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Toxicology Feb 2021We report the development, automation and validation of a 3D, microfluidic liver-on-a-chip for high throughput hepatotoxicity screening, the OrganoPlate LiverTox™. The...
We report the development, automation and validation of a 3D, microfluidic liver-on-a-chip for high throughput hepatotoxicity screening, the OrganoPlate LiverTox™. The model is comprised of aggregates of induced pluripotent stem cell (iPSC)-derived hepatocytes (iHep) seeded in an extracellular matrix in the organ channel and co-cultured with endothelial cells and THP-1 monoblasts differentiated to macrophages seeded in the vascular channel of the 96 well Mimetas OrganoPlate 2-lane. A key component of high throughput screening is automation and we report a protocol to seed, dose, collect and replenish media and add assay reagents in the OrganoPlate 2-lane using a standard laboratory liquid handling robot. A combination of secretome measurements and image-based analysis was used to demonstrate stable 15 day cell viability, albumin and urea secretion. Over the same time-period, CYP3A4 activity increased and alpha-fetoprotein secretion decreased suggesting further maturation of the iHeps. Troglitazone, a clinical hepatotoxin, was chosen as a control compound for validation studies. Albumin, urea, hepatocyte nuclear size and viability staining provided Robust Z'factors > 0.2 in plates treated 72 h with 180 μM troglitazone compared with a vehicle control. The viability assay provided the most robust statistic for a Robust Z' factor = 0.6. A small library of 159 compounds with known liver effects was added to the OrganoPlate LiverTox model for 72 h at 50 μM and the Toxicological Prioritization scores were calculated. A follow up dose-response evaluation of select hits revealed the albumin assay to be the most sensitive in calculating TC values. This platform provides a robust, novel model which can be used for high throughput hepatotoxicity screening.
Topics: Cell Culture Techniques; Cell Survival; Cytochrome P-450 CYP3A; Dose-Response Relationship, Drug; Hepatocytes; High-Throughput Screening Assays; Humans; Induced Pluripotent Stem Cells; Liver; Microfluidics; Toxicity Tests; Troglitazone
PubMed: 33359578
DOI: 10.1016/j.tox.2020.152667 -
Diabetes Care Apr 1999The Diabetes Prevention Program is a randomized clinical trial testing strategies to prevent or delay the development of type 2 diabetes in high-risk individuals with... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
The Diabetes Prevention Program is a randomized clinical trial testing strategies to prevent or delay the development of type 2 diabetes in high-risk individuals with elevated fasting plasma glucose concentrations and impaired glucose tolerance. The 27 clinical centers in the U.S. are recruiting at least 3,000 participants of both sexes, approximately 50% of whom are minority patients and 20% of whom are > or = 65 years old, to be assigned at random to one of three intervention groups: an intensive lifestyle intervention focusing on a healthy diet and exercise and two masked medication treatment groups--metformin or placebo--combined with standard diet and exercise recommendations. Participants are being recruited during a 2 2/3-year period, and all will be followed for an additional 3 1/3 to 5 years after the close of recruitment to a common closing date in 2002. The primary outcome is the development of diabetes, diagnosed by fasting or post-challenge plasma glucose concentrations meeting the 1997 American Diabetes Association criteria. The 3,000 participants will provide 90% power to detect a 33% reduction in an expected diabetes incidence rate of at least 6.5% per year in the placebo group. Secondary outcomes include cardiovascular disease and its risk factors; changes in glycemia, beta-cell function, insulin sensitivity, obesity, diet, physical activity, and health-related quality of life; and occurrence of adverse events. A fourth treatment group--troglitazone combined with standard diet and exercise recommendations--was included initially but discontinued because of the liver toxicity of the drug. This randomized clinical trial will test the possibility of preventing or delaying the onset of type 2 diabetes in individuals at high risk.
Topics: Adult; Aged; Blood Glucose; Cardiovascular Diseases; Chromans; Diabetes Mellitus; Diabetes Mellitus, Type 2; Energy Intake; Exercise Therapy; Female; Glucose Tolerance Test; Health Policy; Humans; Hypoglycemic Agents; Insulin Resistance; Islets of Langerhans; Life Style; Liver; Male; Metformin; Middle Aged; Obesity; Outcome and Process Assessment, Health Care; Quality of Life; Research Design; Risk Factors; Thiazoles; Thiazolidinediones; Troglitazone
PubMed: 10189543
DOI: 10.2337/diacare.22.4.623 -
Toxicologic Pathology Oct 2023Drug-induced liver injury (DILI) remains a major concern in drug development from a patient safety perspective because it is the leading cause of acute liver failure.... (Review)
Review
Drug-induced liver injury (DILI) remains a major concern in drug development from a patient safety perspective because it is the leading cause of acute liver failure. One mechanism of DILI is altered bile acid homeostasis and involves several hepatic bile acid transporters. Functional impairment of some hepatic bile acid transporters by drugs, disease, or genetic mutations may lead to toxic accumulation of bile acids within hepatocytes and increase DILI susceptibility. This review focuses on the role of hepatic bile acid transporters in DILI. Model systems, primarily and modeling tools, such as DILIsym, used in assessing transporter-mediated DILI are discussed. Due to species differences in bile acid homeostasis and drug-transporter interactions, key aspects and challenges associated with the use of preclinical animal models for DILI assessment are emphasized. Learnings are highlighted from three case studies of hepatotoxic drugs: troglitazone, tolvaptan, and tyrosine kinase inhibitors (dasatinib, pazopanib, and sorafenib). The development of advanced models and novel biomarkers that can reliably predict DILI is critical and remains an important focus of ongoing investigations to minimize patient risk for liver-related adverse reactions associated with medication use.
Topics: Animals; Humans; Chemical and Drug Induced Liver Injury; Drug-Related Side Effects and Adverse Reactions; Bile Acids and Salts; Carrier Proteins; Membrane Glycoproteins
PubMed: 37982363
DOI: 10.1177/01926233231212255 -
Cancer Letters Apr 2009The thiazolidinedione (TZD) family of PPARgamma agonists, especially troglitazone and ciglitazone, induce cell cycle arrest, differentiation, and apoptosis in cancer... (Review)
Review
The thiazolidinedione (TZD) family of PPARgamma agonists, especially troglitazone and ciglitazone, induce cell cycle arrest, differentiation, and apoptosis in cancer cells. Mounting evidence indicates that TZDs interfere with multiple signaling mechanisms independently of PPARgamma activation, which affect many aspects of cellular functions governing cell cycle progression and survival of cancer cells. Here, we review the "off-target" mechanisms that underlie the antitumor effects of TZDs with emphasis on three key pathways, namely, inhibition of Bcl-2/Bcl-xL function, proteasomal degradation of cell cycle- and apoptosis-regulatory proteins, and transcriptional repression of androgen receptor (AR) through Sp1 degradation. Relative to tumor cells, nonmalignant cells are resistant to these PPARgamma-independent antitumor effects, which underscores the translational potential of these agents. Furthermore, dissociation of these antitumor effects from their PPARgamma agonist activity provides a rationale for using TZDs as scaffolds for lead optimization to develop a novel class of antitumor agents with a unique mode of mechanism.
Topics: Animals; Antineoplastic Agents; Chromans; Humans; PPAR gamma; Proteasome Endopeptidase Complex; Proto-Oncogene Proteins c-bcl-2; Receptors, Androgen; Signal Transduction; Sp1 Transcription Factor; Thiazolidinediones; Troglitazone; bcl-X Protein
PubMed: 18790559
DOI: 10.1016/j.canlet.2008.08.008 -
Diabetes & Metabolism Jun 2001Thiazolidinediones or glitazones specifically target insulin resistance. They have proven efficacy for reducing plasma glucose levels of type 2 diabetic patients treated... (Review)
Review
Thiazolidinediones or glitazones specifically target insulin resistance. They have proven efficacy for reducing plasma glucose levels of type 2 diabetic patients treated with diet alone, sulphonylureas, metformin or insulin. In addition, they may be associated to some improvement of cardiovascular risk profile. However, troglitazone, the first compound approved by the FDA in the US, proved to be hepatotoxic and was withdrawn from the market after the report of several dozens of deaths or cases of severe hepatic failure requiring liver transplantation. It remains unclear whether or not hepatotoxicity is a class effect or is related to the unique tocopherol side chain of troglitazone. Rosiglitazone and pioglitazone, two other glitazones, appear to have similar efficacy on blood glucose control of type 2 diabetic patients as compared to troglitazone. In controlled clinical trials, the incidence of significant increases in liver enzyme levels (ALT) was similar with rosiglitazone or pioglitazone as compared to placebo, whereas troglitazone was associated with a threefold greater incidence. In contrast to the numerous case reports of acute liver failure in patients receiving troglitzone, only two cases of severe reversible liver failure have been reported in patients treated with rosiglitazone, with a causal relationship remaining uncertain. Furthermore, no single case of severe hepatotoxicity has been reported yet with pioglitazone. While regular monitoring of liver enzymes is still recommended and more long-term data are desirable, current clinical evidence supports the conclusion that rosiglitazone and pioglitazone do not share the hepatotoxic profile of troglitazone.
Topics: Blood Glucose; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Incidence; Liver; Liver Failure; Thiazoles; United States; United States Food and Drug Administration
PubMed: 11431595
DOI: No ID Found -
Pharmacogenomics Dec 2014The most important goal in the treatment of patients with diabetes is to prevent the risk of cardiovascular disease (CVD), the first cause of mortality in these... (Review)
Review
The most important goal in the treatment of patients with diabetes is to prevent the risk of cardiovascular disease (CVD), the first cause of mortality in these subjects. Thiazolidinediones (TZDs), a class of antidiabetic drugs, act as insulin sensitizers increasing insulin-dependent glucose disposal and reducing hepatic glucose output. TZDs including pioglitazone, rosiglitazone and troglitazone, by activating PPAR-γ have shown pleiotropic effects in reducing vascular risk factors and atherosclerosis. However, troglitazone was removed from the market due to its hepatoxicity, and rosiglitazone and pioglitazone both have particular warnings due to being associated with heart diseases. Specific genetic variations in genes involved in the pathways regulated by TDZs have demonstrated to modify the variability in treatment with these drugs, especially in their side effects. Therefore, pharmacogenomics and pharmacogenetics are an important tool in further understand intersubject variability per se but also to assess the therapeutic potential of such variability in drug individualization and therapeutic optimization.
Topics: Cardiovascular Diseases; Chromans; Diabetes Mellitus; Humans; Pharmacogenetics; Pioglitazone; Precision Medicine; Risk Factors; Rosiglitazone; Thiazolidinediones; Troglitazone
PubMed: 25521362
DOI: 10.2217/pgs.14.162 -
Diabetes/metabolism Research and Reviews 2002This supplement focuses on the benefits of targeting insulin resistance through therapy with a new class of oral antidiabetic agents, the thiazolidinediones (TZDs) or... (Review)
Review
This supplement focuses on the benefits of targeting insulin resistance through therapy with a new class of oral antidiabetic agents, the thiazolidinediones (TZDs) or 'glitazones'. There are important differences between the three TZD class members that warrant discussion to enable physicians to make rational and informed therapeutic choices between the agents. Overall the TZDs appear to be similar in their effects on blood glucose, as all class members have demonstrated effective glycaemic control, both as monotherapy and in combination with sulphonylureas, metformin or exogenous insulin. The safety profiles of the three agents are more diverse, with what appear to be 'TZD class effects', (probably mediated via activation of peroxisome proliferator-activated receptor gamma [PPAR gamma]) and 'TZD-specific effects', which are unique to each agent and may be a consequence of differing chemical structures. While rosiglitazone and pioglitazone share some class effects with troglitazone, they have several characteristics that define them as unique agents. By tackling the control of type 2 diabetes through direct effects on insulin resistance, the TZDs represent an important new therapeutic tool for healthcare professionals.
Topics: Chromans; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Molecular Structure; Pioglitazone; Rosiglitazone; Thiazoles; Thiazolidinediones; Troglitazone
PubMed: 11921431
DOI: No ID Found