scholarly journals Intron retention as a new marker of the pre-disease state and its recovery to the normal state by a traditional Japanese multi-herbal medicine

2020 ◽  
Author(s):  
Norihiro Okada ◽  
Kenshiro Oshima ◽  
Yuki Iwasaki ◽  
Akiko Maruko ◽  
Erica Iioka ◽  
...  
Keyword(s):  
Herbal Medicine ◽  
Normal State ◽  
Molecular Mechanisms ◽  
Intron Retention ◽  
Disease State ◽  
Healthy State ◽  
Protein Functions ◽  
The Ancient Chinese ◽  
Retained Introns ◽  
Splicing Patterns

AbstractIntron retention (IR) is an important regulatory mechanism that affects gene expression and protein functions. Using klotho mice as a model, we proposed that retained introns are an excellent marker for the pre-disease state. Surprisingly, among widespread retained introns that accumulated during aging in the liver, a subset was recovered to the normal state by a Japanese traditional herbal medicine. IR-recovered genes fell into two categories: (1) those involved in the spliceosome and (2) those involved in liver-specific metabolism. By integrating data for splicing patterns, transcriptomes, and metabolomes, we hypothesize that this medicine-related IR recovery under the pre-disease state reflects the actual recovery of liver-specific function to the healthy state. Accordingly, the study provides proof-of-concept evidence related to the ancient Chinese statement proposing the medicine’s usefulness for treating the pre-disease state. This approach lays out a method for elucidating unknown molecular mechanisms of an herbal medicine with multiple ingredients.

scholarly journals Intron retention as a new pre-symptomatic marker of aging and its recovery to the normal state by a traditional Japanese multi-herbal medicine

Gene ◽  
2021 ◽  
pp. 145752
Author(s):  
Norihiro Okada ◽  
Kenshiro Oshima ◽  
Yuki Iwasaki ◽  
Akiko Maruko ◽  
Kenya Matsumura ◽  
...  
Keyword(s):  
Herbal Medicine ◽  
Normal State ◽  
Intron Retention

scholarly journals Protein Co-Aggregation Related to Amyloids: Methods of Investigation, Diversity, and Classification

2018 ◽  
Vol 19 (8) ◽  
pp. 2292 ◽  
Author(s):  
Stanislav Bondarev ◽  
Kirill Antonets ◽  
Andrey Kajava ◽  
Anton Nizhnikov ◽  
Galina Zhouravleva
Keyword(s):  
Binding Site ◽  
Molecular Mechanisms ◽  
Amyloid Fibrils ◽  
Specific Binding ◽  
Protein S ◽  
Functional Protein ◽  
Functional Roles ◽  
Protein Fibrils ◽  
Protein Functions ◽  
Functional Amyloids

Amyloids are unbranched protein fibrils with a characteristic spatial structure. Although the amyloids were first described as protein deposits that are associated with the diseases, today it is becoming clear that these protein fibrils play multiple biological roles that are essential for different organisms, from archaea and bacteria to humans. The appearance of amyloid, first of all, causes changes in the intracellular quantity of the corresponding soluble protein(s), and at the same time the aggregate can include other proteins due to different molecular mechanisms. The co-aggregation may have different consequences even though usually this process leads to the depletion of a functional protein that may be associated with different diseases. The protein co-aggregation that is related to functional amyloids may mediate important biological processes and change of protein functions. In this review, we survey the known examples of the amyloid-related co-aggregation of proteins, discuss their pathogenic and functional roles, and analyze methods of their studies from bacteria and yeast to mammals. Such analysis allow for us to propose the following co-aggregation classes: (i) titration: deposition of soluble proteins on the amyloids formed by their functional partners, with such interactions mediated by a specific binding site; (ii) sequestration: interaction of amyloids with certain proteins lacking a specific binding site; (iii) axial co-aggregation of different proteins within the same amyloid fibril; and, (iv) lateral co-aggregation of amyloid fibrils, each formed by different proteins.

scholarly journals Bioinformatic resources for the investigation of proteins and proteomes

Peptidomics ◽  
2016 ◽  
Vol 2 (1) ◽  
Author(s):  
Angelo Facchiano
Keyword(s):  
Experimental Data ◽  
Data Management ◽  
Protein Identification ◽  
Molecular Mechanisms ◽  
Strong Support ◽  
Biological Processes ◽  
Functional Interpretation ◽  
Huge Data ◽  
Protein World ◽  
Protein Functions

AbstractExperimental techniques in omics sciences need strong support of bioinformatics tools for the data management, analysis and interpretation. Scientific community develops continuously new databases and tools. They make it possible the comparison of new experimental data with the existing ones, to gain new knowledge. Bioinformatics assists proteomics scientists for protein identification from experimental data, management of the huge data produced, investigation of molecular mechanisms of protein functions, their roles in biochemical pathways, and functional interpretation of biological processes. This article introduces the main bioinformatics resources for investigation in the protein world, with references to analyses performed by means of free tools available on the net.

scholarly journals Perturbations in HNRNPH1 Splicing and Abundance Affect Global Splicing and Proliferation in Mantle Cell Lymphoma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 23-24
Author(s):  
Krysta M Coyle ◽  
Quratulain Qureshi ◽  
Prasath Pararajalingam ◽  
Nicole Thomas ◽  
Timothy E Audas ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
Intron Retention ◽  
Gene List ◽  
Protein Abundance ◽  
Mantle Cell ◽  
Sirna Knockdown ◽  
Retained Introns

Objectives Mantle cell lymphoma (MCL) is an uncommon B-cell non-Hodgkin lymphoma that is incurable with standard therapies. The genetic drivers of this cancer have not been firmly established and the features known to contribute to differences in clinical course remain limited. We previously discovered non-coding and silent mutations in HNRNPH1 that affect its splicing and contribute to poor outcomes for patients with MCL. We sought to extend our understanding of the mechanisms by which HNRNPH1 contributes to MCL pathology using a combination of in vitro models and integrative analysis of RNA sequencing from MCL tumors. Methods We previously sequenced ribosomal RNA-depleted RNA from 130 MCL tumors. Based on our earlier identification of mutations in HNRNPH1 and altered splicing of this gene, we performed differential splicing analyses using rMATS and leafcutter. We investigated the functional and phenotypic effect of deregulated hnRNP H1 protein through siRNA knockdown. Results Our previous work identified that splicing of HNRNPH1, and not total mRNA expression, correlated with protein abundance in MCL tumors. As a result, our analysis of alternative splicing focused on events associated with altered splicing of HNRNPH1. We identified 155 unique alternative splicing events (ΔPSI > 0.1, FDR < 0.1). Gene ontology analysis identified various aspects of RNA processing which are significantly enriched within this gene list, including mRNA splicing, transport, and metabolic process. This nominates HNRNPH1 as part of the complex network controlling alternative splicing within MCL. Available CLIP-seq in HeLa cells provides evidence for direct interactions between hnRNP H1 and transcripts identified by our analysis (e.g. RBM25, EIF4A1, HNRNPA2B1). Of the 155 events we identified, more than half involved retained introns. Generally, retained introns result in non-productive RNA species, which indicates that this program of intron retention in MCL is a mechanism by which protein abundance can be regulated by hnRNP H1. For all cases with available Mantle Cell Lymphoma International Prognostic Indicator (MIPI) classification, we determined the splicing ratio for HNRNPH1 and observed a general association between high MIPI scores and a lower ratio of non-productive HNRNPH1 transcripts. This suggested that the increased hnRNP H1 abundance we observed in HNRNPH1-mutant tumors contributes to increased proliferation of MCL cells. We verified this in vitro with siRNA knockdown of HNRNPH1 in HEK cells, which resulted in a significant decrease in cell proliferation. Conclusions We have described a pattern of alternative splicing in MCL that is associated with alterations in HNRNPH1 splicing and related protein abundance. The prevalence of retained introns suggests that hnRNP H1 regulates the abundance of protein-coding transcripts via alternative splicing coupled to nonsense-mediated decay. We continue to explore targets of hnRNP H1, a novel oncoprotein in MCL. Disclosures Morin: Celgene: Consultancy.

Involvement of YAP/TAZ Signaling Pathway in Anti-obesity Activity of Moringa oleifera Leaf Extract

2021 ◽  
Vol 17 ◽  
Author(s):  
Titing Nurhayati ◽  
Anton ◽  
Iwan Setiawan ◽  
Vita Murniati Tarawan ◽  
Ronny Lesmana
Keyword(s):  
Herbal Medicine ◽  
Signaling Pathway ◽  
Leaf Extract ◽  
Moringa Oleifera ◽  
Molecular Mechanisms ◽  
Therapeutic Agent ◽  
Efficacy And Safety ◽  
Main Principle ◽  
Experimental Researches ◽  
Reducing Energy

Introduction: Obesity has taken world concern since it has become a pandemic chronic disease. The main principle of obesity treatment is regulating energy balance by reducing energy intake and increasing energy expenditure. These target mechanisms become the point attention in herbal medicine studies. Several molecular mechanism of actions conducted by Moringa oleifera leaf extract (MLE) have been studied in many experimental researches. Objective: In this mini review, we encompass the mechanisms of MLE in demonstrating the anti-obesity activity, including the potential involvement of YAP/TAZ activity. Methods: Several major electronic databases including PubMed, Google Scholar, and Scopus were engaged in conceiving articles. The period was between August 2011 and August 2020. Results: From 18 established literatures, we demonstrated the anti-obesity activity of MLE in detail. Several citations accompanied the results of these researched-based studies to explain and illustrate the molecular mechanisms, including YAP/TAZ signaling pathway. Conclusion: MLE through its phytochemistry contents shows significant benefits on herbal medicine, especially the anti-obesity activity. MLE potentially contributes to modify the lipid metabolism in YAP/TAZ pathway. However, the study demonstrating this involvement has still not yet published. In the future, more exploration may provide hope for its efficacy and safety as the therapeutic agent of obesity.

scholarly journals Genetics of alternative splicing evolution during sunflower domestication

2018 ◽  
Vol 115 (26) ◽  
pp. 6768-6773 ◽  
Author(s):  
Chris C. R. Smith ◽  
Silas Tittes ◽  
J. Paul Mendieta ◽  
Erin Collier-zans ◽  
Heather C. Rowe ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Intron Retention ◽  
Population Divergence ◽  
Evolutionary Transition ◽  
Differential Splicing ◽  
Evolutionary Transitions ◽  
Protein Coding ◽  
Standing Variation ◽  
Splice Forms ◽  
Splicing Patterns

Alternative splicing enables organisms to produce the diversity of proteins necessary for multicellular life by using relatively few protein-coding genes. Although differences in splicing have been identified among divergent taxa, the shorter-term evolution of splicing is understudied. The origins of novel splice forms, and the contributions of alternative splicing to major evolutionary transitions, are largely unknown. This study used transcriptomes of wild and domesticated sunflowers to examine splice differentiation and regulation during domestication. We identified substantial splicing divergence between wild and domesticated sunflowers, mainly in the form of intron retention. Transcripts with divergent splicing were enriched for seed-development functions, suggesting that artificial selection impacted splicing patterns. Mapping of quantitative trait loci (QTLs) associated with 144 differential splicing cases revealed primarilytrans-acting variation affecting splicing patterns. A large proportion of identified QTLs contain known spliceosome proteins and are associated with splicing variation in multiple genes. Examining a broader set of wild and domesticated sunflower genotypes revealed that most differential splicing patterns in domesticated sunflowers likely arose from standing variation in wildHelianthus annuusand gained frequency during the domestication process. However, several domesticate-associated splicing patterns appear to be introgressed from otherHelianthusspecies. These results suggest that sunflower domestication involved selection on pleiotropic regulatory alleles. More generally, our findings indicate that substantial differences in isoform abundances arose rapidly during a recent evolutionary transition and appear to contribute to adaptation and population divergence.

scholarly journals Toxicity Assessment of Herbal Medicine Using Zebrafish Embryos: A Systematic Review

2019 ◽  
Vol 2019 ◽  
pp. 1-17 ◽  
Author(s):  
Chanika D. Jayasinghe ◽  
Uthpala A. Jayawardena
Keyword(s):  
Herbal Medicine ◽  
Molecular Mechanisms ◽  
Zebrafish Embryo ◽  
Toxicity Testing ◽  
Toxicity Assessment ◽  
Scientific Data ◽  
Herbal Remedies ◽  
Laboratory Animals ◽  
Genetic Redundancy ◽  
Crude Extracts

Herbal remedies have been practiced by humans over centuries and therefore possess time-proven safety. However, it is imperative to evaluate the toxic effects of herbal medicine to confirm their safety, particularly when developing therapeutic leads. Use of laboratory animals such as rats, mice, and rabbits was considered as gold standard in herbal toxicity assessments. However, in the last few decades, the ethical consideration of using higher vertebrates for toxicity testing has become more contentious. Thus, possible alternative models entailing lower vertebrates such as zebrafish were introduced. The zebrafish embryotoxicity model is at the forefront of toxicology assessment due to the transparent nature of embryos, low cost, short cycle, higher fecundity, and genetic redundancy to the humans. Recently, its application has been extended to herbal toxicology. The present review intends to provide a comprehensive assembly of studies that applied the zebrafish embryo model for the assessment of herbal toxicity. A systematic literature survey was carried out in popular scientific databases. The literature search identified a total of 1014 articles in PubMed = 12, Scopus SciVerse® = 623, and Google Scholar = 1000. After screening, 25 articles were included in this review, and they were categorized into three groups in which the zebrafish embryotoxicity assay has been applied to investigate the toxicity of (1) polyherbal formulae/medical prescription (2 full texts), (2) crude extracts (12 full texts), and (3) phytocompounds/isolated constituents (11 full texts). These studies have investigated the toxicity of 6 polyherbal formulae, 16 crude extracts, and more than 30 phytocompounds/isolated constituents using the zebrafish embryotoxicity model. Moreover, this model has explicated the teratogenic effects and specific organ toxicities such as the kidney, heart, and liver. Furthermore, in some studies, the molecular mechanisms underlying the toxicity of herbal medicine have been elucidated. This comprehensive collection of scientific data solidifies the zebrafish embryo model as an effective model system for studying toxicological effects of a broad spectrum of herbal remedies. Henceforth, it provides a novel insight into the toxicity assessment of herbal medicine.

scholarly journals The Quest for Cellular Prion Protein Functions in the Aged and Neurodegenerating Brain

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 591 ◽  
Author(s):  
Rosalina Gavín ◽  
Laia Lidón ◽  
Isidre Ferrer ◽  
José Antonio del Río
Keyword(s):  
Prion Protein ◽  
Scientific Community ◽  
Molecular Mechanisms ◽  
Cellular Prion Protein ◽  
Pathogenic Role ◽  
Knock Out ◽  
Protein Functions ◽  
A Cell ◽  
Knock Out Mice ◽  
Vast Range

Cellular (also termed ‘natural’) prion protein has been extensively studied for many years for its pathogenic role in prionopathies after misfolding. However, neuroprotective properties of the protein have been demonstrated under various scenarios. In this line, the involvement of the cellular prion protein in neurodegenerative diseases other than prionopathies continues to be widely debated by the scientific community. In fact, studies on knock-out mice show a vast range of physiological functions for the protein that can be supported by its ability as a cell surface scaffold protein. In this review, we first summarize the most commonly described roles of cellular prion protein in neuroprotection, including antioxidant and antiapoptotic activities and modulation of glutamate receptors. Second, in light of recently described interaction between cellular prion protein and some amyloid misfolded proteins, we will also discuss the molecular mechanisms potentially involved in protection against neurodegeneration in pathologies such as Alzheimer’s, Parkinson’s, and Huntington’s diseases.

scholarly journals Nonsequential Splicing Events Alter Antisense-Mediated Exon Skipping Outcome in COL7A1

2020 ◽  
Vol 21 (20) ◽  
pp. 7705
Author(s):  
Kristin A. Ham ◽  
May Thandar Aung-Htut ◽  
Sue Fletcher ◽  
Steve D. Wilton
Keyword(s):  
Intron Retention ◽  
Genetic Disorders ◽  
Exon Skipping ◽  
Monogenic Disease ◽  
Dystrophic Epidermolysis Bullosa ◽  
Mature Mrna ◽  
Intron Removal ◽  
Phosphorodiamidate Morpholino Oligomers ◽  
Splicing Patterns ◽  
Antisense Oligomer

The COL7A1 gene encodes homotrimer fibrils essential for anchoring dermal and epidermal layers, and pathogenic mutations in COL7A1 can cause recessive or dominant dystrophic epidermolysis bullosa. As a monogenic disease gene, COL7A1 constitutes a potential target for antisense oligomer-mediated exon skipping, a therapy applicable to a growing number of other genetic disorders. However, certain characteristics of COL7A1: many exons, low average intron size, and repetitive and guanine-cytosine rich coding sequence, present challenges to the design of specific and effective antisense oligomers. While targeting COL7A1 exons 10 and 73 for excision from the mature mRNA, we discovered that antisense oligomers comprised of 2′-O-methyl modified bases on a phosphorothioate backbone and phosphorodiamidate morpholino oligomers produced similar, but distinctive, splicing patterns including excision of adjacent nontargeted exons and/or retention of nearby introns in some transcripts. We found that the nonsequential splicing of certain introns may alter pre-mRNA processing during antisense oligomer-mediated exon skipping and, therefore, additional studies are required to determine if the order of intron removal influences multiexon skipping and/or intron retention in processing of the COL7A1 pre-mRNA.

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