PCSK9 Affects Astrocyte Cholesterol Metabolism and Reduces Neuron Cholesterol Supplying In Vitro: Potential Implications in Alzheimer’s Disease

The Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) involvement in Alzheimer’s disease (AD) is poorly investigated. We evaluated the in vitro PCSK9 modulation of astrocyte cholesterol metabolism and neuronal cholesterol supplying, which is fundamental for neuronal functions. Moreover, we investigated PCSK9 neurotoxic effects. In human astrocytoma cells, PCSK9 reduced cholesterol content (−20%; p < 0.05), with a greater effect in presence of beta amyloid peptide (Aβ) (−37%; p < 0.01). PCSK9 increased cholesterol synthesis and reduced the uptake of apoE-HDL-derived cholesterol (−36%; p < 0.0001), as well as the LDL receptor (LDLR) and the apoE receptor 2 (ApoER2) expression (−66% and −31%, respectively; p < 0.01). PCSK9 did not modulate ABCA1- and ABCG1-cholesterol efflux, ABCA1 levels, or membrane cholesterol. Conversely, ABCA1 expression and activity, as well as membrane cholesterol, were reduced by Aβ (p < 0.05). In human neuronal cells, PCSK9 reduced apoE-HDL-derived cholesterol uptake (−41%; p < 0.001) and LDLR/apoER2 expression (p < 0.05). Reduced cholesterol internalization occurred also in PCSK9-overexpressing neurons exposed to an astrocyte-conditioned medium (−39%; p < 0.001). PCSK9 reduced neuronal cholesterol content overall (−29%; p < 0.05) and increased the Aβ-induced neurotoxicity (p < 0.0001). Our data revealed an interfering effect of PCSK9, in cooperation with Aβ, on brain cholesterol metabolism leading to neuronal cholesterol reduction, a potentially deleterious effect. PCSK9 also exerted a neurotoxic effect, and thus represents a potential pharmacological target in AD.     

Reticulated Porous Foam Ceramics with Different Surface Chemistries

The aim of this study was to discuss the influence of different filter surface chemistries on the properties of foam filters. For reliable results, it is essential to ensure comparable structural properties (cell size and strut thickness) for all different surface chemistries (Al₂O₃, MgAl₂O₄, 3Al₂O₃·2SiO₂, SiO₂, and TiO₂) possess the same structural properties (cell size and strut thickness). Filters made of 100% of the investigated materials and alumina skeletons coated with the investigated materials were prepared. The coated alumina samples were sintered in one and two steps. The processing route with two sintering steps resulted in improved mechanical properties and comparable shrinkage and strut thickness. The 100% bulk foams possessed different pore sizes due to the differences of the material shrinkage. In this study, a comparison of the experimental investigated properties of the ceramic foam filters and the theoretically calculated values for foam materials derived from the bulk material properties is established.     

Modulation of human dermal microvascular endothelial cell and human gingival fibroblast behavior by micropatterned silica coating surfaces for zirconia dental implant applications

Dental ceramic implants have shown superior esthetic behavior and the absence of induced allergic disorders when compared to titanium implants. Zirconia may become a potential candidate to be used as an alternative to titanium dental implants if surface modifications are introduced. In this work, bioactive micropatterned silica coatings were produced on zirconia substrates, using a combined methodology of sol–gel processing and soft lithography. The aim of the work was to compare the in vitro behavior of human gingival fibroblasts (HGFs) and human dermal microvascular endothelial cells (HDMECs) on three types of silica-coated zirconia surfaces: flat and micropatterned (with pillars and with parallel grooves). Our results showed that cells had a higher metabolic activity (HGF, HDMEC) and increased gene expression levels of fibroblast-specific protein-1 (FSP-1) and collagen type I (COL I) on surfaces with pillars. Nevertheless, parallel grooved surfaces were able to guide cell growth. Even capillary tube-like networks of HDMEC were oriented according to the surface geometry. Zirconia and silica with different topographies have shown to be blood compatible and silica coating reduced bacteria adhesion. All together, the results indicated that microstructured bioactive coating seems to be an efficient strategy to improve soft tissue integration on zirconia implants, protecting implants from peri-implant inflammation and improving long-term implant stabilization. This new approach of micropatterned silica coating on zirconia substrates can generate promising novel dental implants, with surfaces that provide physical cues to guide cells and enhance their behavior.     

Simultaneous modelling of rock freezing and water seepage and its practical applications

All existing models of the rock freezing process are able to simulate the conductive heat transfer, but, however the convective terms are dominant in many cases, when water seepage also occurs. The origin of the majority of failures were caused by the effect of water seepage. A new integrated finite difference simulation technique has been developed to model rock freezing and water seepage simultaneously. The mathematical model, the base of numerical algorithm, the input and output data, the verification of the model using analytical solutions and a rather sophisticated practical case history are discussed in the paper. Finally, the first practical application of the model to support decisions on the proper system of freezing and on the proper combination with depressurization of water bearing layers is presented as well.     

Fertilizer value and nitrogen transfer efficiencies with clover-grass ley biomass based fertilizers

In temperate regions, legume-based green manures are a key element of organic rotations. However, specialized farms lack sufficient mobile organic fertilizers. To gain a better understanding of the N flows and the nitrogen (N) and phosphorus (P) fertilizer value of different clover-grass-based fertilizers (biogas digestate, compost, silage and fresh clover-grass obtained from clover-grass ley biomass), we assessed their fertilizer value. Nitrogen and P offtake by the ryegrass was used to assess the short-term effects. The data were completed using model calculations to assess the field-to-field N-transfer efficiencies and the overall N-transfer efficiencies. The greatest plant N offtake was achieved with digestates (64%) and the lowest from the compost (6%) and solid farmyard manure (14%). The mineralization rate was positively related to the NH₄ ⁺–N/total N ratio (P < 0.01, r² = 0.82). The model calculations indicate that the overall short-term N-transfer efficiencies are driven by the field-to-field N-transfer efficiency and the field-to-crop transfer efficiency. However, in the long term, model calculations indicate that a high field-to-field N-transfer efficiency is the key strategic approach when aiming to achieve cropping systems with a high overall long-term N-transfer efficiency. Consequently, the results showed that aerobic decomposition (composting) significantly lowered field-to-field as well as field-to-crop N-transfer rates. The relative P use efficiency strongly differed among the fertilizers. In particular, freshly cut clover-grass and solid manure increased P availability and led to an increase of plant P offtake that was higher than the amount of P supplied.     

Cover Image,Volume 66, Issue 7

The cover image, by Maria Pia Di Bello et al., is based on the Research Article Towards a new strategy of a chitosan‐based molecularly imprinted membrane for removal of 4‐nitrophenol in real water samples, DOI: 10.1002/pi.5360 .

     

Coated contacts: a strain approach

A strain approach for the design of coated contacts is described, allowing a simple evaluation of the risk of coating failure, once the elastic modulus of the coating and the substrate and the coating thickness are known. Examples are provided for hard and soft coatings. The approach is shown to be particularly useful for hard coatings, where failure is mainly related to tensile longitudinal stresses at the interface. Results from the proposed strain approach compare well with data from a standard stress analysis. Finally, the level of approximation introduced by evaluating the strain field for the reference Hertzian case is discussed, showing that the error introduced is not acceptable.     

Tilting the Balance: Therapeutic Prospects of CD83 as a Checkpoint Molecule Controlling Resolution of Inflammation

Chronic inflammatory diseases and transplant rejection represent major challenges for modern health care. Thus, identification of immune checkpoints that contribute to resolution of inflammation is key to developing novel therapeutic agents for those conditions. In recent years, the CD83 (cluster of differentiation 83) protein has emerged as an interesting potential candidate for such a “pro-resolution” therapy. This molecule occurs in a membrane-bound and a soluble isoform (mCD83 and sCD83, respectively), both of which are involved in resolution of inflammation. Originally described as a maturation marker on dendritic cells (DCs), mCD83 is also expressed by activated B and T cells as well as regulatory T cells (Tregs) and controls turnover of MHC II molecules in the thymus, and thereby positive selection of CD4⁺ T cells. Additionally, it serves to confine overshooting (auto-)immune responses. Consequently, animals with a conditional deletion of CD83 in DCs or regulatory T cells suffer from impaired resolution of inflammation. Pro-resolving effects of sCD83 became evident in pre-clinical autoimmune and transplantation models, where application of sCD83 reduced disease symptoms and enhanced allograft survival, respectively. Here, we summarize recent advances regarding CD83-mediated resolution of inflammatory responses, its binding partners as well as induced signaling pathways, and emphasize its therapeutic potential for future clinical trials.     

Synergistic Antiviral Activity of Pamapimod and Pioglitazone against SARS-CoV-2 and Its Variants of Concern

The SARS-CoV-2 pandemic remains a major public health threat, especially due to newly emerging SARS-CoV-2 Variants of Concern (VoCs), which are more efficiently transmitted, more virulent, and more able to escape naturally acquired and vaccine-induced immunity. Recently, the protease inhibitor Paxlovid^® and the polymerase inhibitor molnupiravir, both targeting mutant-prone viral components, were approved for high-risk COVID-19 patients. Nevertheless, effective therapeutics to treat COVID-19 are urgently needed, especially small molecules acting independently of VoCs and targeting genetically stable cellular pathways which are crucial for viral replication. Pamapimod is a selective inhibitor of p38 Mitogen-Activated Protein Kinase alpha (p38 MAPKα) that has been extensively clinically evaluated for the treatment of rheumatoid arthritis. Signaling via p38 has recently been described as a key pathway for the replication of SARS-CoV-2. Here, we reveal that the combination of pamapimod with pioglitazone, an anti-inflammatory and approved drug for the treatment of type 2 diabetes, possesses potent and synergistic activity to inhibit SARS-CoV-2 replication in vitro. Both drugs showed similar antiviral potency across several cultured cell types and similar antiviral activity against SARS-CoV-2 Wuhan type, and the VoCs Alpha, Beta, Gamma, Delta, and Omicron. These data support the combination of pamapimod and pioglitazone as a potential therapy to reduce duration and severity of disease in COVID-19 patients, an assumption currently evaluated in an ongoing phase II clinical study.