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1.
Roles for α-Synuclein in Gene Expression.
Somayaji, M, Lanseur, Z, Choi, SJ, Sulzer, D, Mosharov, EV
Genes. 2021;(8)
Abstract
α-Synuclein (α-Syn) is a small cytosolic protein associated with a range of cellular compartments, including synaptic vesicles, the nucleus, mitochondria, endoplasmic reticulum, Golgi apparatus, and lysosomes. In addition to its physiological role in regulating presynaptic function, the protein plays a central role in both sporadic and familial Parkinson's disease (PD) via a gain-of-function mechanism. Because of this, several recent strategies propose to decrease α-Syn levels in PD patients. While these therapies may offer breakthroughs in PD management, the normal functions of α-Syn and potential side effects of its depletion require careful evaluation. Here, we review recent evidence on physiological and pathological roles of α-Syn in regulating activity-dependent signal transduction and gene expression pathways that play fundamental role in synaptic plasticity.
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Role of Phytonutrients in Nutrigenetics and Nutrigenomics Perspective in Curing Breast Cancer.
Bhattacharya, T, Dutta, S, Akter, R, Rahman, MH, Karthika, C, Nagaswarupa, HP, Murthy, HCA, Fratila, O, Brata, R, Bungau, S
Biomolecules. 2021;(8)
Abstract
Breast cancer (BC) is one of the most common type of cancer and an important contributor to female mortality. Several genes and epigenetic modifications are involved in the development and progression of BC. Research in phytochemistry, nutrigenomics, and nutrigenetics has provided strong evidence that certain phytonutrients are able to modulate gene expression at transcriptional and post-transcriptional levels. Such phytonutrients may also be beneficial to prevent and treat BC. In this review, we will focus on the nutrigenomic effects of various phytochemicals including polyphenols, phytosterols, terpenoids, alkaloids, and other compounds from different sources. Overall, these phytonutrients are found to inhibit BC cell proliferation, differentiation, invasion, metastasis, angiogenesis, and induce apoptotic cell death by targeting various molecular pathways. They also alter epigenetic mechanisms and enhance the chemosensitivity and radiosensitivity of cancer cells. Such phytochemicals may be used for the effective management of BC patients in the clinical setting in the future. The present article aims to summarize the specific molecular pathways involved in the genetic effects of phytochemicals in BC.
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3.
Beyond cholesterol metabolism: The pleiotropic effects of proprotein convertase subtilisin/kexin type 9 (PCSK9). Genetics, mutations, expression, and perspective for long-term inhibition.
Cesaro, A, Bianconi, V, Gragnano, F, Moscarella, E, Fimiani, F, Monda, E, Scudiero, O, Limongelli, G, Pirro, M, Calabrò, P
BioFactors (Oxford, England). 2020;(3):367-380
Abstract
Proprotein convertase subtilisin/kexin type 9 (PCSK9) has a crucial role in lipid metabolism, particularly due to its function in low-density lipoprotein receptor degradation. Gain-of-function genetic mutations of PCSK9 result in autosomal dominant familial hypercholesterolemia, characterized by high levels of low-density lipoprotein cholesterol (LDL-C) and clinical signs of early atherosclerosis. In recent years, PCSK9 has become an important therapeutic target for cholesterol-lowering therapy. Particularly, its inhibition with monoclonal antibodies has shown excellent efficacy in decreasing LDL-C and reducing cardiovascular events. However, PCSK9, first identified in the brain, seems to be a ubiquitous protein with different tissue-specific functions also independent of cholesterol metabolism. Accordingly, it appears to be involved in the immune response, haemostasis, glucose metabolism, neuronal survival, and several other biological functions. This review provides a comprehensive overview of the genetics, biochemical structure, expression, and function of PCSK9 and discusses the potential implications of its long-term pharmacological inhibition.
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4.
The Diagnostic Performance of Afirma Gene Expression Classifier for the Indeterminate Thyroid Nodules: A Meta-Analysis.
Liu, Y, Pan, B, Xu, L, Fang, D, Ma, X, Lu, H
BioMed research international. 2019;:7150527
Abstract
BACKGROUND Approximately 15 to 30% of thyroid nodules evaluated by fine-needle aspiration (FNA) were classified as indeterminate; the accurate diagnostic molecular tests of these nodules remain a challenge. We aimed to evaluate the diagnostic performance of Afirma gene expression classifier (GEC) for the indeterminate thyroid nodules (ITNs). METHODS Studies published from January 2005 to December 2018 were systematically reviewed. The gold reference standard relied on the histopathologic results diagnosis from thyroidectomy surgical specimens. MetaDisc software was used to investigate the pooled sensitivity, specificity, negative predictive value (NPV), positive predictive value (PPV), diagnostic odds ratio (DOR), and summary receiver operating characteristic (SROC) curves. RESULTS A total of 18 studies involving 5290 patients with 3290 cases of ITNs were included. Collected data revealed that the pooled sensitivity of GEC was 95.5% (95% CI 93.3%-97.0%, p < 0.001), the specificity was 22.1% (95% CI 19.4%-24.9%, p < 0.001), the NPV was 88.2% (95% CI 0.833-0.921, p < 0.001), the PPV was 44.3% (95% CI 0.416-0.471, p < 0.001), and the DOR was 5.25 (95% CI 3.42-8.04, p= 0.855). CONCLUSION The GEC has quite high sensitivity of 95.5% but low specificity of 22.1%. The high sensitivity makes it probable to rule out malignant nodules. Thus, over half of nodules with GEC-suspicious results still require further validation like molecular markers, diagnostic surgery, or long follow-up, which limits its use in future clinical practice.
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5.
UTR-Dependent Control of Gene Expression in Plants.
Srivastava, AK, Lu, Y, Zinta, G, Lang, Z, Zhu, JK
Trends in plant science. 2018;(3):248-259
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Abstract
Throughout their lives, plants sense many developmental and environmental stimuli, and activation of optimal responses against these stimuli requires extensive transcriptional reprogramming. To facilitate this activation, plant mRNA contains untranslated regions (UTRs) that significantly increase the coding capacity of the genome by producing multiple mRNA variants from the same gene. In this review we compare UTRs of arabidopsis (Arabidopsis thaliana) and rice (Oryza sativum) at the genome scale to highlight their complexity in crop plants. We discuss different modes of UTR-based regulation with emphasis on genes that regulate multiple plant processes, including flowering, stress responses, and nutrient homeostasis. We demonstrate functional specificity in genes with variable UTR length and propose future research directions.
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Synthetic Nucleic Acids and Treatment of Neurological Diseases.
Corey, DR
JAMA neurology. 2016;(10):1238-1242
Abstract
IMPORTANCE The ability to control gene expression with antisense oligonucleotides (ASOs) could provide a new treatment strategy for disease. OBJECTIVE To review the use of ASOs for the treatment of neurological disorders. EVIDENCE REVIEW Articles were identified through a search of PubMed references from 2000 to 2016 for articles describing the use of ASOs to treat disease, with specific attention to neurological disease. We concentrated our review on articles pertaining to activation of frataxin expression (Friedreich's ataxia) and production of active survival motor neuron 2 (SMN2, spinal muscular atrophy). FINDINGS Many neurological diseases are caused by inappropriate expression of a protein. Mutations may reduce expression of a wild-type protein, and strategies to activate expression may provide therapeutic benefit. For other diseases, a mutant protein may be expressed too highly and methods that reduce mutant protein expression might form the basis for drug development. Synthetic ASOs can recognize cellular RNA and control gene expression. Antisense oligonucleotides are not a new concept, but successful clinical development has proceeded at a slow pace. Advances in ASO chemistry, biological understanding, and clinical design are making successful applications more likely. CONCLUSIONS AND RELEVANCE Both laboratory and clinical studies are demonstrating the potential of ASOs as a source of drugs to treat neurological disease.
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Gene Expression Profiling and Molecular Signaling of Various Cells in Response to Tricalcium Silicate Cements: A Systematic Review.
Rathinam, E, Rajasekharan, S, Chitturi, RT, Declercq, H, Martens, L, De Coster, P
Journal of endodontics. 2016;(12):1713-1725
Abstract
INTRODUCTION The aim of this study was to present a systematic review investigating the gene expression of various cells (other than dental pulp cells) in response to different variants of tricalcium silicate cements (TSCs). METHODS A systematic search of the literature was performed by 2 independent reviewers followed by article selection and data extraction. Studies analyzing any cell type except dental pulp stem cells and any variant of tricalcium silicate cement either as the experimental or as the control group were included. RESULTS A total of 41 relevant articles were included in this review. Among the included studies, ProRoot MTA (Dentsply, Tulsa, OK) was the most commonly studied (69.1%) TSC variant, and 11 cell types were identified, with 13 articles investigating gene expression in osteoblasts. A total of 39 different genes/molecules expressed were found in the selected studies. The experimental group (irrespective of the TSC variant) was identified to express significantly increased gene expression compared with the control group (untreated) in all included studies. Recent studies have provided useful insight into the gene expression and molecular signaling of various cells in response to TSCs, and new elements have been supplied on the pathways activated in this process. CONCLUSIONS TSCs are capable of eliciting a favorable cellular response in periapical regeneration.
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Endocrine disruptors in 2015: Epigenetic transgenerational inheritance.
Skinner, MK
Nature reviews. Endocrinology. 2016;(2):68-70
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Abstract
Endocrine disruptors are critical environmental exposures that influence health and can promote epigenetic transgenerational inheritance of disease and abnormal physiology. Advances in 2015 included analyses of the effects of endocrine disruptors on human disease, further examples of endocrine disruptors promoting transgenerational behavioural effects, insights into effects of endocrine disruptors on epigenetic programming of primordial germ cells and the finding that endocrine disruptors can transgenerationally promote genetic mutations.
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Skin aging, gene expression and calcium.
Rinnerthaler, M, Streubel, MK, Bischof, J, Richter, K
Experimental gerontology. 2015;:59-65
Abstract
The human epidermis provides a very effective barrier function against chemical, physical and microbial insults from the environment. This is only possible as the epidermis renews itself constantly. Stem cells located at the basal lamina which forms the dermoepidermal junction provide an almost inexhaustible source of keratinocytes which differentiate and die during their journey to the surface where they are shed off as scales. Despite the continuous renewal of the epidermis it nevertheless succumbs to aging as the turnover rate of the keratinocytes is slowing down dramatically. Aging is associated with such hallmarks as thinning of the epidermis, elastosis, loss of melanocytes associated with an increased paleness and lucency of the skin and a decreased barrier function. As the differentiation of keratinocytes is strictly calcium dependent, calcium also plays an important role in the aging epidermis. Just recently it was shown that the epidermal calcium gradient in the skin that facilitates the proliferation of keratinocytes in the stratum basale and enables differentiation in the stratum granulosum is lost in the process of skin aging. In the course of this review we try to explain how this calcium gradient is built up on the one hand and is lost during aging on the other hand. How this disturbed calcium homeostasis is affecting the gene expression in aged skin and is leading to dramatic changes in the composition of the cornified envelope will also be discussed. This loss of the epidermal calcium gradient is not only specific for skin aging but can also be found in skin diseases such as Darier disease, Hailey-Hailey disease, psoriasis and atopic dermatitis, which might be very helpful to get a deeper insight in skin aging.
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The genetic signatures of pediatric high-grade glioma: no longer a one-act play.
Diaz, AK, Baker, SJ
Seminars in radiation oncology. 2014;(4):240-7
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Abstract
Advances in understanding pediatric high-grade glioma (pHGG) genetics have revealed key differences between pHGG and adult HGG and have uncovered unique molecular drivers among subgroups within pHGG. The 3 core adult HGG pathways, the receptor tyrosine kinase-Ras-phosphatidylinositide 3-kinase, p53, and retinoblastoma networks, are also disrupted in pHGG, but they exhibit a different spectrum of effectors targeted by mutation. There are also similarities and differences in the genomic landscape of diffuse intrinsic pontine glioma (DIPG) and pediatric nonbrainstem (pNBS)-HGG. In 2012, histone H3 mutations were identified in nearly 80% of DIPGs and ~35% of pNBS-HGG. These were the first reports of histone mutations in human cancer, implicating novel biology in pediatric gliomagenesis. Additionally, DIPG and midline pNBS-HGG vary in the frequency and specific histone H3 amino acid substitution compared with pNBS-HGGs arising in the cerebral hemispheres, demonstrating a molecular difference among pHGG subgroups. The gene expression signatures as well as DNA methylation signatures of these tumors are also distinctive, reflecting a combination of the driving mutations and the developmental context from which they arise. These data collectively highlight unique selective pressures within the developing brainstem and solidify DIPG as a specific molecular and biological entity among pHGGs. Emerging studies continue to identify novel mutations that distinguish subgroups of pHGG. The molecular heterogeneity among pHGGs will undoubtedly have clinical implications moving forward. The discovery of unique oncogenic drivers is a critical first step in providing patients with appropriate, targeted therapies. Despite these insights, our vantage point has been largely limited to an in-depth analysis of protein coding sequences. Given the clear importance of histone mutations in pHGG, it will be interesting to see how aberrant epigenetic regulation contributes to tumorigenesis in the pediatric context. New mechanistic insights may allow for the identification of distinct vulnerabilities in this devastating spectrum of childhood tumors.