3D cell culture models: Drug pharmacokinetics, safety assessment, and regulatory consideration

Wang, Hongbing; Brown, Paul C.; Chow, Edwin; Ewart, Lorna; Ferguson, Stephen S. G.; Fitzpatrick, Suzanne; Freedman, Benjamin; Guo, Grace L.; Hedrich, William D.; Heyward, Scott; Hickman, James J.; Isoherranen, Nina; Li, Albert P.; Liu, Qi; Mumenthaler, Shannon M.; Polli, James E.; Proctor, William R.; Ribeiro, Alexandre J. S.; Wang, Jian Ying; Wange, Ronald L.; Huang, Shiew Mei

doi:10.1111/cts.13066

Cited by 103 publications

(67 citation statements)

References 105 publications

(246 reference statements)

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“…In terms of the limitations of this study, first, animal studies present significant drawbacks with inherited species-specific differences, 48 so the effect of ANGPTL8/betatrophin on glucose metabolism should be studied in other mouse models, for example, C57BL/6 mouse. Moreover, long-term usage of recombinant ANGPTL8/betatrophin in insulin-resistant or diabetic mouse models should also be explored to study its potential therapeutic effect.…”

Section: Discussionmentioning

confidence: 99%

ANGPTL8/Betatrophin Improves Glucose Tolerance in Older Mice and Metabolomic Analysis Reveals Its Role in Insulin Resistance in HepG2 Cells

Xu¹,

Wang²,

Li³

et al. 2021

DMSO

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Background: Insulin resistance is a determining factor in the pathophysiology of type 2 diabetes mellitus (T2DM). Angiopoietin-like protein 8 (ANGPTL8, also known as betatrophin), associated with glucose homeostasis and lipid metabolism, has attracted attention. But its mechanism in glucose metabolism remains unclear. This study aimed to explore the effect of ANGPTL8/betatrophin on glucose tolerance in Kunming (KM) mice of different ages and metabolic profiles in insulin-resistant HepG2 cells. Our study may provide a new perspective of ANGPTL8/betatrophin in insulin resistance from the metabolic changes. Methods: Oral glucose tolerance test was performed in KM mice of different ages. Insulin concentration was measured by using a quantitative enzyme-linked immunosorbent assay (ELISA). ANGPTL8/betatrophin knockouts in HepG2 cells were established with clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated (Cas) protein 9 (CRISPR/Cas9) system. Cell counting kit-8 (CCK-8) assay was used to determine cell viability after gene knockout. The effect of ANGPTL8/betatrophin on the metabolomic changes was evaluated in high insulin-induced insulin-resistant HepG2 cells by an ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method. Results: ANGPTL8/betatrophin improved glucose tolerance in older mice not by altering the concentration of insulin. Cell growth was affected in ANGPTL8/betatrophin knockout HepG2. Based on UPLC-MS/MS, compared with wild type insulin-resistant HepG2 cells, we identified 83 differential metabolites in ANGPTL8/betatrophin knockout HepG2 cells after high insulin induction. Among the 14 differential up-regulated metabolites, D-mannose had the highest fold change. In insulin-resistant HepG2 cells, ANGPTL8/betatrophin knockout exerted an effect on the amino acid metabolism, carbohydrate metabolism, metabolism of cofactors and vitamins, lipid metabolism, nucleotide metabolism, and genetic information processing pathway. Conclusion:This study identified the effect of ANGPTL8/betatrophin on glucose tolerance in mice of different ages and metabolic profiles in insulin-resistant HepG2 cells. These findings may contribute to a new understanding of its role in glucose metabolism in the context of insulin resistance.

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Section: Discussionmentioning

confidence: 99%

ANGPTL8/Betatrophin Improves Glucose Tolerance in Older Mice and Metabolomic Analysis Reveals Its Role in Insulin Resistance in HepG2 Cells

Xu¹,

Wang²,

Li³

et al. 2021

DMSO

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“…A 3D culture system, a novel model system that mimics the rich in vivo microenvironment and complex processes in which cells grow, is superior to the traditional 2D cell culture system, which has been extensively used in previous studies [ 26–28 ]. Thus, a 3D culture system offers great promise for the preclinical evaluation of drug efficacy and associated risks.…”

Section: Discussionmentioning

confidence: 99%

Establishment and characterization of organoids from a patient with adenomyoepithelioma of the breast

Luo

She

et al. 2021

Bioengineered

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Adenomyoepithelioma (AME) of the breast is a rare tumor that is composed of proliferating epithelial and myoepithelial cells. The pathogenesis of AME remains unclear, and no breast cancer cells have been identified in such tumor tissues. In this study, we established patient-derived breast cancer organoids from the surgical tumor samples of an elderly Chinese woman with an AME of the breast. Our findings confirmed the successful establishment of organoids from an AME of the breast of this patient. A short tandem repeat analysis revealed that the DNA signature of the AME of the breast organoids matched the DNA signature of the original tumor specimen. Moreover, diameter assay confirmed that the organoids from the breast AME showed sensitivity to paclitaxel and doxorubicin treatments, which was similar to, but lesser than that of primary culture cells. In conclusion, we established an efficient 3-dimensional breast cancer organoid culture platform from an AME of the breast. This platform can be effectively used for exploring clinicopathological and genomic characteristics of AME of the breast to identify possible treatments and increase awareness about this disease entity.

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“…Many researchers already notice the limits of cell lines. The recent development of organoids will help us to study tight junctions, physiological relevance, host–microbial interactions, and drug discovery [ 145 , 161 , 168 , 169 , 170 , 171 , 172 ]. As shown in Figure 4 , claudin-7 is well maintained and distributes in the cell membranes in the mouse organoids.…”

Section: Limits and Future Directionsmentioning

confidence: 99%

Vitamin D Receptor Influences Intestinal Barriers in Health and Disease

Sun

Zhang

2022

Cells

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Vitamin D receptor (VDR) executes most of the biological functions of vitamin D. Beyond this, VDR is a transcriptional factor regulating the expression levels of many target genes, such as genes for tight junction proteins claudin-2, -5, -12, and -15. In this review, we discuss the progress of research on VDR that influences intestinal barriers in health and disease. We searched PubMed and Google Scholar using key words vitamin D, VDR, tight junctions, cancer, inflammation, and infection. We summarize the literature and progress reports on VDR regulation of tight junction distribution, cellular functions, and mechanisms (directly or indirectly). We review the impacts of VDR on barriers in various diseases, e.g., colon cancer, infection, inflammatory bowel disease, and chronic inflammatory lung diseases. We also discuss the limits of current studies and future directions. Deeper understanding of the mechanisms by which the VDR signaling regulates intestinal barrier functions allow us to develop efficient and effective therapeutic strategies based on levels of tight junction proteins and vitamin D/VDR statuses for human diseases.

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3D cell culture models: Drug pharmacokinetics, safety assessment, and regulatory consideration

Cited by 103 publications

References 105 publications

ANGPTL8/Betatrophin Improves Glucose Tolerance in Older Mice and Metabolomic Analysis Reveals Its Role in Insulin Resistance in HepG2 Cells

ANGPTL8/Betatrophin Improves Glucose Tolerance in Older Mice and Metabolomic Analysis Reveals Its Role in Insulin Resistance in HepG2 Cells

Establishment and characterization of organoids from a patient with adenomyoepithelioma of the breast

Vitamin D Receptor Influences Intestinal Barriers in Health and Disease

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