The Action of Four Carcinogenic Hydrocarbons on the Ovaries of IF Mice and the Histogenesis of Induced Tumours*

are concerned with the state of the ovaries including the process of tumour formation, following skin applications of four chemical carcinogens to virgin mice of the IF strain. Howell, Marchant and Orr (1954) showed that skin applications of 9: 10-dimethyl-I:2-benzanthracene induced a bigh incidence of ovarian tumours in inbred or hydrid virgin mice of this strain as compared with three other inbred strains. Marchant (1957) also tested 20methylcholanthrene in a small number of mice of IF origin and obtained a few microscopical tumours. In a previous paper (Mody, 1960) the normal virgin IF ovary at various ages was described and it was shown that frequent spontaneous pseudopregnancy occurs in grouped virgins. MATERIAL AND METHODS IF virgin females, approximately sixteen weeks old, were subjected to four fortnightly skin applications of an 0-5 per cent solution of a chemical carcinogen (obtained from L. Light & Co. Ltd., Colnbrook) in aracbis oil. At each painting I ml. of the solution was applied as 8 drops to the dorsal and 8 drops to the ventral side of the entire trunk surface. The animals in each group were killed in batches at 0-3, 4-7. 8-1 1, and 12-15 weeks from the date of commencement of painting and from then onwards at 8-weekly intervals until 70 weeks. The organs were examined and the tissues fixed, cut and stained as described by Mody (1960). Between 8 and 12 weeks after the start of treatment a batch of 4 mice from each group was used for a dailv three-week study of the vaginal smear. The groups comprised: (i) Sixty females treated with 9: 10-dimethyl-I:2-benzanthracene (DMB). (h) Fifty-three females treated with 3: 4-benzpyrene (BP)

Evolution of Geriatric Medicine: Midcareer Faculty Continuing the Dialogue

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/137692/1/jgs14842_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/137692/2/jgs14842.pd

PNIPAM Poly (N-isopropylacrylamide): A Thermoresponsive “Smart” Polymer in Novel Drug Delivery Systems

Over the past years, extensive research has been carried out in designing and optimizing various drug delivery systems in order to maximize therapeutic effect and minimize unwanted effects of drugs. Many drug carrier systems have been developed on the basis of nanotechnology including systems based on polymeric nanoparticles. Polymeric drug delivery research has been extended to targeting of the drug at the specific site by utilizing various stimuli responsive systems which depend upon physiological conditions of the body such as pH of biological fluids and temperature of the human body. Thermoresponsive polymers with Lower Critical Solution Temperature (LCST) have been investigated for various biomedical and pharmaceutical formulations. One such polymer of considerable focus is PNIPAM Poly (N-isopropylacrylamide). PNIPAM is a thermosensitive polymer which has been utilized in many drug delivery systems including for cancer therapeutics. The present article deals with the properties of PNIPAM and their applications in different drug delivery systems.Keywords: PNIPAM; LCST; Properties; Synthesis; ApplicationsInternet Journal of Medical Update 2012 July;7(2):59-6

Neuronal human BACE1 knock-in induces systemic diabetes in mice

Acknowledgements The authors thank S. Tammireddy (Diabetes and Cardiovascular Science, University of the Highlands and Islands, Inverness, UK) for technical support with the lipidomics component. Funding We would like to thank R. Simcox, Romex Oilfield Chemicals, for financial support for KP, and acknowledge additional contributions from the Scottish Alzheimer’s Research UK network for the lipidomics work. The College of Life Science and Medicine, University of Aberdeen, sponsored the imaging study. MD was funded by British Heart Foundation and Diabetes UK; NM was funded by a British Heart Foundation Intermediate Fellowship; KS was funded by a European Foundation for the Study of Diabetes/Lilly programme grant; and RD was funded by an Institute of Medical Sciences PhD studentship.Peer reviewedPublisher PDFPublisher PD

Myeloid protein tyrosine phosphatase 1B (PTP1B) deficiency protects against atherosclerotic plaque formation in the ApoE-/- mouse model of atherosclerosis with alterations in IL10/AMPKa pathway

Objective: Cardiovascular disease (CVD) is the most prevalent cause of mortality among patients with Type 1 or Type 2 diabetes, due to accelerated atherosclerosis. Recent evidence suggests a strong link between atherosclerosis and insulin resistance due to impaired insulin receptor (IR) signaling. Moreover, inflammatory cells, in particular macrophages, play a key role in pathogenesis of atherosclerosis and insulin resistance in humans. We hypothesized that inhibiting the activity of protein tyrosine phosphatase 1B (PTP1B), the major negative regulator of the IR, specifically in macrophages, would have beneficial anti-inflammatory effects and lead to protection against atherosclerosis and CVD. Methods: We generated novel macrophage-specific PTP1B knockout mice on atherogenic background (ApoE−/−/LysM-PTP1B). Mice were fed standard or pro-atherogenic diet, and body weight, adiposity (echoMRI), glucose homeostasis, atherosclerotic plaque development, and molecular, biochemical and targeted lipidomic eicosanoid analyses were performed. Results: Myeloid-PTP1B knockout mice on atherogenic background (ApoE−/−/LysM-PTP1B) exhibited a striking improvement in glucose homeostasis, decreased circulating lipids and decreased atherosclerotic plaque lesions, in the absence of body weight/adiposity differences. This was associated with enhanced phosphorylation of aortic Akt, AMPKα and increased secretion of circulating anti-inflammatory cytokine interleukin-10 (IL-10) and prostaglandin E2 (PGE2), without measurable alterations in IR phosphorylation, suggesting a direct beneficial effect of myeloid-PTP1B targeting. Conclusions: Here we demonstrate that inhibiting the activity of PTP1B specifically in myeloid lineage cells protects against atherosclerotic plaque formation, under atherogenic conditions, in an ApoE−/− mouse model of atherosclerosis. Our findings suggest for the first time that macrophage PTP1B targeting could be a therapeutic target for atherosclerosis treatment and reduction of CVD risk

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Silica Vesicle Nanovaccine Formulations Stimulate Long-Term Immune Responses to the Bovine Viral Diarrhoea Virus E2 Protein

Bovine Viral Diarrhoea Virus (BVDV) is one of the most serious pathogen, which causes tremendous economic loss to the cattle industry worldwide, meriting the development of improved subunit vaccines. Structural glycoprotein E2 is reported to be a major immunogenic determinant of BVDV virion. We have developed a novel hollow silica vesicles (SV) based platform to administer BVDV-1 Escherichia coli-expressed optimised E2 (oE2) antigen as a nanovaccine formulation. The SV-140 vesicles (diameter 50 nm, wall thickness 6 nm, perforated by pores of entrance size 16 nm and total pore volume of 0.934 cm(3)g(-1)) have proven to be ideal candidates to load oE2 antigen and generate immune response. The current study for the first time demonstrates the ability of freeze-dried (FD) as well as non-FD oE2/SV140 nanovaccine formulation to induce long-term balanced antibody and cell mediated memory responses for at least 6 months with a shortened dosing regimen of two doses in small animal model. The in vivo ability of oE2 (100 mu g)/SV-140 (500 mu g) and FD oE2 (100 mu g)/SV-140 (500 mu g) to induce long-term immunity was compared to immunisation with oE2 (100 mu g) together with the conventional adjuvant Quil-A from the Quillaja saponira (10 mu g) in mice. The oE2/SV-140 as well as the FD oE2/SV-140 nanovaccine generated oE2-specific antibody and cell mediated responses for up to six months post the final second immunisation. Significantly, the cell-mediated responses were consistently high in mice immunised with oE2/SV-140 (1,500 SFU/million cells) at the six-month time point. Histopathology studies showed no morphological changes at the site of injection or in the different organs harvested from the mice immunised with 500 mu g SV-140 nanovaccine compared to the unimmunised control. The platform has the potential for developing single dose vaccines without the requirement of cold chain storage for veterinary and human applications

Methionine restriction restores a younger metabolic phenotype in adult mice with alterations in fibroblast growth factor 21.

Methionine restriction (MR) decreases body weight and adiposity and improves glucose homeostasis in rodents. Similar to caloric restriction, MR extends lifespan, but is accompanied by increased food intake and energy expenditure. Most studies have examined MR in young animals; therefore, the aim of this study was to investigate the ability of MR to reverse age-induced obesity and insulin resistance in adult animals. Male C57BL/6J mice aged 2 and 12 months old were fed MR (0.172% methionine) or control diet (0.86% methionine) for 8 weeks or 48 h. Food intake and whole-body physiology were assessed and serum/tissues analyzed biochemically. Methionine restriction in 12-month-old mice completely reversed age-induced alterations in body weight, adiposity, physical activity, and glucose tolerance to the levels measured in healthy 2-month-old control-fed mice. This was despite a significant increase in food intake in 12-month-old MR-fed mice. Methionine restriction decreased hepatic lipogenic gene expression and caused a remodeling of lipid metabolism in white adipose tissue, alongside increased insulin-induced phosphorylation of the insulin receptor (IR) and Akt in peripheral tissues. Mice restricted of methionine exhibited increased circulating and hepatic gene expression levels of FGF21, phosphorylation of eIF2a, and expression of ATF4, with a concomitant decrease in IRE1α phosphorylation. Short-term 48-h MR treatment increased hepatic FGF21 expression/secretion and insulin signaling and improved whole-body glucose homeostasis without affecting body weight. Our findings suggest that MR feeding can reverse the negative effects of aging on body mass, adiposity, and insulin resistance through an FGF21 mechanism. These findings implicate MR dietary intervention as a viable therapy for age-induced metabolic syndrome in adult humans