Long-term retention of gold nanoparticles in the liver is not affected by their physicochemical characteristics.

Gold nanoparticles (GNPs) are considered promising candidates for healthcare applications, however, their toxicity after long-term exposure to the material remains uncertain. Since the liver is the main filter organ for nanomaterials, this work was aimed at evaluating hepatic accumulation, internalisation and overall safety of well-characterised and endotoxin-free GNPs in healthy mice from 15 minutes to 7 weeks after a single administration. Our data demonstrate that GNPs were rapidly segregated into lysosomes of endothelial cells (LSEC) or Kupffer cells regardless of coating or shape but with different kinetics.

Harnessing the reverse cholesterol transport pathway to favor differentiation of monocyte-derived APCs and antitumor responses.

Lipid and cholesterol metabolism play a crucial role in tumor cell behavior and in shaping the tumor microenvironment. In particular, enzymatic and non-enzymatic cholesterol metabolism, and derived metabolites control dendritic cell (DC) functions, ultimately impacting tumor antigen presentation within and outside the tumor mass, dampening tumor immunity and immunotherapeutic attempts. The mechanisms accounting for such events remain largely to be defined.

Continuous sensing of IFNα by hepatic endothelial cells shapes a vascular antimetastatic barrier.

Hepatic metastases are a poor prognostic factor of colorectal carcinoma (CRC) and new strategies to reduce the risk of liver CRC colonization are highly needed. Herein, we used mouse models of hepatic metastatization to demonstrate that the continuous infusion of therapeutic doses of interferon-alpha (IFNα) controls CRC invasion by acting on hepatic endothelial cells (HECs). Mechanistically, IFNα promoted the development of a vascular antimetastatic niche characterized by liver sinusoidal endothelial cells (LSECs) defenestration extracellular matrix and glycocalyx deposition, thus strengthening the liver vascular barrier impairing CRC trans-sinusoidal migration, without requiring a direct action on tumor cells, hepatic stellate cells, hepatocytes, or liver dendritic cells (DCs), Kupffer cells (KCs) and liver capsular macrophages (LCMs).

Food-Grade Titanium Dioxide Induces Toxicity in the Nematode and Acute Hepatic and Pulmonary Responses in Mice.

Food-grade titanium dioxide (E171) contains variable percentages of titanium dioxide (TiO) nanoparticles (NPs), posing concerns for its potential effects on human and animal health. Despite many studies, the actual relationship between the physicochemical properties of E171 NPs and their interaction with biological targets is still far from clear. We evaluated the impact of acute E171 administration on invertebrate and vertebrate animals.

Organosilica Cages Target Hepatic Sinusoidal Endothelial Cells Avoiding Macrophage Filtering.

Over the last years, advancements in the use of nanoparticles for biomedical applications have clearly showcased their potential for the preparation of improved imaging and drug-delivery systems. However, compared to the vast number of currently studied nanoparticles for such applications, only a few successfully translate into clinical practice. A common "barrier" that prevents nanoparticles from efficiently delivering their payload to the target site after administration is related to liver filtering, mainly due to nanoparticle uptake by macrophages.

Advances in Bio-Based Polymers for Colorectal CancerTreatment: Hydrogels and Nanoplatforms.

Adenocarcinoma of the colon is the most common malignant neoplasia of the gastrointestinal tract and is a major contributor to mortality worldwide. Invasiveness and metastatic behavior are typical of malignant tumors and, because of its portal drainage, the liver is the closest capillary bed available in this case, hence the common site of metastatic dissemination. Current therapies forecast total resection of primary tumor when possible and partial liver resection at advanced stages, along with systemic intravenous therapies consisting of chemotherapeutic agents such as 5-fluorouracil.

Oxidation of HMGB1 Is a Dynamically Regulated Process in Physiological and Pathological Conditions.

Acute inflammation is a complex biological response of tissues to harmful stimuli, such as pathogens or cell damage, and is essential for immune defense and proper healing. However, unresolved inflammation can lead to chronic disorders, including cancer and fibrosis. The High Mobility Group Box 1 (HMGB1) protein is a Damage-Associated Molecular Pattern (DAMP) molecule that orchestrates key events in inflammation by switching among mutually exclusive redox states.

Repeated administration of the food additive E171 to mice results in accumulation in intestine and liver and promotes an inflammatory status.

Titanium dioxide (TiO) is widely used in pharmaceuticals preparations, cosmetics, and as a food additive (E171). It contains microparticles and a fraction of nanoparticles (NPs) which can be absorbed systemically by humans after ingestion. Increasing concern has been aroused about the impact of oral exposure to TiO NPs from dietary and non-dietary sources on human health.

On the use of superparamagnetic hydroxyapatite nanoparticles as an agent for magnetic and nuclear in vivo imaging.

Unlabelled: The identification of alternative biocompatible magnetic NPs for advanced clinical application is becoming an important need due to raising concerns about iron accumulation in soft issues associated to the administration of superparamagnetic iron oxide nanoparticles (NPs). Here, we report on the performance of previously synthetized iron-doped hydroxyapatite (FeHA) NPs as contrast agent for magnetic resonance imaging (MRI). The MRI contrast abilities of FeHA and Endorem® (dextran coated iron oxide NPs) were assessed by H nuclear magnetic resonance relaxometry and their performance in healthy mice was monitored by a 7 Tesla scanner.

High mobility group box 1 orchestrates tissue regeneration via CXCR4.

Inflammation and tissue regeneration follow tissue damage, but little is known about how these processes are coordinated. High Mobility Group Box 1 (HMGB1) is a nuclear protein that, when released on injury, triggers inflammation. We previously showed that HMGB1 with reduced cysteines is a chemoattractant, whereas a disulfide bond makes it a proinflammatory cytokine.

Preclinical modeling highlights the therapeutic potential of hematopoietic stem cell gene editing for correction of SCID-X1.

Targeted genome editing in hematopoietic stem/progenitor cells (HSPCs) is an attractive strategy for treating immunohematological diseases. However, the limited efficiency of homology-directed editing in primitive HSPCs constrains the yield of corrected cells and might affect the feasibility and safety of clinical translation. These concerns need to be addressed in stringent preclinical models and overcome by developing more efficient editing methods.

IFNα gene/cell therapy curbs colorectal cancer colonization of the liver by acting on the hepatic microenvironment.

Colorectal cancer (CRC) metastatic dissemination to the liver is one of the most life-threatening malignancies in humans and represents the leading cause of CRC-related mortality. Herein, we adopted a gene transfer strategy into mouse hematopoietic stem/progenitor cells to generate immune-competent mice in which TEMs-a subset of Tie2(+) monocytes/macrophages found at peritumoral sites-express interferon-alpha (IFNα), a pleiotropic cytokine with anti-tumor effects. Utilizing this strategy in mouse models of CRC liver metastasis, we show that TEMs accumulate in the proximity of hepatic metastatic areas and that TEM-mediated delivery of IFNα inhibits tumor growth when administered prior to metastasis challenge as well as on established hepatic lesions, improving overall survival.

Immunosurveillance of the liver by intravascular effector CD8(+) T cells.

Effector CD8(+) T cells (CD8 TE) play a key role during hepatotropic viral infections. Here, we used advanced imaging in mouse models of hepatitis B virus (HBV) pathogenesis to understand the mechanisms whereby these cells home to the liver, recognize antigens, and deploy effector functions. We show that circulating CD8 TE arrest within liver sinusoids by docking onto platelets previously adhered to sinusoidal hyaluronan via CD44.

Chronic hepatitis B: role of anti-platelet therapy in inflammation control.

Platelets play a known role in the maintenance of vascular homeostasis, but these cells are emerging as important cellular mediators of acute and chronic inflammatory diseases. Platelets are key elements in the pathogenesis of acute and chronic liver disease associated with hepatitis B virus (HBV) infection by promoting the accumulation of virus-specific CD8(+) T cells and nonspecific inflammatory cells into the liver parenchyma. This review discusses major platelet functions in immune and inflammatory responses, with an emphasis on recent pre-clinical studies that suggest that the inhibition of platelet activation pathways represent an alternative therapeutic strategy with potential use in the reduction of virus-specific T cell-mediated chronic inflammation, liver fibrosis and hepatocellular carcinoma in patients who are chronically infected with HBV.

Platelets promote liver immunopathology contributing to hepatitis B virus-mediated hepatocarcinogenesis.

Chronic hepatitis B virus (HBV) infection is a major risk factor for the development of hepatocellular carcinoma (HCC). Among the pathogenetic factors triggered by HBV, virus-specific CD8(+) T cells play and important role in disease pathogenesis by promoting necroinflammatory liver damage. Accordingly, amelioration of immune-mediated chronic liver injury may prevent HCC.

The COP9 signalosome is a repressor of replicative stress responses and polyploidization in the regenerating liver.

Unlabelled: Aberrant DNA replication induced by deregulated or excessive proliferative stimuli evokes a "replicative stress response" leading to cell cycle restriction and/or apoptosis. This robust fail-safe mechanism is eventually bypassed by transformed cells, due to ill-defined epistatic interactions. The COP9 signalosome (CSN) is an evolutionarily conserved regulator of cullin ring ligases (CRLs), the largest family of ubiquitin ligases in metazoans.

Emerging role of dual antiplatelet therapy in the prevention of hepatitis B virus-associated hepatocellular carcinoma.

Platelets, the chief effectors of vascular homeostasis, have been identified as important players in the pathogenesis of both acute and chronic liver disease in preclinical models of hepatitis B viral infection. Platelets are thought to promote the accumulation of virus-specific T-cells into the liver parenchyma. Importantly, the inhibition of platelet activation by clinically relevant doses of aspirin and clopidogrel was able to reduce immune-mediated necroinflammatory liver disease, extracellular matrix deposition, and hepatocellular carcinoma development; the same treatment was able to improve overall survival.

Bisphosphonates target B cells to enhance humoral immune responses.

Bisphosphonates are a class of drugs that are widely used to inhibit loss of bone mass in patients. We show here that the administration of clinically relevant doses of bisphosphonates in mice increases antibody responses to live and inactive viruses, proteins, haptens, and existing commercial vaccine formulations. Bisphosphonates exert this adjuvant-like activity in the absence of CD4(+) and γδ T cells, neutrophils, or dendritic cells, and their effect does not rely on local macrophage depletion, Toll-like receptor signaling, or the inflammasome.

Anti-platelet therapy in the prevention of hepatitis B virus-associated hepatocellular carcinoma.

Previous studies in mouse models of self-limited viral hepatitis showed that platelets contribute to acute liver damage by promoting the intrahepatic accumulation of virus-specific CD8 T cells and, secondarily, virus-non-specific inflammatory cells. Built on these observations, a recent preclinical study took advantage of a previously established hepatitis B virus (HBV) transgenic mouse model of immune-mediated chronic hepatitis that progresses to hepatocellular carcinoma (HCC), to demonstrate that clinically achievable doses of the anti-platelet drugs aspirin and clopidogrel - administered continuously after the onset of liver disease - can prevent hepatocarcinogenesis and greatly improve overall survival. These outcomes were preceded by and associated with reduced hepatic accumulation of virus-specific CD8 T cells and virus-non-specific inflammatory cells, reduced hepatocellular injury and hepatocellular proliferation, and reduced severity of liver fibrosis.

Nkx2-5(+)islet1(+) mesenchymal precursors generate distinct spleen stromal cell subsets and participate in restoring stromal network integrity.

Secondary lymphoid organ stromal cells comprise different subsets whose origins remain unknown. Herein, we exploit a genetic lineage-tracing approach to show that splenic fibroblastic reticular cells (FRCs), follicular dendritic cells (FDCs), marginal reticular cells (MRCs), and mural cells, but not endothelial cells, originate from embryonic mesenchymal progenitors of the Nkx2-5(+)Islet1(+) lineage. This lineage include embryonic mesenchymal cells with lymphoid tissue organizer (LTo) activity capable also of supporting ectopic lymphoid-like structures and a subset of resident spleen stromal cells that proliferate and regenerate the splenic stromal microenvironment following resolution of a viral infection.