Abstract
Protein complexes that mediate secretion and adhesion are located on the plasma membrane of pancreatic β cells. Neuroligins and their binding partners, the neurexins, are among these complexes. β cell maturation and physiologically regulated insulin secretion, as a response to high levels of blood glucose, are dependent on their three-dimensional (3D) arrangement. Both insulin secretion and the proliferation rates of β cells dramatically increase when β cells are co-cultured with clusters of a member of the neuroligin family: NL-2. A membranal protein, such as NL-2, has very limited drugability owing to its low biostability and bioavailability. Thus, based on in silico modeling, a short NL-2 peptide (HSA-28), which was able to mimic NL-2-positive effects on β cells, was designed, as we described in previous publication. However, the peptide was active only as a cluster, created by the covering the maghemite (γ-Fe2O3)-based nanoparticles (NPs) with limited biocompatibility. In this brief communication, we will show that conjugation of HSA-28 to biocompatible hydrogel NPs exhibits an impressive protective effect on INS-1E β cells under oxidative stress and induces their proliferation rate via augmentation of PDX1 nuclear translocation. The diameter of coated by the peptide NPs was 206 ± 63 nm (DLS) and 114 ± 27 nm (cryo-TEM). This significant change in size can be explained by the very hydrophilic character of the proteinoid NPs, inducing adsorption of many water molecules on their surface, which are accounted only by the DLS. The ability of biocompatible hydrogel NPs to prevent apoptosis and increase β cell mass might be used for developing novel β cell protective therapies.
![](http://media.springernature.com/lw685/springer-static/image/art%3A10.1007%2Fs11051-018-4323-2/MediaObjects/11051_2018_4323_Figa_HTML.png)
Effect of covered by bioactive peptide NPs on PDX1 nuclei translocation.
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs11051-018-4323-2/MediaObjects/11051_2018_4323_Fig1_HTML.png)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs11051-018-4323-2/MediaObjects/11051_2018_4323_Sch1_HTML.png)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs11051-018-4323-2/MediaObjects/11051_2018_4323_Fig2_HTML.png)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs11051-018-4323-2/MediaObjects/11051_2018_4323_Fig3_HTML.png)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs11051-018-4323-2/MediaObjects/11051_2018_4323_Fig4_HTML.png)
References
Aviv PZ, Shubely M, Moskovits Y, Viskind O, Albeck A, Vertommen D, Ruthstein S, Shoken M, Gruzman A (2016) A new oxopiperazin-based peptidomimetic molecule inhibits prostatic acid phosphatase secretion and induces prostate cancer cell apoptosis. ChemistrySelect 1:4658–4667. https://doi.org/10.1002/slct.201600987
Bosco D, Orci L, Meda P (1989) Homologous but not heterologous contact increases the insulin secretion of individual pancreatic β-cells. Exp Cell Res 184:72–80. https://doi.org/10.1016/0014-4827(89)90365-0
Calafiore R, Montanucci P, Basta G (2014) Stem cells for pancreatic β-cell replacement in diabetes mellitus: actual perspectives. Curr Opin Organ Transplant 19:162–168. https://doi.org/10.1097/MOT.0000000000000055
Chaumet-Riffaud P, Martinez-Duncker I, Marty AL, Richard C, Prigent A, Moati F, Sarda-Mantel L, Scherman D, Bessodes M, Mignet N (2010) Synthesis and application of lactosylated, 99mTc chelating albumin for measurement of liver function. Bioconjug Chem 21:589–596. https://doi.org/10.1021/bc900275f
Chen C, Cohrs CM, Stertmann J, Bozsak R, Speier S (2017) Human beta cell mass and function in diabetes: recent advances in knowledge and technologies to understand disease pathogenesis. Mol Metab 6:943–957. https://doi.org/10.1016/j.molmet.2017.06.019
Hanini A, Schmitt A, Kacem K, Chau F, Ammar S, Gavard J (2011) Evaluation of iron oxide nanoparticle biocompatibility. Int J Nanomedicine 6:787–794. https://doi.org/10.2147/IJN.S17574
Hopkins KD (2002) Update on islet-cell transplantation for type 1 diabetes. Lancet 359:2172
Khandadash R, Machtey V, Shainer I, Gottlieb HE, Gothilf Y, Ebenstein Y, Weiss A, Byk G (2014) Novel biocompatible hydrogel nanoparticles: generation and size-tuning of nanoparticles by the formation of micelle templates obtained from thermo-responsive monomers mixtures. J Nanopart Res 16:1–18. https://doi.org/10.1007/s11051-014-2796-1
Kolitz-Domb M, Corem-Salkmon E, Grinberg I, Margel S (2014) Synthesis and characterization of bioactive conjugated near-infrared fluorescent proteinoid-poly (L-lactic acid) hollow nanoparticles for optical detection of colon cancer. Int J Nanomedicine 9:5041, 5013 pp–5053. https://doi.org/10.2147/IJN.S68582
Lenzen S (2017) Chemistry and biology of reactive species with special reference to the antioxidative defence status in pancreatic beta-cells. BBA 1861:1929–1942. https://doi.org/10.1016/j.bbagen.2017.05.013
Lin Y, Sun Z (2010) Current views on type 2 diabetes. J Endocrinol 204:1–11. https://doi.org/10.1677/JOE-09-0260
Liu X, Yan F, Yao H, Chang M, Qin J, Li Y, Wang Y, Pei X (2014) Involvement of RhoA/ROCK in insulin secretion of pancreatic β-cells in 3D culture. Cell Tissue Res 358:359–369. https://doi.org/10.1007/s00441-014-1961-2
Mera T, Itoh T, Kita S, Kodama S, Kojima D, Nishinakamura H, Okamoto K, Ohkura M, Nakai J, Iyoda T, Iwamoto T, Matsuda T, Baba A, Omori K, Ono J, Watarai H, Taniguchi M, Yasunami Y (2013) Pretreatment of donor islets with the Na(+) /ca(2+) exchanger inhibitor improves the efficiency of islet transplantation. Am J Transplant 13:2154–2160. https://doi.org/10.1111/ajt.12306
Munder A, Israel LL, Kahremany S, Ben-Shabat-Binyamini R, Zhang C, Kolitz-Domb M, Viskind O, Levine A, Senderowitz H, Chessler S, Lellouche JP, Gruzman A (2017) Mimicking Neuroligin-2 functions in β-cells by functionalized nanoparticles as a novel approach for antidiabetic therapy. ACS Appl Mater Interfaces 9:1189–1206. https://doi.org/10.1021/acsami.6b10568
Olokoba AB, Obateru OA, Olokoba LB (2012) Type 2 diabetes mellitus: a review of current trends. Oman Med J 27:269–273. https://doi.org/10.5001/omj.2012.68
Potter KJ, Westwell-Roper CY, Klimek-Abercrombie AM, Warnock GL, Verchere CB (2014) Death and dysfunction of transplanted β-cells: lessons learned from type 2 diabetes? Diabetes 63:12–19. https://doi.org/10.2337/db12-0364
Rozentul N, Avrahami Y, Shubely M, Levy L, Munder A, Cohen G, Cerasi E, Sasson S, Gruzman A (2017) A novel Phenylchromane derivative increases the rate of glucose uptake in L6 Myotubes and augments insulin secretion from pancreatic Beta-cells by activating AMPK. Pharm Res 34:2873–2890. https://doi.org/10.1007/s11095-017-2271-7
Sarbacker GB, Urteaga EM (2016) Adherence to Insulin Therapy Diabetes spectrum: a publication of the American Diabetes Association 29:166–170 https://doi.org/10.2337/diaspect.29.3.166
Stitzel ML, Kycia I, Kursawe R, Ucar D (2015) Transcriptional Regulation of the Pancreatic Islet: Implications for Islet Function Current diabetes reports 15:66 https://doi.org/10.1007/s11892-015-0635-0, Transcriptional Regulation of the Pancreatic Islet: Implications for Islet Function
Sun J, Mao LQ, Polonsky KS, Ren DC (2016) Pancreatic beta-cell death due to Pdx-1 deficiency requires multi-BH domain protein Bax but not Bak. J Biol Chem 291:13529–13534. https://doi.org/10.1074/jbc.M115.705293
Thurman RG, Ley HG, Scholz R (1972) Hepatic microsomal ethanol oxidation. Hydrogen peroxide formation and the role of catalase. Eur J Biochem 25:420–430. https://doi.org/10.1111/j.1432-1033.1972.tb01711.x
Wallner K, Pedroza RG, Awotwe I, Piret JM, Senior PA, Shapiro AMJ, McCabe C (2018) Stem cells and beta cell replacement therapy: a prospective health technology assessment study. BMC Endocr Disord 18:6. https://doi.org/10.1186/s12902-018-0233-7
Wang H, Maechler P, Ritz-Laser B, Hagenfeldt KA, Ishihara H, Philippe J, Wollheim CB (2001) Pdx1 level defines pancreatic gene expression pattern and cell lineage differentiation. J Biol Chem 276:25279–25286. https://doi.org/10.1074/jbc.M101233200
Wang W, Jin S, Ye K (2017) Development of islet organoids from H9 human embryonic stem cells in biomimetic 3D scaffolds. Stem Cells Dev 26:394–404. https://doi.org/10.1089/scd.2016.0115
Zhang C, Caldwell TA, Mirbolooki MR, Duong D, Park EJ, Chi NW, Chessler SD (2016) Extracellular CADM1 interactions influence insulin secretion by rat and human islet beta-cells and promote clustering of syntaxin-1. Am J Physiol Endocrinol Metab 310:E874–E885. https://doi.org/10.1152/ajpendo.00318.2015
Funding
This study was supported by a Bar-Ilan University new faculty grant, a D-cure (Diabetes Care in Israel) Young Investigator Award, a NOFAR program (Israel Ministry of Industry), and The Israel Science Foundation (application number 117/2014) for A.G. G.C. is partially supported by Israel Ministry of Science and Technology.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Rights and permissions
About this article
Cite this article
Shtriker, E., Bretler, S., Munder, A. et al. Hydrogel nanoparticles covered by neuroligin-2-derived peptide-protected β cells under oxidative stress and increase their proliferation. J Nanopart Res 20, 221 (2018). https://doi.org/10.1007/s11051-018-4323-2
Received:
Accepted:
Published:
DOI: https://doi.org/10.1007/s11051-018-4323-2