Cellular senescence enhances adaptive anticancer immunosurveillance

Cancer therapy often induces senescence in some cancer cells. Senescent cells, due to their profoundly altered biology, may conceivably interact with the adaptive immune system in novel ways that may boost cancer immunosurveillance, triggering the clearance of both senescent and non-senescent neoplastic cells. In this regard, we have recently reported that senescent cancer cells exhibit potent antigenicity and adjuvanticity and can elicit strong CD8(+) T cell-dependent anticancer effects when used as vaccination agents

Antibacterial activity of different root canal sealers against Enterococcus faecalis

The aim of the present study was to compare in vitro the antimicrobial activity of different root canal sealers against Enterococcus faecalis, prior and subsequent to setting. Agar diffusion test (ADT) was used for evaluating the antibacterial activity of non-set sealer while the direct contact test (DCT) was used for after setting. ADT: Except for TotalFill BC Sealer all the others sealers tested showed antibacterial activity. BioRoot?RCS, MTA Fillapex and Sealapex Root Canal Sealer showed the lowest antibacterial activity, a significant increase in antibacterial effect for both Pulp Canal Sealer? and AH plus sealers were found. Significantly higher were the mean diameters of the bacterial inhibition zone by both EasySeal or N2 sealers. DCT: AH plus and Sealapex Root Canal Sealer doesn?t show any bactericidal effect after 6 min of contact. After 15 and 60 min of contact a significant increment for AH plus and for Sealapex Root Canal Sealer of the bactericidal effect was found. Significantly much higher was the antibacterial effect of Sealapex Root Canal Sealer compare to that observed for AH plus. BioRootTMRCS, MTA Fillapex, Pulp Canal Sealer? and N2 showed at least means of the number of colonies formed in milliliter after 6 min of contact. Except for N2, a significant increase in bactericidal effect after 15 and 60 min for the other compared sealers (BioRootTMRCS, MTA Fillapex and Pulp Canal Sealer?). For every contact times considered, both TotalFill BC Sealer and EasySeal were bactericidal against E. faecalis and killed all bacteria

Autophagy in major human diseases

Autophagy is a core molecular pathway for the preservation of cellular and organismal homeostasis. Pharmacological and genetic interventions impairing autophagy responses promote or aggravate disease in a plethora of experimental models. Consistently, mutations in autophagy-related processes cause severe human pathologies. Here, we review and discuss preclinical data linking autophagy dysfunction to the pathogenesis of major human disorders including cancer as well as cardiovascular, neurodegenerative, metabolic, pulmonary, renal, infectious, musculoskeletal, and ocular disorders

Biological and antibacterial properties of a new silver fiber post : in vitro evaluation

The incorporation of nano silver particles (AgNPs) to improve antibacterial properties of dental materials has become increasingly common. The aim of the present study was to compare the antibacterial activity and cytotoxicity effects of different fiber posts: glass fiber post, quartz fiber post, nano fiber post and silver fiber post. The antibacterial activity against S. mutans, S. salivarius and S. sanguis was evaluated by using the agar disc diffusion test (ADT). Four wells of 3x2 mm (one for each material) were made with a punch by removing the agar and filled with the materials to be evaluated. The size of the inhibition zone was calculated. An extract was made eluting the posts in cell culture medium using the surface area-to-volume ratio of approximately 1.25cm²/ml between the surface of the samples and the volume of medium. Cell cultures were then exposed to 100 ?L of the extracts medium. After 24 h, cell viability was determined using the MTT assay. Silver fiber post was the only material showing a fair antibacterial effect against all the three streptococcal strains. The level of cytotoxicity of all the fiber posts tested was higher than 90% and therefore they were considered not cytotoxic. The new silver fiber post reported a fair antibacterial activity. On the other hand all the fiber posts tested (including the post with incorporated AgNPs) proved to be biocompatible, suggesting that their application does not represent a threat to human health

Acetyl Coenzyme A: A Central Metabolite and Second Messenger

Acetyl-coenzyme A (acetyl-CoA) is a central metabolic intermediate. The abundance of acetyl-CoA in distinct subcellular compartments reflects the general energetic state of the cell. Moreover, acetyl-CoA concentrations influence the activity or specificity of multiple enzymes, either in an allosteric manner or by altering substrate availability. Finally, by influencing the acetylation profile of several proteins, including histones, acetyl-CoA controls key cellular processes, including energy metabolism, mitosis, and autophagy, both directly and via the epigenetic regulation of gene expression. Thus, acetyl-CoA determines the balance between cellular catabolism and anabolism by simultaneously operating as a metabolic intermediate and as a second messenger

Targeting Autophagy to Counteract Obesity-Associated Oxidative Stress

Reactive oxygen species (ROS) operate as key regulators of cellular homeostasis within a physiological range of concentrations, yet they turn into cytotoxic entities when their levels exceed a threshold limit. Accordingly, ROS are an important etiological cue for obesity, which in turn represents a major risk factor for multiple diseases, including diabetes, cardiovascular disorders, non-alcoholic fatty liver disease, and cancer. Therefore, the implementation of novel therapeutic strategies to improve the obese phenotype by targeting oxidative stress is of great interest for the scientific community. To this end, it is of high importance to shed light on the mechanisms through which cells curtail ROS production or limit their toxic effects, in order to harness them in anti-obesity therapy. In this review, we specifically discuss the role of autophagy in redox biology, focusing on its implication in the pathogenesis of obesity. Because autophagy is specifically triggered in response to redox imbalance as a quintessential cytoprotective mechanism, maneuvers based on the activation of autophagy hold promises of efficacy for the prevention and treatment of obesity and obesity-related morbidities

Biological and physico-chemical properties of new root canal sealers

The purpose of the present study was to compare the biological and the physico-chemical properties of bioceramic-based root canal sealers, calcium hydroxide-based, MTA-based and epoxy resin-based root canal sealers. Two bioceramic-based sealers, one calcium hydroxide-based sealer, one MTA-based sealer and two epoxy resin-based sealers were tested. EasySeal and MTA Fillapex showed severe citotoxic activity, AH Plus and SealapexTM moderate cytotoxicity, BioRoot? RCS and TotalFill BC Sealer were both cytocompatible. Except for TotalFill BC Sealer, all root canal sealers caused inhibition zones when tested with E. faecalis. The highest inhibition zone was observed for EasySeal, followed by AH Plus. BioRoot? RCS, SealapexTM and MTA Fillapex showed the lowest inhibition zone. All the tested materials showed different degree of antibacterial activity by using direct contact test (DCT). The highest values were observed for BioRoot? RCS, TotalFill BC Sealer and EasySeal, followed by MTA Fillapex and SealapexTM. Except for BioRoot RCS and TotalFill BC Sealer, all the root canal sealers fulfilled the requirements of the ISO 6876 standard, demonstrating a weight loss less than 3%. Bioroot RCS, TotalFill BC Sealer and SealapexTM exhibited high alkaline pH with an increase both for BioRoot? RCS and TotalFill BC Sealer after 24 hours. The new bioceramic-based sealers showed acceptable physico-chemical properties, but BioRoot? RCS and TotalFill BC Sealer seems to be too soluble, not respecting ISO 6876 requirements

Autophagy Alteration in ApoA‐I Related Systemic Amyloidosis

Amyloidoses are characterized by the accumulation and aggregation of misfolded proteins into fibrils in different organs, leading to cell death and consequent organ dysfunction. The specific substitution of Leu 75 for Pro in Apolipoprotein A-I protein sequence (ApoA-I; L75P-ApoA-I) results in late onset amyloidosis, where deposition of extracellular protein aggregates damages the normal functions of the liver. In this work, we describe that the autophagic process is inhibited in the presence of the L75P-ApoA-I amyloidogenic variant in stably transfected human hepatocyte carcinoma cells. The L75P-ApoA-I amyloidogenic variant alters the redox status of the cells, resulting into excessive mitochondrial stress and consequent cell death. Moreover, L75P-ApoA-I induces an impairment of the autophagic flux. Pharmacological induction of autophagy or transfection-enforced overexpression of the pro-autophagic transcription factor EB (TFEB) restores proficient proteostasis and reduces oxidative stress in these experimental settings, suggesting that pharmacological stimulation of autophagy could be a promising target to alleviate ApoA-I amyloidosis

Natural killer cells act as an extrinsic barrier for <i>in vivo</i> reprogramming

The ectopic expression of transcription factors Oct4, Sox2, Klf4 and Myc (OSKM) enables reprogramming of differentiated cells into pluripotent embryonic stem cells. Methods based on partial and reversible in vivo reprogramming are a promising strategy for tissue regeneration and rejuvenation. However, little is known about the barriers that impair reprogramming in an in vivo context. We report that natural killer (NK) cells significantly limit reprogramming, both in vitro and in vivo. Cells and tissues at the intermediate states of reprogramming upregulate the expression of NK activating ligands, such as MULT1 and ICAM1. NK cells recognize and kill partially reprogrammed cells in a degranulation-dependent manner. Importantly, in vivo partial reprogramming is strongly reduced by adoptive transfer of NK cells, whereas it is significantly improved by depletion of NK cells. Notably, in the absence of NK cells, the pancreatic organoids derived from OSKM-expressing mice are remarkably large, suggesting the generation of cells with progenitor properties. We conclude that NK cells pose an important barrier for in vivo reprogramming, and this concept may apply to other contexts of transient cellular plasticity

Human senescent fibroblasts trigger progressive lung fibrosis in mice

Cell senescence has recently emerged as a potentially relevant pathogenic mechanism in fibrosing interstitial lung diseases (f-ILDs), particularly in idiopathic pulmonary fibrosis. We hypothesized that senescent human fibroblasts may suffice to trigger a progressive fibrogenic reaction in the lung. To address this, senescent human lung fibroblasts, or their secretome (SASP), were instilled into the lungs of immunodeficient mice. We found that: (1) human senescent fibroblasts engraft in the lungs of immunodeficient mice and trigger progressive lung fibrosis associated to increasing levels of mouse senescent cells, whereas non-senescent fibroblasts do not trigger fibrosis; (2) the SASP of human senescent fibroblasts is pro-senescence and pro-fibrotic both in vitro when added to mouse recipient cells and in vivo when delivered into the lungs of mice, whereas the conditioned medium (CM) from non-senescent fibroblasts lacks these activities; and, (3) navitoclax, nintedanib and pirfenidone ameliorate lung fibrosis induced by senescent human fibroblasts in mice, albeit only navitoclax displayed senolytic activity. We conclude that human senescent fibroblasts, through their bioactive secretome, trigger a progressive fibrogenic reaction in the lungs of immunodeficient mice that includes the induction of paracrine senescence in the cells of the host, supporting the concept that senescent cells actively contribute to disease progression in patients with f-ILDs