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Bissoyi, A. ; Reicher, N. ; Chasnitsky, M. ; Arad, S. ; Koop, T. ; Rudich, Y. ; Braslavsky, I. Ice Nucleation Properties of Ice-binding Proteins from Snow Fleas. Biomolecules 2019, 9.Abstract
Ice-binding proteins (IBPs) are found in many organisms, such as fish and hexapods, plants, and bacteria that need to cope with low temperatures. Ice nucleation and thermal hysteresis are two attributes of IBPs. While ice nucleation is promoted by large proteins, known as ice nucleating proteins, the smaller IBPs, referred to as antifreeze proteins (AFPs), inhibit the growth of ice crystals by up to several degrees below the melting point, resulting in a thermal hysteresis (TH) gap between melting and ice growth. Recently, we showed that the nucleation capacity of two types of IBPs corresponds to their size, in agreement with classical nucleation theory. Here, we expand this finding to additional IBPs that we isolated from snow fleas (the arthropod Collembola), collected in northern Israel. Chemical analyses using circular dichroism and Fourier-transform infrared spectroscopy data suggest that these IBPs have a similar structure to a previously reported snow flea antifreeze protein. Further experiments reveal that the ice-shell purified proteins have hyperactive antifreeze properties, as determined by nanoliter osmometry, and also exhibit low ice-nucleation activity in accordance with their size.
Abeliovich, H. New gadget in the membrane trafficking toolbox: A novel inhibitor of SNARE priming. Journal of Biological Chemistry 2019, 294, 17186-17187. Publisher's VersionAbstract
NSF (N-ethylmaleimide sensitive factor) and its yeast counterpart Sec18 are highly conserved homohexameric proteins that play vital roles in eukaryotic membrane trafficking. Sec18 functions by disrupting SNARE complexes formed in cis, on the same membrane. However, the molecular mechanisms of this process are poorly understood, in large part due to the lack of selective, reversible inhibitors. A new study by Sparks et al. now reports a small molecule that appears to selectively inhibit Sec18 action in an in vitro assay. Their finding now paves the way to elucidate further details of Sec18-mediated SNARE priming. © 2019 Abeliovich.
Tal, Y. ; Chapnik, N. ; Froy, O. Non-obesogenic doses of palmitate disrupt circadian metabolism in adipocytes. Adipocyte 2019, 8 392-400. Publisher's VersionAbstract
Saturated fatty acids, such as palmitate, lead to circadian disruption. We aimed at studying the effect of low doses of palmitate on circadian metabolism and to decipher the mechanism by which fatty acids convey their effect in adipocytes. Mice were fed non-obesogenic doses of palm or olive oil and adipocytes were treated with palmitate and oleate. Cultured adipocytes treated with oleate showed increased AMPK activity and induced the expression of mitochondrial genes indicating increased fatty acid oxidation, while palmitate increased ACC activity and induced the expression of lipogenic genes, indicating increased fatty acid synthesis. Low doses of palmitate were sufficient to alter circadian rhythms, due to changes in the expression and/or activity of key metabolic proteins including GSK3β and AKT. Palmitate-induced AKT and GSK3β activation led to the phosphorylation of BMAL1 that resulted in low levels as well as high amplitude of circadian clock expression. In adipocytes, the detrimental metabolic alteration of palmitate manifests itself early on even at non-obesogenic levels. This is accompanied by modulating BMAL1 expression and phosphorylation levels, which lead to dampened clock gene expression. © 2019, © 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
Jakubowicz, D. ; Landau, Z. ; Tsameret, S. ; Wainstein, J. ; Raz, I. ; Ahren, B. ; Chapnik, N. ; Barnea, M. ; Ganz, T. ; Menaged, M. ; et al. Reductioninglycatedhemoglobin and daily insulin dose alongside circadian clock upregulation in patients with type 2 diabetes consuming a three-meal diet: A randomized clinical trial. Diabetes Care 2019, 42, 2171-2180. Publisher's VersionAbstract
OBJECTIVE In type 2 diabetes, insulin resistance and progressive b-cell failure require treatment with high insulin doses, leading to weight gain. Our aim was to study whether a three-meal diet (3Mdiet) with a carbohydrate-rich breakfast may upregulate clock gene expression and, as a result, allow dose reduction of insulin, leading to weight loss and better glycemic control compared with an isocaloric six-meal diet (6Mdiet). RESEARCH DESIGN AND METHODS Twenty-eight volunteers with diabetes (BMI 32.4 6 5.2 kg/m2 and HbA1c 8.1 6 1.1% [64.5 6 11.9 mmol/mol]) were randomly assigned to 3Mdiet or 6Mdiet. Body weight, glycemic control, continuous glucose monitoring (CGM), appetite, and clock gene expression were assessed at baseline, after 2 weeks, and after 12 weeks. RESULTS 3Mdiet, but not 6Mdiet, led to a significant weight loss (25.4 6 0.9 kg) (P < 0.01) and decreased HbA1c (212 mmol/mol [21.2%]) (P < 0.0001) after 12 weeks. Fasting glucose and daily and nocturnal glucose levels were significantly lower on the 3Mdiet. CGM showed a significant decrease in the time spent in hyperglycemia only on the 3Mdiet. Total daily insulin dose was significantly reduced by 26 6 7 units only on the 3Mdiet. There was a significant decrease in the hunger and cravings only in the 3Mdiet group. Clock genes exhibited oscillation, increased expression, and higher amplitude on the 3Mdiet compared with the 6Mdiet. CONCLUSIONS A 3Mdiet, in contrast to an isocaloric 6Mdiet, leads to weight loss and significant reduction in HbA1c, appetite, and overall glycemia, with a decrease in daily insulin. Upregulation of clock genes seen in this diet intervention could contribute to the improved glucose metabolism. © 2019 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at
Rozenblit-Susan, S. ; Chapnik, N. ; Froy, O. Serotonin Prevents Differentiation of Brown Adipocytes by Interfering with Their Clock. Obesity 2019, 27, 2018-2024. Publisher's VersionAbstract
Objective: Serotonin was shown to interfere with the differentiation of brown adipocytes. In addition, clock components inhibit brown adipogenesis through direct transcriptional control of key components of the transforming growth factor β pathway. The aim of this study was to investigate whether serotonin abrogates brown adipogenesis by affecting clock functionality. Methods: Nondifferentiated and differentiated HIB1B brown adipocytes were treated with serotonin, and their clock expression and functionality and differentiation state were examined. Results: Nondifferentiated HIB1B brown adipocytes treated with serotonin showed increased brown adipocyte markers alongside increased brain-muscle Arnt-like protein 1 (Bmal1) and RAR related orphan receptor A (Rora) but decreased nuclear receptor Rev-erbα mRNA levels. BMAL1 overexpression together with serotonin led to significantly lower brown adipocyte markers. Serotonin in the differentiation cocktail led to reduced brown adipocyte markers as well as clock gene expression. After differentiation, serotonin treatment significantly decreased brown adipocyte markers and reduced BMAL1 and RORα but increased REV-ERBα protein levels. Addition of serotonin to the differentiation medium or addition after differentiation reduced activity of calcium/calmodulin-dependent protein kinase type II subunit gamma, which interferes with circadian locomoter output cycles protein kaput (CLOCK):BMAL1 dimerization and transactivation. Conclusions: Clock expression is required at the early stages of differentiation to brown adipocytes, and serotonin interferes with this process by modulating clock functionality. Serotonin interferes with clock functionality by reducing the levels of the active form of calcium/calmodulin-dependent protein kinase type II subunit gamma. © 2019 The Obesity Society
Basheer, L. ; Dag, A. ; Yermiyahu, U. ; Ben-Gal, A. ; Zipori, I. ; Kerem, Z. Effects of reclaimed wastewater irrigation and fertigation level on olive oil composition and quality. Journal of the Science of Food and Agriculture 2019, 99, 6342-6349. Publisher's VersionAbstract
BACKGROUND: Irrigation of olives increases fruit and oil yields. Due to scarcity of freshwater, low-quality water including recycled wastewater (RWW) is utilized in orchards. Here, effects of irrigation with RWW and of fertilization on the composition and quality of olive oil were studied. RESULTS: Long-term RWW irrigation of ‘Barnea’ and ‘Leccino’ olive had no significant negative effects on either oil composition or quality parameters, including free fatty acids (FFAs), peroxide value (PV), total phenolics content (TPC), fatty acid profiles and organoleptic characteristics. The average FFA contents for both cultivars were less than 0.8% during most of the experimental period, except the seasons 2009 and 2012–2013 for Barnea where the values were raised up to 1.4%. The measured PV levels were less than 9 and 5 mmol O2 kg-1 oil for Barnea and Leccino, respectively. In the last season of the experiment for each cultivar, higher TPC were observed in oils obtained from RWW irrigation with reduced fertilization (Re–) as compared to the treatments with the recommended fertilization [freshwater irrigation (Fr) and RWW irrigation (Re+) with standard dose of fertilizers], where the TPC increment exceeded 70% in Barnea and 25% in Leccino. The treatments had only minor effects on the fatty acid profile, reflected in slightly altered levels of C18:2 and C18:3 fatty acids. CONCLUSION: The use of RWW, combined with the consideration of nutrients arriving with such water to provide appropriate fertilization, was found suitable for olive irrigation to ensure optimal yields while preserving oil quality. © 2019 Society of Chemical Industry. © 2019 Society of Chemical Industry
Goldental-Cohen, S. ; Biton, I. ; Many, Y. ; Tavrizov, K. ; Dourou, A. M. ; Zemach, H. ; Tonutti, P. ; Kerem, Z. ; Avidan, B. ; Sperling, O. ; et al. Removal of flowers or inflorescences affects ‘Barnea’ olive fruitlet post-anthesis abscission. Journal of Horticultural Science and Biotechnology 2019, 94, 488-498. Publisher's VersionAbstract
A typical olive (Olea europaea L.) inflorescence consists of about 20 flowers. However, in many cultivars, only one fruit develops. This is due to massive abscission of flowers and fruitlets, which occurs during the first month after anthesis. In this study, we used the olive cultivar 'Barnea' to characterize the abscission mechanism and to try to increase fruit set by increasing the number of developed fruit per inflorescence. Removing the lateral flowers 3 weeks before anthesis increased fruit set by more than 50%. Removing all inflorescences but one from a branch increased the number of developed fruits from 0.93 to 2.8 during 2017 and from 0.91 to 3.34 fruits per inflorescence in 2018. Sugar quantification in the pistil revealed that starch level is high on the day of anthesis and low 25 days later in abscised as well as in developed fruit. Soluble carbohydrates are low on the day of anthesis, low in abscised flowers/fruitlets 25 days after anthesis and high in developed fruit. Screening the natural variation found in the Israeli germplasm collection revealed that in most cultivars less than one fruit per inflorescence has developed. However, there are unique cultivars with a higher fruit set. © 2018, © 2018 The Journal of Horticultural Science & Biotechnology Trust.
Yedidia, I. ; Schultz, K. ; Golan, A. ; Gottlieb, H. E. ; Kerem, Z. Structural elucidation of three novel kaempferol otri-glycosides that are involved in the defense response of hybrid ornithogalum to pectobacterium carotovorum. Molecules 2019, 24. Publisher's VersionAbstract
Ornithogalum is an ornamental flowering species that grows from a bulb and is highly susceptible to soft-rot disease caused by Pectobacterium carotovorum (Pc). Interspecific hybridization between O. thyrsoides and O. dubium yielded hybrids with enhanced resistance to that pathogen. The hybrids displayed distinct phenolic-compound profiles with several peaks that were specifically heightened following Pc infection. Three of these compounds were isolated and identified as novel kaempferol O-tri-glycosides. The structures of these compounds were elucidated using reversed phase high-performance liquid chromatography (RP-LC), RP-LC coupled to high-resolution mass spectrometry (RP-LC-MS), and nuclear magnetic resonance (NMR) (1D 1H and 13C, DEPT, HMQC, HMBC, COSY, and NOE), in order to achieve pure and defined compounds data. The new compounds were finally identified as kaempferol 3-O-[4-O-α-L-(3-O-acetic)-rhamnopyranosyl-6-O- β-D-xylopyranosyl]-β-D-glucopyranoside, kaempferol 3-O-[4-O-α-L-(2-O-acetic)-rhamnopyranosyl- 6-O-β-D-xylopyranosyl]-β-D-glucopyranoside and kaempferol 3-O-[4-O-α-L-(2,3-O-diacetic)- rhamnopyranosyl-6-O-β-D-xylopyranosyl]-β-D-glucopyranoside. © 2019 MDPI AG. All rights reserved.
de Roos, B. ; Aura, A. - M. ; Bronze, M. ; Cassidy, A. ; Conesa, M. - T. G. ; Gibney, E. R. ; Greyling, A. ; Kaput, J. ; Kerem, Z. ; Knežević, N. ; et al. Targeting the delivery of dietary plant bioactives to those who would benefit most: from science to practical applications. European Journal of Nutrition 2019, 58, 65-73. Publisher's VersionAbstract
Background: A healthy diet and optimal lifestyle choices are amongst the most important actions for the prevention of cardiometabolic diseases. Despite this, it appears difficult to convince consumers to select more nutritious foods. Furthermore, the development and production of healthier foods do not always lead to economic profits for the agro-food sector. Most dietary recommendations for the general population represent a “one-size-fits-all approach” which does not necessarily ensure that everyone has adequate exposure to health-promoting constituents of foods. Indeed, we now know that individuals show a high variability in responses when exposed to specific nutrients, foods, or diets. Purpose: This review aims to highlight our current understanding of inter-individual variability in response to dietary bioactives, based on the integration of findings of the COST Action POSITIVe. We also evaluate opportunities for translation of scientific knowledge on inter-individual variability in response to dietary bioactives, once it becomes available, into practical applications for stakeholders, such as the agro-food industry. The potential impact from such applications will form an important impetus for the food industry to develop and market new high quality and healthy foods for specific groups of consumers in the future. This may contribute to a decrease in the burden of diet-related chronic diseases. © 2019, The Author(s).
Milenkovic, D. ; Declerck, K. ; Guttman, Y. ; Kerem, Z. ; Claude, S. ; Weseler, A. R. ; Bast, A. ; Schroeter, H. ; Morand, C. ; Vandenberghe, W. (−)-Epicatechin metabolites promote vascular health through epigenetic reprogramming of endothelial-immune cell signaling and reversing systemic low-grade inflammation. Biochemical Pharmacology 2019. Publisher's VersionAbstract
Ingestion of (−)-epicatechin flavanols reverses endothelial dysfunction by increasing flow mediated dilation and by reducing vascular inflammation and oxidative stress, monocyte-endothelial cell adhesion and transendothelial monocyte migration in vitro and in vivo. This involves multiple changes in gene expression and epigenetic DNA methylation by poorly understood mechanisms. By in silico docking and molecular modeling we demonstrate favorable binding of different glucuronidated, sulfated or methylated (−)-epicatechin metabolites to different DNA methyltransferases (DNMT1/DNMT3A). In favor of this model, genome-wide DNA methylation profiling of endothelial cells treated with TNF and different (−)-epicatechin metabolites revealed specific DNA methylation changes in gene networks controlling cell adhesion-extravasation endothelial hyperpermeability as well as gamma-aminobutyric acid, renin-angiotensin and nitric oxide hypertension pathways. Remarkably, blood epigenetic profiles of an 8 weeks intervention with monomeric and oligomeric flavanols (MOF) including (−)-epicatechin in male smokers revealed individual epigenetic gene changes targeting similar pathways as the in vitro exposure experiments in endothelial cells. Furthermore, epigenetic changes following MOF diet intervention oppose atherosclerosis associated epigenetic changes. In line with biological data, the individual epigenetic response to a MOF diet is associated with different vascular health parameters (glutathione peroxidase 1 and endothelin-1 expression, acetylcholine-mediated microvascular response), in part involving systemic shifts in blood immune cell types which reduce the neutrophil–lymphocyte ratio (NLR). Altogether, our study suggests that different (−)-epicatechin metabolites promote vascular health in part via epigenetic reprogramming of endothelial-immune cell signaling and reversing systemic low-grade inflammation. © 2019 Elsevier Inc.
Ofir, O. ; Buch, A. ; Rouach, V. ; Goldsmith, R. ; Stern, N. ; Monsonego-Ornan, E. Association between abdominal obesity and fragility fractures among elderly Israeli women. Aging Clinical and Experimental Research 2019. Publisher's VersionAbstract
Background: Obesity has been traditionally viewed as a protective factor for fractures. Recent studies have challenged this concept, particularly regarding abdominal obesity. We aimed to investigate the association between abdominal obesity, body mass index (BMI) and fragility fractures prevalence in a sample of community-dwelling elderly Israeli women. Methods: The data in this cross-sectional study were based on ‘Mabat Zahav’—a survey of a nationally representative sample of elderly Israelis. The study population included 669 women. Data on fragility fractures site and circumstances were self-reported, and height, weight, waist and calf circumferences were measured. Waist circumference (WC) variable was divided into tertiles: < 88 cm, 88–99 cm and > 99 cm. Results: Sixty-five women reported fragility fractures (14 hip fractures, 18 vertebral fractures and 39 wrist fractures). Mean age was 73.9 ± 5.9 years, mean BMI was 29.9 ± 5 kg/m2 and mean WC was 93.9 ± 12 cm. While BMI was not associated with osteoporotic fractures, abdominal obesity (WC > 88 cm) was positively associated with fragility fractures, independently of age, smoking, physical activity [middle and high WC tertiles 3.15 (95% CI 1.41–7.02), 2.78 (95% CI 1.05–7.31), respectively]. Conclusions: Among this sample of elderly women, abdominal obesity was positively associated with fragility fractures, independently of age, smoking, physical activity and BMI. Waist circumference, an easily measured anthropometric indicator, may be useful for assessing the risk of fragility fractures in elderly women, particularly among those with normal or high BMI—a vast population which has been traditionally considered as having lower fracture risk. © 2019, Springer Nature Switzerland AG.
Demishtein, K. ; Reifen, R. ; Shemesh, M. Antimicrobial properties of magnesium open opportunities to develop healthier food. Nutrients 2019, 11. Publisher's VersionAbstract
Magnesium is a vital mineral that takes part in hundreds of enzymatic reactions in the human body. In the past several years, new information emerged in regard to the antibacterial effect of magnesium. Here we elaborate on the recent knowledge of its antibacterial effect with emphasis on its ability to impair bacterial adherence and formation complex community of bacterial cells called biofilm. We further talk about its ability to impair biofilm formation in milk that provides opportunity for developing safer and qualitative dairy products. Finally, we describe the pronounced advantages of enrichment of food with magnesium ions, which result in healthier and more effcient food products. © 2019 by the authors.
Nimri, L. ; Peri, I. ; Yehuda-Shnaidman, E. ; Schwartz, B. Adipocytes Isolated from Visceral and Subcutaneous Depots of Donors Differing in BMI Crosstalk with Colon Cancer Cells and Modulate their Invasive Phenotype. Translational Oncology 2019, 12, 1404-1415. Publisher's VersionAbstract
PURPOSE: Mechanisms related the crosstalk between adipocytes and colon cancer cells are still not clear. We hypothesize that molecules and adipocytokines generated from the adipose tissue of obese individuals accentuate the effect on the metabolic reprogramming in colon cancer cells, i.e. induce disarray in energy metabolism networks of the targeted affected colonic epithelial cells, prompting their malignant phenotype. METHODS: To explore the mechanistic behind this crosstalk we conducted a co-culture model system using human colon cancer cells having different malignant abilities and adipocytes from different depots and subjects. RESULTS: The results demonstrate that co-culturing aggressive colon cancer cells such as HM-7 cells, with Visceral or Subcutaneous adipocytes (VA or SA respectively) from lean/obese subjects significantly up-regulate the secretion of the adipokines IL-8, MCP1, and IL-6 from the adipocytes. Surprisingly, the response of co-culturing HM-7 cells with obese SA was substantially more significant. In addition, these effects were significantly more pronounced when using HM-7 cells as compared to the less malignant HCT116 colon cancer cells. Moreover, the results showed that HM-7 cells, co-cultured with VA or SA from obese subjects, expressed higher levels of fatty acid binding protein 4; thus, the conditioned media obtained from the wells contained HM-7 cells and adipocytes from obese subjects was significantly more efficient in promoting invasion of HM-7 cells. CONCLUSIONS: We conclude that interaction between adipocytes and colon cancer cells, especially the highly malignant cells, results in metabolic alterations in colon cancer cells and in highly hypertrophy phenotype which characterized by increasing adipokines secretion from the adipocytes. © 2019 The Authors
Vetvicka, V. ; Gover, O. ; Karpovsky, M. ; Hayby, H. ; Danay, O. ; Ezov, N. ; Hadar, Y. ; Schwartz, B. Immune-modulating activities of glucans extracted from Pleurotus ostreatus and Pleurotus eryngii. Journal of Functional Foods 2019, 54, 81-91. Publisher's VersionAbstract
We compared the immune-modulating activity of glucans extracted from P. ostreatus and P. eryngii on phagocytosis of peripheral blood neutrophils, and superoxide release from HL-60 cells. The results suggest that the anti-inflammatory properties of these glucans are partially mediated through modulation of neutrophil effector functions (P. eryngii was more effective). Additionally, both glucans dose-dependently competed for the anti-Dectin-1 and anti-CR3 antibody binding. We then tested the putative anti-inflammatory effects of the extracted glucans in inflammatory bowel disease (IBD) using the dextran sulfate sodium (DSS)–induced model in mice. The clinical symptoms of IBD were efficiently relieved by the treatment with two different doses of the glucan from both fungi. Glucan fractions, from either P. ostreatus or P. eryngii, markedly prevented TNF-α mediated inflammation in the DSS–induced inflamed intestine. These results suggest that there are variations in glucan preparations from different fungi in their anti-inflammatory ability. © 2018 Elsevier Ltd
Vetvicka, V. ; Gover, G. ; Hayby, H. ; Danay, O. ; Ezov, N. ; Hadar, Y. ; Schwartz, B. Immunomodulating effects exerted by glucans extracted from the king oyster culinary-medicinal mushroom pleurotus eryngii (agaricomycetes) grown in substrates containing various concentrations of olive mill waste. International Journal of Medicinal Mushrooms 2019, 21, 765-781. Publisher's VersionAbstract
We have recently demonstrated that we could enhance glucan content in Pleurotus eryngii following cultivation of the mushrooms on a substrate containing different concentrations of olive mill solid waste (OMSW). These changes are directly related to the content of OMSW in the growing substrate. Using dextran sulfate sodium (DSS)-inflammatory bowel disease (IBD) mice model, we measured the colonic inflammatory response to the different glucan preparations. We found that the histology damaging score (HDS) resulting from DSS treatment reach a value of 11.8 ± 2.3 were efficiently downregulated by treatment with the fungal extracted glucans. Glucans extracted from stalks cultivated at 20% OMSW downregulated to a HDS value of 6.4 ± 0.5 whereas those cultivated at 80% OMSW showed the strongest effects (5.5 ± 0.6). Similar downregulatory effects were obtained for expression of various intestinal cytokines. All tested glucans were equally effective in regulating the number of CD14/CD16 monocytes from 18.2 ± 2.7% for DSS to 6.4 ± 2.0 for DSS + glucans extracted from stalks cultivated at 50% OMSW. We tested the effect of glucans on lipopolysaccharide- induced production of TNF-α, which demonstrated that stalk-derived glucans were more effective than caps-derived glucans. Isolated glucans competed with anti-Dectin-1 and anti-CR3 antibodies, indicating that they contain β-glucans recognized by these receptors. In conclusion, the most effective glucans in ameliorating IBD-associated symptoms induced by DSS treatment in mice were glucan extracts prepared from the stalk of P. eryngii grown at higher concentrations of OMSW. We conclude that these stress-induced growing conditions may be helpful in selecting more effective glucans derived from edible mushrooms. © 2019 by Begell House, Inc.
Israeli, E. ; Adler Berken, N. ; Gover, O. ; Waechtershaeuser, E. ; Graeve, L. ; Schwartz, B. Recombinant ostreolysin (rOly) inhibits the anti-adipogenic Hedgehog (Hh) signaling pathway in 3T3-L1 cells. Journal of Functional Foods 2019, 59, 185-193. Publisher's VersionAbstract
Obesity is a nutrition-associated disorder result of an imbalance between energy intake and energy expenditure. Changing adipocytes differentiation patterns is considered as a strategy to treat obesity-related disorders. Recently, much interest is focused on the role of posttranslational modifications of tubulin on adipocyte differentiation. We recently demonstrated that a recombinant version of the fungal protein Ostreolysin (rOly) drastically affects metabolism of adipose tissue. The aim of the present study is to extend our understanding of the in vitro effects of rOly on different adipocytes. We demonstrate that rOly inhibits the anti-adipogenic Hedgehog (Hh) signaling pathway in 3T3-L1 cells. Additionally, rOly affected the gene expression levels of SQSTM1 and Collagen type 1, which are mediated by AMP-activated protein kinase (AMPK) activity in 3T3-L1 cells. We provide a potential molecular mechanistic approach describing that the effect of rOly on adipocytes is mediated by tubulin acetylation and AMPK phosphorylation. © 2019 Elsevier Ltd
Miron, N. ; Tirosh, O. Cholesterol Prevents Hypoxia-Induced Hypoglycemia by Regulation of a Metabolic Ketogenic Shift. Oxidative Medicine and Cellular Longevity 2019, 2019. Publisher's VersionAbstract
Blood cholesterol levels have been connected to high-altitude adaptation. In the present study, we treated mice with high-cholesterol diets following exposure to acute hypoxic stress and evaluated the effects of the diets on whole-body, liver glucose, and liver fat metabolism. For rapid cholesterol liver uptake, 6-week-old male C57BL/J6 mice were fed with high-cholesterol/cholic acid (CH) diet for 6 weeks and then were exposed to gradual oxygen level reduction for 1 h and hypoxia at 7% oxygen for additional 1 hour using a hypoxic chamber. Animals were than sacrificed, and metabolic markers were evaluated. Hypoxic treatment had a strong hypoglycemic effect that was completely blunted by CH treatment. Decreases in gluconeogenesis and glycogenolysis as well as an increase in ketone body formation were observed. Such changes indicate a metabolic shift from glucose to fat utilization due to activation of the inducible nitric oxide synthase/AMPK axis in the CH-treated animals. Increased ketogenesis was also observed in vitro in hepatocytes after cholesterol treatment. In conclusion, our results show for the first time that cholesterol contributes to metabolic shift and adaptation to hypoxia in vivo and in vitro through induction of HIF-1α and iNOS expression. © 2019 Naama Miron and Oren Tirosh.
Anavi, S. ; Tirosh, O. iNOS as a metabolic enzyme under stress conditions. Free Radical Biology and Medicine 2019. Publisher's VersionAbstract
Nitric oxide (NO) is a free radical acting as a cellular signaling molecule in many different biochemical processes. NO is synthesized from L-arginine through the action of the nitric oxide synthase (NOS) family of enzymes, which includes three isoforms: endothelial NOS (eNOS), neuronal NOS (nNOS) and inducible NOS (iNOS). iNOS-derived NO has been associated with the pathogenesis and progression of several diseases, including liver diseases, insulin resistance, obesity and diseases of the cardiovascular system. However, transient NO production can modulate metabolism to survive and cope with stress conditions. Accumulating evidence strongly imply that iNOS-derived NO plays a central role in the regulation of several biochemical pathways and energy metabolism including glucose and lipid metabolism during inflammatory conditions. This review summarizes current evidence for the regulation of glucose and lipid metabolism by iNOS during inflammation, and argues for the role of iNOS as a metabolic enzyme in immune and non-immune cells. © 2019
Kanner, J. ; Shpaizer, A. ; Nelgas, L. ; Tirosh, O. S-Nitroso- N-acetylcysteine (NAC-SNO) as an Antioxidant in Cured Meat and Stomach Medium. Journal of Agricultural and Food Chemistry 2019, 67, 10930-10936. Publisher's VersionAbstract
The stability of lipids in meat products depends on the initial concentration of hydroperoxides, the catalytic involvement of metal ions and myoglobin, endogenous antioxidants, and biological and technological factors. Ground meat was treated with additives, sealed in vacuum bags, heated to 75 °C, and stored opened to air at 4 °C. S-Nitroso-N-acetylcysteine (NAC-SNO) at concentration like nitrite used by the industry prevents lipid peroxidation in the product, even after storage for 1 month at 4 °C. The same simulated treatments at different concentrations of both compounds show that NAC-SNO acts as an antioxidant ∼4-fold better than nitrite at pH 6.2 or 3.0. Ascorbic acid significantly improves nitrite antioxidant effect. NAC-SNO was found to prevent, much better than nitrite, accumulation of reactive aldehydes and hydroxynonenal protein modification. In condition like those used by the industry for meat products processing, NAC-SNO acts better than nitrite to provide antioxidant protection without the side effect of N-nitrosation, oxidation, and the loss of nutrient generated by nitrite. © 2019 American Chemical Society.
Alber, J. ; Alladi, S. ; Bae, H. - J. ; Barton, D. A. ; Beckett, L. A. ; Bell, J. M. ; Berman, S. E. ; Biessels, G. J. ; Black, S. E. ; Bos, I. ; et al. White matter hyperintensities in vascular contributions to cognitive impairment and dementia (VCID): Knowledge gaps and opportunities. Alzheimer's and Dementia: Translational Research and Clinical Interventions 2019, 5 107-117. Publisher's VersionAbstract
White matter hyperintensities (WMHs) are frequently seen on brain magnetic resonance imaging scans of older people. Usually interpreted clinically as a surrogate for cerebral small vessel disease, WMHs are associated with increased likelihood of cognitive impairment and dementia (including Alzheimer's disease [AD]). WMHs are also seen in cognitively healthy people. In this collaboration of academic, clinical, and pharmaceutical industry perspectives, we identify outstanding questions about WMHs and their relation to cognition, dementia, and AD. What molecular and cellular changes underlie WMHs? What are the neuropathological correlates of WMHs? To what extent are demyelination and inflammation present? Is it helpful to subdivide into periventricular and subcortical WMHs? What do WMHs signify in people diagnosed with AD? What are the risk factors for developing WMHs? What preventive and therapeutic strategies target WMHs? Answering these questions will improve prevention and treatment of WMHs and dementia. © 2019 The Authors