Particulate and drug-induced toxicity assessed in novel quadruple cell human primary hepatic disease models of steatosis and pre-fibrotic NASH

AbstractIn an effort to replace, reduce and refine animal experimentation, there is an unmet need to advance current in vitro models that offer features with physiological relevance and enhanced predictivity of in vivo toxicological output. Hepatic toxicology is key following chemical, drug and nanomaterials (NMs) exposure, as the liver is vital in metabolic detoxification of chemicals as well as being a major site of xenobiotic accumulation (i.e., low solubility particulates). With the ever-increasing production of NMs, there is a necessity to evaluate the probability of consequential adverse effects, not only in health but also in clinically asymptomatic liver, as part of risk stratification strategies. In this study, two unique disease initiation and maintenance protocols were developed and utilised to mimic steatosis and pre-fibrotic NASH in scaffold-free 3D liver microtissues (MT) composed of primary human hepatocytes, hepatic stellate cells, Kupffer cells and sinusoidal endothelial cells. The characterized diseased MT were utilized for the toxicological assessment of a panel of xenobiotics. Highlights from the study included: 1. Clear experimental evidence for the pre-existing liver disease is important in the augmentation of xenobiotic-induced hepatotoxicity and 2. NMs are able to activate stellate cells. The data demonstrated that pre-existing disease is vital in the intensification of xenobiotic-induced liver damage. Therefore, it is imperative that all stages of the wide spectrum of liver disease are incorporated in risk assessment strategies. This is of significant consequence, as a substantial number of the general population suffer from sub-clinical liver injury without any apparent or diagnosed manifestations.

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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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Mechanism-Based Markers of Drug-Induced Liver Injury to Improve the Physiological Relevance and Predictivity of In Vitro Models

Applied In Vitro Toxicology ◽

10.1089/aivt.2015.0001 ◽

2015 ◽

Vol 1 (3) ◽

pp. 175-186 ◽

Cited By ~ 4

Author(s):

Chris Goldring ◽

Alan Norris ◽

Neil Kitteringham ◽

Michael D. Aleo ◽

Daniel J. Antoine ◽

...

Keyword(s):

Liver Injury ◽

In Vitro Models ◽

Drug Induced ◽

Drug Induced Liver Injury ◽

Physiological Relevance

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Studying non-alcoholic fatty liver disease: the ins and outs of in vivo, ex vivo and in vitro human models

Hormone Molecular Biology and Clinical Investigation ◽

10.1515/hmbci-2018-0038 ◽

2018 ◽

Vol 0 (0) ◽

Cited By ~ 3

Author(s):

Charlotte J. Green ◽

Siôn A. Parry ◽

Pippa J. Gunn ◽

Carlo D.L. Ceresa ◽

Fredrik Rosqvist ◽

...

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

Fatty Liver Disease ◽

In Vitro Models ◽

Ex Situ ◽

Whole Body ◽

Alcoholic Fatty Liver ◽

Alcoholic Fatty Liver Disease

AbstractThe prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing. Determining the pathogenesis and pathophysiology of human NAFLD will allow for evidence-based prevention strategies, and more targeted mechanistic investigations. Various in vivo, ex situ and in vitro models may be utilised to study NAFLD; but all come with their own specific caveats. Here, we review the human-based models and discuss their advantages and limitations in regards to studying the development and progression of NAFLD. Overall, in vivo whole-body human studies are advantageous in that they allow for investigation within the physiological setting, however, limited accessibility to the liver makes direct investigations challenging. Non-invasive imaging techniques are able to somewhat overcome this challenge, whilst the use of stable-isotope tracers enables mechanistic insight to be obtained. Recent technological advances (i.e. normothermic machine perfusion) have opened new opportunities to investigate whole-organ metabolism, thus ex situ livers can be investigated directly. Therefore, investigations that cannot be performed in vivo in humans have the potential to be undertaken. In vitro models offer the ability to perform investigations at a cellular level, aiding in elucidating the molecular mechanisms of NAFLD. However, a number of current models do not closely resemble the human condition and work is ongoing to optimise culturing parameters in order to recapitulate this. In summary, no single model currently provides insight into the development, pathophysiology and progression across the NAFLD spectrum, each experimental model has limitations, which need to be taken into consideration to ensure appropriate conclusions and extrapolation of findings are made.

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Best Practices and Progress in Precision-Cut Liver Slice Cultures

International Journal of Molecular Sciences ◽

10.3390/ijms22137137 ◽

2021 ◽

Vol 22 (13) ◽

pp. 7137

Author(s):

Liza Dewyse ◽

Hendrik Reynaert ◽

Leo A. van Grunsven

Keyword(s):

Liver Disease ◽

In Vitro Model ◽

Liver Slice ◽

In Vitro Models ◽

Promising Tool ◽

Cell Matrix ◽

Vitro Model ◽

Cell Matrix Interactions

Thirty-five years ago, precision-cut liver slices (PCLS) were described as a promising tool and were expected to become the standard in vitro model to study liver disease as they tick off all characteristics of a good in vitro model. In contrast to most in vitro models, PCLS retain the complex 3D liver structures found in vivo, including cell–cell and cell–matrix interactions, and therefore should constitute the most reliable tool to model and to investigate pathways underlying chronic liver disease in vitro. Nevertheless, the biggest disadvantage of the model is the initiation of a procedure-induced fibrotic response. In this review, we describe the parameters and potential of PCLS cultures and discuss whether the initially described limitations and pitfalls have been overcome. We summarize the latest advances in PCLS research and critically evaluate PCLS use and progress since its invention in 1985.

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Innovative In Vitro Models for the Study of Lung Diseases

10.5772/intechopen.95300 ◽

2020 ◽

Author(s):

Vittorio Picchio ◽

Vittoria Cammisotto ◽

Francesca Pagano ◽

Roberto Carnevale ◽

Isotta Chimenti

Keyword(s):

In Vitro Models ◽

New Drugs ◽

In Vivo Studies ◽

Chronic Obstructive ◽

Obstructive Pulmonary Disease ◽

Physiological Relevance ◽

Complex Models ◽

On Chip

Basic and translational research on lung biology and pathology can greatly benefit from the development of 3D in vitro models with physiological relevance. Lung organoids and lungs-on-chip allow the creation of different kinds of in vitro microenvironments, that can be useful for the elucidation of novel pathogenetic pathways, for example concerning tissue fibrosis in chronic diseases. Moreover, they represent important translational models for the identification of novel therapeutic targets, and for preliminary testing of new drugs. In this chapter, we provide a selected overview of recent studies on innovative 3D in vitro models that have enhanced our knowledge on chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF), particularly concerning oxidative stress and pro-fibrotic pathogenetic mechanisms. Despite several limitations, these complex models must be considered as complementary in all respects to in vivo studies on animal models and clinical research.

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An in vivo CRISPR screening platform for prioritizing therapeutic targets in AML

10.1101/2020.12.28.424340 ◽

2020 ◽

Author(s):

Shan Lin ◽

Clément Larrue ◽

Bo Kyung A. Seong ◽

Neekesh V. Dharia ◽

Miljan Kuljanin ◽

...

Keyword(s):

Hematologic Malignancy ◽

Unmet Need ◽

Therapeutic Targets ◽

Poor Overall Survival ◽

Screening Approach ◽

Physiological Relevance ◽

Screening Platform ◽

Clinical Potential

AbstractCRISPR-Cas9-based genetic screens have successfully identified cell type-dependent liabilities in cancers, including acute myeloid leukemia (AML), a devastating hematologic malignancy with poor overall survival. Because most of these screens have been performed in vitro, evaluating the physiological relevance of these targets is critical. We have established a CRISPR screening approach using orthotopic xenograft models to prioritize AML-enriched dependencies in vivo, complemented by the validation in CRISPR-competent AML patient-derived xenograft (PDX) models tractable for genome editing. Our integrated pipeline has revealed several targets with translational value, including SLC5A3 as a metabolic vulnerability for AML addicted to exogenous myo-inositol and MARCH5 as a critical guardian to prevent apoptosis in AML. MARCH5 repression enhanced the efficacy of BCL2 inhibitors such as venetoclax, highlighting the clinical potential of targeting MARCH5 in AML. Our study provides a valuable strategy for discovery and prioritization of new candidate AML therapeutic targets.Statement of significanceThere is an unmet need to improve the clinical outcome of AML. We developed an integrated in vivo screening approach to prioritize and validate AML dependencies with high translational potential. We identified SLC5A3 as a metabolic vulnerability and MARCH5 as a critical apoptosis regulator in AML, representing novel therapeutic opportunities.

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Tamarix articulata (T. articulata) - An Important Halophytic Medicinal Plant with Potential Pharmacological Properties

Current Pharmaceutical Biotechnology ◽

10.2174/1389201020666190318120103 ◽

2019 ◽

Vol 20 (4) ◽

pp. 285-292 ◽

Cited By ~ 5

Author(s):

Abdullah M. Alnuqaydan ◽

Bilal Rah

Keyword(s):

Medicinal Plant ◽

Biological Activities ◽

Wide Spectrum ◽

Biological Properties ◽

In Vivo Model ◽

Drug Candidate ◽

Phytochemical Analysis ◽

Pharmacological Properties

Background:Tamarix Articulata (T. articulata), commonly known as Tamarisk or Athal in Arabic region, belongs to the Tamaricaece species. It is an important halophytic medicinal plant and a good source of polyphenolic phytochemical(s). In traditional medicines, T. articulata extract is commonly used, either singly or in combination with other plant extracts against different ailments since ancient times.Methods:Electronic database survey via Pubmed, Google Scholar, Researchgate, Scopus and Science Direct were used to review the scientific inputs until October 2018, by searching appropriate keywords. Literature related to pharmacological activities of T. articulata, Tamarix species, phytochemical analysis of T. articulata, biological activities of T. articulata extracts. All of these terms were used to search the scientific literature associated with T. articulata; the dosage of extract, route of administration, extract type, and in-vitro and in-vivo model.Results:Numerous reports revealed that T. articulata contains a wide spectrum of phytochemical(s), which enables it to have a wide window of biological properties. Owing to the presence of high content of phytochemical compounds like polyphenolics and flavonoids, T. articulata is a potential source of antioxidant, anti-inflammatory and antiproliferative properties. In view of these pharmacological properties, T. articulata could be a potential drug candidate to treat various clinical conditions including cancer in the near future.Conclusion:In this review, the spectrum of phytochemical(s) has been summarized for their pharmacological properties and the mechanisms of action, and the possible potential therapeutic applications of this plant against various diseases discussed.

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Ferula hermonis: A Review of Current Use and Pharmacological Studies of its Sesquiterpene Ester Ferutinin

Current Drug Targets ◽

10.2174/1389450120666191029155053 ◽

2020 ◽

Vol 21 (5) ◽

pp. 499-508 ◽

Cited By ~ 1

Author(s):

Rémi Safi ◽

Marwan El-Sabban ◽

Fadia Najjar

Keyword(s):

Wide Spectrum ◽

Endemic Plant ◽

Anti Cancer ◽

Pharmacological Studies ◽

Sexual Impotence ◽

Novel Applications ◽

Anti Fungal ◽

Sesquiterpene Ester

Ferula hermonis Boiss, is an endemic plant of Lebanon, locally known as “shilsh Elzallouh”. It has been extensively used in the traditional medicine as an aphrodisiac and for the treatment of sexual impotence. Crude extracts and isolated compounds of ferula hermonis contain phytoestrogenic substances having a wide spectrum of in vitro and in vivo pharmacological properties including anti-osteoporosis, anti-inflammatory, anti-microbial and anti-fungal, anti-cancer and as sexual activity enhancer. The aim of this mini-review is to highlight the traditional and novel applications of this plant’s extracts and its major sesquiterpene ester, ferutinin. The phytochemical constituents and the pharmacological uses of ferula hermonis crude extract and ferutinin specifically will be discussed.

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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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