Engineering Novel Targeted Boron‐10‐Enriched Theranostic Nanomedicine to Combat against Murine Brain Tumors via MR Imaging‐Guided Boron Neutron Capture Therapy

Glioblastoma multiforme (GBM) is a very common type of “incurable” malignant brain tumor. Although many treatment options are currently available, most of them eventually fail due to its recurrence. Boron neutron capture therapy (BNCT) emerges as an alternative noninvasive therapeutic treatment modality. The major challenge in treating GBMs using BNCT is to achieve selective imaging, targeting, and sufficient accumulation of boron‐containing drug at the tumor site so that effective destruction of tumor cells can be achieved without harming the normal brain cells. To tackle this challenge, this study demonstrates for the first time that an unprecedented ¹⁰B‐enriched (96% ¹⁰B enrichment) boron nanoparticle nanomedicine (¹⁰BSGRF NPs) surface‐modified with a Fluorescein isothiocyanate (FITC)‐labeled RGD‐K peptide can pass through the brain blood barrier, selectively target at GBM brain tumor sites, and deliver high therapeutic dosage (50.5 µg ¹⁰B g^?1 cells) of boron atoms to tumor cells with a good tumor‐to‐blood boron ratio of 2.8. The ¹⁰BSGRF NPs not only can enhance the contrast of magnetic resonance (MR) imaging to help diagnose the location/size/progress of brain tumor, but also effectively suppress murine brain tumors via MR imaging‐guided BNCT, prolonging the half‐life of mice from 22 d (untreated group) to 39 d.     

Integrin-targeting with peptide-bioconjugated semiconductor-magnetic nanocrystalline heterostructures

Binary asymmetric nanocrystals (BNCs), composed of a photoactive TiO₂ nanorod joined with a superparamagnetic γ-Fe₂O₃ spherical domain, were embedded in polyethylene glycol modified phospholipid micelle and successfully bioconjugated to a suitably designed peptide containing an RGD motif. BNCs represent a relevant multifunctional nanomaterial, owing to the coexistence of two distinct domains in one particle, characterized by high photoactivity and magnetic properties, that is particularly suited for use as a phototherapy and hyperthermia agent as well as a magnetic probe in biological imaging. We selected the RGD motif in order to target integrin expressed on activated endothelial cells and several types of cancer cells. The prepared RGD-peptide/BNC conjugates, comprehensively monitored by using complementary optical and structural techniques, demonstrated a high stability and uniform dispersibility in biological media. The cytotoxicity of the RGD-peptide/BNC conjugates was studied in vitro. The cellular uptake of RGD-peptide conjugates in the cells, assessed by means of two distinct approaches, namely confocal microscopy analysis and emission spectroscopy determination in cell lysates, displayed selectivity of the RGD-peptide-BNC conjugate for the αvβ3 integrin. These RGD-peptide-BNC conjugates have a high potential for theranostic treatment of cancer.

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PEGylated TiO2 nanoparticles mediated inhibition of cell migration via integrin beta 1

Nanoparticles (NPs) elicit various physiological responses in cellular environment, and the effect of NPs on cell migration is of high interest. In this work, the effects of NPs on cell migration and their possible mechanisms were studied. Here, we showed that after exposure to pegylated titanium dioxide nanoparticles (TiO₂-PEG NPs, where PEG stands for the polyethylene glycol), NCI-H292 cells exhibited slower migration than control cells. Furthermore, larger NPs inhibited cell migration much stronger than smaller NPs. Following NP exposure, the cells showed decreased expression of integrin beta 1 and phosphorylated focal adhesion kinase (pFAK), and disrupted F-actin structures. We demonstrated that a possible mechanism involved NP-mediated promotion of the lysosomal degradation of integrin beta 1, thus leading to reduced expression of pFAK and cytoskeletal disruption and inhibited cell migration. Therefore, our results showed that inhibition of NCI-H292 cell migration by NPs is mediated through integrin beta 1, which provides useful information for the application of NPs in cancer therapy and related fields.     

Adhesion Molecule Targeted Therapy for Non-Infectious Uveitis

Non-infectious uveitis (NIU) is an inflammatory eye disease initiated via CD4⁺ T-cell activation and transmigration, resulting in focal retinal tissue damage and visual acuity disturbance. Cell adhesion molecules (CAMs) are activated during the inflammatory process to facilitate the leukocyte recruitment cascade. Our review focused on CAM-targeted therapies in experimental autoimmune uveitis (EAU) and NIU. We concluded that CAM-based therapies have demonstrated benefits for controlling EAU severity with decreases in immune cell migration, especially via ICAM-1/LFA-1 and VCAM-1/VLA-4 (integrin) pathways. P-selectin and E-selectin are more involved specifically in uveitis related to vasculitis. These therapies have potential clinical applications for the development of a more personalized and specific treatment. Localized therapies are the future direction to avoid serious systemic side effects.     

The Intriguing Thyroid Hormones–Lung Cancer Association as Exemplification of the Thyroid Hormones–Cancer Association: Three Decades of Evolving Research

Exemplifying the long-pursued thyroid hormones (TH)–cancer association, the TH–lung cancer association is a compelling, yet elusive, issue. The present narrative review provides background knowledge on the molecular aspects of TH actions, with focus on the contribution of TH to hallmarks of cancer. Then, it provides a comprehensive overview of data pertinent to the TH–lung cancer association garnered over the last three decades and identifies obstacles that need to be overcome to enable harnessing this association in the clinical setting. TH contribute to all hallmarks of cancer through integration of diverse actions, currently classified according to molecular background. Despite the increasingly recognized implication of TH in lung cancer, three pending queries need to be resolved to empower a tailored approach: (1) How to stratify patients with TH-sensitive lung tumors? (2) How is determined whether TH promote or inhibit lung cancer progression? (3) How to mimic the antitumor and/or abrogate the tumor-promoting TH actions in lung cancer? To address these queries, research should prioritize the elucidation of the crosstalk between TH signaling and oncogenic signaling implicated in lung cancer initiation and progression, and the development of efficient, safe, and feasible strategies leveraging this crosstalk in therapeutics.     

宰后猪肉pH值、骨架蛋白表达水平和持水性之间的关系

以20头猪的背最长肌为材料,分别于宰后45 min和3、9、12、24 h测定猪背最长肌的pH值和整联蛋白、黏着斑蛋白、踝蛋白表达水平,并测定汁液流失率,探讨它们之间的关系.结果显示:高pH组(pH45 min≥6.00,n=6)的汁液流失率和踝蛋白表达水平低于低pH组(pH45 min≤5.78,n=14),整联蛋白...     

CCL4 Stimulates Cell Migration in Human Osteosarcoma via the mir-3927-3p/Integrin αvβ3 Axis

Osteosarcoma is the most common type of primary malignant bone cancer, and it is associated with high rates of pulmonary metastasis. Integrin αvβ3 is critical for osteosarcoma cell migratory and invasive abilities. Chemokine (C-C motif) ligand 4 (CCL4) has diverse effects on different cancer cells through its interaction with its specific receptor, C-C chemokine receptor type 5 (CCR5). Analysis of mRNA expression in human osteosarcoma tissue identified upregulated levels of CCL4, integrin αv and β3 expression. Similarly, an analysis of records from the Gene Expression Omnibus (GEO) dataset showed that CCL4 was upregulated in human osteosarcoma tissue. Importantly, the expression of both CCL4 and integrin αvβ3 correlated positively with osteosarcoma clinical stages and lung metastasis. Analysis of osteosarcoma cell lines identified that CCL4 promotes integrin αvβ3 expression and cell migration by activating the focal adhesion kinase (FAK), protein kinase B (AKT), and hypoxia inducible factor 1 subunit alpha (HIF-1α) signaling pathways, which can downregulate microRNA-3927-3p expression. Pharmacological inhibition of CCR5 by maraviroc (MVC) prevented increases in integrin αvβ3 expression and cell migration. This study is the first to implicate CCL4 as a potential target in the treatment of metastatic osteosarcoma.     

SNOM and AFM microscopy techniques to study the effect of non-ionizing radiation on the morphological and biochemical properties of human keratinocytes cell line (HaCaT)

In this study we have employed atomic force microscopy (AFM) and scanning near‐field optical microscopy (SNOM) techniques to study the effect of the interaction between human keratinocytes (HaCaT) and electromagnetic fields at low frequency. HaCaT cells were exposed to a sinusoidal magnetic field at a density of 50 Hz, 1 mT. AFM analysis revealed modification in shape and morphology in exposed cells with an increase in the areas of adhesion between cells. This latter finding was confirmed by SNOM indirect immunofluorescence analysis performed with a fluorescent antibody against the adhesion marker β4 integrin, which revealed an increase of β4 integrin segregation in the cell membrane of 50‐Hz exposed cells, suggesting that a higher percentage of these cells shows a modified pattern of this adhesion marker.     

Analysis of integrin (CD11b/CD18) movement during neutrophil adhesion and migration on endothelial cells

Little is known of the distribution of cell surface molecules during the adhesion and migration of leucocytes on endothelial cells. We have used confocal microscopy and a Fab fragment of a non-inhibitory monoclonal antibody recognizing the integrin CD11b/CD18 (Mac-1) to study the movement of this adhesion molecule over time. We found that during the initial stage of neutrophil contact with TNF-α activated human umbilical vein endothelial cells (HUVEC), there is a rapid accumulation of Mac-1 at the contact area between the two cell types. As the neutrophil spreads, Mac-1 redistributes away from this initial contact area. During neutrophil migration on HUVEC, Mac-1 was redistributed to the leading edge of the migrating cell, suggesting that the existing cell surface pool of adhesion molecules is dynamic and can be recruited to the leading front as the cell changes direction. As neutrophils migrate on HUVEC, Mac-1-dense macroaggregates are rapidly formed and broken down at the contact plane between the two cells. The confocal microscope, coupled with the use of non-inhibitory antibodies labelled with photostable fluorophores, is a useful tool for the study of the movement of cell surface molecules over time.     

Biomimetic Chiral Nanotopography for Manipulating Immunological Response

Immune response regulates implanted biomaterial−tissue integration and tissue regeneration, in which macrophages play a key role due to their plasticity and polarization. Chirality, an inherent property of carbon-based life, can also exist in biomaterials such as gold monolayer. Constructing chiral nanostructured surfaces of implants can imitate the chirality of extracellular environment in a biomimetic manner, but the manipulation and mechanism of chiral nanotopography on macrophages remain poorly understood. Here, highly ordered gold nanoparticle arrays with 300 or 900 nm spacing are fabricated and modified with L- or D-chirality. The D-nanoarrays can promote M2 polarization and related cytokine secretion of macrophages, thus facilitating the reduction of inflammatory reaction and promoting tissue healing and regeneration. The mechanistic analysis further suggests that D -nanoarrays proceeded these regulations through enhancing the expression of integrin αv/α8/β3-p-FAK pathway in macrophages, which may be largely attributed to its higher stereo-affinity for fibronectin as revealed by quantitative experiments and molecular dynamics simulations. Overall, this study demonstrates that biomimetic chiral nanotopography can promote biomaterial−tissue integration by manipulating macrophage phenotype, bringing a novel strategy for immunomodulation.