Drug-induced hepatotoxicity studied in a 3D, <em>in vitro</em> model of the liver

Drug development is a high failure rate process; too many drugs fail during clinical trials because of severe hepatotoxicity. This situation can be significantly improved by redesigning preclinical trials, and privileging the use of high-throughput in vitro models, by combining cell-based in vitro models and material-based models.

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Modulation of Matrix Metalloproteinases by Plant-Derived Products

Current Cancer Drug Targets ◽

10.2174/1568009620666201120144838 ◽

2020 ◽

Vol 20 ◽

Author(s):

Nur Najmi Mohamad Anuar ◽

Nurul Iman Natasya Zulkafali ◽

Azizah Ugusman

Keyword(s):

Clinical Trials ◽

Natural Products ◽

Matrix Metalloproteinases ◽

Animal Studies ◽

Current Knowledge ◽

In Vitro Models ◽

In Vivo Studies ◽

Extracellular Matrix Components

: Matrix metalloproteinases (MMPs) are a group of zinc-dependent metallo-endopeptidase that are responsible towards the degradation, repair and remodelling of extracellular matrix components. MMPs play an important role in maintaining a normal physiological function and preventing diseases such as cancer and cardiovascular diseases. Natural products derived from plants have been used as traditional medicine for centuries. Its active compounds, such as catechin, resveratrol and quercetin, are suggested to play an important role as MMPs inhibitors, thereby opening new insights into their applications in many fields, such as pharmaceutical, cosmetic and food industries. This review summarises the current knowledge on plant-derived natural products with MMP-modulating activities. Most of the reviewed plant-derived products exhibit an inhibitory activity on MMPs. Amongst MMPs, MMP-2 and MMP-9 are the most studied. The expression of MMPs is inhibited through respective signalling pathways, such as MAPK, NF-κB and PI3 kinase pathways, which contribute to the reduction in cancer cell behaviours, such as proliferation and migration. Most studies have employed in vitro models, but a limited number of animal studies and clinical trials have been conducted. Even though plant-derived products show promising results in modulating MMPs, more in vivo studies and clinical trials are needed to support their therapeutic applications in the future.

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O23: CHARACTERISING PATIENT-DERIVED COLORECTAL CANCER TISSUE-ORIGINATED ORGANOIDAL SPHEROIDS FOR HIGH-THROUGHPUT MICROFLUIDIC APPLICATIONS

British Journal of Surgery ◽

10.1093/bjs/znab117.023 ◽

2021 ◽

Vol 108 (Supplement_1) ◽

Author(s):

MI Khot ◽

M Levenstein ◽

R Coppo ◽

J Kondo ◽

M Inoue ◽

...

Keyword(s):

Colorectal Cancer ◽

Fluid Flow ◽

High Throughput ◽

Microfluidic Devices ◽

In Vitro Models ◽

Fluorescent Imaging ◽

Cancer Tissue ◽

Cell Models

Abstract Introduction Three-dimensional (3D) cell models have gained reputation as better representations of in vivo cancers as compared to monolayered cultures. Recently, patient tumour tissue-derived organoids have advanced the scope of complex in vitro models, by allowing patient-specific tumour cultures to be generated for developing new medicines and patient-tailored treatments. Integrating 3D cell and organoid culturing into microfluidics, can streamline traditional protocols and allow complex and precise high-throughput experiments to be performed with ease. Method Patient-derived colorectal cancer tissue-originated organoidal spheroids (CTOS) cultures were acquired from Kyoto University, Japan. CTOS were cultured in Matrigel and stem-cell media. CTOS were treated with 5-fluorouracil and cytotoxicity evaluated via fluorescent imaging and ATP assay. CTOS were embedded, sectioned and subjected to H&E staining and immunofluorescence for ABCG2 and Ki67 proteins. HT29 colorectal cancer spheroids were produced on microfluidic devices using cell suspensions and subjected to 5-fluorouracil treatment via fluid flow. Cytotoxicity was evaluated through fluorescent imaging and LDH assay. Result 5-fluorouracil dose-dependent reduction in cell viability was observed in CTOS cultures (p<0.01). Colorectal CTOS cultures retained the histology, tissue architecture and protein expression of the colonic epithelial structure. Uniform 3D HT29 spheroids were generated in the microfluidic devices. 5-fluorouracil treatment of spheroids and cytotoxic analysis was achieved conveniently through fluid flow. Conclusion Patient-derived CTOS are better complex models of in vivo cancers than 3D cell models and can improve the clinical translation of novel treatments. Microfluidics can streamline high-throughput screening and reduce the practical difficulties of conventional organoid and 3D cell culturing. Take-home message Organoids are the most advanced in vitro models of clinical cancers. Microfluidics can streamline and improve traditional laboratory experiments.

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A high-throughput screen for TMPRSS2 expression identifies FDA-approved compounds that can limit SARS-CoV-2 entry

Nature Communications ◽

10.1038/s41467-021-24156-y ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Yanwen Chen ◽

Travis B. Lear ◽

John W. Evankovich ◽

Mads B. Larsen ◽

Bo Lin ◽

...

Keyword(s):

Rational Design ◽

Surface Expression ◽

In Vitro Models ◽

Lung Epithelial Cells ◽

Cell Surface Receptor ◽

Pharmacokinetic Data ◽

Drug Induced ◽

Global Pandemic ◽

Surface Receptor

AbstractSARS-CoV-2 (2019-nCoV) is the pathogenic coronavirus responsible for the global pandemic of COVID-19 disease. The Spike (S) protein of SARS-CoV-2 attaches to host lung epithelial cells through the cell surface receptor ACE2, a process dependent on host proteases including TMPRSS2. Here, we identify small molecules that reduce surface expression of TMPRSS2 using a library of 2,560 FDA-approved or current clinical trial compounds. We identify homoharringtonine and halofuginone as the most attractive agents, reducing endogenous TMPRSS2 expression at sub-micromolar concentrations. These effects appear to be mediated by a drug-induced alteration in TMPRSS2 protein stability. We further demonstrate that halofuginone modulates TMPRSS2 levels through proteasomal-mediated degradation that involves the E3 ubiquitin ligase component DDB1- and CUL4-associated factor 1 (DCAF1). Finally, cells exposed to homoharringtonine and halofuginone, at concentrations of drug known to be achievable in human plasma, demonstrate marked resistance to SARS-CoV-2 infection in both live and pseudoviral in vitro models. Given the safety and pharmacokinetic data already available for the compounds identified in our screen, these results should help expedite the rational design of human clinical trials designed to combat active COVID-19 infection.

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A systematic review of in vitro models of drug induced kidney injury

Current Opinion in Toxicology ◽

10.1016/j.cotox.2021.06.001 ◽

2021 ◽

Author(s):

Alasdair R. Irvine ◽

Damiën van Berlo ◽

Rawan Shekani ◽

Rosalinde Masereeuw

Keyword(s):

Systematic Review ◽

Kidney Injury ◽

In Vitro Models ◽

Drug Induced

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Advances in predictive in vitro models of drug-induced nephrotoxicity

Nature Reviews Nephrology ◽

10.1038/s41581-018-0003-9 ◽

2018 ◽

Vol 14 (6) ◽

pp. 378-393 ◽

Cited By ~ 37

Author(s):

Joanne Y.-C. Soo ◽

Jitske Jansen ◽

Rosalinde Masereeuw ◽

Melissa H. Little

Keyword(s):

In Vitro Models ◽

Drug Induced

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The Use of Erythropoietin in the Treatment of Post-bone Marrow Transplatation Anemia

The International Journal of Artificial Organs ◽

10.1177/039139889301605s02 ◽

1993 ◽

Vol 16 (5_suppl) ◽

pp. 8-12 ◽

Cited By ~ 1

Author(s):

A.M. Vannucchi ◽

A. Bosi ◽

A. Grossi ◽

S. Guidi ◽

R. Saccardi ◽

...

Keyword(s):

Bone Marrow ◽

Clinical Trials ◽

Bone Marrow Transplantation ◽

Blood Transfusion ◽

In Vitro Models ◽

Immunosuppressive Drug ◽

Number Of Patients

The issue of the role of erythropoietin (Epo) in the erythroid reconstitution after bone marrow transplantation (BMT) has been addressed in several recent studies. A defective Epo production in response to anemia has been shown to occur in patients undergoing allogeneic BMT unlike in most of those subjected to an autologous rescue. The factors involved in the inadeguate Epo production in BMT are discussed, with particular attention to the role of the immunosuppressive drug cyclosporin-A, which has been shown to inhibit Epo production in both in vivo and in vitro models. The observation of defective Epo production eventually led to the development of clinical trials of recombinant human Epo (rhEpo) administration in BMT patients; the aims of these studies were to stimulate erythroid engraftment, hence reducing blood transfusion exposure. Although the number of patients studied up to now is relatively small, a benefit from rhEpo administration in terms of accelerated erythroid engraftment seems very likely, and it may also be associated with decreased transfusional needs in most treated patients. However, further studies are needed to better define indications, dosages and schedules of rhEpo in BMT patients.

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Mechanisms and in vitro models of drug-induced cholestasis

Archives of Toxicology ◽

10.1007/s00204-019-02437-2 ◽

2019 ◽

Vol 93 (5) ◽

pp. 1169-1186 ◽

Cited By ~ 6

Author(s):

Eva Gijbels ◽

Vânia Vilas-Boas ◽

Neel Deferm ◽

Lindsey Devisscher ◽

Hartmut Jaeschke ◽

...

Keyword(s):

In Vitro Models ◽

Drug Induced

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Computational toxicology

Human & Experimental Toxicology ◽

10.1177/0960327115605440 ◽

2015 ◽

Vol 34 (12) ◽

pp. 1304-1309 ◽

Cited By ~ 14

Author(s):

RT Naven ◽

S Louise-May

Keyword(s):

Critical Role ◽

Pharmaceutical Research ◽

In Vitro Models ◽

New Drugs ◽

Data Sets ◽

Predictive Toxicology ◽

Drug Induced ◽

Chemical Toxicology

Predictive toxicology plays a critical role in reducing the failure rate of new drugs in pharmaceutical research and development. Despite recent gains in our understanding of drug-induced toxicity, however, it is urgent that the utility and limitations of our current predictive tools be determined in order to identify gaps in our understanding of mechanistic and chemical toxicology. Using recently published computational regression analyses of in vitro and in vivo toxicology data, it will be demonstrated that significant gaps remain in early safety screening paradigms. More strategic analyses of these data sets will allow for a better understanding of their domain of applicability and help identify those compounds that cause significant in vivo toxicity but which are currently mis-predicted by in silico and in vitro models. These ‘outliers’ and falsely predicted compounds are metaphorical lighthouses that shine light on existing toxicological knowledge gaps, and it is essential that these compounds are investigated if attrition is to be reduced significantly in the future. As such, the modern computational toxicologist is more productively engaged in understanding these gaps and driving investigative toxicology towards addressing them.

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