scholarly journals A CellAgeClock for expedited discovery of anti-ageing compounds

2019 ◽  
Author(s):  
Celia Lujan ◽  
Eleanor J. Tyler ◽  
Simone Ecker ◽  
Amy P. Webster ◽  
Eleanor R. Stead ◽  
...  
Keyword(s):  
Cpg Methylation ◽  
Human Cells ◽  
Epigenetic Clock ◽  
The Novel ◽  
Drug Treatments ◽  
Screening Platform ◽  
Methylation Profiling ◽  
Primary Human Cells

AbstractWe aim to improve anti-ageing drug discovery, currently achieved through laborious and lengthy longevity analysis. Recent studies demonstrated that the most accurate molecular method to measure human age is based on CpG methylation profiles, as exemplified by several epigenetics clocks that can accurately predict an individual’s age. Here, we developed CellAgeClock, a new epigenetic clock that measures subtle ageing changes in primary human cells in vitro. As such, it provides a unique tool to measure effects of relatively short pharmacological treatments on ageing. We validated the CellAgeClock against known longevity drugs such as rapamycin and trametinib. Moreover, we uncovered novel anti-ageing drugs, torin2 and Dactolisib (BEZ-235), demonstrating the value of our approach as a screening and discovery platform for anti-ageing strategies. The CellAgeClock outperforms other epigenetic clocks in measuring subtle ageing changes in primary human cells in culture. The tested drug treatments reduced senescence and other ageing markers, further consolidating our approach as a screening platform. Finally, we show that the novel anti-ageing drugs we uncovered in vitro, indeed increased longevity in vivo. Our method expands the scope of CpG methylation profiling from measuring human chronological and biological age from human samples in years, to accurately and rapidly detecting anti-ageing potential of drugs using human cells in vitro, providing a novel accelerated discovery platform to test sought after geroprotectors.

scholarly journals Cathepsin L plays a key role in SARS-CoV-2 infection in humans and humanized mice and is a promising target for new drug development

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Miao-Miao Zhao ◽  
Wei-Li Yang ◽  
Fang-Yuan Yang ◽  
Li Zhang ◽  
Wei-Jin Huang ◽  
...  
Keyword(s):  
Drug Development ◽  
Cathepsin L ◽  
Human Cells ◽  
New Drugs ◽  
Disease Course ◽  
Promising Target ◽  
First Time

AbstractTo discover new drugs to combat COVID-19, an understanding of the molecular basis of SARS-CoV-2 infection is urgently needed. Here, for the first time, we report the crucial role of cathepsin L (CTSL) in patients with COVID-19. The circulating level of CTSL was elevated after SARS-CoV-2 infection and was positively correlated with disease course and severity. Correspondingly, SARS-CoV-2 pseudovirus infection increased CTSL expression in human cells in vitro and human ACE2 transgenic mice in vivo, while CTSL overexpression, in turn, enhanced pseudovirus infection in human cells. CTSL functionally cleaved the SARS-CoV-2 spike protein and enhanced virus entry, as evidenced by CTSL overexpression and knockdown in vitro and application of CTSL inhibitor drugs in vivo. Furthermore, amantadine, a licensed anti-influenza drug, significantly inhibited CTSL activity after SARS-CoV-2 pseudovirus infection and prevented infection both in vitro and in vivo. Therefore, CTSL is a promising target for new anti-COVID-19 drug development.

scholarly journals Characterization of the SARS-CoV-2 coronavirus X4-like accessory protein

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Olanrewaju Ayodeji Durojaye ◽  
Nkwachukwu Oziamara Okoro ◽  
Arome Solomon Odiba
Keyword(s):  
Rapid Development ◽  
Protein A ◽  
The Novel ◽  
Quality Model ◽  
A Value ◽  
Model Protein ◽  
Novel Coronavirus ◽  
Global Threat

Abstract Background The novel coronavirus SARS-CoV-2 is currently a global threat to health and economies. Therapeutics and vaccines are in rapid development; however, none of these therapeutics are considered as absolute cure, and the potential to mutate makes it necessary to find therapeutics that target a highly conserved regions of the viral structure. Results In this study, we characterized an essential but poorly understood coronavirus accessory X4 protein, a core and stable component of the SARS-CoV family. Sequence analysis shows a conserved ~ 90% identity between the SARS-CoV-2 and previously characterized X4 protein in the database. QMEAN Z score of the model protein shows a value of around 0.5, within the acceptable range 0–1. A MolProbity score of 2.96 was obtained for the model protein and indicates a good quality model. The model has Ramachandran values of φ = − 57o and ψ = − 47o for α-helices and values of φ = − 130o and ψ = + 140o for twisted sheets. Conclusions The protein data obtained from this study provides robust information for further in vitro and in vivo experiment, targeted at devising therapeutics against the virus. Phylogenetic analysis further supports previous evidence that the SARS-CoV-2 is positioned with the SL-CoVZC45, BtRs-BetaCoV/YN2018B and the RS4231 Bat SARS-like corona viruses.

In vitro and in vivo evaluation of a sustained-release once-a-day formulation of the novel antihypertensive drug MT-1207

2021 ◽  
Vol 26 (3) ◽  
pp. 349-361
Author(s):  
Napoleon-Nikolaos Vrettos ◽  
Peng Wang ◽  
Yan Zhou ◽  
Clive J. Roberts ◽  
Jinyi Xu ◽  
...  
Keyword(s):  
Sustained Release ◽  
Antihypertensive Drug ◽  
The Novel ◽  
In Vivo Evaluation

scholarly journals Overcoming multidrug-resistance in vitro and in vivo using the novel P-glycoprotein inhibitor 1416

2012 ◽  
Vol 32 (6) ◽  
pp. 559-566 ◽  
Author(s):  
Yan Xu ◽  
Feng Zhi ◽  
Guangming Xu ◽  
Xiaolei Tang ◽  
Sheng Lu ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Cancer Chemotherapy ◽  
Antitumour Activity ◽  
Multidrug Resistant ◽  
The Novel ◽  
Mice Model ◽  
P Glycoprotein ◽  
Channel Currents

MDR (multidrug-resistance) represents a major obstacle to successful cancer chemotherapy and is usually accomplished by overexpression of P-gp (P-glycoprotein). Much effort has been devoted to developing P-gp inhibitors to modulate MDR. However, none of the inhibitors on the market have been successful. 1416 [1-(2,6-dimethylphenoxy)-2-(3,4-dimethoxyphenylethylamino)propane hydrochloride (phenoprolamine hydrochloride)] is a new VER (verapamil) analogue with a higher IC50 for blocking calcium channel currents than VER. In the present paper, we examined the inhibition effect of 1416 on P-gp both in vitro and in vivo. 1416 significantly enhanced cytotoxicity of VBL (vinblastine) in P-gp-overexpressed human multidrug-resistant K562/ADM (adriamycin) and KBV cells, but had no such effect on the parent K562 and KB cells. The MDR-modulating function of 1416 was further confirmed by increasing intracellular Rh123 (rhodanmine123) content in MDR cells. Human K562/ADM xenograft-nude mice model verified that 1416 potentiates the antitumour activity of VBL in vivo. RT-PCR (reverse transcriptase-PCR) and FACS analysis demonstrated that the expression of MDR1/P-gp was not affected by 1416 treatment. All these observations suggest that 1416 could be a promising agent for overcoming MDR in cancer chemotherapy.

The novel calpain inhibitor A-705253 prevents stress-induced tau hyperphosphorylation in vitro and in vivo

2012 ◽  
Vol 63 (4) ◽  
pp. 606-612 ◽  
Author(s):  
Arthur L. Nikkel ◽  
Brenda Martino ◽  
Stella Markosyan ◽  
Jill-Desiree Brederson ◽  
Rodrigo Medeiros ◽  
...  
Keyword(s):  
Calpain Inhibitor ◽  
Tau Hyperphosphorylation ◽  
The Novel

scholarly journals The Novel Arylamidine T-2307 MaintainsIn VitroandIn VivoActivity against Echinocandin-Resistant Candida albicans

2014 ◽  
Vol 59 (2) ◽  
pp. 1341-1343 ◽  
Author(s):  
Nathan P. Wiederhold ◽  
Laura K. Najvar ◽  
Annette W. Fothergill ◽  
Rosie Bocanegra ◽  
Marcos Olivo ◽  
...  
Keyword(s):  
Body Weight ◽  
Candida Albicans ◽  
Invasive Candidiasis ◽  
Placebo Control ◽  
The Novel ◽  
Content Type ◽  
Fungal Burden ◽  
Potential Use

ABSTRACTWe evaluated thein vitroandin vivoactivities of the investigational arylamidine T-2307 against echinocandin-resistantCandida albicans. T-2307 demonstrated potentin vitroactivity, and daily subcutaneous doses between 0.75 and 6 mg/kg of body weight significantly improved survival and reduced fungal burden compared to placebo control and caspofungin (10 mg/kg/day) in mice with invasive candidiasis caused by an echinocandin-resistant strain. Thus, T-2307 may have potential use in the treatment of echinocandin-resistantC. albicansinfections.

scholarly journals A NewIn VivoModel System to Assess the Toxicity of Semiconductor Nanocrystals

2011 ◽  
Vol 2011 ◽  
pp. 1-8 ◽  
Author(s):  
Angela Tino ◽  
Alfredo Ambrosone ◽  
Lucia Mattera ◽  
Valentina Marchesano ◽  
Andrei Susha ◽  
...  
Keyword(s):  
Semiconductor Nanocrystals ◽  
Minimal Risk ◽  
The Novel ◽  
Toxicological Evaluation ◽  
Hydra Vulgaris ◽  
Population Growth Rates ◽  
Single Structure

In the emerging area of nanotechnology, a key issue is related to the potential impacts of the novel nanomaterials on the environment and human health, so that this technology can be used with minimal risk. Specifically designed to combine on a single structure multipurpose tags and properties, smart nanomaterials need a comprehensive characterization of both chemicophysical properties and adequate toxicological evaluation, which is a challenging endeavour; thein vitrotoxicity assays that are often employed for nanotoxicity assessments do not accurately predictin vivoresponse. To overcome these limitations and to evaluate toxicity characteristics of cadmium telluride quantum dots in relation to surface coatings, we have employed the freshwater polypHydra vulgarisas a model system. We assessedin vivoacute and sublethal toxicity by scoring for alteration of morphological traits, population growth rates, and influence on the regenerative capabilities providing new investigation clues for nanotoxicology purposes.

Development of Novel Bioactive PMMA-Based Bone Cement and its In Vitro and In Vivo Evaluation

2006 ◽  
Vol 309-311 ◽  
pp. 801-804 ◽  
Author(s):  
S.B. Cho ◽  
Akari Takeuchi ◽  
Ill Yong Kim ◽  
Sang Bae Kim ◽  
Chikara Ohtsuki ◽  
...  
Keyword(s):  
Mechanical Property ◽  
Compressive Strength ◽  
Bone Cement ◽  
The Novel ◽  
In Vivo Evaluation ◽  
Natural Bone ◽  
Pmma Bone Cement ◽  
Rabbit Tibia

In order to overcome the disadvantage of commercialized PMMA bone cement, we have developed novel PMMA-based bone cement(7P3S) reinforced by 30 wt.% of bioactive CaO-SiO2 gel powders to induce the bioactivity as well as to increase mechanical property for the PMMA bone cement. The novel 7P3S bone cement hardened after mixing for about 7 minutes. For in vitro evaluation, apatite forming ability of it was investigated using SBF. When the novel 7P3S bone cement was soaked into SBF, it formed apatite on its surfaces within 1 week Furthermore; there is no decrease in its compressive strength within 9 weeks soaking in SBF. It is though that hardly decrease in compressive strength of 7P3S bone cement in SBF is due to the relative small amount of gel powder or its spherical shape and monosize. In vivo evaluation of the novel 7P3S bone cement was carried out using rabbit. After implantion into rabbit tibia for several periods, the interface between novel bone cement and natural bone was evaluated by CT images. According to the results, the novel bone cement directly contact to the natural bone without fibrous tissue after implantation for 4 weeks. This results indicates that the newly developed 7P3S bone cement can bond to the living bone and also be effectively used as bioactive bone cement without decrease in mechanical property.

The novel dual topoisomerase inhibitor P8-D6 shows anti-myeloma activity in vitro and in vivo

2021 ◽  
pp. molcanther.0119.2021
Author(s):  
Katja Klausz ◽  
Christian Kellner ◽  
Carina Lynn Gehlert ◽  
Steffen Krohn ◽  
Hauke Wilcken ◽  
...  
Keyword(s):  
The Novel ◽  
Topoisomerase Inhibitor

The phylogenetically invariant ACAGAGA and AGC sequences of U6 small nuclear RNA are more tolerant of mutation in human cells than in Saccharomyces cerevisiae

1993 ◽  
Vol 13 (9) ◽  
pp. 5377-5382
Author(s):  
B Datta ◽  
A M Weiner
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Transient Expression ◽  
Human Cells ◽  
Mrna Splicing ◽  
Small Nuclear Rna ◽  
Transient Expression Assay ◽  
U6 Snrna ◽  
Nuclear Rna

U6 small nuclear RNA (snRNA) is the most highly conserved of the five spliceosomal snRNAs that participate in nuclear mRNA splicing. The proposal that U6 snRNA plays a key catalytic role in splicing [D. Brow and C. Guthrie, Nature (London) 337:14-15, 1989] is supported by the phylogenetic conservation of U6, the sensitivity of U6 to mutation, cross-linking of U6 to the vicinity of the 5' splice site, and genetic evidence for extensive base pairing between U2 and U6 snRNAs. We chose to mutate the phylogenetically invariant 41-ACAGAGA-47 and 53-AGC-55 sequences of human U6 because certain point mutations within the homologous regions of Saccharomyces cerevisiae U6 selectively block the first or second step of mRNA splicing. We found that both sequences are more tolerant to mutation in human cells (assayed by transient expression in vivo) than in S. cerevisiae (assayed by effects on growth or in vitro splicing). These differences may reflect different rate-limiting steps in the particular assays used or differential reliance on redundant RNA-RNA or RNA-protein interactions. The ability of mutations in U6 nucleotides A-45 and A-53 to selectively block step 2 of splicing in S. cerevisiae had previously been construed as evidence that these residues might participate directly in the second chemical step of splicing; an indirect, structural role seems more likely because the equivalent mutations have no obvious phenotype in the human transient expression assay.

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