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Titanium and titanium alloys are the prevailing dental implant materials owing to their favorable mechanical properties and biocompatibility, but how roughness dictates the biological response is still a matter of debate. In this study, laser texturing was used to generate eight paradigmatic roughened surfaces, with the aim of studying the early biological response elicited on MC3T3-E1 pre-osteoblasts. Prior to cell tests, the samples underwent SEM analysis, optical profilometry, protein adsorption assay, and optical contact angle measurement with water and diiodomethane to determine surface free energy. While all the specimens proved to be biocompatible, supporting similar cell viability at 1, 2, and 3 days, surface roughness could impact significantly on cell adhesion. Factorial analysis and linear regression showed, in a robust and unprecedented way, that an isotropic distribution of deep and closely spaced valleys provides the best condition for cell adhesion, to which both protein adsorption and surface free energy were highly correlated. Overall, here the authors provide, for the first time, a thorough investigation of the relationship between roughness parameters and osteoblast adhesion that may be applied to design and produce new tailored interfaces for implant materials. [ABSTRACT FROM AUTHOR]

Endothelial cells (ECs) are highly plastic, capable of differentiating into various cell types. Endothelial-to-mesenchymal transition (EndMT) is crucial during embryonic development and contributes substantially to vascular dysfunction in many cardiovascular diseases (CVDs). While targeting EndMT holds therapeutic promise, understanding its mechanisms and modulating its pathways remain challenging. Using single-cell RNA sequencing on three in vitro EndMT models, we identified conserved gene signatures. We validated original regulators in vitro and in vivo during embryonic heart development and peripheral artery disease. EndMT induction led to global expression changes in all EC subtypes rather than in mesenchymal clusters. We identified mitochondrial calcium uptake as a key driver of EndMT; inhibiting mitochondrial calcium uniporter (MCU) prevented EndMT in vitro, and conditional Mcu deletion in ECs blocked mesenchymal activation in a hind limb ischemia model. Tissues from patients with critical limb ischemia with EndMT features exhibited significantly elevated endothelial MCU. These findings highlight MCU as a regulator of EndMT and a potential therapeutic target. [ABSTRACT FROM AUTHOR]

Living organisms are multiscale complex systems that have evolved high degrees of multifunctionality and redundancy in the structure–function relationship. A number of factors, only in part determined genetically, affect the jobs of proteins. The overall structural organization confers unique molecular properties that provide the potential to perform a pattern of activities, some of which are co‐opted by specific environments. The variety of multifunctional proteins is expanding, but most cases are handled individually and according to the still dominant 'one structure–one function' approach, which relies on the attribution of canonical names typically referring to the first task identified for a given protein. The present topical review focuses on the multifunctionality of ion channels as a paradigmatic example. Mounting evidence reports the ability of many ion channels (including members of voltage‐dependent, ligand‐gated and transient receptor potential families) to exert biological effects independently of their ion conductivity. 'Functionally based' nomenclature (the practice of naming a protein or family of proteins based on a single purpose) is a conceptual bias for three main reasons: (i) it increases the amount of ambiguity, deceiving our understanding of the multiple contributions of biomolecules that is the heart of the complexity; (ii) it is in stark contrast to protein evolution dynamics, largely based on multidomain arrangement; and (iii) it overlooks the crucial role played by the microenvironment in adjusting the actions of cell structures and in tuning protein isoform diversity to accomplish adaptational requirements. Biological information in protein physiology is distributed among different entwined layers working as the primary 'locus' of natural selection and of evolutionary constraints. [ABSTRACT FROM AUTHOR]

The mechanical and biological behaviors of PMMA/Al2O3 composites incorporating 30 wt.%, 40 wt.%, and 50 wt.% of Al2O3 were thoroughly characterized as regards to their possible application in implant-supported prostheses. The Al2O3 particles accounted for an increase in the flexural modulus of PMMA. The highest value was recorded for the composite containing 40 wt.% Al2O3 (4.50 GPa), which was about 18% higher than that of its unfilled counterpart (3.86 GPa). The Al2O3 particles caused a decrease in the flexural strength of the composites, due to the presence of filler aggregates and voids, though it was still satisfactory for the intended application. The roughness (Ra) and water contact angle had the same trend, ranging from 1.94 µm and 77.2° for unfilled PMMA to 2.45 µm and 105.8° for the composite containing the highest alumina loading, respectively, hence influencing both the protein adsorption and cell adhesion. No cytotoxic effects were found, confirming that all the specimens are biocompatible and capable of sustaining cell growth and proliferation, without remarkable differences at 24 and 48 h. Finally, Al2O3 was able to cause strong cell responses (cell orientation), thus guiding the tissue formation in contact with the composite itself and not enhancing its osteoconductive properties, supporting the PMMA composite's usage in the envisaged application. [ABSTRACT FROM AUTHOR]

Extensive efforts have been devoted to the development of near-infrared (NIR) dyes for biological applications, especially for photodynamic therapy (PDT) [1]. In this context, polymethine dyes can be considered as innovative photosensitizers (PS) due to the easy and low-cost synthesis along with remarkable absorption property in the far-red NIR region, perfectly matching the biological tissues' transparency window (600-900 nm) [2]. NIR cyanines (CY) and squaraines (SQ) are well suited for this purpose and have been extensively studied for many biomedical applications, thanks to their high molar absorption coefficients, remarkable brightness, fluorescence and photostability, especially in organic media.[3]The present contribution deals with the design and synthesis of a new series of CY and SQ polymethine dyes based on indolenine and quinaldine ring and with different substitution groups synthetized by microwave irradiation and photophysically characterized by UV-Vis and fluorescence spectroscopy, with the aim to highlight a structure-activity relationship. To assess the suitability of these dyes to be used in PDT, the Reactive Oxygen Species (ROS) production ability of the CY and SQ samples has been evaluated by using the 1,3-diphenylisobenzofuran (DPBF) probe and compared with standards PS well-known in literature. In addition, the in vitro biological assessments were examined by exposing the MCF-7 cells to increasing concentration of each PSs to select the maximum non-cytotoxic concentration suitable for performing the in vitro PDT. The potential photocytotoxicity of each dye was evaluated by performing an in vitro photodynamic treatment, showing low cytotoxicity in dark but promoting phototoxic effect upon irradiation. Moreover, internalization studies to understand the dye localization have also been performed. [ABSTRACT FROM AUTHOR]

Photodynamic therapy (PDT) is an emerging, minimally invasive therapeutic modality approved by the U.S Food and Drug Administration for the treatment of several conditions including oncological applications 1. The approach is based on light-induced photosensitizers (PS) activation which, in turn, promotes the intersystem crossing and triplet state that easily reacts with molecular oxygen, thus generating free radicals and singlet oxygen species which in turn involve intracellular Ca2+ signals as well as other messengers with a final increase in apoptosis, necrosis, and autophagy processes and tumor mass reduction 1,2. In this context, the development of new PS for the PTD is of great interest to increase the treatment efficacy minimizing side effects3,4. In the present work, we investigated the structure-functional role of SQ by comparing the phototoxic activity of unsubstituted SQ, carboxyl (COOH)- and bromine (Br)-substituted SQ, as well SQ in which the oxygen atoms of the squaryl ring were replaced with sulfur atoms (S-SQ). Indeed, the presence of heavy atoms such as Br and the replacement of oxygen with sulfur are predicted to shift the emission to the far NIR region and increase the quantum yield of singlet oxygen, thus improving the overall effect in PDT. As expected, Br-SQ and S-SQ demonstrate a higher phototoxicity on MCF-7 cells compared to the COOH-SQ dye, which showed no effect. However, surprisingly, our data reveal that also the unsubstituted SQ has a strong phototoxic activity. To deeper analyze the the molecular mechanisms underlying SQ phototoxicity, we studied the role of Ca2+ signals and ROS generation in light induced PS activation. Our results clearly show that Br-SQ promote ROS production as well as significant increase in cytosolic Ca2+ signals mainly due to Ca2+ release form ER stores which in turn promotes a sustained Ca2+ uptake in the mitochondria while no effect was observed for the COOH-SQ. Our results shed new light on the structure-function relationship of SQ and the intracellular pathways involved in their exploitable photo-activity in PDT, demonstrating a critical role for intracellular Ca2+ signals in ROS activation and cell death. [ABSTRACT FROM AUTHOR]

Opuntia ficus indica (Opuntia) fruit has been shown to contain several bioavailable phytochemicals with effective anti-oxidative and antiinflammatory properties and, among these, the betalain pigment indicaxanthin. In the light of the strong interconnections between oxidative stress, inflammation and atherosclerosis, this work has evaluated the effects of a methanolic extract of Opuntia fruit (OFE), at nutritionally relevant concentrations, in an in vitro model of oxLDL-induced ED. [Extracted from the article]

Background: Transient receptor potential (TRP) channels control multiple processes involved in cancer progression by modulating cell proliferation, survival, invasion and intravasation, as well as, endothelial cell (EC) biology and tumor angiogenesis. Nonetheless, a complete TRP expression signature in tumor vessels, including in prostate cancer (PCa), is still lacking. Methods: In the present study, we profiled by qPCR the expression of all TRP channels in human prostate tumor-derived ECs (TECs) in comparison with TECs from breast and renal tumors. We further functionally characterized the role of the 'prostate-associated' channels in proliferation, sprout formation and elongation, directed motility guiding, as well as in vitro and in vivo morphogenesis and angiogenesis. Results: We identified three 'prostate-associated' genes whose expression is upregulated in prostate TECs: TRPV2 as a positive modulator of TEC proliferation, TRPC3 as an endothelial PCa cell attraction factor and TRPA1 as a critical TEC angiogenic factor in vitro and in vivo. Conclusions: We provide here the full TRP signature of PCa vascularization among which three play a profound effect on EC biology. These results contribute to explain the aggressive phenotype previously observed in PTEC and provide new putative therapeutic targets. [ABSTRACT FROM AUTHOR]