scholarly journals Bioengineered Liver Cell Models of Hepatotropic Infections

Viruses ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 773
Author(s):  
Francisca Arez ◽  
Ana F. Rodrigues ◽  
Catarina Brito ◽  
Paula M. Alves
Keyword(s):  
Drug Development ◽  
Molecular Mechanisms ◽  
3D Cell Culture ◽  
Cell Models ◽  
Hepatitis Viruses ◽  
Liver Stage ◽  
Host Pathogen ◽  
Culture Strategies ◽  
Dimensional Cell

Hepatitis viruses and liver-stage malaria are within the liver infections causing higher morbidity and mortality rates worldwide. The highly restricted tropism of the major human hepatotropic pathogens—namely, the human hepatitis B and C viruses and the Plasmodium falciparum and Plasmodium vivax parasites—has hampered the development of disease models. These models are crucial for uncovering the molecular mechanisms underlying the biology of infection and governing host–pathogen interaction, as well as for fostering drug development. Bioengineered cell models better recapitulate the human liver microenvironment and extend hepatocyte viability and phenotype in vitro, when compared with conventional two-dimensional cell models. In this article, we review the bioengineering tools employed in the development of hepatic cell models for studying infection, with an emphasis on 3D cell culture strategies, and discuss how those tools contributed to the level of recapitulation attained in the different model layouts. Examples of host–pathogen interactions uncovered by engineered liver models and their usefulness in drug development are also presented. Finally, we address the current bottlenecks, trends, and prospect toward cell models’ reliability, robustness, and reproducibility.

scholarly journals Transport of Drugs and Endogenous Compounds Mediated by Human OCT1: Studies in Single- and Double-Transfected Cell Models

2021 ◽  
Vol 12 ◽  
Author(s):  
Bastian Haberkorn ◽  
Martin F. Fromm ◽  
Jörg König
Keyword(s):  
Drug Interactions ◽  
Molecular Mechanisms ◽  
Transport Processes ◽  
Gene Symbol ◽  
Cell Models ◽  
Cell Systems ◽  
Endogenous Compounds ◽  
Substrate Spectrum ◽  
Hepatobiliary Elimination

Organic Cation Transporter 1 (OCT1, gene symbol: SLC22A1) is predominately expressed in human liver, localized in the basolateral membrane of hepatocytes and facilitates the uptake of endogenous compounds (e.g. serotonin, acetylcholine, thiamine), and widely prescribed drugs (e.g. metformin, fenoterol, morphine). Furthermore, exogenous compounds such as MPP+, ASP+ and Tetraethylammonium can be used as prototypic substrates to study the OCT1-mediated transport in vitro. Single-transfected cell lines recombinantly overexpressing OCT1 (e.g., HEK-OCT1) were established to study OCT1-mediated uptake and to evaluate transporter-mediated drug-drug interactions in vitro. Furthermore, double-transfected cell models simultaneously overexpressing basolaterally localized OCT1 together with an apically localized export protein have been established. Most of these cell models are based on polarized grown MDCK cells and can be used to analyze transcellular transport, mimicking the transport processes e.g. during the hepatobiliary elimination of drugs. Multidrug and toxin extrusion protein 1 (MATE1, gene symbol: SLC47A1) and the ATP-driven efflux pump P-glycoprotein (P-gp, gene symbol: ABCB1) are both expressed in the canalicular membrane of human hepatocytes and are described as transporters of organic cations. OCT1 and MATE1 have an overlapping substrate spectrum, indicating an important interplay of both transport proteins during the hepatobiliary elimination of drugs. Due to the important role of OCT1 for the transport of endogenous compounds and drugs, in vitro cell systems are important for the determination of the substrate spectrum of OCT1, the understanding of the molecular mechanisms of polarized transport, and the investigation of potential drug-drug interactions. Therefore, the aim of this review article is to summarize the current knowledge on cell systems recombinantly overexpressing human OCT1.

scholarly journals Cell Models and Omics Techniques for the Study of Nonalcoholic Fatty Liver Disease: Focusing on Stem Cell-Derived Cell Models

Antioxidants ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 86
Author(s):  
María Pelechá ◽  
Estela Villanueva-Bádenas ◽  
Enrique Timor-López ◽  
María Teresa Donato ◽  
Laia Tolosa
Keyword(s):  
Stem Cell ◽  
Liver Disease ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Fatty Liver Disease ◽  
Molecular Mechanisms ◽  
Cell Models ◽  
Nonalcoholic Fatty Liver ◽  
Advantages And Disadvantages

Nonalcoholic fatty liver disease (NAFLD) is now the leading cause of chronic liver disease in western countries. The molecular mechanisms leading to NAFLD are only partially understood, and effective therapeutic interventions are clearly needed. Therefore, preclinical research is required to improve knowledge about NAFLD physiopathology and to identify new therapeutic targets. Primary human hepatocytes, human hepatic cell lines, and human stem cell-derived hepatocyte-like cells exhibit different hepatic phenotypes and have been widely used for studying NAFLD pathogenesis. In this paper, apart from employing the different in vitro cell models for the in vitro assessment of NAFLD, we also reviewed other approaches (metabolomics, transcriptomics, and high-content screening). We aimed to summarize the characteristics of different cell types and methods and to discuss their major advantages and disadvantages for NAFLD modeling.

scholarly journals Testing in vitro toxicity of nanoparticles in 3D cell culture with various extracellular matrix scaffold

2021 ◽  
Author(s):  
Jae Won Choi ◽  
Song-Hwa Bae ◽  
In Young Kim ◽  
Minjeong Kwak ◽  
Tae Geol Lee ◽  
...  
Keyword(s):  
Cell Culture ◽  
3D Cell Culture ◽  
Cancer Cell Line ◽  
Culture Method ◽  
Sio2 Nanoparticles ◽  
Toxicity Assessment ◽  
In Vitro Toxicity ◽  
Dimensional Cell

Nanomaterials are used in a variety of fields and toxicity assessment is paramount for their development and application. Although most toxicity assessments have been performed in 2D (2-Dimensional) cell culture, the inability to adequately replicate the in vivo environment and toxicity is a limitation. To overcome the limitation, a 3D (3-Dimensional) cell culture method has been developed to make an environment closer to an in vivo system. In this study, 20 nm SiO2 nanoparticles were dispersed in serum-containing (SC) and serum-free (SF) media to compare 2D cell culture and 3D cell culture toxicity. The cells were subjected to a 3D cell culture method in which HepG2, a human-derived liver cancer cell line, was mixed on a scaffold. We found that nanoparticles induced toxicity in 2D cell culture, but toxicity was not observed in 3D cell culture similar to in vivo environment. However, differences in toxicity were observed between the three types of scaffolds in the absence of serum as the number of cells decreased.

scholarly journals Next-Generation Human Liver Models for Antimalarial Drug Assays

Antibiotics ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 642
Author(s):  
Kasem Kulkeaw
Keyword(s):  
Drug Development ◽  
Antimalarial Drug ◽  
Adult Stem Cells ◽  
Ethical Issues ◽  
Clinical Manifestations ◽  
Malaria Prevention ◽  
New Drugs ◽  
Global Public Health ◽  
Liver Stage

Advances in malaria prevention and treatment have significantly reduced the related morbidity and mortality worldwide, however, malaria continues to be a major threat to global public health. Because Plasmodium parasites reside in the liver prior to the appearance of clinical manifestations caused by intraerythrocytic development, the Plasmodium liver stage represents a vulnerable therapeutic target to prevent progression. Currently, a small number of drugs targeting liver-stage parasites are available, but all cause lethal side effects in glucose-6-phosphate dehydrogenase-deficient individuals, emphasizing the necessity for new drug development. Nevertheless, a longstanding hurdle to developing new drugs is the availability of appropriate in vitro cultures, the crucial conventional platform for evaluating the efficacy and toxicity of drugs in the preclinical phase. Most current cell culture systems rely primarily on growing immortalized or cancerous cells in the form of a two-dimensional monolayer, which is not very physiologically relevant to the complex cellular architecture of the human body. Although primary human cells are more relevant to human physiology, they are mainly hindered by batch-to-batch variation, limited supplies, and ethical issues. Advances in stem cell technologies and multidimensional culture have allowed the modelling of human infectious diseases. Here, current in vitro hepatic models and toolboxes for assaying the antimalarial drug activity are summarized. Given the physiological potential of pluripotent and adult stem cells to model liver-stage malaria, the opportunities and challenges in drug development against liver-stage malaria is highlighted, paving the way to assess the efficacy of hepatic plasmodicidal activity.

scholarly journals Cell-based approaches in drug development – a concise review

2020 ◽  
Vol 8 (1) ◽  
pp. 44-49
Author(s):  
Ievgeniia Kocherova ◽  
Bartosz Kempisty ◽  
Greg Hutchings ◽  
Lisa Moncrieff ◽  
Claudia Dompe ◽  
...  
Keyword(s):  
Drug Development ◽  
Development Process ◽  
Molecular Mechanisms ◽  
Ex Vivo ◽  
Cytotoxic Effects ◽  
Safety Issues ◽  
Third Phase ◽  
Concise Review

AbstractIn vitro models represent an alternative technique to in vivo or ex vivo studies in the drug development process. Cell-based assays are used to measure the level of proliferation and toxicity, as well as activation of signalling pathways and changes in morphology in cultivated cells. The studies conducted in vitro are aimed to estimate the newly synthesised drugs’ ability to permeate biological barriers and exert their therapeutic or cytotoxic effects. However, more than half of all studied drugs fail in the second or third phase of clinical trials due to a lack of confirmed efficacy. About a third of drugs fail because of safety issues, such as unacceptable levels of toxicity. To reduce attrition level in drug development, it is crucial to consider the implementation of translational phenotypic assays as well as to decipher various molecular mechanisms of action for new molecular entities. In this review, we summarise the existing cell-based methods most frequently used in the studies on drugs, taking into account their advantages and drawbacks.Running title: Cell-based approaches in drug development

High resolution mapping of nucleic acid containing complexes in vitro and in situ

1996 ◽  
Vol 54 ◽  
pp. 48-49
Author(s):  
D. P. Bazett-Jones ◽  
M. J. Hendzel
Keyword(s):  
Nucleic Acid ◽  
High Resolution ◽  
Transcription Initiation ◽  
Molecular Mechanisms ◽  
Heavy Atom ◽  
Regulation Of Transcription ◽  
High Exposure ◽  
Resolution Mapping ◽  
Tata Sequence

Structural analysis of combinations of nucleosomes and transcription factors on promoter and enhancer elements is necessary in order to understand the molecular mechanisms responsible for the regulation of transcription initiation. Such complexes are often not amenable to study by high resolution crystallographic techniques. We have been applying electron spectroscopic imaging (ESI) to specific problems in molecular biology related to transcription regulation. There are several advantages that this technique offers in studies of nucleoprotein complexes. First, an intermediate level of spatial resolution can be achieved because heavy atom contrast agents are not necessary. Second, mass and stoichiometric relationships of protein and nucleic acid can be estimated by phosphorus detection, an element in much higher proportions in nucleic acid than protein. Third, wrapping or bending of the DNA by the protein constituents can be observed by phosphorus mapping of the complexes. Even when ESI is used with high exposure of electrons to the specimen, important macromolecular information may be provided. For example, an image of the TATA binding protein (TBP) bound to DNA is shown in the Figure (top panel). It can be seen that the protein distorts the DNA away from itself and much of its mass sits off the DNA helix axis. Moreover, phosphorus and mass estimates demonstrate whether one or two TBP molecules interact with this particular promoter TATA sequence.

The research of the molecular mechanisms of endothelial dysfunction in vitro

2019 ◽  
Vol XIV (1) ◽  
Author(s):  
R.E. Kalinin ◽  
I.A. Suchkov ◽  
N.V. Korotkova ◽  
N.D. Mzhavanadze
Keyword(s):  
Endothelial Dysfunction ◽  
Molecular Mechanisms

Natural products from the traditional Moroccan pharmacopoeia: A potential lead for the prevention and treatment of COVID-19

2020 ◽  
Vol 11 (SPL1) ◽  
pp. 1278-1285
Author(s):  
Mohamed Yafout ◽  
Amine Ousaid ◽  
Ibrahim Sbai El Otmani ◽  
Youssef Khayati ◽  
Amal Ait Haj Said
Keyword(s):  
Medicinal Plants ◽  
Plant Extracts ◽  
Molecular Mechanisms ◽  
Scientific Literature ◽  
Treatment Protocol ◽  
World Health ◽  
The World ◽  
Health Organization ◽  
Promising Source

The new SARS-CoV-2 belonging to the coronaviruses family has caused a pandemic affecting millions of people around the world. This pandemic has been declared by the World Health Organization as an international public health emergency. Although several clinical trials involving a large number of drugs are currently underway, no treatment protocol for COVID-19 has been officially approved so far. Here we demonstrate through a search in the scientific literature that the traditional Moroccan pharmacopoeia, which includes more than 500 medicinal plants, is a fascinating and promising source for the research of natural molecules active against SARS-CoV-2. Multiple in-silico and in-vitro studies showed that some of the medicinal plants used by Moroccans for centuries possess inhibitory activity against SARS-CoV or SARS-CoV-2. These inhibitory activities are achieved through the different molecular mechanisms of virus penetration and replication, or indirectly through stimulation of immunity. Thus, the potential of plants, plant extracts and molecules derived from plants that are traditionally used in Morocco and have activity against SARS-CoV-2, could be explored in the search for a preventive or curative treatment against COVID-19. Furthermore, safe plants or plant extracts that are proven to stimulate immunity could be officially recommended by governments as nutritional supplements.

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