Rony Kalman

Prevention of insulin resistance and beta-cell loss by abrogating PKCε-induced serine phosphorylation of muscle IRS-1 in Psammomys obesus

Psammomys obesus gerbil exhibits PKCε over‐expression on high‐energy (HE) diet. Muscle insulin receptor (IR) signalling and tyrosine kinase activity are inhibited eliciting insulin resistance. We aimed at preventing diabetes by inhibiting PKCε‐induced serine phosphorylation of IRS‐1 with novel PKCε abrogating peptides.

Suppression of Hepatocellular Carcinoma by Inhibition of Overexpressed Ornithine Aminotransferase

Hepatocellular carcinoma is the second leading cause of cancer death worldwide. DNA microarray analysis identified the ornithine aminotransferase (OAT) gene as a prominent gene overexpressed in hepatocellular carcinoma (HCC) from Psammomys obesus. In vitro studies demonstrated inactivation of OAT by gabaculine (1), a neurotoxic natural product, which suppressed in vitro proliferation of two HCC cell lines. Alpha-fetoprotein (AFP) secretion, a biomarker for HCC, was suppressed by gabaculine in both cell lines, but not significantly. Because of the active site similarity between GABA aminotransferase (GABA-AT) and OAT, a library of 24 GABA-AT inhibitors was screened to identify a more selective inhibitor of OAT. (1S,3S)-3-Amino-4-(hexafluoropropan-2-ylidene)cyclopentane-1-carboxylic acid (2) was found to be an inactivator of OAT that only weakly inhibits GABA-AT, l-aspartate aminotransferase, and l-alanine aminotransferase. In vitro administration of 2 significantly suppressed AFP secretion in both Hep3B and HepG2 HCC cells; in vivo, 2 significantly suppressed AFP serum levels and tumor growth in HCC-harboring mice, even at 0.1 mg/kg. Overexpression of the OAT gene in HCC and the ability to block the growth of HCC by OAT inhibitors support the role of OAT as a potential therapeutic target to inhibit HCC growth. This is the first demonstration of suppression of HCC by an OAT inactivator.

A high oleic sunflower oil fatty acid esters of plant sterols mixed with dietary diacylglycerol reduces plasma insulin and body fat accumulation in Psammomys obesus

BackgroundMetabolic syndrome is associated with subsequent development of cardiovascular diseases and type 2 diabetes. It is characterized by reduced response to insulin, central obesity, and dyslipidemia. Intake of plant sterols (PS) has been shown to confer a healthier lipid profile and ameliorate cardiovascular disease risk factors in experimental animals and humans. In this study we used an animal model of type 2 diabetes to assess the effects of a preparation of PS esterified to high oleic sunflower oil fatty acids mixed with dietary diacylglycerol (PS-HOSO) on diabetic related metabolic parameters. Psammomys obesus (P. obesus) were fed high energy (HE) diet supplemented by either PS-HOSO or control oil. Following 4.5 weeks of intervention, animals were divided into fasting and non-fasting modes prior to outcome measurements. Glucose and insulin levels as well as blood lipid profile, body weight, and fat accumulation were evaluated in fasting and non-fasting modes.ResultsP. obesus fed with a HE diet displayed a characteristic heterogeneity in their blood glucose and insulin levels with a subset group displaying type 2 diabetes symptoms. PS-HOSO treatment significantly reduced total cholesterol (24%, P < 0.001) and non-HDL cholesterol (34%, P < 0.01) compared to the control diet. Among fasting animals, body weight at end point and epididymal fat-to-liver weight ratio were significantly (P < 0.05 each) reduced (7% and 16%, respectively) compared to controls. Interestingly, fasting blood glucose levels were similar between groups, whereas plasma insulin level at end point was 44% lower in the PS-HOSO group compared to control group (P < 0.0001)ConclusionPS-HOSO supplementation to diabetes-prone gerbils counteracts the increase in body weight and epididymal fat accumulation, and also results in a drop in circulating insulin levels. These effects are pointing out that PS-HOSO may serve as a functional ingredient for metabolic syndrome or diabetic sufferers, which not only influences body weight, but also prevents or reverses insulin resistance and hyperlipidemia.

Chapter 54 – Sand Rat

Publisher Summary The focus of this chapter is to illustrate the use of a rodent other than the mouse or rat to serve as a model of an important human disease. This chapter provides limited information on basic species biology and husbandry, and instead concentrates on the research uses of sand rats. Psammomys, or the sand rat, is a rodent belonging to the subfamily Gerbillinae. Diabetes in sand rats ranges from mild hyperglycemia with hyperinsulinemia to hypoinsulinemia with ketoacidosis, which is a terminal stage with short survival. Psammomys are mainly important because it is found to be an intermediate host of the parasite Leishmania tropica, which is transmitted to humans by the sand fly. Psammomys attained additional interest when it was found to be an intermediate host of the parasite Leishmania tropica, which displays a range of phenotypic characteristics, as might be expected for noninbred progeny, when given free access to standard laboratory diet labeled as high-energy (HE) diet (Digestible energy—2.93 kcal/g).

Chapter 6 – Israeli Legislation and Regulation on the Use of Animals in Biological and Medical Research

Abstract Animal care and use has been regulated in Israel since 1994 when the Animal Welfare Law—Animal Experiments (Law) was legislated. At the heart of the Law is the National Council (Council), which operates in the Ministry of Health. The chairman is appointed by the Minister of Health from the National Academy of Sciences. The Council has all legal authority regarding animal testing, and is entrusted with regulation and supervision duties. Every institution that wishes to carry out research with animals has to establish an Animal Care and Use Program (Program) and appoint an attending veterinarian (AV). All the experiments with animals require an Animal Experiment Permit (Permit), which can be obtained from an Institutional Animal Care and Use Committee. Applications can be submitted by an appropriately trained principal investigator. The Council places a particular importance to the issue of training, and each of the training courses is approved by the Council. All courses are built on a unified national framework of two levels: a basic training part and specific supplementary practical part for each animal species not covered by the basic course. The legal basis for animal experimentation in Israel is comprised of the Law, Council regulations, and the instructions of the American NRC Guide for the Care and Use of Laboratory Animals (Guide) which has an official status in Israel. The Law places special importance to the role of the AV, whose post is a legal requirement, and who is entrusted among other things with supervisory duties at the institution. Institutions are required to report to the Council on all approved permits, on the actual progress of the research projects, and on the veterinary conditions. Institutions are also supervised by the professionals of the Council who have all the authority to carry out their duty and can even instruct the revoking of permits.