Lipid Peroxidation as a Possible Factor Affecting Bone Resorption in Obese Subjects-Preliminary Research.

Oxidative stress, which promotes bone catabolism, also affects the quality of bone tissue. We aimed to assess the impact of metabolic disorders and oxidant-antioxidant imbalance associated with primary obesity on bone resorption and formation processes. Anthropometric parameters, metabolic variables, oxidative stress indicators (malondialdehyde, vitamins A and E, uric acid, superoxide dismutase, catalase, glutathione peroxidase, type 1 paraoxonase, iron-reducing plasma antioxidant power) and markers of bone turnover (type I procollagen N-terminal propeptide and the type I collagen C-terminal cross-linked telopeptide; P1NP and CTX) were assessed in 108 Polish participants.

GS-SMD server for steered molecular dynamics of peptide substrates in the active site of the γ-secretase complex.

Despite recent advances in research, the mechanism of Alzheimer's disease is not fully understood yet. Understanding the process of cleavage and then trimming of peptide substrates, can help selectively block γ-secretase (GS) to stop overproduction of the amyloidogenic products. Our GS-SMD server (https://gs-smd.

Can targeted nanoparticles distinguish cancer metastasis from inflammation?

Targeting ligands have been widely used to increase the intratumoral accumulation of nanoparticles and their uptake by cancer cells. However, these ligands aim at targets that are often also upregulated in inflamed tissues. Here, we assessed the ability of targeted nanoparticles to distinguish metastatic cancer from sites of inflammation.

Comparison of the uptake of untargeted and targeted immunostimulatory nanoparticles by immune cells in the microenvironment of metastatic breast cancer.

To alter the immunosuppressive tumor microenvironment (TME), we developed an immunostimulatory nanoparticle (NP) to reprogram a tumor's dysfunctional and inhibitory antigen-presenting cells (APCs) into properly activated APCs that stimulate tumor-reactive cytotoxic T cells. Importantly, systemic delivery allowed NPs to efficiently utilize the entire microvasculature and gain access into the majority of the perivascular TME, which coincided with the APC-rich tumor areas leading to uptake of the NPs predominantly by APCs. In this work, a 60 nm NP was loaded with a STING agonist, which triggered robust production of interferon β, resulting in activation of APCs.

Hyperthermia-mediated changes in the tumor immune microenvironment using iron oxide nanoparticles.

Iron oxide nanoparticles (IONPs) have often been investigated for tumor hyperthermia. IONPs act as heating foci in the presence of an alternating magnetic field (AMF). It has been shown that hyperthermia can significantly alter the tumor immune microenvironment.

The effect of PEGylation on the efficacy and uptake of an immunostimulatory nanoparticle in the tumor immune microenvironment.

The efficacy of immunotherapies is often limited by the immunosuppressive tumor microenvironment, which is populated with dysfunctional innate immune cells. To reprogram the tumor-resident innate immune cells, we developed immunostimulatory silica mesoporous nanoparticles (immuno-MSN). The cargo of immuno-MSN is a Stimulator of Interferon Gene (STING) agonist, which activates innate immune cells leading to production of interferon (IFN) β.

Immunostimulatory silica nanoparticle boosts innate immunity in brain tumors.

The high mortality associated with glioblastoma multiforme (GBM) is attributed to its invasive nature, hypoxic core, resistant cell subpopulations and a highly immunosuppressive tumor microenvironment (TME). To support adaptive immune function and establish a more robust antitumor immune response, we boosted the local innate immune compartment of GBM using an immunostimulatory mesoporous silica nanoparticle, termed immuno-MSN. The immuno-MSN was specifically designed for systemic and proficient delivery of a potent innate immune agonist to dysfunctional antigen-presenting cells (APCs) in the brain TME.

Stimuli-Responsive Iron Oxide Nanotheranostics: A Versatile and Powerful Approach for Cancer Therapy.

Recent advancements in unravelling elements of cancer biology involved in disease progression and treatment resistance have highlighted the need for a holistic approach to effectively tackle cancer. Stimuli-responsive nanotheranostics based on iron oxide nanoparticles are an emerging class of versatile nanomedicines with powerful capabilities to "seek, sense, and attack" multiple components of solid tumors. In this work, the rationale for using iron oxide nanoparticles and the basic physical principles that impact their function in biomedical applications are reviewed.

Immunostimulatory nanoparticle incorporating two immune agonists for the treatment of pancreatic tumors.

Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant disease, where even surgical resection and aggressive chemotherapy produce dismal outcomes. Immunotherapy is a promising alternative to conventional treatments, possessing the ability to elicit T cell-mediated killing of tumor cells and prevent disease recurrence. Immunotherapeutic approaches thus far have seen limited success in PDAC due to a poorly immunogenic and exceedingly immunosuppressive tumor microenvironment, which is enriched with dysfunctional and immunosuppressed antigen-presenting cells (APCs).

Treatment of glioblastoma using multicomponent silica nanoparticles.

Glioblastomas (GBMs) remain highly lethal. This partially stems from the presence of brain tumor initiating cells (BTICs), a highly plastic cellular subpopulation that is resistant to current therapies. In addition to resistance, the blood-brain barrier limits the penetration of most drugs into GBMs.

PTPmu-targeted nanoparticles label invasive pediatric and adult glioblastoma.

Poor prognosis for glioblastoma (GBM) is a consequence of the aggressive and infiltrative nature of gliomas where individual cells migrate away from the main tumor to distant sites, making complete surgical resection and treatment difficult. In this manuscript, we characterize an invasive pediatric glioma model and determine if nanoparticles linked to a peptide recognizing the GBM tumor biomarker PTPmu can specifically target both the main tumor and invasive cancer cells in adult and pediatric glioma models. Using both iron and lipid-based nanoparticles, we demonstrate by magnetic resonance imaging, optical imaging, histology, and iron quantification that PTPmu-targeted nanoparticles effectively label adult gliomas.

Delivery of drugs into brain tumors using multicomponent silica nanoparticles.

Glioblastomas are highly lethal cancers defined by resistance to conventional therapies and rapid recurrence. While new brain tumor cell-specific drugs are continuously becoming available, efficient drug delivery to brain tumors remains a limiting factor. We developed a multicomponent nanoparticle, consisting of an iron oxide core and a mesoporous silica shell that can effectively deliver drugs across the blood-brain barrier into glioma cells.

Imaging breast cancer using a dual-ligand nanochain particle.

Nanoparticles often only exploit the upregulation of a receptor on cancer cells to enhance intratumoral deposition of therapeutic and imaging agents. However, a single targeting moiety assumes that a tumor is homogenous and static. Tumoral microenvironments are both heterogenous and dynamic, often displaying variable spatial and temporal expression of targetable receptors throughout disease progression.

Precise targeting of cancer metastasis using multi-ligand nanoparticles incorporating four different ligands.

Metastasis displays a highly heterogeneous cellular population with cancer cells continuously evolving. As a result, a single-ligand nanoparticle cannot account for the continuously changing expression of targetable biomarkers over time and space. To effectively direct nanoparticles to metastasis, we developed a multi-ligand nanoparticle by using four different types of ligands on the same nanoparticle that target biomarkers on the endothelium associated with metastatic disease.

Transmembrane redox control and proteolysis of PdeC, a novel type of c-di-GMP phosphodiesterase.

The nucleotide second messenger c-di-GMP nearly ubiquitously promotes bacterial biofilm formation, with enzymes that synthesize and degrade c-di-GMP being controlled by diverse N-terminal sensor domains. Here, we describe a novel class of widely occurring c-di-GMP phosphodiesterases (PDE) that feature a periplasmic "CSS domain" with two highly conserved cysteines that is flanked by two transmembrane regions (TM1 and TM2) and followed by a cytoplasmic EAL domain with PDE activity. Using PdeC, one of the five CSS domain PDEs of K-12 we show that DsbA/DsbB-promoted disulfide bond formation in the CSS domain reduces PDE activity.

One-pot synthesis of nanochain particles for targeting brain tumors.

To synthesize multi-component nanochains, we developed a simple 'one-pot' synthesis, which exhibited high yield and consistency. The nanochains particles consist of parent nanospheres chemically linked into a higher-order, chain-like assembly. The one-pot synthesis is based on the addition of two types of parent nanospheres in terms of their surface chemical functionality (e.

Function and developmental origin of a mesocortical inhibitory circuit.

Midbrain ventral tegmental neurons project to the prefrontal cortex and modulate cognitive functions. Using viral tracing, optogenetics and electrophysiology, we found that mesocortical neurons in the mouse ventrotegmental area provide fast glutamatergic excitation of GABAergic interneurons in the prefrontal cortex and inhibit prefrontal cortical pyramidal neurons in a robust and reliable manner. These mesocortical neurons were derived from a subset of dopaminergic progenitors, which were dependent on prolonged Sonic Hedgehog signaling for their induction.

Salmonella enterica invasion of polarized epithelial cells is a highly cooperative effort.

The invasion of polarized epithelial cells by Salmonella enterica requires the cooperative activity of the Salmonella pathogenicity island 1 (SPI1)-encoded type III secretion system (T3SS) and the SPI4-encoded adhesin SiiE. The invasion of polarized cells is more efficient than that of nonpolarized cells, and we observed the formation of clusters of bacteria on infected cells. Here we demonstrate that the invasion of polarized cells is a highly cooperative activity.

Type I TARPs promote dendritic growth of early postnatal neocortical pyramidal cells in organotypic cultures.

The ionotropic α-amino-3-hydroxy-5-methyl-4-isoxazole propionate glutamate receptors (AMPARs) have been implicated in the establishment of dendritic architecture. The transmembrane AMPA receptor regulatory proteins (TARPs) regulate AMPAR function and trafficking into synaptic membranes. In the current study, we employ type I and type II TARPs to modulate expression levels and function of endogenous AMPARs and investigate in organotypic cultures (OTCs) of rat occipital cortex whether this influences neuronal differentiation.