Applications of microphysiological systems to disease models in the biopharmaceutical industry: Opportunities and challenges.

Disease models enable researchers to investigate, test, and identify therapeutic targets that would alter the patients’ disease condition and improve quality of life. Advances in genetic alteration and analytical techniques have enabled rapid devel­opment of disease models using preclinical animals and cell cultures. However, success rates of drug development remain low due to limited recapitulation of clinical pathophysiology by these models.

Potential mechanisms of target-independent uptake and toxicity of antibody-drug conjugates.

Antibody-drug conjugates (ADCs) are a promising therapeutic modality for oncology indications. The concept of an ADC platform is to increase the therapeutic index (TI) of chemotherapeutics through more selective delivery of cytotoxic agents to tumor cells while limiting exposure to healthy normal cells. Despite the use of antibodies targeting antigens abundantly and/or exclusively expressed on cancer cells (i.

Repression of hepatobiliary transporters and differential regulation of classic and alternative bile acid pathways in mice during pregnancy.

During pregnancy, proper hepatobiliary transport and bile acid synthesis protect the liver from cholestatic injury and regulate the maternal and fetal exposure to bile acids, drugs, and environmental chemicals. The objective of this study was to determine the temporal messenger RNA (mRNA) and protein profiles of uptake and efflux transporters as well as bile acid synthetic and conjugating enzymes in livers from virgin and pregnant mice on gestational days (GD) 7, 11, 14, and 17 and postnatal days (PND) 1, 15, and 30. Compared with virgins, the mRNAs of most transporters were reduced approximately 50% in pregnant dams between GD11 and 17.

Use of mixed-effect models and tolerance limits to evaluate control cynomolgus monkey body weight change and variability during preclinical toxicology studies.

Cynomolgus monkeys are an important and widely used species in preclinical toxicology studies. During the in-life phase of study, body weight effects may be indicative of toxicity; however, trends in body weight and body weight variability are often difficult to interpret due to small sample size and/or inter- and intra-animal variability. The present analysis utilizes mixed-effect modelling, which incorporates random and fixed effects into linear regression models, to evaluate control monkey body weight trends and variability relative to baseline (initial) weight and study duration.

Enhanced expression of Nrf2 in mice attenuates the fatty liver produced by a methionine- and choline-deficient diet.

Oxidative stress has been proposed as an important promoter of the progression of fatty liver diseases. The current study investigates the potential functions of the Nrf2-Keap1 signaling pathway, an important hepatic oxidative stress sensor, in a rodent fatty liver model. Mice with no (Nrf2-null), normal (wild type, WT), and enhanced (Keap1 knockdown, K1-kd) expression of Nrf2 were fed a methionine- and choline-deficient (MCD) diet or a control diet for 5 days.

Nuclear factor erythroid 2-related factor 2 deletion impairs glucose tolerance and exacerbates hyperglycemia in type 1 diabetic mice.

The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) induces a battery of cytoprotective genes after oxidative stress. Nrf2 aids in liver regeneration by altering insulin signaling; however, whether Nrf2 participates in hepatic glucose homeostasis is unknown. Compared with wild-type mice, mice lacking Nrf2 (Nrf2-null) have lower basal serum insulin and prolonged hyperglycemia in response to an intraperitoneal glucose challenge.

Ontogenic expression of hepatic Ahr mRNA is associated with histone H3K4 di-methylation during mouse liver development.

The aryl hydrocarbon receptor (Ahr) is a xenobiotic sensor that regulates the expression of a battery of drug-metabolizing genes. However, Ahr is also important for normal liver development. The purpose of the present study was to examine the ontogeny of Ahr mRNA in mouse liver, and determine the epigenetic mechanisms regulating Ahr gene transcription during postnatal liver development.

Introducing the "TCDD-inducible AhR-Nrf2 gene battery".

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) induces genes via the transcription factor aryl hydrocarbon receptor (AhR), including Cyp1a1, NAD(P)H:quinone oxidoreductase 1 (Nqo1), UDP-glucuronosyltransferase 1a6 (Ugt1a6), and glutathione S-transferase a1 (Gsta1). These genes are referred to as the "AhR gene battery." However, Nqo1 is also considered a prototypical target gene of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2).

Nrf2 activation enhances biliary excretion of sulfobromophthalein by inducing glutathione-S-transferase activity.

Sulfobromophthalein (BSP) is used to study hepatobiliary excretory function. BSP is conjugated with glutathione (GSH), whereas its dibrominated analog disulfobromophthalein (DBSP) is not conjugated with GSH prior to biliary excretion. In addition, both BSP and DBSP are transported into hepatocytes via organic anion-transporting polypeptides and excreted into bile via multidrug resistance-associated protein 2 (Mrp2).

Increased Nrf2 activation in livers from Keap1-knockdown mice increases expression of cytoprotective genes that detoxify electrophiles more than those that detoxify reactive oxygen species.

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor critical for protection against electrophilic and oxidative stress. In a recently engineered mouse with knockdown of kelch-like ECH associated protein 1 (Keap1-kd mice), the cytosolic repressor of Nrf2, there is a 55% decrease in Keap1 mRNA and a 200% increase in Nrf2 protein in liver. Experiments with Nrf2-null mice have demonstrated the effects of a lack of Nrf2.

Circadian expression profiles of drug-processing genes and transcription factors in mouse liver.

Temporal coordination of hepatic drug-processing gene (DPG) expression facilitates absorption, biotransformation, and excretion of exogenous and endogenous compounds. To further elucidate the circadian rhythm of hepatic DPG expression, male C57BL/6 mice were subjected to a standard 12-h light/dark cycle, and livers were collected at 2:00, 6:00, and 10:00 AM and 2:00, 6:00, and 10:00 PM. The mRNAs of hepatic phase I enzymes (cytochromes P450, aldehyde dehydrogenases, and carboxylesterases), phase II enzymes (glucuronosyltransferases, sulfotransferases, and glutathione S-transferases), uptake and efflux transporters, and transcription factors were quantified.

Attenuation of TCDD-induced oxidative stress by 670 nm photobiomodulation in developmental chicken kidney.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), a potent developmental teratogen inducing oxidative stress and sublethal changes in multiple organs, provokes developmental renal injuries. In this study, we investigated TCDD-induced biochemical changes and the therapeutic efficacy of photobiomodulation (670 nm; 4 J/cm(2)) on oxidative stress in chicken kidneys during development. Eggs were injected once prior to incubation with TCDD (2 pg/g or 200 pg/g) or sunflower oil vehicle control.

NF-E2-related factor 2 inhibits lipid accumulation and oxidative stress in mice fed a high-fat diet.

NF-E2-related factor 2 (Nrf2) is a transcription factor that is activated by oxidative stress and electrophiles that regulates the expression of numerous detoxifying and antioxidant genes. Previous studies have shown that Nrf2 protects the liver from xenobiotic toxicity; however, whether Nrf2 plays a role in lipid homeostasis in liver is not known. Accordingly, wild-type and Nrf2-null mice were fed a high-fat diet (HFD) for up to 4 weeks.

Melatonin as a principal component of red light therapy.

Melatonin is well recognized for its role as a potent antioxidant and is directly implicated in the free radical theory of aging [1] [Reiter RJ, Pablos MI, Agapito TT, Guerrero JM. Melatonin in the context of the free radical theory of aging. Ann N Y Acad Sci 1996;786:362-78].

670 nanometer light treatment attenuates dioxin toxicity in the developing chick embryo.

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is an acutely toxic anthropogenic chemical. Treatment with a red to near-infrared (630-1000 nm) light-emitting diode (LED) attenuates the toxicant-induced oxidative stress and energy deficit in neuronal cell culture. For this study, fertile chicken (Gallus gallus) eggs were injected once at the start of incubation with sunflower oil vehicle or 200 pg TCDD/g egg (200 parts per trillion), an environmentally relevant dose.

Brief report: embryonic growth and hatching implications of developmental 670-nm phototherapy and dioxin co-exposure.

Objective: We assessed the effect of 670-nm light therapy on growth and hatching kinetics in chickens (Gallus gallus) exposed to dioxin.

Background Data: Photobiomodulation has been shown to stimulate signaling pathways resulting in improved energy metabolism, antioxidant production, and cell survival. In ovo treatment with 670-nm light-emitting diode (LED) arrays improves hatching success and increases hatchling size in control chickens.

Clinical and experimental applications of NIR-LED photobiomodulation.

This review presents current research on the use of far-red to near-infrared (NIR) light treatment in various in vitro and in vivo models. Low-intensity light therapy, commonly referred to as "photobiomodulation," uses light in the far-red to near-infrared region of the spectrum (630-1000 nm) and modulates numerous cellular functions. Positive effects of NIR-light-emitting diode (LED) light treatment include acceleration of wound healing, improved recovery from ischemic injury of the heart, and attenuated degeneration of injured optic nerves by improving mitochondrial energy metabolism and production.

External heart deformities in passerine birds exposed to environmental mixtures of polychlorinated biphenyls during development.

Necropsy-observable cardiac deformities were evaluated from 283 nestling passerines collected from one reference site and five polychlorinated biphenyl (PCB)-contaminated sites around Bloomington and Bedford, Indiana, USA. Hearts were weighed and assessed on relative scales in three dimensions (height, length, and width) and for externally visible deformities. Heart weights normalized to body weight (heart somatic index) were decreased significantly at the more contaminated sites in both house wren (Troglodytes aedon) and tree swallow (Tachycineta bicolor).

Survivorship and mortality implications of developmental 670-nm phototherapy: dioxin co-exposure.

Objective: We assessed the effect of 670-nm light therapy on dioxin-induced embryonic mortality in chickens (Gallus gallus).

Background Data: Developmental photobiomodulation using 670-nm light-emitting diode (LED) arrays improves hatching success and increases body size in hatchling chickens. Photobiomodulation also stimulates signaling pathways resulting in improved energy metabolism, antioxidant production and cell survival.

Effects of 670-nm phototherapy on development.

Objective: The objective of the present study was to assess the survival and hatching success of chickens (Gallus gallus) exposed in ovo to far-red (670-nm) LED therapy.

Background Data: Photobiomodulation by light in the red to near-infrared range (630-1000 nm) using low-energy lasers or light-emitting diode (LED) arrays has been shown to accelerate wound healing and improve recovery from ischemic injury. The mechanism of photobiomodulation at the cellular level has been ascribed to the activation of mitochondrial respiratory chain components resulting in initiation of a signaling cascade that promotes cellular proliferation and cytoprotecton.