PARP14 Contributes to the Development of the Tumor-Associated Macrophage Phenotype.

Cancers reprogram macrophages (MΦs) to a tumor-growth-promoting TAM (tumor-associated MΦ) phenotype that is similar to the anti-inflammatory M2 phenotype. Poly(ADP-ribose) polymerase (PARP) enzymes regulate various aspects of MΦ biology, but their role in the development of TAM phenotype has not yet been investigated. Here, we show that the multispectral PARP inhibitor (PARPi) PJ34 and the PARP14 specific inhibitor MCD113 suppress the expression of M2 marker genes in IL-4-polarized primary murine MΦs, in THP-1 monocytic human MΦs, and in primary human monocyte-derived MΦs. MΦs isolated from PARP14 knockout mice showed a limited ability to differentiate to M2 cells. In a murine model of TAM polarization (4T1 breast carcinoma cell supernatant transfer to primary MΦs) and in a human TAM model (spheroids formed from JIMT-1 breast carcinoma cells and THP-1-MΦs), both PARPis and the PARP14 KO phenotype caused weaker TAM polarization. Increased JIMT-1 cell apoptosis in co-culture spheroids treated with PARPis suggested reduced functional TAM reprogramming. Protein profiling arrays identified lipocalin-2, macrophage migration inhibitory factor, and plasminogen activator inhibitor-1 as potential (ADP-ribosyl)ation-dependent mediators of TAM differentiation. Our data suggest that PARP14 inhibition might be a viable anticancer strategy with a potential to boost anticancer immune responses by reprogramming TAMs.

From Dysbiosis to Neurodegenerative Diseases through Different Communication Pathways: An Overview.

The microbiome research field has rapidly evolved over the last few decades, becoming a major topic of scientific and public interest. The gut microbiota (GM) is the microbial population living in the gut. The GM has many functions, such as maintaining gut homeostasis and host health, providing defense against enteric pathogens, and involvement in immune system development. Several studies have shown that GM is implicated in dysbiosis and is presumed to contribute to neurodegeneration. This review focuses mainly on describing the connection between the intestinal microbiome alterations (dysbiosis) and the onset of neurodegenerative diseases to explore the mechanisms that link the GM to nervous system health, such as the gut-brain axis, as well as the mitochondrial, the adaptive humoral immunity, and the microvesicular pathways. The gut-brain communication depends on a continuous bidirectional flow of molecular signals exchanged through the neural and the systemic circulation. These pathways represent a possible new therapeutic target against neuroinflammation and neurodegeneration. Progress in this context is desperately needed, considering the severity of most neurodegenerative diseases and the current lack of effective treatments.

A dynamic air-liquid interface system for in vitro mimicking of the nasal mucosa.

The development of an in vitro 3D model for the growth of the nasal mucosa cells can improve the therapy and the study of pathological states for subjects with chronic airway conditions. We have previously characterized a system consisting of a scaffold with an internal channel and a perfusion bioreactor with two independent flows provided by an external and an internal circuit, respectively. In this paper, this system was designed as a model of the nasal cavity, in which cells, grown on the inner surface of the scaffold channel, would be in contact at the same time with both culture medium, supplied by the external circuit, and air, provided with the internal flow. To ensure adequate nutrient supply to the cells in the scaffold channel, the radial diffusion of the culture medium through the porous matrix was evaluated first in qualitative and, then, in quantitative terms, demonstrating the capability of the system to control the value and direction of this flux. As a preliminary study, the culture of epithelial cells in the scaffold channel is also discussed in static, maintaining the air-liquid interface condition for up to 3 weeks. Despite minor abnormalities, such as a gap between cell layers and some detachments from the scaffold, the scaffold ensured cell survival and growth during the experimental time.

Correlation of Metabolic Syndrome with Redox Homeostasis Biomarkers: Evidence from High-Fat Diet Model in Wistar Rats.

Metabolic Syndrome (MetS) is an extremely complex disease. A non-balanced diet such as high-fat diet (HFD) induces metabolic dysfunction that could modify redox homeostasis. We here aimed at exploring redox homeostasis in male Wistar rats, following 8 weeks of HFD, correlating the eventual modification of selected biomarkers that could be associated with the clinical manifestations of MetS. Therefore, we selected parameters relative to both the glucose tolerance and lipid altered metabolism, but also oxidative pattern. We assessed some biomarkers of oxidative stress i.e., thiols balance, lipid peroxidation and antioxidant barriers, via the use of specific biochemical assays, individuating eventual cross correlation with parameters relative to MetS through a Principal Component Analysis (PCA). The present study shows that 8 weeks of HFD induce MetS in rats, altering glucose and lipid homeostasis and increasing visceral adipose tissue, but also impairing the physiological antioxidant responses that could not counteract the oxidative stress condition. Crucially, cross-correlation analysis suggested that the assessment of specific oxidative stress parameters reported here can provide information comparable to the more widely acquired biomarkers of Mets such as glucose tolerance. Lastly, hepatic steatosis in association with the oxidative stress condition was also highlighted by histological analysis. This research will elucidate the fundamental impact of these oxidative stress parameters on MetS induced in the HFD rat model, tracing paths for developing prevention approaches.