Mechanistic safety assessment via multi-omic characterisation of systemic pathway perturbations following in vivo MAT2A inhibition.

The tumour suppressor p16/CDKN2A and the metabolic gene, methyl-thio-adenosine phosphorylase (MTAP), are frequently co-deleted in some of the most aggressive and currently untreatable cancers. Cells with MTAP deletion are vulnerable to inhibition of the metabolic enzyme, methionine-adenosyl transferase 2A (MAT2A), and the protein arginine methyl transferase (PRMT5). This synthetic lethality has paved the way for the rapid development of drugs targeting the MAT2A/PRMT5 axis.

Simultaneously discovering the fate and biochemical effects of pharmaceuticals through untargeted metabolomics.

Untargeted metabolomics is an established approach in toxicology for characterising endogenous metabolic responses to xenobiotic exposure. Detecting the xenobiotic and its biotransformation products as part of the metabolomics analysis provides an opportunity to simultaneously gain deep insights into its fate and metabolism, and to associate the internal relative dose directly with endogenous metabolic responses. This integration of untargeted exposure and response measurements into a single assay has yet to be fully demonstrated.

Preclinical Characterization of AZD5305, A Next-Generation, Highly Selective PARP1 Inhibitor and Trapper.

Purpose: We hypothesized that inhibition and trapping of PARP1 alone would be sufficient to achieve antitumor activity. In particular, we aimed to achieve selectivity over PARP2, which has been shown to play a role in the survival of hematopoietic/stem progenitor cells in animal models. We developed AZD5305 with the aim of achieving improved clinical efficacy and wider therapeutic window.

Pharmacological inhibition of MERTK induces in vivo retinal degeneration: a multimodal imaging ocular safety assessment.

The receptor tyrosine kinase, MERTK, plays an essential role in homeostasis of the retina via efferocytosis of shed outer nuclear segments of photoreceptors. The Royal College of Surgeons rat model of retinal degeneration has been linked to loss-of-function of MERTK, and together with the MERTK knock-out mouse, phenocopy retinitis pigmentosa in humans with MERTK mutations. Given recent efforts and interest in MERTK as a potential immuno-oncology target, development of a strategy to assess ocular safety at an early pre-clinical stage is critical.

Validation and utilisation of a digital version of the survey instrument for natural history, Aetiology and Prevalence of Patellofemoral pain studies (eSNAPPS).

Objective: This study validated the newly adapted electronic SNAPPS (eSNAPPS) against the original paper SNAPPS. Subsequently, the study estimated the prevalence of PFP in running participants and spectators attending three mass-participant running events in the United Kingdom by using the eSNAPPS tool.

Design: This study had two parts.

Method to Investigate the Distribution of Water-Soluble Drug-Delivery Systems in Fresh Frozen Tissues Using Imaging Mass Cytometry.

Imaging mass cytometry (IMC) offers the opportunity to image metal- and heavy halogen-containing xenobiotics in a highly multiplexed experiment with other immunochemistry-based reagents to distinguish uptake into different tissue structures or cell types. However, in practice, many xenobiotics are not amenable to this analysis, as any compound which is not bound to the tissue matrix will delocalize during aqueous sample-processing steps required for IMC analysis. Here, we present a strategy to perform IMC experiments on a water-soluble polysarcosine-modified dendrimer drug-delivery system (S-Dends).

Development of microdialysis methodology for interstitial insulin measurement in rodents.

Introduction: Accurate assessment of muscle insulin sensitivity requires measurement of insulin concentration in interstitial fluid (ISF), but has proved difficult. We aimed to optimise measurement of ISF insulin concentrations in rat muscles in vivo using microdialysis.

Methods: Factorial experimental design experiments were performed in vitro to determine optimal conditions for insulin recovery with microdialysis probes.

Processed foods: contributions to nutrition.

Both fresh and processed foods make up vital parts of the food supply. Processed food contributes to both food security (ensuring that sufficient food is available) and nutrition security (ensuring that food quality meets human nutrient needs). This ASN scientific statement focuses on one aspect of processed foods: their nutritional impacts.

Aggressive prostate cancer is prevented in ERαKO mice and stimulated in ERβKO TRAMP mice.

Previous evidence suggests soy genistein may be protective against prostate cancer, but whether this protection involves an estrogen receptor (ER)-dependent mechanism is unknown. To test the hypothesis that phytoestrogens may act through ERα or ERβ to play a protective role against prostate cancer, we bred transgenic mice lacking functional ERα or ERβ with transgenic adenocarcinoma of mouse prostate (TRAMP) mice. Dietary genistein reduced the incidence of cancer in ER wild-type (WT)/transgenic adenocarcinoma of mouse prostate mice but not in ERα knockout (KO) or ERβKO mice.

Influence of dietary phytochemicals and microbiota on colon cancer risk.

Colon cancer is the third most commonly diagnosed type of cancer in the United States. Lifestyle and dietary patterns influence colon cancer risk both positively and negatively. Among the dietary factors, several plant-derived compounds have been found to afford colon cancer protection.

Soy protein diet, but not Lactobacillus rhamnosus GG, decreases mucin-1, trefoil factor-3, and tumor necrosis factor-α in colon of dextran sodium sulfate-treated C57BL/6 mice.

The incidence of inflammatory bowel diseases has increased during recent decades. Within the colon, the families of mucins (MUC) and trefoil factors (TFF) facilitate mucosal protection. Probiotic administration influences the intestinal MUC layer.

Common botanical compounds inhibit the hedgehog signaling pathway in prostate cancer.

Many botanical compounds have been proposed to prevent cancer. We investigated the cancer treatment and prevention abilities of apigenin, baicalein, curcumin, epigallocatechin 3-gallate (EGCG), genistein, quercetin, and resveratrol both in vivo in transgenic adenocarcinoma of the mouse prostate (TRAMP) mice as well as in vitro in prostate cancer cell lines. In our experiments, these seven compounds act similarly to the Hedgehog antagonist cyclopamine, a teratogenic plant alkaloid, which had been previously shown to "cure" prostate cancer in a mouse xenograft model.

Soy protein isolate extruded with high moisture retains high nutritional quality.

High-moisture extrusion of soy protein isolate generates a highly palatable meat substitute. No systematic evaluation of the nutritional quality of soy processed in this manner has been performed. This study compared the growth rate of male and female mice fed diets containing soy protein isolate without extrusion or with high-moisture extrusion.

Soy isoflavones have an antiestrogenic effect and alter mammary promoter hypermethylation in healthy premenopausal women.

We determined if soy isoflavones have dose-related estrogenic and methylation effects. Thirty-four healthy premenopausal women were randomized to 40 mg or 140 mg isoflavones daily through one menstrual cycle. Breast specific and systemic estrogenic effects were assessed measuring the estrogenic marker complement (C)3 and changes in cytology, whereas methylation assessment of 5 cancer related genes (p16, RASSF1A, RARbeta2, ER, and CCND2) was performed on intraductal specimens.

Zinc deficiency induces vascular pro-inflammatory parameters associated with NF-kappaB and PPAR signaling.

Objectives: Marginal intake of dietary zinc can be associated with increased risk of cardiovascular diseases. In the current study we hypothesized that vascular dysfunction and associated inflammatory events are activated during a zinc deficient state.

Design: We tested this hypothesis using both vascular endothelial cells and mice lacking the functional LDL-receptor gene.

Genistein affects HER2 protein concentration, activation, and promoter regulation in BT-474 human breast cancer cells.

The HER2 proto-oncogene, a member of the epidermal growth factor receptor family, is overexpressed in 20-30% of breast cancers. Genistein, the main soy isoflavone, interacts with estrogen receptors (ER) and it is also a potent tyrosine kinase inhibitor. Previously, our laboratory found that genistein delayed mammary tumor onset in transgenic mice that overexpress HER2 gene.

Zinc deficiency alters lipid metabolism in LDL receptor deficient mice treated with rosiglitazone.

Zinc is a structural and functional component of PPAR and zinc deficiency may be associated with an increased risk for cardiovascular diseases. We tested the hypothesis that zinc deficiency compromises lipid metabolism in rosiglitazone (RSG)-treated mice lacking the LDL-receptor (LDL-R) gene. LDL-R-deficient mice were maintained for 3 wk on low-fat (7 g/100 g) diets that were either zinc deficient or zinc adequate.

Effects of diets enriched in omega-3 and omega-6 polyunsaturated fatty acids on offspring sex-ratio and maternal behavior in mice.

There have been many trials describing the effects of polyunsaturated fatty acids (PUFA) on fecundity, neonatal development, and maternal behavior in humans, but few controlled studies in rodents. We examined the effects of a maternal diet high in omega 3 (N-3) or omega 6 (N-6) PUFA on NIH Swiss mice. Female mice were ad libitum fed one of three complete and balanced diets (N-3, enriched in menhaden oil; N-6, enriched in corn oil; C, control diet, Purina 5015) from age 4 wk until the end of the study.

Phytosterol Pygeum africanum regulates prostate cancer in vitro and in vivo.

Background: Prostate cancer is an important public health problem. It is an excellent candidate disease for chemoprevention because prostate cancer is typically slow growing and is usually diagnosed in elderly males. Pygeum africanum (Prunus africana or Rosaceae) is an African prune (plum) tree found in tropical Africa.

Zinc deficiency increases plasma lipids and atherosclerotic markers in LDL-receptor-deficient mice.

Low zinc concentration can be associated with an increased risk of cardiovascular diseases. In the current study, we hypothesize that zinc deficiency can increase and zinc supplementation can decrease proatherosclerotic events in LDL receptor knock-out (LDL-R-/-) mice fed a moderate-fat diet. Mice were fed either a zinc-deficient (0 micromol Zn/g), a control (0.

Neuroprotective mechanisms of curcumin against cerebral ischemia-induced neuronal apoptosis and behavioral deficits.

Increased oxidative stress has been regarded as an important underlying cause for neuronal damage induced by cerebral ischemia/reperfusion (I/R) injury. In recent years, there has been increasing interest in investigating polyphenols from botanical source for possible neuroprotective effects against neurodegenerative diseases. In this study, we investigated the mechanisms underlying the neuroprotective effects of curcumin, a potent polyphenol antioxidant enriched in tumeric.

Environmental influences on isoflavones and saponins in soybeans and their role in colon cancer.

Soybeans have long been recognized as an excellent source of high-quality protein. The soybean also contains a wide variety of chemical compounds that have potent bioactivity. Among these compounds are the isoflavones and the saponins.

Dietary grape supplement ameliorates cerebral ischemia-induced neuronal death in gerbils.

Oxidative damage has been implicated as one of the leading causes for neuronal cell death in a number of neurodegenerative diseases including stroke. Many vegetables and fruits are enriched in polyphenolic compounds known to exhibit antioxidant properties. This study is to investigate whether dietary supplement with grape powder (GP) may offer protection against neuronal damage due to global cerebral ischemia induced to Mongolian gerbils by occlusion of the common carotid arteries, a model known to cause delayed neuronal death (DND) in the hippocampal CA1 area.

Phytoestrogens in common herbs regulate prostate cancer cell growth in vitro.

Prostate cancer is an important public health problem in the United States. Seven phytoestrogens found in common herbal products were screened for estrogen receptor binding and growth inhibition of androgen-insensitive (PC-3) and androgen-sensitive (LNCaP) human prostate tumor cells. In a competitive 3H-estradiol ligand binding assay using mouse uterine cytosol, 2.

Dietary soy isoflavones and estrone protect ovariectomized ERalphaKO and wild-type mice from carcinogen-induced colon cancer.

Consumption of soy foods has been weakly associated with reduced colon cancer risk. Colon cancer risk is influenced by estrogen exposure, although the mechanism through which this occurs is not defined. Conversion of estradiol (E2) to estrone (E1) may be protective in the colon.