CXCR2 deficient mice display macrophage-dependent exaggerated acute inflammatory responses

CXCR2 is an essential regulator of neutrophil recruitment to inflamed and damaged sites and plays prominent roles in inflammatory pathologies and cancer. It has therefore been highlighted as an important therapeutic target. However the success of the therapeutic targeting of CXCR2 is threatened by our relative lack of knowledge of its precise in vivo mode of action. Here we demonstrate that CXCR2-deficient mice display a counterintuitive transient exaggerated inflammatory response to cutaneous and peritoneal inflammatory stimuli. In both situations, this is associated with reduced expression of cytokines associated with the resolution of the inflammatory response and an increase in macrophage accumulation at inflamed sites. Analysis using neutrophil depletion strategies indicates that this is a consequence of impaired recruitment of a non-neutrophilic CXCR2 positive leukocyte population. We suggest that these cells may be myeloid derived suppressor cells. Our data therefore reveal novel and previously unanticipated roles for CXCR2 in the orchestration of the inflammatory response

The proangiogenic capacity of polymorphonuclear neutrophils delineated by microarray technique and by measurement of neovascularization in wounded skin of CD18-deficient mice

Growing evidence supports the concept that polymorphonuclear neutrophils (PMN) are critically involved in inflammation-mediated angiogenesis which is important for wound healing and repair. We employed an oligonucleotide microarray technique to gain further insight into the molecular mechanisms underlying the proangiogenic potential of human PMN. In addition to 18 known angiogenesis-relevant genes, we detected the expression of 10 novel genes, namely midkine, erb-B2, ets-1, transforming growth factor receptor-beta(2) and -beta(3), thrombospondin, tissue inhibitor of metalloproteinase 2, ephrin A2, ephrin B2 and restin in human PMN freshly isolated from the circulation. Gene expression was confi rmed by the RT-PCR technique. In vivo evidence for the role of PMN in neovascularization was provided by studying neovascularization in a skin model of wound healing using CD18-deficient mice which lack PMN infi ltration to sites of lesion. In CD18-deficient animals, neo- vascularization was found to be signifi cantly compromised when compared with wild- type control animals which showed profound neovascularization within the granulation tissue during the wound healing process. Thus, PMN infiltration seems to facilitate inflammation mediated angiogenesis which may be a consequence of the broad spectrum of proangiogenic factors expressed by these cells. Copyright (c) 2006 S. Karger AG, Basel

Tumor-Derived Retinoic Acid Regulates Intratumoral Monocyte Differentiation To Promote Immune Suppression

The immunosuppressive tumor microenvironment (TME) is a major barrier to immunotherapy. Within solid tumors, why monocytes preferentially differentiate into immunosuppressive tumor associated macrophages (TAMs) but not immunostimulatory dendritic cells (DCs) remains unclear. Using multiple murine sarcoma models, we found that the TME induced tumor cells to produce retinoic acid (RA), which polarized intratumoral monocyte differentiation towards TAMs and away from DCs via suppression of DC-promoting transcription factor Irf4. Genetic inhibition of RA production by tumor cells or pharmacologic inhibition of RA signaling within the TME increased stimulatory monocyte-derived cells, enhanced T cell-dependent anti-tumor immunity and demonstrated striking synergy with immune checkpoint blockade. Further, an RA responsive gene signature in human monocytes correlated with an immunosuppressive TME in multiple human tumors. RA has been long considered as an anti-cancer agent, but our work demonstrates its tumorigenic capability via myeloid-mediated immune suppression and provides proof of concept for targeting this pathway for tumor immunotherapy

Antibodies Against Human BLyS and APRIL Attenuate EAE Development in Marmoset Monkeys

B lymphocyte stimulator (BLyS, also indicated as BAFF (B-cell activating factor) and CD257), and A Proliferation Inducing Ligand (APRIL, CD256) are two members of the TNF superfamily with a central role in B cell survival. Antibodies against these factors have potential therapeutic relevance in autoimmune inflammatory disorders with a proven pathogenic contribution of B cells, such as multiple sclerosis (MS). In the current study we performed a multi-parameter efficacy comparison of monoclonal antibodies against human anti-BLyS and anti-APRIL in a common marmoset (Callithrix jacchus) model of experimental autoimmune encephalomyelitis (EAE). A MS-like disease was induced by immunization with recombinant human myelin/oligodendrocyte glycoprotein (rhMOG) in complete Freund's adjuvant. The results show that the anti-BLyS and anti-APRIL antibody cause significant depletion of circulating CD20+ B cells, but a small subset of CD20 + CD40(high) B cells was not depleted. Induction of CD20+ B cell depletion from lymph nodes was only observed in the anti-BLyS treated monkeys. Both antibodies had a significant inhibitory effect on disease development, but all monkeys developed clinically evident EAE. Anti-BLyS treated monkeys were sacrificed with the same clinical signs as saline-treated monkeys, but nevertheless displayed significantly reduced spinal cord demyelination. This effect was not observed in the anti-APRIL treated monkeys. The two antibodies had a different effect on T cell subset activation and the profiles of ex vivo released cytokines. In conclusion, treatment with anti-BLyS and anti-APRIL delays the development of neurological disease in a relevant preclinical model of MS. The two mAbs achieve this effect via different mechanisms

Antibodies Against Human BLyS and APRIL Attenuate EAE Development in Marmoset Monkeys

B lymphocyte stimulator (BLyS, also indicated as BAFF (B-cell activating factor) and CD257), and A Proliferation Inducing Ligand (APRIL, CD256) are two members of the TNF superfamily with a central role in B cell survival. Antibodies against these factors have potential therapeutic relevance in autoimmune inflammatory disorders with a proven pathogenic contribution of B cells, such as multiple sclerosis (MS). In the current study we performed a multi-parameter efficacy comparison of monoclonal antibodies against human anti-BLyS and anti-APRIL in a common marmoset (Callithrix jacchus) model of experimental autoimmune encephalomyelitis (EAE). A MS-like disease was induced by immunization with recombinant human myelin/oligodendrocyte glycoprotein (rhMOG) in complete Freund's adjuvant. The results show that the anti-BLyS and anti-APRIL antibody cause significant depletion of circulating CD20+ B cells, but a small subset of CD20 + CD40highB cells was not depleted. Induction of CD20+ B cell depletion from lymph nodes was only observed in the anti-BLyS treated monkeys. Both antibodies had a significant inhibitory effect on disease development, but all monkeys developed clinically evident EAE. Anti-BLyS treated monkeys were sacrificed with the same clinical signs as saline-treated monkeys, but nevertheless displayed significantly reduced spinal cord demyelination. This effect was not observed in the anti-APRIL treated monkeys. The two antibodies had a different effect on T cell subset activation and the profiles of ex vivo released cytokines. In conclusion, treatment with anti-BLyS and anti-APRIL delays the development of neurological disease in a relevant preclinical model of MS. The two mAbs achieve this effect via different mechanisms

Novel cytokine and chemokine markers of hidradenitis suppurativa reflect chronic inflammation and itch

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/148237/1/all13665-sup-0001-SupInfo.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/148237/2/all13665_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/148237/3/all13665.pd

Modelling Osmotic dehydration of lemon slices using newsweeteners

Lemon slices were osmotically dehydrated using the following healthy sweeteners as osmotic agents: tagatose, isomaltulose, oligofructose and aqueous extract of stevia. A kinetic study using a Fickian approach was performed, which also analysed the changes in water activity, total mass, mass of water and mass of soluble solids in lemon slices. The results showed that the greatest value of effective diffusivity (De) in osmodehydrated lemon slices was obtained from a combination of oligofructose and stevia. However, the level of water activity (aw) reached with this syrup was the highest, meaning that the product might be less stable. Additionally, isomaltulose favoured the total mass, whereas tagatose did the opposite. Finally, the syrup recommended for dehydrating lemon slices would be a combination of tagatose, oligofructose and aqueous extract of stevia since its De was similar to the value obtained when only oligofructose and stevia were used, but aw values were lower.The authors would like to thank the Serigio-Andres family for donating the raw materials and also the GVA projects GV/2013/029, GV/2014/012 as well as the Universitat Politecnica de Valencia (Spain) for the financial support given to this research study (UPV PAID-06-12 SP20120889).Rubio Arraez, S.; Capella Hernández, JV.; Ortolá Ortolá, MD.; Castelló Gómez, ML. (2015). Modelling Osmotic dehydration of lemon slices using newsweeteners. International Journal of Food Science and Technology. 50(9):2046-2051. https://doi.org/10.1111/ijfs.12859S20462051509Azoubel, P. M., & Elizabeth Xidieh Murr, F. (2004). Mass transfer kinetics of osmotic dehydration of cherry tomato. Journal of Food Engineering, 61(3), 291-295. doi:10.1016/s0260-8774(03)00132-8Castelló, M. L., Fito, P. J., & Chiralt, A. (2006). Effect of osmotic dehydration and vacuum impregnation on respiration rate of cut strawberries. LWT - Food Science and Technology, 39(10), 1171-1179. doi:10.1016/j.lwt.2005.07.001Castelló, M. L., Igual, M., Fito, P. J., & Chiralt, A. (2009). Influence of osmotic dehydration on texture, respiration and microbial stability of apple slices (Var. Granny Smith). Journal of Food Engineering, 91(1), 1-9. doi:10.1016/j.jfoodeng.2008.07.025Castelló, M. L., Fito, P. J., & Chiralt, A. (2010). Changes in respiration rate and physical properties of strawberries due to osmotic dehydration and storage. Journal of Food Engineering, 97(1), 64-71. doi:10.1016/j.jfoodeng.2009.09.016Castro-Giráldez, M., Tylewicz, U., Fito, P. J., Dalla Rosa, M., & Fito, P. (2011). Analysis of chemical and structural changes in kiwifruit (Actinidia deliciosa cv Hayward) through the osmotic dehydration. Journal of Food Engineering, 105(4), 599-608. doi:10.1016/j.jfoodeng.2011.03.029CHÁFER, M., GONZÁLEZ-MARTÍNEZ, C., ORTOLÁ, M. D., CHIRALT, A., & FITO, P. (2001). KINETICS OF OSMOTIC DEHYDRATION IN ORANGE AND MANDARIN PEELS. Journal of Food Process Engineering, 24(4), 273-289. doi:10.1111/j.1745-4530.2001.tb00544.xChatsudthipong, V., & Muanprasat, C. (2009). Stevioside and related compounds: Therapeutic benefits beyond sweetness. Pharmacology & Therapeutics, 121(1), 41-54. doi:10.1016/j.pharmthera.2008.09.007Derossi, A., De Pilli, T., Severini, C., & McCarthy, M. J. (2008). Mass transfer during osmotic dehydration of apples. Journal of Food Engineering, 86(4), 519-528. doi:10.1016/j.jfoodeng.2007.11.007Devalaraja, S., Jain, S., & Yadav, H. (2011). Exotic fruits as therapeutic complements for diabetes, obesity and metabolic syndrome. Food Research International, 44(7), 1856-1865. doi:10.1016/j.foodres.2011.04.008FAO/WHO 2003 Report of the sixty-first meeting of the Joint FAO/WHO Expert Committee on Food Additives, Rome, 10-19 June 2003Goyal, S. K., Samsher, & Goyal, R. K. (2009). Stevia (Stevia rebaudiana) a bio-sweetener: a review. International Journal of Food Sciences and Nutrition, 61(1), 1-10. doi:10.3109/09637480903193049Kim, I.-S., Yang, M., Lee, O.-H., & Kang, S.-N. (2011). The antioxidant activity and the bioactive compound content of Stevia rebaudiana water extracts. LWT - Food Science and Technology, 44(5), 1328-1332. doi:10.1016/j.lwt.2010.12.003Lemus-Mondaca, R., Vega-Gálvez, A., Zura-Bravo, L., & Ah-Hen, K. (2012). Stevia rebaudiana Bertoni, source of a high-potency natural sweetener: A comprehensive review on the biochemical, nutritional and functional aspects. Food Chemistry, 132(3), 1121-1132. doi:10.1016/j.foodchem.2011.11.140Lina, B. A. R., Jonker, D., & Kozianowski, G. (2002). Isomaltulose (Palatinose®): a review of biological and toxicological studies. Food and Chemical Toxicology, 40(10), 1375-1381. doi:10.1016/s0278-6915(02)00105-9Masmoudi, M., Besbes, S., Blecker, C., & Attia, H. (2007). Preparation and Characterization of Osmodehydrated Fruits from Lemon and Date By-products. Food Science and Technology International, 13(6), 405-412. doi:10.1177/1082013208089562Oh, D.-K. (2007). Tagatose: properties, applications, and biotechnological processes. Applied Microbiology and Biotechnology, 76(1), 1-8. doi:10.1007/s00253-007-0981-1Park, K. J., Bin, A., Reis Brod, F. P., & Brandini Park, T. H. K. (2002). Osmotic dehydration kinetics of pear D’anjou (Pyrus communis L.). Journal of Food Engineering, 52(3), 293-298. doi:10.1016/s0260-8774(01)00118-2Patra, F., Tomar, S. K., & Arora, S. (2009). Technological and Functional Applications of Low-Calorie Sweeteners from Lactic Acid Bacteria. Journal of Food Science, 74(1), R16-R23. doi:10.1111/j.1750-3841.2008.01005.xPeinado, I., Rosa, E., Heredia, A., Escriche, I., & Andrés, A. (2013). Influence of processing on the volatile profile of strawberry spreads made with isomaltulose. Food Chemistry, 138(1), 621-629. doi:10.1016/j.foodchem.2012.09.104Periche, A., Heredia, A., Escriche, I., Andrés, A., & Castelló, M. L. (2014). Optical, mechanical and sensory properties of based-isomaltulose gummy confections. Food Bioscience, 7, 37-44. doi:10.1016/j.fbio.2014.05.006Rao, V. A. (2001). The prebiotic properties of oligofructose at low intake levels. Nutrition Research, 21(6), 843-848. doi:10.1016/s0271-5317(01)00284-6Raschka, L., & Daniel, H. (2005). Mechanisms underlying the effects of inulin-type fructans on calcium absorption in the large intestine of rats. Bone, 37(5), 728-735. doi:10.1016/j.bone.2005.05.015Shankar, P., Ahuja, S., & Sriram, K. (2013). Non-nutritive sweeteners: Review and update. Nutrition, 29(11-12), 1293-1299. doi:10.1016/j.nut.2013.03.024Shi, X. Q., & Maupoey, P. F. (1994). Mass Transfer in Vacuum Osmotic Dehydration of Fruits: A Mathematical Model Approach. LWT - Food Science and Technology, 27(1), 67-72. doi:10.1006/fstl.1994.1014Silva, M. A. da C., Silva, Z. E. da, Mariani, V. C., & Darche, S. (2012). Mass transfer during the osmotic dehydration of West Indian cherry. LWT - Food Science and Technology, 45(2), 246-252. doi:10.1016/j.lwt.2011.07.032İspir, A., & Toğrul, İ. T. (2009). Osmotic dehydration of apricot: Kinetics and the effect of process parameters. Chemical Engineering Research and Design, 87(2), 166-180. doi:10.1016/j.cherd.2008.07.01

Extensive profiling of three varieties of Opuntia spp. fruit for innovative food ingredients

[EN] Consumer interest in the use of natural ingredients is creating a growing trend in the food industry, leading to research into the development of natural products such as colorants, antimicrobials and antioxidant compounds. This work involves an extensive morphological (using physico-chemical assays), chemical (antioxidant activity assays) and microbiological (Gram-positive and negative strains) characterization of prickly peras (Opuntia ficusindica (OFI) var. sanguigna, gialla and Opuntia engelmannii) fruits. Through chromatographic assays, these species have shown interesting contents of hydrophilic (sugars, organic acids and betalains) and lipophilic (tocopherols and fatty acids) compounds. While Opuntia engelmannii exhibited higher content of betacyanins and mucilage, OFI varieties sanguigna and gialla displayed greater organic acid content. The sanguigna variety also showed the highest ¿-tocopherol content. All this compounds could be the responsible of enhancing the bioactivity of this variety, which can be observed in its antimicrobial potential, tested in the studied strains too. Results revealed that Opuntia spp. could be used as a nutraceutical and/or food additive, maintaining and promoting health and life quality.The authors are grateful to the Foundation for Science and Technology (FCT, Portugal) and FEDER under Programme PT2020 for financial support to CIMO (UID/AGR/00690/2013) and L. Barros contract. This work is funded by the European Structural and Investment Funds (FEEI) through the Regional Operational Program North 2020, within the scope of Project NORTE-01-0145-FEDER-023289 (DeCodE) and ValorNatural (R). B. Melgar (No. 329930) also thanks CONACyT for his grant. The authors are grateful for a grant from the Serbian Ministry of Education, Sciences and Technological Development (no. 173032). The authors would also like to thank Dr. Carlos Aguiar for the botanical identification of these species.Melgar-Castañeda, B.; Pereira, E.; Oliveira, MBP.; Garcia-Castello, EM.; Rodríguez López, AD.; Sokovic, M.; Barros, L.... (2017). Extensive profiling of three varieties of Opuntia spp. fruit for innovative food ingredients. Food Research International. 101:259-265. https://doi.org/10.1016/j.foodres.2017.09.024S25926510

The complexities of breast cancer desmoplasia

The stromal, or 'desmoplastic', responses seen histologically in primary breast carcinomas can vary from being predominantly cellular (fibroblasts/myofibroblasts) with little collagen to being a dense acellular tissue. The mechanisms underlying the stromal response are complex; paracrine activation of myofibroblasts by growth factors is important but the contribution of cytokines/chemokines should not be ignored. A recent xenograft study has proposed that platelet-derived growth factor (PDGF) is the initiator of the desmoplastic response, but this has not been confirmed by (limited) analyses in vivo. Further studies are required to elaborate the mechanisms of the desmoplastic response, to determine its role in breast cancer progression and whether it is the same for all carcinomas