biomedical sciences.This article is part of a discussion meeting issue 'Frontiers in epigenetic chemical biology'.
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Proprotein convertase subtilisin/kexin type 9: from genetics to clinical trials.
Stoekenbroek, RM, Kastelein, JJP
Current opinion in cardiology. 2018;(3):269-275
Abstract
PURPOSE OF REVIEW This review describes the pivotal role of genetic insights and technologies in the discovery of proprotein convertase subtilisin/kexin type 9 (PCSK9) and the rapid development of PCSK9 inhibitors - a revolutionary new class of lipid-lowering agents. RECENT FINDINGS PCSK9 was discovered as a the third gene implicated in familial hypercholesterolemia. Population genetics studies, enabled by technological advances, were instrumental in validating PCSK9 as a therapeutic target. Monoclonal antibodies against PCSK9 were introduced in the clinic after an unprecedently rapid development path, in which clinical trial results confirmed that these drugs robustly lower cholesterol and improve clinical outcomes regardless of disease indication or background therapy. New strategies to PCSK9 inhibition are underway and have delivered promising preliminary results, including inhibition of PCSK9 synthesis by targeting the cellular gene expression machinery and vaccination. The future will tell whether directly targeting the genome through editing techniques will ultimately enable us to virtually eliminate many of the traditional CVD risk factors. SUMMARY The extraordinary PCSK9 narrative highlights the opportunities offered by genetics-driven drug development and holds valuable lessons for future development programs.
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An Exciting Couple.
Etlinger, JD
Journal of pediatric ophthalmology and strabismus. 2018;(3):149-150
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10.
The nuclear receptor superfamily: A structural perspective.
Weikum, ER, Liu, X, Ortlund, EA
Protein science : a publication of the Protein Society. 2018;(11):1876-1892
Abstract
Nuclear receptors (NRs) are a family of transcription factors that regulate numerous physiological processes such as metabolism, reproduction, inflammation, as well as the circadian rhythm. NRs sense changes in lipid metabolite levels to drive differential gene expression, producing distinct physiologic effects. This is an allosteric process whereby binding a cognate ligand and specific DNA sequences drives the recruitment of diverse transcriptional co-regulators at chromatin and ultimately transactivation or transrepression of target genes. Dysregulation of NR signaling leads to various malignances, metabolic disorders, and inflammatory disease. Given their important role in physiology and ability to respond to small lipophilic ligands, NRs have emerged as valuable therapeutic targets. Here, we summarize and discuss the recent progress on understanding the complex mechanism of action of NRs, primarily from a structural perspective. Finally, we suggest future studies to improve our understanding of NR signaling and better design drugs by integrating multiple structural and biophysical approaches.