Browsing by Author "Benito de las Heras, Manuel"

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    Human amylin aggregates release within exosomes as a protective mechanism in pancreatic β cells: Pancreatic β-hippocampal cell communication
    (Elsevier, 2021-01-27) Burillo Maldonado, Jesús; Fernández Rhodes, M.; Piquero, M.; López-Alvarado Gutiérrez, María del Pilar; Menéndez Ramos, José Carlos; Jiménez, B.; González Blanco, C.; Marqués, P.; Guillén Viejo, Carlos; Benito de las Heras, Manuel
    Pancreatic β cells are essential in the maintenance of glucose homeostasis during the progression to type 2 Diabetes Mellitus (T2DM), generating compensatory hyperinsulinemia to counteract insulin resistance. It is well known, that throughout the process there is an increased mTORC1 signaling pathway, with an impairment in different quality control systems including ubiquitin-proteasome system and autophagy. In addition, under this situation, pancreatic β cells start to accumulate amylin protein (IAPP) in aggregates, and this accumulation contributes to the failure of autophagy, damaging different organelles such as plasma membrane, endoplasmic reticulum, mitochondria, and others. Here, we report that IAPP can be incorporated to multivesicular bodies (MVB) and secreted into exosomes, a mechanism responsible for the exportation of these toxic aggregates as vehicles of cell to cell communication. On this regard, we have demonstrated that the exosomes bearing toxic hIAPP released from pancreatic β cells are capable to induce hyperactivation of mTORC1 signaling, a failure in the autophagic cellular quality control, and favor pro-fission status of the mitochondrial dynamics in hippo-campal cells. In summary, our results show that harmful accumulation of hIAPP in pancreatic β cells may be detoxified by the release of exosomes, which may be captured by endocytosis mechanism damaging neuronal hippocampal cells, which suggest an underlying molecular mechanism to the link between type 2 diabetes and neurodegenerative diseases.
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    Osteoporosis Remission and New Bone Formation with Mesoporous Silica Nanoparticles
    (Wiley-VCH GmbH, 2021-06-06) Mora Raimundo, Patricia; Lozano Borregón, Daniel; Benito de las Heras, Manuel; Mulero, Francisca; Manzano García, Miguel; Vallet Regí, María
    Nanotechnology changed the concept of treatment for a variety of diseases, producing a huge impact regarding drug and gene delivery. Among the different targeted diseases, osteoporosis has devastating clinical and economic consequences. Since current osteoporosis treatments present several side effects, new treatment approaches are needed. Recently, the application of small interfering RNA (siRNA) has become a promising alternative. Wnt/β-catenin signaling pathway controls bone development and formation. This pathway is negatively regulated by sclerostin, which knock-down through siRNA application would potentially promote bone formation. However, the major bottleneck for siRNA-based treatments is the necessity of a delivery vector, bringing nanotechnology as a potential solution. Among the available nanocarriers, mesoporous silica nanoparticles (MSNs) have attracted great attention for intracellular delivery of siRNAs. The mesoporous structure of MSNs permits the delivery of siRNAs together with another biomolecule, achieving a combination therapy. Here, we evaluate the effectiveness of a new potential osteoporosis treatment based on MSNs. Our proposed system was effective in delivering SOST siRNA and osteostatin through systemic injection to bone tissue. The nanoparticle administration produced an increase expression of osteogenic related genes improving the bone microarchitecture. The treated osteoporotic mice recovered values of a healthy situation approaching to osteoporosis remission.