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## Recent Publications

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Head of Institute: Prof. Ido Braslavsky

Institute of Biochemistry, Food Science and Nutrition,
Robert H. Smith Faculty of Agriculture, Food and Environment,
The Hebrew University of Jerusalem,
Herzl 229, Rehovot 7610001, ISRAEL

Tel: +972 - (0)8-9489385
Fax: +972 - (0)8-9363208

# Publications

2017
Kalish-Achrai, N. ; Monsonego-Ornan, E. ; Shahar, R. Structure, composition, mechanics and growth of spines of the dorsal fin of blue tilapia Oreochromis aureus and common carp Cyprinus carpio. Journal of Fish BiologyJournal of Fish BiologyJ Fish Biol 2017, 90, 2073 - 2096. Publisher's VersionAbstract
The structural, compositional and mechanical properties of the spines of the dorsal fin in mature anosteocytic blue tilapia Oreochromis aureus and osteocytic common carp Cyprinus carpio are described, as well as their temporal growth pattern and regenerative capacities. The three-dimensional architecture of both spines, from macro to sub-micron levels, is shown to be axially oriented and therefore highly anisotropic and the spines of both species are able to regenerate after partial amputation.
Oren, T. ; Nimri, L. ; Yehuda-Shnaidman, E. ; Staikin, K. ; Hadar, Y. ; Friedler, A. ; Amartely, H. ; Slutzki, M. ; Di Pizio, A. ; Niv, M. Y. ; et al. Recombinant ostreolysin induces brown fat-like phenotype in HIB-1B cells. Mol Nutr Food Res 2017, 61.Abstract
SCOPE: Brown adipose tissue (BAT) is the main regulator of thermogenesis by increasing energy expenditure through the uncoupling of oxidative metabolism from ATP synthesis. There is a growing body of evidence for BAT being the key responsible organ in combating obesity and its related disorders. Herein we propose the fungal protein ostreolysin (Oly), which has been previously shown to bind to cholesterol-enriched raft-like membrane domains (lipid rafts) of mammalian cells, as a suitable candidate for interaction with brown preadipocytes. The aim of the present study was therefore to characterize the mechanism by which a recombinant version of ostreolysin (rOly) induces brown adipocyte differentiation. METHODS AND RESULTS: Primary isolated brown preadipocytes or HIB-1B brown preadipocyte cells were treated with rOly and the effects on morphology, lipid accumulation, respiration rate, and associated gene and protein expression were measured. rOly upregulated mRNA and protein levels of factors related to brown adipocyte differentiation, induced lipid droplet formation, and increased cellular respiration rate due to expression of uncoupling protein 1. rOly also upregulated β-tubulin expression, and therefore microtubules might be involved in its mechanism of action. CONCLUSION: rOly promotes brown adipocyte differentiation, suggesting a new mechanism for rOly's contribution to the battle against obesity.
Hatting, M. ; Rines, A. K. ; Luo, C. ; Tabata, M. ; Sharabi, K. ; Hall, J. A. ; Verdeguer, F. ; Trautwein, C. ; Puigserver, P. Adipose Tissue CLK2 Promotes Energy Expenditure during High-Fat Diet Intermittent Fasting. Cell Metab 2017, 25, 428-437.Abstract
A promising approach to treating obesity is to increase diet-induced thermogenesis in brown adipose tissue (BAT), but the regulation of this process remains unclear. Here we find that CDC-like kinase 2 (CLK2) is expressed in BAT and upregulated upon refeeding. Mice lacking CLK2 in adipose tissue exhibit exacerbated obesity and decreased energy expenditure during high-fat diet intermittent fasting. Additionally, tissue oxygen consumption and protein levels of UCP1 are reduced in CLK2-deficient BAT. Phosphorylation of CREB, a transcriptional activator of UCP1, is markedly decreased in BAT cells lacking CLK2 due to enhanced CREB dephosphorylation. Mechanistically, CREB dephosphorylation is rescued by the inhibition of PP2A, a phosphatase that targets CREB. Our results suggest that CLK2 is a regulatory component of diet-induced thermogenesis in BAT through increased CREB-dependent expression of UCP1.
Sharabi, K. ; Lin, H. ; Tavares, C. D. J. ; Dominy, J. E. ; Camporez, J. P. ; Perry, R. J. ; Schilling, R. ; Rines, A. K. ; Lee, J. ; Hickey, M. ; et al. Selective Chemical Inhibition of PGC-1α Gluconeogenic Activity Ameliorates Type 2 Diabetes. Cell 2017, 169, 148-160.e15.Abstract
Type 2 diabetes (T2D) is a worldwide epidemic with a medical need for additional targeted therapies. Suppression of hepatic glucose production (HGP) effectively ameliorates diabetes and can be exploited for its treatment. We hypothesized that targeting PGC-1α acetylation in the liver, a chemical modification known to inhibit hepatic gluconeogenesis, could be potentially used for treatment of T2D. Thus, we designed a high-throughput chemical screen platform to quantify PGC-1α acetylation in cells and identified small molecules that increase PGC-1α acetylation, suppress gluconeogenic gene expression, and reduce glucose production in hepatocytes. On the basis of potency and bioavailability, we selected a small molecule, SR-18292, that reduces blood glucose, strongly increases hepatic insulin sensitivity, and improves glucose homeostasis in dietary and genetic mouse models of T2D. These studies have important implications for understanding the regulatory mechanisms of glucose metabolism and treatment of T2D.
Myers, E. F. ; Trostler, N. ; Varsha, V. ; Voet, H. Insights from the Diabetes in India Nutrition Guidelines Study: Adopting Innovations Using a Knowledge Transfer Model. Topics in Clinical Nutrition 2017, 32, 69-86. Publisher's VersionAbstract
This 12-month prospective randomized cluster trial of 20 dietitians in India compared usual care (UC) and evidence-based nutrition practice guideline (EBNPG) care for patients with type 2 diabetes mellitus. Baseline, 6-month, and 12-month data from 238 patients were analyzed. EBNPG implementation was evaluated using the Ottawa Model for Knowledge Transfer. EBNPG and UC groups achieved significant hemoglobin A1C improvements. EBNPG-treated participants were significantly more likely to meet low-density lipoprotein, high-density lipoprotein, and triglyceride goals at 6 or 12 months. Dietitian dropout, implementation barriers, and undetermined EBNPG intervention fidelity are limitations. Future research should assess barriers/supports and degree of EBNPG use. © 2017 Wolters Kluwer Health, Inc.
Swan, W. I. ; Vivanti, A. ; Hakel-Smith, N. A. ; Hotson, B. ; Orrevall, Y. ; Trostler, N. ; Beck Howarter, K. ; Papoutsakis, C. Nutrition Care Process and Model Update: Toward Realizing People-Centered Care and Outcomes Management. Journal of the Academy of Nutrition and Dietetics 2017, 117, 2003-2014. Publisher's Version
Soon, J. M. ; Saguy, I. Crowdsourcing: A new conceptual view for food safety and quality. Trends in Food Science and Technology 2017, 66, 63-72. Publisher's VersionAbstract
Background Crowdsourcing is a new tool offered mainly over the internet for obtaining ideas, content, funding by seeking contributions from a large group of people and especially from the online community rather than from traditional employees or suppliers. Crowdsourcing is widespread in numerous food applications (e.g., technology, entrepreneurial projects, start-ups funding, innovative product developments). Scope and approach Although the use of crowdsourcing has increased rapidly, there is still much untapped potential in harnessing its vast innovative potential in food quality and safety solutions. This paper aims to review recent utilization of crowdsourcing practices in the food domain. Additionally, to furnish a conceptual view on possible application where crowdsourcing can be harnessed in enhancing food quality, safety and reducing risks. Key findings and conclusions It argues that crowdsourcing initiative is potentially a very useful tool as a part of the big data by utilizing the crowd's data in shelf-life monitoring, inventory control, foodborne illness surveillance, identification of contaminated products and to improve food businesses’ hygiene, enhance food safety, communication and allergen management and minimizing risk. The limitations include the number of reports and data generated may overwhelm the food industry or authority due to lack of internal resources i.e. time and technical expert to process the information. There is also risk of lack of crowd participation and loss of control. Hence, a mechanism to facilitate, evaluate and process the data should be in place. © 2017 Elsevier Ltd
Belkin, S. ; Yagur-Kroll, S. ; Kabessa, Y. ; Korouma, V. ; Septon, T. ; Anati, Y. ; Zohar-Perez, C. ; Rabinovitz, Z. ; Nussinovitch, A. ; Agranat, A. J. Remote detection of buried landmines using a bacterial sensor. Nature Biotechnology 2017, 35, 308-310. Publisher's Version
Rachman-Elbaum, S. ; Stark, A. H. ; Kachal, J. ; Johnson, T. W. ; Porat-Katz, B. S. A New System of Documentation to Improve Dietitian-Physician Crosstalk. Isr Med Assoc J 2017, 19, 360-364.Abstract
BACKGROUND: Standardization of the dietetic care process allows for early identification of malnutrition and metabolic disorders, interdisciplinary collaboration among the medical team, and improved quality of patient care. Globally, dietitians are adopting a nutrition care model that integrates national regulations with professional scope of practice. Currently, Israel lacks a standardized dietetic care process and documentation terminology. OBJECTIVES: To assess the utilization of a novel sectoral documentation system for nutrition care in Israel. METHODS: Seventy dietitians working in 63 geriatric facilities completed an online training program presenting the proposed patient-sectoral-model. Training was followed by submission of sample case studies from clinical practice or completion of a case simulation. Application of the proposed model was assessed by measuring the frequency participants implemented different sections of the model and responses to an approval questionnaire. RESULTS: Fifty-four participants (77%) provided completed cases. Over 80% of participants reported each step of the proposed dietary care process with 100% reporting the "nutrition diagnosis". Fifty-one dietitians (72.8%) completed the approval survey with the section on nutrition diagnosis receiving a highly favorable response (95%), indicating that the new documentation system was beneficial. Over 80% of participants rated the model useful in clinical practice. CONCLUSIONS: A sectoral approach for documenting dietetic care may be the ideal model for dietitians working in specific patient populations with the potential for improving interdisciplinary collaboration in patient care.
Nimri, L. ; Spivak, O. ; Tal, D. ; Schälling, D. ; Peri, I. ; Graeve, L. ; Salame, T. M. ; Yarden, O. ; Hadar, Y. ; Schwartz, B. A recombinant fungal compound induces anti-proliferative and pro-apoptotic effects on colon cancer cells. Oncotarget 2017, 8 28854-28864.Abstract
Finding intracellular pathways and molecules that can prevent the proliferation of colon cancer cells can provide significant bases for developing treatments for this disease. Ostreolysin (Oly) is a protein found in the mushroom Pleurotus ostreatus, and we have produced a recombinant version of this protein (rOly).We measured the viability of several colon cancer cells treated with rOly. Xenografts and syngeneic colon cancer cells were injected into in vivo mouse models, which were then treated with this recombinant protein.rOly treatment induced a significant reduction in viability of human and mouse colon cancer cells. In contrast, there was no reduction in the viability of normal epithelial cells from the small intestine. In the search for cellular targets of rOly, we showed that it enhances the anti-proliferative activity of drugs targeting cellular tubulin. This was accompanied by a reduction in the weight and volume of tumours in mice injected with rOly as compared to their respective control mice in two in vivo models.Our results advance the functional understanding of rOly as a potential anti-cancer treatment associated with pro-apoptotic activities preferentially targeting colon cancer cells.
Bein, A. ; Zilbershtein, A. ; Golosovsky, M. ; Davidov, D. ; Schwartz, B. LPS Induces Hyper-Permeability of Intestinal Epithelial Cells. Journal of Cellular Physiology 2017, 232, 381-390. Publisher's VersionAbstract
Necrotizing Enterocolitis (NEC) is a severe inflammatory disorder leading to high morbidity and mortality rates. A growing body of evidence demonstrate the key role of the Toll like receptor 4 (TLR4) in NEC. This membranal receptor recognizes lipopolysaccharides (LPS) from the bacterial wall and triggers an inflammatory response. The aim of the present study was to elucidate the effect of LPS on paracellular permeability known to be severely affected in NEC. IEC-18 cells were treated with LPS and the effects on morphology, paracellular permeability and their associated gene and protein expressions were measured. Our results show that LPS down regulated the expression of occludin and ZO-1 mRNAs while up regulating Cdkn1a. In addition LPS caused a significant increase in paracellular permeability and epithelial barrier damage. Finally ZO-1 protein was found to be spatially disarrayed in the intercellular junctions in response to LPS. We conclude that LPS adversely affected the functionality of the intestinal epithelial barrier suggesting a new mechanism by which bacterial infection may contribute to the development of NEC. J. Cell. Physiol. 232: 381–390, 2017. © 2016 Wiley Periodicals, Inc.
Avni, S. ; Ezove, N. ; Hanani, H. ; Yadid, I. ; Karpovsky, M. ; Hayby, H. ; Gover, O. ; Hadar, Y. ; Schwartz, B. ; Danay, O. Olive Mill Waste Enhances α-Glucan Content in the Edible Mushroom Pleurotus eryngii. Int J Mol Sci 2017, 18.Abstract
Mushroom polysaccharides are edible polymers that have numerous reported biological functions; the most common effects are attributed to β-glucans. In recent years, it became apparent that the less abundant α-glucans also possess potent effects in various health conditions. Here we explore several species for their total, β and α-glucan content. was found to have the highest total glucan concentrations and the highest α-glucans proportion. We also found that the stalks (stipe) of the fruit body contained higher glucan content then the caps (pileus). Since mushrooms respond markedly to changes in environmental and growth conditions, we developed cultivation methods aiming to increase the levels of α and β-glucans. Using olive mill solid waste (OMSW) from three-phase olive mills in the cultivation substrate. We were able to enrich the levels mainly of α-glucans. Maximal total glucan concentrations were enhanced up to twice when the growth substrate contained 80% of OMSW compared to no OMSW. Taking together this study demonstrate that can serve as a potential rich source of glucans for nutritional and medicinal applications and that glucan content in mushroom fruiting bodies can be further enriched by applying OMSW into the cultivation substrate.
Oren, T. ; Nimri, L. ; Yehuda-Shnaidman, E. ; Staikin, K. ; Hadar, Y. ; Friedler, A. ; Amartely, H. ; Slutzki, M. ; Di Pizio, A. ; Niv, M. Y. ; et al. Recombinant ostreolysin induces brown fat-like phenotype in HIB-1B cells. Molecular Nutrition & Food ResearchMolecular Nutrition & Food ResearchMol. Nutr. Food Res. 2017, 61, 1700057. Publisher's VersionAbstract
Scope Brown adipose tissue (BAT) is the main regulator of thermogenesis by increasing energy expenditure through the uncoupling of oxidative metabolism from ATP synthesis. There is a growing body of evidence for BAT being the key responsible organ in combating obesity and its related disorders. Herein we propose the fungal protein ostreolysin (Oly), which has been previously shown to bind to cholesterol-enriched raft-like membrane domains (lipid rafts) of mammalian cells, as a suitable candidate for interaction with brown preadipocytes. The aim of the present study was therefore to characterize the mechanism by which a recombinant version of ostreolysin (rOly) induces brown adipocyte differentiation. Methods and results Primary isolated brown preadipocytes or HIB-1B brown preadipocyte cells were treated with rOly and the effects on morphology, lipid accumulation, respiration rate, and associated gene and protein expression were measured. rOly upregulated mRNA and protein levels of factors related to brown adipocyte differentiation, induced lipid droplet formation, and increased cellular respiration rate due to expression of uncoupling protein 1. rOly also upregulated ?-tubulin expression, and therefore microtubules might be involved in its mechanism of action. Conclusion rOly promotes brown adipocyte differentiation, suggesting a new mechanism for rOly's contribution to the battle against obesity.
Argov-Argaman, N. ; Mandel, D. ; Lubetzky, R. ; Kedem, M. H. ; Cohen, B. - C. ; Berkovitz, Z. ; Reifen, R. Human milk fatty acids composition is affected by maternal age. J Matern Fetal Neonatal Med 2017, 30, 34-37.Abstract
Human colostrums and transition milk were collected from women under the age of 37 years and women aged 37 years and older. Transition milk of the younger group had lower fat content and 10-fold higher concentrations of omega 6 FA, eicosadecanoic, and arachdonic acids. Gestational age affected the colostrum concentration of total fat and omega 3 and omega 6 FA composition only in the older group. We concluded that age may be a factor in the FA composition of human milk. This should be taken into account when planning diets for pregnant women of different ages.
Bar-El Dadon, S. ; Reifen, R. Vitamin A and the epigenome. Critical Reviews in Food Science and Nutrition 2017, 57, 2404-2411. Publisher's VersionAbstract
ABSTRACTThe epigenetic phenomena refer to heritable changes in gene expression other than those in the DNA sequence, such as DNA methylation and histone modifications. Major research progress in the last few years has provided further proof that environmental factors, including diet and nutrition, can influence physiologic and pathologic processes through epigenetic alterations, which in turn influence gene expression. This influence is termed nutritional epigenetics, and one prominent example is the regulation of gene transcription by vitamin A through interaction to its nuclear receptor.Vitamin A is critical throughout life. Together with its derivatives, it regulates diverse processes including reproduction, embryogenesis, vision, growth, cellular differentiation and proliferation, maintenance of epithelial cellular integrity and immune function.Here we review the epigenetic role of vitamin A in cancer, stem cells differentiation, proliferation, and immunity. The data presented here show that retinoic acid is a potent agent capable of inducing alterations in epigenetic modifications that produce various effects on the phenotype. Medical benefits of vitamin A as an epigenetic modulator, especially with respect to its chronic use as nutritional supplement, should rely on our further understanding of its epigenetic effects during health and disease, as well as through different generations.
Wiseman, E. M. ; Bar-El Dadon, S. ; Reifen, R. The vicious cycle of vitamin a deficiency: A review. Critical Reviews in Food Science and Nutrition 2017, 57, 3703-3714. Publisher's VersionAbstract
ABSTRACTVitamin A deficiency (VAD) is a serious and widespread public health problem and the leading cause of preventable blindness in young children. It is also associated with increased rates of death from severe infections, especially in developing countries. Over the past 35 years, researchers have examined the numerous activities of vitamin A in different tissues of the human body. VAD can lead to a series of ocular symptoms, anemia, and weak resistance to infection, which can increase the severity of infectious diseases and the risk of death. Cell development, vision, growth, and normal metabolism are among the vital processes that are insufficiently supported in the presence of VAD. VAD leads to impaired tissue function especially during the developmental periods of infancy, childhood, pregnancy, and lactation. We describe a multidirectional model of VAD that demonstrates how VAD can have progressive, negative effects on vital processes of the human body throughout the life cycle. This model starts with impaired intake and its link to decreased absorption and digestion and includes outcomes such as malnutrition, inflammation, and improper growth processes, including possible mechanisms. Together, these clinical and biochemical manifestations contribute to the vicious cycle of VAD.
Slutzki, M. ; Ben-Shimon, A. ; Niv, M. Y. AnchorDock for Blind Flexible Docking of Peptides to Proteins. In Modeling Peptide-Protein Interactions: Methods and Protocols; Schueler-Furman, O. ; London, N., Ed. Modeling Peptide-Protein Interactions: Methods and Protocols; Springer New York: New York, NY, 2017; pp. 95–108. Publisher's VersionAbstract
Due to increasing interest in peptides as signaling modulators and drug candidates, several methods for peptide docking to their target proteins are under active development. The blind'' docking problem, where the peptide-binding site on the protein surface is unknown, presents one of the current challenges in the field. AnchorDock protocol was developed by Ben-Shimon and Niv to address this challenge.
Cheled-Shoval, S. ; Behrens, M. ; Korb, A. ; Di Pizio, A. ; Meyerhof, W. ; Uni, Z. ; Niv, M. Y. From Cell to Beak: In-Vitro and In-Vivo Characterization of Chicken Bitter Taste Thresholds. Molecules 2017, 22.Abstract
Bitter taste elicits an aversive reaction, and is believed to protect against consuming poisons. Bitter molecules are detected by the Tas2r family of G-protein-coupled receptors, with a species-dependent number of subtypes. Chickens demonstrate bitter taste sensitivity despite having only three bitter taste receptors-ggTas2r1, ggTas2r2 and ggTas2r7. This minimalistic bitter taste system in chickens was used to determine relationships between in-vitro (measured in heterologous systems) and in-vivo (behavioral) detection thresholds. ggTas2r-selective ligands, nicotine (ggTas2r1), caffeine (ggTas2r2), erythromycin and (+)-catechin (ggTas2r7), and the Tas2r-promiscuous ligand quinine (all three ggTas2rs) were studied. Ligands of the same receptor had different in-vivo:in-vitro ratios, and the ggTas2r-promiscuous ligand did not exhibit lower in-vivo:in-vitro ratios than ggTas2r-selective ligands. In-vivo thresholds were similar or up to two orders of magnitude higher than the in-vitro ones.
Cheled-Shoval, S. L. ; Reicher, N. ; Niv, M. Y. ; Uni, Z. Detecting thresholds for bitter, umami, and sweet tastants in broiler chicken using a 2-choice test method. Poultry Science 2017, 96, 2206 - 2218. Publisher's VersionAbstract
The sense of taste has a key role in nutrient sensing and food intake in animals. A standardized and simple method for determination of tastant-detection thresholds is required for chemosensory research in poultry. We established a 24-h, 2-alternative, forced-choice solution-consumption method and applied it to measure detection thresholds for 3 G-protein-coupled receptor-mediated taste modalities—bitter, sweet, and umami—in chicken. Four parameters were used to determine a significant response: 1) tastant-solution consumption; 2) water (tasteless) consumption; 3) total consumption (tastant and water together); 4) ratio of tastant consumption to total consumption. Our results showed that assignment of the taste solutions and a water control to 2 bottles on random sides of the pen can be reliably used for broiler chicks, even though 47% of the chicks groups demonstrated a consistently preferred side. The detection thresholds for quinine (bitter), L-monosodium glutamate (MSG) (umami), and sucrose (sweet) were determined to be 0.3 mM, 300 mM, and 1 M, respectively. The threshold results for quinine were similar to those for humans and rodents, but the chicks were found to be less sensitive to sucrose and MSG. The described method is useful for studying detection thresholds for tastants that have the potential to affect feed and water consumption in chickens.
Oren, T. ; Nimri, L. ; Yehuda-Shnaidman, E. ; Staikin, K. ; Hadar, Y. ; Friedler, A. ; Amartely, H. ; Slutzki, M. ; Di Pizio, A. ; Niv, M. Y. ; et al. Recombinant ostreolysin induces brown fat-like phenotype in HIB-1B cells. Molecular Nutrition & Food Research 2017, 61, 1700057. Publisher's VersionAbstract
Scope Brown adipose tissue (BAT) is the main regulator of thermogenesis by increasing energy expenditure through the uncoupling of oxidative metabolism from ATP synthesis. There is a growing body of evidence for BAT being the key responsible organ in combating obesity and its related disorders. Herein we propose the fungal protein ostreolysin (Oly), which has been previously shown to bind to cholesterol-enriched raft-like membrane domains (lipid rafts) of mammalian cells, as a suitable candidate for interaction with brown preadipocytes. The aim of the present study was therefore to characterize the mechanism by which a recombinant version of ostreolysin (rOly) induces brown adipocyte differentiation. Methods and results Primary isolated brown preadipocytes or HIB-1B brown preadipocyte cells were treated with rOly and the effects on morphology, lipid accumulation, respiration rate, and associated gene and protein expression were measured. rOly upregulated mRNA and protein levels of factors related to brown adipocyte differentiation, induced lipid droplet formation, and increased cellular respiration rate due to expression of uncoupling protein 1. rOly also upregulated β-tubulin expression, and therefore microtubules might be involved in its mechanism of action. Conclusion rOly promotes brown adipocyte differentiation, suggesting a new mechanism for rOly's contribution to the battle against obesity.