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Noninsulin-Dependent Animal Models of Diabetes Mellitus
Published in John H. McNeill, Experimental Models of Diabetes, 2018
Christopher H. S. McIntosh, Raymond A. Pederson
The agouti mouse is believed to have first appeared in China, where it was treated as a curiosity because of its brilliant yellow hair color. The agouti locus was identified as a result of studies on coat color pigments, and was named after the South American rodent Dasyprocta aguti, which has a banded pattern of hair color.129,130
The melanocyte and melaninogenesis
Published in Dimitris Rigopoulos, Alexander C. Katoulis, Hyperpigmentation, 2017
Dimitrios Xekardakis, Sabine Krueger-Krasagakis, Konstantinos Krasagakis
Several inhibitors of melanin formation have been reported, such as para-aminobenzoic acid (PABA), quinolines, and benzopyrone.40 Melaninogenesis is also inhibited by hormonal inhibitors and their receptors. These inhibitors include melanocortin’s antagonists, growth factor cytokines and their receptors, G protein–coupled receptors, and other negative regulators. Melanocortin’s antagonists are the melanin-concentrating hormone, the Agouti protein, and the Agouti modifiers. The growth factor cytokines that inhibit melaninogenesis are IL-1, IL-6, interferon (IFN)-α, and IFN-γ and their receptors, and tumor necrosis factor (TNF)-α, TNF-β, and transforming growth factor (TGF)-β1 and their receptors. The G protein–coupled receptors are serotonin, melatonin, dopamine, and acetylocholine and their receptors. Other known negative regulators are the thyroid gland hormones and vitamin E.12 Epidermal growth factor (EGF) and tranexamic acid diminish laser-induced melaninogenesis. Although the mechanism of diminution of melaninogenesis by EGF is not known yet, tranexamic acid reduces melanin contents and tyrosinase activity.41,42 Pleiotrophin (a secreted heparin-binding protein) inhibits melaninogenesis through MITF degradation via the Erk1/2 activation in melanocytes.43 Finally, proton pump inhibitors (PPIs) seem to inhibit melanin biosynthesis via the downregulation of melaninogenesis-associated genes.44
Etiologies of obesity
Published in G. Michael Steelman, Eric C. Westman, Obesity, 2016
In 1992, the first obesity gene characterized at a molecular level was the agouti gene. Agouti is expressed in various tissues, including adipose, suggesting that it may be involved in the regulation of energy homeostasis. However, since then, a better-known gene mutation was discovered. This mutation involves the satiety hormone leptin and its receptors ob and db (68).
From leptin to lasers: the past and present of mouse models of obesity
Published in Expert Opinion on Drug Discovery, 2021
Joshua R. Barton, Adam E. Snook, Scott A. Waldman
Pharmacological cures for obesity in the early-to-mid 20th century were underscored by a fundamental lack of understanding about the regulation of weight gain. Moreover, the weight loss market had been flooded with ‘curealls’ and hoax remedies (like Fatoff) for decades, minimizing public and academic perceptions of anti-obesity drugs [9]. At the time, animal models to study obesity in the laboratory setting were not widely used. While the agouti mouse was known to have increased weight, the dermatological features interested researchers more than the overweight phenotype [10]. Without preclinical models, weight loss drugs were stumbled upon incidentally in the clinic, with unfortunate results. Amphetamines are a prime example. In 1937, a study using the amphetamine beta-aminopropylbenzene to treat ‘nervous exhaustion’ noted that 25% of patients showed rapid, sustained weight loss [11]. Shortly thereafter, amphetamines became widely developed and prescribed as weight loss drugs with limited understanding of their physiological effects. After years of rampant prescription, amphetamines were removed from the market due to multiple side effects, including addiction and numerous fatalities [12].
NZO/HlLtJ as a novel model for the studies on the role of metabolic syndrome in acute radiation toxicity
Published in International Journal of Radiation Biology, 2020
Laura E. Ewing, Isabelle R. Miousse, Rupak Pathak, Charles M. Skinner, Stanley Kosanke, Marjan Boerma, Martin Hauer-Jensen, Igor Koturbash
We report that obese NZO/HlLtJ male mice are characterized by lower sensitivity to IR at doses of 6.37 Gy and under, compared to other strains, including those of the agouti phenotype, such as CBA/CaJ mice, (Figure 1(A)) (Booth et al. 2012). The higher resistance could be potentially explained by the dose distribution via fat tissue and lower internal doses to the gut and bone marrow, however, this hypothesis requires further investigation with lean NZO/HlLtJ mice using the caloric restriction/exercise model. The lower sensitivity in this range of doses could be considered a somewhat positive outcome in regards to TBI. At the same time, radiation oncologists may incur differential toxicity effects in patients with metabolic syndrome. This is because of the radiation absorption by adipose tissue and its associated necessity for dose escalation in order to reach target tissues. With the latter, the risk of developing IR-induced normal tissue injury could be greater in these patients.
Chemotherapy-induced mucositis development in a murine model of colitis-associated colorectal cancer
Published in Scandinavian Journal of Gastroenterology, 2020
Lauren C. Chartier, Gordon S. Howarth, Suzanne Mashtoub
Intestinal mucositis is characterised by ulceration and deterioration of mucosal membranes and can occur anywhere along the gastrointestinal tract from mouth to anus. Surprisingly, approximately 40–60% of patients undergoing chemotherapy treatment will be diagnosed with mucositis [14–16]. Mucositis develops due to the inability of 5-FU to discriminate between normal and neoplastic cells [17,18]. The Dark Agouti rat mammary adenocarcinoma (DAMA) model has been developed to investigate the effects of chemotherapies and chemo-protectants on tumour burden and associated gut-toxicities [19,20]. However, this model results in the development of breast cancer, following subcutaneous injection of cancer cells, and therefore has limitations as it does not mimic an inflammation-associated cancer phenotype.