scholarly journals Wild-Type Zebrafish (Danio rerio) Larvae as a Vertebrate Model for Diabetes and Comorbidities: A Review

Animals ◽  
2020 ◽  
Vol 11 (1) ◽  
pp. 54
Author(s):  
Maryna van de Venter ◽  
Jenske Didloff ◽  
Shanika Reddy ◽  
Bresler Swanepoel ◽  
Sharlene Govender ◽  
...  
Keyword(s):  
Pharmaceutical Research ◽  
Wild Type ◽  
Drug Candidates ◽  
Advantages And Disadvantages ◽  
Zebrafish Larvae ◽  
Vertebrate Model ◽  
Associated Conditions ◽  
Stable Mutant ◽  
Mutant Lines ◽  
Research Facilities

Zebrafish have become a popular alternative to higher animals in biomedical and pharmaceutical research. The development of stable mutant lines to model target specific aspects of many diseases, including diabetes, is well reported. However, these mutant lines are much more costly and challenging to maintain than wild-type zebrafish and are simply not an option for many research facilities. As an alternative to address the disadvantages of advanced mutant lines, wild-type larvae may represent a suitable option. In this review, we evaluate organ development in zebrafish larvae and discuss established methods that use wild-type zebrafish larvae up to seven days post fertilization to test for potential drug candidates for diabetes and its commonly associated conditions of oxidative stress and inflammation. This provides an up to date overview of the relevance of wild-type zebrafish larvae as a vertebrate antidiabetic model and confidence as an alternative tool for preclinical studies. We highlight the advantages and disadvantages of established methods and suggest recommendations for future developments to promote the use of zebrafish, specifically larvae, rather than higher animals in the early phase of antidiabetic drug discovery.

scholarly journals Mutant Lines of Spring Wheat with Increased Iron, Zinc, and Micronutrients in Grains and Enhanced Bioavailability for Human Health

2019 ◽  
Vol 2019 ◽  
pp. 1-10 ◽  
Author(s):  
Saule Kenzhebayeva ◽  
Alfia Abekova ◽  
Saule Atabayeva ◽  
Gulzira Yernazarova ◽  
Nargul Omirbekova ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Protein Content ◽  
Spring Wheat ◽  
Grain Protein Content ◽  
Grain Protein ◽  
Cereal Products ◽  
Molar Ratios ◽  
Stable Mutant ◽  
Micronutrient Malnutrition ◽  
Mutant Lines

Deficiency of metals, primarily Fe and Zn, affects over half of the world’s population. Human diets dominated by cereal products cause micronutrient malnutrition, which is common in many developing countries where populations depend heavily on staple grain crops such as wheat, maize, and rice. Biofortification is one of the most effective approaches to alleviate malnutrition. Genetically stable mutant spring wheat lines (M7 generation) produced via 100 or 200 Gy gamma treatments to broaden genetic variation for grain nutrients were analyzed for nutritionally important minerals (Ca, Fe, and Zn), their bioavailability, and grain protein content (GPC). Variation was 172.3–883.0 mg/kg for Ca, 40.9–89.0 mg/kg for Fe, and 22.2–89.6 mg/kg for Zn. In mutant lines, among the investigated minerals, the highest increases in concentrations were observed in Fe, Zn, and Ca when compared to the parental cultivar Zhenis. Some mutant lines, mostly in the 100 Gy-derived germplasm, had more than two-fold higher Fe, Zn, and Ca concentrations, lower phytic acid concentration (1.4–2.1-fold), and 6.5–7% higher grain protein content compared to the parent. Variation was detected for the molar ratios of Ca:Phy, Phy:Fe, and Phy:Zn (1.27–10.41, 1.40–5.32, and 1.78–11.78, respectively). The results of this study show how genetic variation generated through radiation can be useful to achieve nutrient biofortification of crops to overcome human malnutrition.

scholarly journals Transcriptome analyses of 7-day-old zebrafish larvae possessing a familial Alzheimer’s disease-like mutation in psen1 indicate effects on oxidative phosphorylation, ECM and MCM functions, and iron homeostasis

BMC Genomics ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Yang Dong ◽  
Morgan Newman ◽  
Stephen M. Pederson ◽  
Karissa Barthelson ◽  
Nhi Hin ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Oxidative Phosphorylation ◽  
Transcriptome Analysis ◽  
Iron Homeostasis ◽  
Late Onset ◽  
Wild Type ◽  
Familial Alzheimer’S Disease ◽  
Zebrafish Larvae ◽  
Familial Alzheimer's Disease

Abstract Background Early-onset familial Alzheimer’s disease (EOfAD) is promoted by dominant mutations, enabling the study of Alzheimer’s disease (AD) pathogenic mechanisms through generation of EOfAD-like mutations in animal models. In a previous study, we generated an EOfAD-like mutation, psen1Q96_K97del, in zebrafish and performed transcriptome analysis comparing entire brains from 6-month-old wild type and heterozygous mutant fish. We identified predicted effects on mitochondrial function and endolysosomal acidification. Here we aimed to determine whether similar effects occur in 7 day post fertilization (dpf) zebrafish larvae that might be exploited in screening of chemical libraries to find ameliorative drugs. Results We generated clutches of wild type and heterozygous psen1Q96_K97del 7 dpf larvae using a paired-mating strategy to reduce extraneous genetic variation before performing a comparative transcriptome analysis. We identified 228 differentially expressed genes and performed various bioinformatics analyses to predict cellular functions. Conclusions Our analyses predicted a significant effect on oxidative phosphorylation, consistent with our earlier observations of predicted effects on ATP synthesis in adult heterozygous psen1Q96_K97del brains. The dysregulation of minichromosome maintenance protein complex (MCM) genes strongly contributed to predicted effects on DNA replication and the cell cycle and may explain earlier observations of genome instability due to PSEN1 mutation. The upregulation of crystallin gene expression may be a response to defective activity of mutant Psen1 protein in endolysosomal acidification. Genes related to extracellular matrix (ECM) were downregulated, consistent with previous studies of EOfAD mutant iPSC neurons and postmortem late onset AD brains. Also, changes in expression of genes controlling iron ion transport were observed without identifiable changes in the prevalence of transcripts containing iron responsive elements (IREs) in their 3′ untranslated regions (UTRs). These changes may, therefore, predispose to the apparent iron dyshomeostasis previously observed in 6-month-old heterozygous psen1Q96_K97del EOfAD-like mutant brains.

scholarly journals Synthesis of oxadiazole-2-oxide derivatives as potential drug candidates for schistosomiasis targeting SjTGR

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Gongming Li ◽  
Qingqing Guo ◽  
Chao Feng ◽  
Huan Chen ◽  
Wenjiao Zhao ◽  
...  
Keyword(s):  
Schistosoma Japonicum ◽  
Inhibitory Activity ◽  
Pyridine Ring ◽  
New Drugs ◽  
Wild Type ◽  
Drug Candidates ◽  
Structure Activity ◽  
Docking Method ◽  
Antigen Protein ◽  
Thioredoxin Glutathione Reductase

Abstract Background Schistosomiasis is a chronic parasitic disease that affects millions of people’s health worldwide. Because of the increasing drug resistance to praziquantel (PZQ), which is the primary drug for schistosomiasis, developing new drugs to treat schistosomiasis is crucial. Oxadiazole-2-oxides have been identified as potential anti-schistosomiasis reagents targeting thioredoxin glutathione reductase (TGR). Methods In this work, one of the oxadiazole-2-oxides derivatives furoxan was used as the lead compound to exploit a series of novel furoxan derivatives for studying inhibitory activity against both recombinant Schistosoma japonicum TGR containing selenium (rSjTGR-Sec) and soluble worm antigen protein (SWAP) containing wild-type Schistosoma japonicum TGR (wtSjTGR), in order to develop a new leading compound for schistosomiasis. Thirty-nine novel derivatives were prepared to test their activity toward both enzymes. The docking method was used to detect the binding site between the active molecule and SjTGR. The structure–activity relationship (SAR) of these novel furoxan derivatives was preliminarily analyzed. Results It was found that several new derivatives, including compounds 6a–6d, 9ab, 9bd and 9be, demonstrated greater activity toward rSjTGR-Sec or SWAP containing wtSjTGR than did furoxan. Interestingly, all intermediates bearing hydroxy (6a–6d) showed excellent inhibitory activity against both enzymes. In particular, compound 6d with trifluoromethyl on a pyridine ring was found to have much higher inhibition toward both rSjTGR-Sec (half-maximal inhibitory concentration, IC50,7.5nM) and SWAP containing wtSjTGR (IC50 55.8nM) than furoxan. Additionally, the docking method identified the possible matching sites between 6d and Schistosoma japonicum TGR (SjTGR), which theoretically lends support to the inhibitory activity of 6d. Conclusion The data obtained herein showed that 6d with trifluoromethyl on a pyridine ring could be a valuable leading compound for further study.

Progress in analgesic development: How to assess its real merits?

2021 ◽  
Vol 16 ◽  
Author(s):  
Igor Kissin
Keyword(s):  
Drug Evaluation ◽  
Previous Treatment ◽  
Widespread Application ◽  
Drug Candidates ◽  
Advantages And Disadvantages ◽  
Inflammatory Drugs ◽  
Pain Analgesics ◽  
Approved Drugs ◽  
Multifactorial Approach ◽  
Opioid Receptor Agonists

Background: Assessing analgesic drugs developed over preceding 50 years demonstrated that very intensive efforts directed at diverse molecular pain targets produced thousands of PubMed articles and the introduction of more than 50 new analgesics. Nevertheless, these analgesics did not have a sufficiently broad spectrum of action and level of effectiveness to demonstrably affect the use of opioids or nonsteroidal anti-inflammatory drugs for the treatment of pain. Analgesics in current are only modestly effective in chronic pain (at least with respect to neuropathic pain), and the widespread application of mu opioid receptor agonists for this purpose culminated in the global "opioid crisis”. The introduction of every new drug is regarded as an important success, at least initially. Assessing the merit of a new analgesic is extremely complicated. Objective: The aim of this article is to describe an approach that combines very different categories of drug evaluation – multifactorial approach to assessment of new analgesics. It is based on conclusiveness of clinical trials, novelty of a drug’s molecular target, a drug’s commercial appeal, and the interest in a drug reflected by scientometric indices. Results: This approach was applied to analgesics developed in 1982-2016. It shows that although several new agents have completely novel mechanisms of action, all newly approved drugs, and drug candidates, demonstrated the same persistent problems: relatively low therapeutic advantage over previous treatment and narrow spectrum of use in different types of pain, compared to opioids or NSAIDs. Conclusion: The use of the suggested multifactorial approach to drug assessment may provide a better view of the whole spectrum of analgesics advantages and disadvantages.

scholarly journals Alpha Carbonic Anhydrase 5 Mediates Stimulation of ATP Synthesis by Bicarbonate in Isolated Arabidopsis Thylakoids

2021 ◽  
Vol 12 ◽  
Author(s):  
Tatiana P. Fedorchuk ◽  
Inga A. Kireeva ◽  
Vera K. Opanasenko ◽  
Vasily V. Terentyev ◽  
Natalia N. Rudenko ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Arabidopsis Thaliana ◽  
Carbonic Anhydrase ◽  
Atp Synthesis ◽  
Thylakoid Membranes ◽  
Wild Type ◽  
Gene Encoding ◽  
Mutant Lines ◽  
Stimulation Of ◽  
Soluble Carbonic Anhydrase

We studied bicarbonate-induced stimulation of photophosphorylation in thylakoids isolated from leaves of Arabidopsis thaliana plants. This stimulation was not observed in thylakoids of wild-type in the presence of mafenide, a soluble carbonic anhydrase inhibitor, and was absent in thylakoids of two mutant lines lacking the gene encoding alpha carbonic anhydrase 5 (αCA5). Using mass spectrometry, we revealed the presence of αCA5 in stromal thylakoid membranes of wild-type plants. A possible mechanism of the photophosphorylation stimulation by bicarbonate that involves αCA5 is proposed.

scholarly journals Genetic analysis of the Arabidopsis TIR1/AFB auxin receptors reveals both overlapping and specialized functions

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Michael J Prigge ◽  
Matthieu Platre ◽  
Nikita Kadakia ◽  
Yi Zhang ◽  
Kathleen Greenham ◽  
...  
Keyword(s):  
Genetic Analysis ◽  
Early Embryo ◽  
Wild Type ◽  
The Family ◽  
Dependent Inhibition ◽  
Root Gravitropism ◽  
Specialized Function ◽  
Mutant Lines

The TIR1/AFB auxin co-receptors mediate diverse responses to the plant hormone auxin. The Arabidopsis genome encodes six TIR1/AFB proteins representing three of the four clades that were established prior to angiosperm radiation. To determine the role of these proteins in plant development we performed an extensive genetic analysis involving the generation and characterization of all possible multiply-mutant lines. We find that loss of all six TIR1/AFB proteins results in early embryo defects and eventually seed abortion, and yet a single wild-type allele of TIR1 or AFB2 is sufficient to support growth throughout development. Our analysis reveals extensive functional overlap between even the most distantly related TIR1/AFB genes except for AFB1. Surprisingly, AFB1 has a specialized function in rapid auxin-dependent inhibition of root growth and early phase of root gravitropism. This activity may be related to a difference in subcellular localization compared to the other members of the family.

scholarly journals Mutagenesis development of actinoplanes sp. KCTC 9161 by N-methyl-N'-nitro-N-nitrosoguanidine (NTG) and screening for acarbose production

2018 ◽  
Vol 14 (4) ◽  
pp. 753-760
Author(s):  
Do Thi Tuyen ◽  
Nguyen The Duong ◽  
Le Thanh Hoang
Keyword(s):  
Type Ii Diabetes ◽  
Wild Type Strain ◽  
Fermentation Medium ◽  
Original Strain ◽  
Wild Type ◽  
Chromatography Method ◽  
Mutant Strains ◽  
Insulin Dependent ◽  
Mutant Lines ◽  
Layer Chromatography

Acarbose has been widely used in the therapy of type II diabetes (non-insulin dependent) because it controls blood sugar contents of patients after meals. Acarbose, a pseudo-oligosaccharide, acts as a competitive -glucosidase inhibitor. Acarbose is produced by the strains of Bacillus, Streptomyces and Actinoplanes sp. The aim of this study was to develop mutagenesis for an Actinoplanes sp. strain and screening for acarbose production. The spores of Actinoplanes sp. KCTC 9161 strain were subjected to be mutated by N-methyl-N'-nitro-N-nitrosoguanidine (NTG) for screening and finding mutant strains that were capable of production of higher acarbose (an inhibitor of α-glucosidase) higher than wild type strain. Firstly, the original NTG solution was prepared in phosphate buffer 0.05 M, pH 6.9 and the safety concentration of NTG was determined at 5 mg/ml. Then, the spores were incubated with different NTG amounts and duration. The living colonies were transferred to fermentation medium. The results obtained showed that 15 mutant strains were produced higher acarbose than wild type when used thin layer chromatography method for analysis and comparing with standard acarbose (Sigma). Three cell lines among total tested 15 mutant lines of Actinoplanes sp. KCTC 9161 produced acarbose at a higher level or indicated a higher inhibitory activity toward α-glucosidase than the original strain. Enzymatic inhibitory ativity of α-glucosidase of three mutant strains (Actinoplanes sp. KCTC- L4, L11, L14) was increased 1.3 fold higher than wild type and Actinoplanes sp. KCTC spores were very sensitive to NTG toxic, 98% spores could not survive at the treatment condition of 50 µg NTG for 30 minutes. In addition, an applicable protocol for mutating Actinoplanes sp. using NTG was suggested for further research.

Multiple effects of the starch synthase II mutation in developing wheat endosperm

2007 ◽  
Vol 34 (5) ◽  
pp. 431 ◽  
Author(s):  
Behjat Kosar-Hashemi ◽  
Zhongyi Li ◽  
Oscar Larroque ◽  
Ahmed Regina ◽  
Makoto Yamamori ◽  
...  
Keyword(s):  
Triticum Aestivum L ◽  
Endosperm Development ◽  
Starch Synthase ◽  
Starch Granules ◽  
Branching Enzyme ◽  
Wild Type ◽  
Drastic Reduction ◽  
Branching Patterns ◽  
Soluble Phase ◽  
Mutant Lines

A line of wheat (Triticum aestivum L.), sgp-1, that does not express starch synthase II (SSII, also known as SGP-1) has previously been reported. In this study, F1 derived doubled haploid lines with homozygous wild type or mutant alleles for SGP-1 genes were identified from a cross between the original mutant and a wild type Australian cultivar. Analysis of the starch granules showed that in the mutant lines they are markedly distorted from 15 days postanthesis during grain development. Starch branching patterns showed an increase in the proportion of short chains (DP 6–10) at an earlier stage, but this increase became much more pronounced at 15 days postanthesis and persisted until maturity. There was also a consistent and drastic reduction throughout seed development in the relative amounts of starch branching enzyme II (SBEII, comprising SBEIIa and SBEIIb) and starch synthase I (SSI) bound to the starch granules. In the soluble phase, however, there was relatively little change in the amount of SBEIIb, SBEIIa or SSI protein. Therefore loss of SSII specifically leads to the loss of SBEIIb, SBEIIa and SSI protein in the granule-bound phase and the effect of this mutation is clearly manifest from the mid-stage of endosperm development in wheat.

A highly divergent picornavirus infecting the gut epithelia of zebrafish (Danio rerio) in research institutions world-wide

2018 ◽  
Author(s):  
Eda Altan ◽  
Steven V. Kubiski ◽  
Ákos Boros ◽  
Gábor Reuter ◽  
Mohammadreza Sadeghi ◽  
...  
Keyword(s):  
World Wide ◽  
Natural Infection ◽  
Model Organism ◽  
Asymptomatic Infection ◽  
Viral Metagenomics ◽  
Vertebrate Development ◽  
Wild Type ◽  
Host Interactions ◽  
Vertebrate Model

AbstractZebrafish have been extensively used as a model system for research in vertebrate development and pathogen-host interactions. We describe the complete genome of a novel picornavirus identified during a viral metagenomics analysis of zebrafish gut tissue. The closest relatives of this virus showed identity of ≤19.8% in their P1 capsids and ≤35.4% in their RdRp qualifying zebrafish picornavirus 1 (ZfPV1) as member of a novel genus with a proposed name of Cyprivirus. RT-PCR testing of zebrafish from 41 institutions from North America, Europe, and Asia showed ZfPV1 to be highly prevalent world-wide. In situ hybridization of whole zebrafish showed viral RNA was restricted to a subset of enterocytes and cells in the subjacent lamina propria of the intestine and the intestinal mucosa. This naturally occurring and apparently asymptomatic infection (in wild type zebrafish lineage AB) provides a natural infection system to study picornavirus-host interactions in an advanced vertebrate model organism. Whether ZfPV1 infection affects any immunological, developmental or other biological processes in wild type or mutant zebrafish lineages remains to be determined.

scholarly journals Virtual screening web servers: designing chemical probes and drug candidates in the cyberspace

2020 ◽  
Author(s):  
Natesh Singh ◽  
Ludovic Chaput ◽  
Bruno O Villoutreix
Keyword(s):  
Virtual Screening ◽  
Drug Repositioning ◽  
Pharmaceutical Research ◽  
Bioactive Molecules ◽  
Screening Methods ◽  
Web Servers ◽  
Web Based ◽  
Drug Candidates ◽  
Screening Experiments ◽  
Molecule Docking

Abstract The interplay between life sciences and advancing technology drives a continuous cycle of chemical data growth; these data are most often stored in open or partially open databases. In parallel, many different types of algorithms are being developed to manipulate these chemical objects and associated bioactivity data. Virtual screening methods are among the most popular computational approaches in pharmaceutical research. Today, user-friendly web-based tools are available to help scientists perform virtual screening experiments. This article provides an overview of internet resources enabling and supporting chemical biology and early drug discovery with a main emphasis on web servers dedicated to virtual ligand screening and small-molecule docking. This survey first introduces some key concepts and then presents recent and easily accessible virtual screening and related target-fishing tools as well as briefly discusses case studies enabled by some of these web services. Notwithstanding further improvements, already available web-based tools not only contribute to the design of bioactive molecules and assist drug repositioning but also help to generate new ideas and explore different hypotheses in a timely fashion while contributing to teaching in the field of drug development.

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