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Osteoblasts are inherently programmed to repel sensory innervation

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Bone Research 2020年第3期8卷 343-355页

作者： Luis Leitao Estrela Neto Francisco Conceicao Ana Monteiro Marina Couto Cecilia JAlves Daniela MSousa Meriem Lamghari instituto de Investigacao e Inovacao em Saude(i3S) Universidade do Porto4200-135 PortoPortugal instituto de engenharia biomedica(ineb) Universidade do Porto4200-135 PortoPortugal instituto de Ciencias biomedicas Abel Salazar(ICBAS) Universidade do Porto4050-313 PortoPortugal

Tissue innervation is a complex process controlled by the expression profile of signaling molecules secreted by tissue-resident cells that dictate the growth and guidance of *** innervation is part of the neuronal network of the bone tissue with a defined spatiotemporal occurrence during bone ***,the current understanding of the mechanisms regulating the map of sensory innervation in the bone tissue is still ***,we demonstrated that differentiation of human mesenchymal stem cells to osteoblasts leads to a marked impairment of their ability to promote axonal growth,evidenced under sensory neurons and osteoblastic-lineage cells *** mechanisms by which osteoblast lineage cells provide this nonpermissive environment for axons include paracrine-induced repulsion and loss of neurotrophic factors *** identified a drastic reduction of NGF and BDNF production and stimulation of Sema3A,Wnt4;and Shh expression culminating at late stage of OB *** noted a correlation between Shh expression profile,OB differentiation stages,and OB-mediated axonal *** of Shh activity and signaling reversed the repulsive action of osteoblasts on sensory ***,to strengthen our model,we localized the expression of Shh by osteoblasts in bone ***,our findings provide evidence that the signaling profile associated with osteoblast phenotype differentiating program can regulate the patterning of sensory innervation,and highlight osteoblast-derived Shh as an essential player in this cue-induced regulation.

关键词： stimulation innervation reversed

Sympathetic activity in breast cancer and metastasis:partners in crime

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Bone Research 2021年第1期9卷 26-36页

作者： Francisco Conceição Daniela M.Sousa Joana Paredes Meriem Lamghari I 3S-instituto de Investigação e Inovação em Saúde Universidade do Porto4200-135 PortoPortugal ineb-instituto nacional de engenharia Biomédica Universidade do Porto4200-135 PortoPortugal ICBAS-instituto de Ciências Biomédicas Abel Salazar Universidade do Porto4050-313 PortoPortugal IPATIMUP-instituto de Patologia e Imunologia Molecular da Universidade do Porto 4200-135 PortoPortugal FMUP-Faculdade de Medicina da Universidade do Porto 4200-319 PortoPortugal

The vast majority of patients with advanced breast cancer present skeletal complications that severely compromise their quality of *** cancer cells are characterized by a strong tropism to the bone *** engraftment and colonization of bone,breast cancer cells interact with native bone cells to hinder the normal bone remodeling process and establish an osteolytic“metastatic vicious cycle”.The sympathetic nervous system has emerged in recent years as an important modulator of breast cancer progression and metastasis,potentiating and accelerating the onset of the vicious cycle and leading to extensive bone ***,sympathetic neurotransmitters and their cognate receptors have been shown to promote several hallmarks of breast cancer,such as proliferation,angiogenesis,immune escape,and invasion of the extracellular *** this review,we assembled the current knowledge concerning the complex interactions that take place in the tumor microenvironment,with a special emphasis on sympathetic modulation of breast cancer cells and stromal ***,the differential action of epinephrine and norepinephrine,through eitherα-orβ-adrenergic receptors,on breast cancer progression prompts careful consideration when designing new therapeutic *** addition,the contribution of sympathetic innervation to the formation of bone metastatic foci is *** particular,we address the remarkable ability of adrenergic signaling to condition the native bone remodeling process and modulate the bone vasculature,driving breast cancer cell engraftment in the bone ***,clinical perspectives and developments on the use ofβ-adrenergic receptor inhibitors for breast cancer management and treatment are discussed.

关键词： breast metastasis invasion

3D Photo-Fabrication for Tissue Engineering and Drug delivery

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Engineering 2015年第1期1卷 90-112页

作者： Rúben F.Pereira Paulo J.Bártolo Centre for Rapid and Sustainable Product development (CDRsp) Polytechnic Institute of Leiria instituto de Investiga??o e Inova??o em Saúde (I3S) Universidade do Porto instituto nacional de engenharia Biomédica (ineb) Universidade do Porto instituto de Ciências Biomédicas Abel Salazar (ICBAS) Universidade do Porto School of Mechanical Aerospace and Civil EngineeringUniversity of Manchester Manchester Institute of Biotechnology University of Manchester

The most promising strategies in tissue engineering involve the integration of a triad of biomaterials, living cells, and biologically active molecules to engineer synthetic environments that closely mimic the healing milieu present in human tissues, and that stimulate tissue repair and regeneration. To be clinically effective, these environments must replicate, as closely as possible, the main characteristics of the native extracellular matrix(ECM) on a cellular and subcellular scale. Photo-fabrication techniques have already been used to generate 3D environments with precise architectures and heterogeneous composition, through a multi-layer procedure involving the selective photocrosslinking reaction of a light-sensitive prepolymer. Cells and therapeutic molecules can be included in the initial hydrogel precursor solution, and processed into 3D constructs. Recently, photofabrication has also been explored to dynamically modulate hydrogel features in real time, providing enhanced control of cell fate and delivery of bioactive compounds. This paper focuses on the use of 3D photo-fabrication techniques to produce advanced constructs for tissue regeneration and drug delivery applications. State-of-the-art photo-fabrication techniques are described, with emphasis on the operating principles and biofabrication strategies to create spatially controlled patterns of cells and bioactive factors. Considering its fast processing, spatiotemporal control, high resolution, and accuracy, photo-fabrication is assuming a critical role in the design of sophisticated 3D constructs. This technology is capable of providing appropriate environments for tissue regeneration, and regulating the spatiotemporal delivery of therapeutics.

关键词： 3D photo-fabrication biomaterials tissueengineering drug delivery

Imbalance in T-cell differentiation as a biomarker of chronic diabetic foot ulceration

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Cellular & Molecular Immunology 2019年第10期16卷 833-834页

作者： Joao Moura Joao Rodrigues Marta Gonçalves Claudia Amaral Margarida Lima Eugenia Carvalho Center for Neuroscience and Cell Biology(CNC) University of CoimbraCoimbraPortugal ineb-instituto nacional de engenharia biomedica University of PortoPortoPortugal I3S-instituto de Investigaçao e Inovaçao em Saude University of PortoPortoPortugal department of Hematology Hospital de Santo Antonio(HSA)Centro Hospitalar Universitario do Porto(CHUP)PortoPortugal Unidade Multidisciplinar de Investigaçao biomedica(UMIB/ICBAS/UP) PortoPortugal department of Endocrinology Hospital de Santo Antonio(HSA)Centro Hospitalar Universitário do Porto(CHUP)PortoPortugal department of Geriatrics University of Arkansas for Medical Sciences(UAMS)and Arkansas Children’s Hospital Research Institute(ACHRI)Little RockArkansas 72202USA

Diabetes is a growing epidemic due to the systematic increase in overweight and obesity,and chronic diabetic foot ulcers(DFUs)are the most debilitating and costly complication of *** is still essential for DFU care,but early detection is limited because we do not have a good DFU ***,we report the preliminary results of a large longitudinal study to test the effectiveness of the use of T-cell phenotype and TCR repertoire diversity as DFU *** results show that the ratio of effector/naïve T-cells and the number of TCR expansions are valuable biomarkers of DFU prognosis.

关键词： diabetic chronic obesity

A prospective cancer chemo-immunotherapy approach mediated by synergistic CD326 targeted porous silicon nanovectors

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Nano Research 2015年第5期8卷 1505-1521页

作者： Mohammad-Ali Shahbazi Neha Shrestha Ermei Makila Francisca Araujo Alexandra Correia Tomas Ramos Bruno Sarmento Jarno Salonen Jouni Hirvonen Helder A. Santos Division of Pharmaceutical Chemistry and Technology Faculty of Pharmacy University ofHelsinki FI-00014 Helsinki Finland Laboratory of Industrial Physics Departmen t of Physics and Astronomy University of Turku FI-20014 Turku Finland ineb - instituto de engenharia biomedica NewTherapies Group Universidade do Porto Rua do Campo Alegre 823 4150-180 Porto Portuga ICBAS - instituto Ciencias biomedicas Abel Salazar University of Porto Rua de Jorge Viterbo Ferreira 4050-313 Porto Portugal Faculty of Pharmacy University of Coimbra 3000-548 Coimbra Portugal IINFACTS - instituto de Investigacao e Formacao Avancada em Ciencias e Tecnologias da Saude Instituto Superior de Ciencias da Saude-Norte Department of Pharmaceutical Sciences CESPU Rua Central de Gandra 4585-116 Gandra Portugal

Combination therapy via nanoparticulate systems has already been proposed as a synergistic approach for cancer treatment. Herein, undecylenic acid modified thermally hydrocarbonized porous silicon nanoparticles （UnTHCPSi NPs） loaded with sorafenib and surface-biofunctionalized with anti-CD326 antibody （Ab） were developed for cancer chemo-immunotherapy in MCF-7 and MDA-MB-231 breast cancer cells. The cytocompatibility study showed no significant toxicity for the bare and antibody-conjugated UnTHCPSi （Un-Ab） NPs at concentrations lower than 200 μg·mL^-1. Compared to the bare UnTHCPSi, Un-Ab NPs loaded with sorafenib reduced the premature drug release in plasma, increasing the probability of proper drug targeting. In addition, high cellular interaction and subsequent internalization of the Un-Ab NPs into the cells expressing CD326 antigen demonstrated the possibility of improving antigen-mediated endocytosis via CD326 targeting. While an in vitro antitumor study revealed a higher inhibitory effect of the sorafenib-loaded Un-Ab NPs compared to the drug-loaded UnTHCPSi NPs in the CD326 positive MCF-7 cells, there was no difference in the anti-proliferation impact of both the abovementioned NPs in the CD326 negative MDA-MB-231 cells, suggesting CD326 as an appropriate receptor for Ab-mediated drug delivery. It was also shown that the anti-CD326 Ab can act as an immunotherapeutic agent by inducing antibody dependent cellular cytotoxicity and enhancing the interaction of effector immune and cancer cells for subsequent phagocytosis and cytokine secretion. Hence, the developed nanovectors can be applied for simultaneous tumor-selective drug targeting and immunotherapy.

关键词： CD326 antibody porous silicon nanopartides chemo-immunotherapy breast cancer drug targeting

Chronic Meningococcemia

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Advances in Infectious Diseases 2016年第3期6卷 97-101页

作者： Rita Veiga Ferraz Filipa Ceia Raquel Duro Ana Cláudia Carvalho Paulo Andrade Susana Silva António Sarmento Infectious Diseases department Instituto de Inovacao e Investigacao em Saúde (I3S) Grupo de I&D em Nefrologia e Doencas Infeciosas Instituto Nacional de Engenharia Biomédica (INEB) Centro Hospitalar de Sao Joao Porto Portugal

Neisseria meningitidis is a gram-negative diplococcus which causes invasive disease. The most frequent clinical manifestations caused by infection with this pathogen, are meningitis and fulminant septic shock. More benign forms with a subacute or chronic pattern are rare but still can evolve to meningitis and have a fatal outcome. This entity is difficult to recognize, as febrile erythema with otherwise good general condition may simulate other diseases, namely viral infections. The authors reported the cases of two healthy young adults who were misdiagnosed with a viral infection. What they really had was a meningococcemia without meningitis presenting with mild and unspecific symptoms, such as, intermittent fever and a discrete macular rash. We pretend to highlight this rare, unspecific and heterogeneous symptoms which can provoke negligence of a potentially life threatening condition.

关键词： Neisseria meningitidis Meningococcal Disease Chronic Meningococemia

Neonatal Fc receptor-targeted lignin-encapsulated porous silicon nanoparticles for enhanced cellular interactions and insulin permeation across the intestinal epithelium

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Bioactive Materials 2022年第3期7卷 299-315页

作者： Joao P.Martins Patrícia Figueiredo Shiqi Wang Erika Espo Elena Celi Beatriz Martins Marianna Kemell Karina Moslova Ermei Makil Jarno Salonen Mauri A.Kostiainen Christian Celia Vincenzo Cerullo Tapani Viitala Bruno Sarmento Jouni Hirvonen Helder A.Santos Drug Research Program Division of Pharmaceutical Chemistry and TechnologyFaculty of PharmacyUniversity of HelsinkiFI-00014HelsinkiFinland department of Pharmacy University of Chieti-Pescara“G d’Annunzio”I-66100ChietiItaly Drug Research Program Division of Pharmaceutical BiosciencesFaculty of PharmacyUniversity of HelsinkiFI-00014HelsinkiFinland department of Chemistry University of HelsinkiFI-00014HelsinkiFinland department of Physics and Astronomy University of TurkuFI-20014TurkuFinland Biohybrid Materials Department of Bioproducts and BiosystemsAalto UniversityFI-00076AaltoFinland i3S-instituto de Investigaçao e Inovaçao em Saúde University of Porto4200-135PortoPortugal ineb-instituto de engenharia biomedica University of Porto4200-135PortoPortugal CESPU-instituto de Investigaçao e Formaçao Avançada em Ciencias e Tecnologias da Saúde 4585-116GandraPortugal Helsinki Institute of Life Science(HiLIFE) University of HelsinkiFI-00014HelsinkiFinland

Oral insulin delivery could change the life of millions of diabetic patients as an effective,safe,easy-to-use,and affordable alternative to insulin injections,known by an inherently thwarted patient ***,we designed a multistage nanoparticle(NP)system capable of circumventing the biological barriers that lead to poor drug absorption and bioavailability after oral *** nanosystem consists of an insulin-loaded porous silicon NP encapsulated into a pH-responsive lignin matrix,and surface-functionalized with the Fc fragment of immunoglobulin G,which acts as a targeting ligand for the neonatal Fc receptor(FcRn).The developed NPs presented small size(211±1 nm)and narrow size *** NPs remained intact in stomach and intestinal pH conditions,releasing the drug exclusively at pH 7.4,which mimics blood *** formulation showed to be highly cytocompatible,and surface plasmon resonance studies demonstrated that FcRn-targeted NPs present higher capacity to interact and being internalized by the Caco-2 cells,which express FcRn,as demonstrated by Western ***,in vitro permeability studies showed that Fc-functionalized NPs induced an increase in the amount of insulin that permeated across a Caco-2/HT29-MTX co-culture model,showing apparent permeability coefficients(Papp)of 2.37×10􀀀6 cm/s,over the 1.66×10􀀀6 cm/s observed for their non-functionalized ***,these results demonstrate the potential of these NPs for oral delivery of anti-diabetic drugs.

关键词： Nanoparticles Porous silicon Lignin FcRn Insulin Oral drug delivery