SSC-ILD mouse model induced by osmotic minipump delivered bleomycin: effect of Nintedanib

AbstractSystemic sclerosis (SSc) is an autoimmune disease characterized by an excessive production and accumulation of collagen in the skin and internal organs often associated with interstitial lung disease (ILD). Its pathogenetic mechanisms are unknown and the lack of animal models mimicking the features of the human disease is creating a gap between the selection of anti-fibrotic drug candidates and effective therapies. In this work, we intended to pharmacologically validate a SSc-ILD model based on 1 week infusion of bleomycin (BLM) by osmotic minipumps in C57/BL6 mice, since it will serve as a tool for secondary drug screening. Nintedanib (NINT) has been used as a reference compound to investigate antifibrotic activity either for lung or skin fibrosis. Longitudinal Micro-CT analysis highlighted a significant slowdown in lung fibrosis progression after NINT treatment, which was confirmed by histology. However, no significant effect was observed on lung hydroxyproline content, inflammatory infiltrate and skin lipoatrophy. The modest pharmacological effect reported here could reflect the clinical outcome, highlighting the reliability of this model to better profile potential clinical drug candidates. The integrative approach presented herein, which combines longitudinal assessments with endpoint analyses, could be harnessed in drug discovery to generate more reliable, reproducible and robust readouts.

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Pharmacological validation of SSc-ILD mouse model bleomycin-induced by osmotic minipump

10.21203/rs.3.rs-493155/v1 ◽

2021 ◽

Author(s):

Francesca Ravanetti ◽

Erica Ferrini ◽

Luisa Ragionieri ◽

Zahra Khalajzeyqami ◽

Maria Nicastro ◽

...

Keyword(s):

Mouse Model ◽

Micro Ct ◽

Internal Organs ◽

Drug Candidates ◽

Fibrosis Progression ◽

Pharmacological Response ◽

Ct Analysis ◽

Clinical Drug ◽

Selection Of

Abstract Systemic sclerosis (SSc) is an autoimmune disease characterized by an excessive production and accumulation of collagen in the skin and internal organs often associated with interstitial lung disease (ILD). The unknown pathogenetic mechanisms of SSc-ILD and the lack of animal models mimicking the features of the human disease contribute to create a gap between the selection of antifibrotic drug candidates and effective therapies. Nintedanib (NINT) was used as a tool compound to validate the pharmacological response either on lung or skin fibrosis in a SSc-ILD mouse model. The model is based on the continuous infusion of bleomycin (BLM) by osmotic minipumps for 1 week in the C57BL/6 female mice. Longitudinal Micro-CT analysis highlighted a significant slowdown in lung fibrosis progression after NINT treatment, then confirmed by histology. However, no significant effect was observed on lung hydroxyproline content, inflammatory infiltrate and skin lipoatrophy. The modest pharmacological effect reported reflects the clinical outcome, lighting up the reliability of this model to serve as secondary screening to profile the best clinical drug candidates. Moreover, we have underlined the pivotal role of Micro-CT imaging, together describing the relevant readouts and the importance of their validation prior to use for drug discovery.

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Thymus Vulgaris Inhibit Lung Fibrosis Progression and Oxidative Stress Induced by Bleomycin in Wistar Rats

Nutrition and Cancer ◽

10.1080/01635581.2021.1952451 ◽

2021 ◽

pp. 1-11

Author(s):

Sana Bahri ◽

Mona Mlika ◽

Afef Nahdi ◽

Ridha Ben Ali ◽

Saloua Jameleddine

Keyword(s):

Oxidative Stress ◽

Lung Fibrosis ◽

Wistar Rats ◽

Thymus Vulgaris ◽

Fibrosis Progression ◽

And Oxidative Stress

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Micro‐CT analysis of the Lisfranc complex reveals higher bone mineral density in dorsal compared to plantar regions

Journal of Orthopaedic Research® ◽

10.1002/jor.25164 ◽

2021 ◽

Author(s):

Melissa R. Requist ◽

Yantarat Sripanich ◽

Tim Rolvien ◽

Amy L. Lenz ◽

Alexej Barg

Keyword(s):

Bone Mineral Density ◽

Bone Mineral ◽

Micro Ct ◽

Mineral Density ◽

Ct Analysis

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A Micro-Computed Tomography Comparison of the Porosity in Additively Fabricated CuCr1 Alloy Parts Using Virgin and Surface-Modified Powders

Materials ◽

10.3390/ma14081995 ◽

2021 ◽

Vol 14 (8) ◽

pp. 1995

Author(s):

Mirko Sinico ◽

Suraj Dinkar Jadhav ◽

Ann Witvrouw ◽

Kim Vanmeensel ◽

Wim Dewulf

Keyword(s):

High Energy ◽

High Energy Density ◽

Micro Ct ◽

Micro Computed Tomography ◽

Powder Bed ◽

Metallurgical Defects ◽

Ct Analysis ◽

Ct Data ◽

Surface Modified ◽

Fusion Pores

Recently, the use of novel CuCr1 surface-modified powder for reliable laser powder-bed fusion (LPBF) manufacturing has been proposed, enabling a broader LPBF processing window and longer powder storage life. Nevertheless, virgin CuCr1 powder is also LPBF processable, on the condition that a high-energy density is employed. In this work, we compare two dense specimens produced from virgin and surface-modified CuCr1 powder. Furthermore, a third sample fabricated from surface-modified powder is characterized to understand an abnormal porosity content initially detected through Archimedes testing. Utilizing high-resolution micro-CT scans, the nature of the defects present in the different samples is revealed. Pores are analyzed in terms of size, morphology and spatial distribution. The micro-CT data reveal that the virgin CuCr1 dense specimen displays keyhole pores plus pit cavities spanning multiple layer thicknesses. On the other hand, the sample fabricated with the surface-modified CuCr1 powder mainly contains small and spherical equi-distributed metallurgical defects. Finally, the CT analysis of the third specimen reveals the presence of a W contamination, favoring lack-of-fusion pores between subsequent LPBF layers. The LPBF melting mode (keyhole or conductive), the properties of the material, and the potential presence of contaminants are connected to the different porosity types and discussed.

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Analysis of Porous Structure in Autoclaved Materials Modified by Glass Sand

Crystals ◽

10.3390/cryst11040408 ◽

2021 ◽

Vol 11 (4) ◽

pp. 408

Author(s):

Anna Stepien

Keyword(s):

Computed Tomography ◽

Building Materials ◽

Micro Ct ◽

Structure Building ◽

Acoustic Insulation ◽

Ct Analysis ◽

Glass Sand ◽

Aerated Concrete ◽

Wall Construction ◽

Dominant Phase

This paper describes the use of glass sand in the production of autoclaved bricks. Traditional autoclaved materials consist of SiO2, CaO, and H2O. The purpose of the tests is to analyze the possibility of using glass sand in autoclaved materials and to determine their properties and durability. Depending on the structure, building materials can have porosities ranging from 0% (glass, metals) to over 90% (thermal insulation materials such as aerated concrete). Porosity of materials is directly related to the strength of materials and their density, and further to the thermal and acoustic insulation properties of products used especially for external wall construction, i.e., bricks, concrete, and aerated concrete. This type of silicate brick is formed at a temperature of 203 °C, therefore the dominant phase forming the microstructure is tobermorite, in contrast to the C-S-H phase, which dominates in concretes and which is characterized by a larger specific surface. The nature of pores, their number, appearance and arrangement in the material can be studied using computer techniques (SEM, XRD, computed tomography, porosimetry). Computed tomography (micro-CT analysis) showed that the number of voids in the material modified by glass sand is about 20% in relation to the weight of the product. The density of the product with glass sand was determined to be 2.2 kg/dm3.

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A Dual-Sensor-Based Screening System for In Vitro Selection of TDP1 Inhibitors

Sensors ◽

10.3390/s21144832 ◽

2021 ◽

Vol 21 (14) ◽

pp. 4832

Author(s):

Ann-Katrine Jakobsen ◽

Josephine Geertsen Keller ◽

María Gonzalez ◽

Endika Martin-Encinas ◽

Francisco Palacios ◽

...

Keyword(s):

Dna Damage ◽

In Vitro Selection ◽

Main Function ◽

Screening System ◽

Drug Candidates ◽

Topoisomerase 1 ◽

High Throughput Drug Screening ◽

Dual Sensor ◽

Selection Of

DNA sensors can be used as robust tools for high-throughput drug screening of small molecules with the potential to inhibit specific enzymes. As enzymes work in complex biological pathways, it is important to screen for both desired and undesired inhibitory effects. We here report a screening system utilizing specific sensors for tyrosyl-DNA phosphodiesterase 1 (TDP1) and topoisomerase 1 (TOP1) activity to screen in vitro for drugs inhibiting TDP1 without affecting TOP1. As the main function of TDP1 is repair of TOP1 cleavage-induced DNA damage, inhibition of TOP1 cleavage could thus reduce the biological effect of the TDP1 drugs. We identified three new drug candidates of the 1,5-naphthyridine and 1,2,3,4-tetrahydroquinolinylphosphine sulfide families. All three TDP1 inhibitors had no effect on TOP1 activity and acted synergistically with the TOP1 poison SN-38 to increase the amount of TOP1 cleavage-induced DNA damage. Further, they promoted cell death even with low dose SN-38, thereby establishing two new classes of TDP1 inhibitors with clinical potential. Thus, we here report a dual-sensor screening approach for in vitro selection of TDP1 drugs and three new TDP1 drug candidates that act synergistically with TOP1 poisons.

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