Moderate Exercise Inhibits Age-Related Inflammation, Liver Steatosis, Senescence, and Tumorigenesis.

Age-related chronic inflammation promotes cellular senescence, chronic disease, cancer, and reduced lifespan. In this study, we wanted to explore the effects of a moderate exercise regimen on inflammatory liver disease and tumorigenesis. We used an established model of spontaneous inflammaging, steatosis, and cancer (nfkb1-/- mouse) to demonstrate whether 3 mo of moderate aerobic exercise was sufficient to suppress liver disease and cancer development. Interventional exercise when applied at a relatively late disease stage was effective at reducing tissue inflammation (liver, lung, and stomach), oxidative damage, and cellular senescence, and it reversed hepatic steatosis and prevented tumor development. Underlying these benefits were transcriptional changes in enzymes driving the conversion of tryptophan to NAD+, this leading to increased hepatic NAD+ and elevated activity of the NAD+-dependent deacetylase sirtuin. Increased SIRT activity was correlated with enhanced deacetylation of key transcriptional regulators of inflammation and metabolism, NF-κB (p65), and PGC-1α. We propose that moderate exercise can effectively reprogram pre-established inflammatory and metabolic pathologies in aging with the benefit of prevention of disease.

High-throughput sequencing identifies aetiology-dependent differences in ductular reaction in human chronic liver disease.

Ductular reaction (DR) represents the activation of hepatic progenitor cells (HPCs) and has been associated with features of advanced chronic liver disease; yet it is not clear whether these cells contribute to disease progression and how the composition of their micro-environment differs depending on the aetiology. This study aimed to identify HPC-associated signalling pathways relevant in different chronic liver diseases using a high-throughput sequencing approach. DR/HPCs were isolated using laser microdissection from patient samples diagnosed with HCV or primary sclerosing cholangitis (PSC), as models for hepatocellular or biliary regeneration. Key signals were validated at the protein level for a cohort of 56 patients (20 early and 36 advanced stage). In total, 330 genes were significantly differentially expressed between the HPCs in HCV and PSC. Recruitment and homing of inflammatory cells were distinctly different depending on the aetiology. HPCs in PSC were characterised by a response to oxidative stress (e.g. JUN, VNN1) and neutrophil-attractant chemokines (CXCL5, CXCL6, IL-8), whereas HPCs in HCV were identified by T- and B-lymphocyte infiltration. Moreover, we found that communication between HPCs and macrophages was aetiology driven. In PSC, a high frequency of CCL28-positive macrophages was observed in the portal infiltrate, already in early disease in the absence of advanced fibrosis, while in HCV, HPCs showed a strong expression of the macrophage scavenger receptor MARCO. Interestingly, DR/HPCs in PSC showed more deposition of ECM (e.g. FN1, LAMC2, collagens) compared to HCV, where an increase of pro-invasive genes (e.g. PDGFRA, IGF2) was observed. Additionally, endothelial cells in the vicinity of DR/HPCs showed differential immunopositivity (e.g. IGF2 and INHBA expression). In conclusion, our data shine light on the role of DR/HPCs in immune signalling, fibrogenesis and angiogenesis in chronic liver disease. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Spatio-temporal Models of Lymphangiogenesis in Wound Healing.

Several studies suggest that one possible cause of impaired wound healing is failed or insufficient lymphangiogenesis, that is the formation of new lymphatic capillaries. Although many mathematical models have been developed to describe the formation of blood capillaries (angiogenesis), very few have been proposed for the regeneration of the lymphatic network. Lymphangiogenesis is a markedly different process from angiogenesis, occurring at different times and in response to different chemical stimuli. Two main hypotheses have been proposed: (1) lymphatic capillaries sprout from existing interrupted ones at the edge of the wound in analogy to the blood angiogenesis case and (2) lymphatic endothelial cells first pool in the wound region following the lymph flow and then, once sufficiently populated, start to form a network. Here, we present two PDE models describing lymphangiogenesis according to these two different hypotheses. Further, we include the effect of advection due to interstitial flow and lymph flow coming from open capillaries. The variables represent different cell densities and growth factor concentrations, and where possible the parameters are estimated from biological data. The models are then solved numerically and the results are compared with the available biological literature.

A mathematical model for lymphangiogenesis in normal and diabetic wounds.

Several studies suggest that one possible cause of impaired wound healing is failed or insufficient lymphangiogenesis, that is the formation of new lymphatic capillaries. Although many mathematical models have been developed to describe the formation of blood capillaries (angiogenesis) very few have been proposed for the regeneration of the lymphatic network. Moreover, lymphangiogenesis is markedly distinct from angiogenesis, occurring at different times and in a different manner. Here a model of five ordinary differential equations is presented to describe the formation of lymphatic capillaries following a skin wound. The variables represent different cell densities and growth factor concentrations, and where possible the parameters are estimated from experimental and clinical data. The system is then solved numerically and the results are compared with the available biological literature. Finally, a parameter sensitivity analysis of the model is taken as a starting point for suggesting new therapeutic approaches targeting the enhancement of lymphangiogenesis in diabetic wounds. The work provides a deeper understanding of the phenomenon in question, clarifying the main factors involved. In particular, the balance between TGF-ß and VEGF levels, rather than their absolute values, is identified as crucial to effective lymphangiogenesis. In addition, the results indicate lowering the macrophage-mediated activation of TGF-ß and increasing the basal lymphatic endothelial cell growth rate, inter alia, as potential treatments. It is hoped the findings of this paper may be considered in the development of future experiments investigating novel lymphangiogenic therapies.

Many Voices in a Choir: Tumor-Induced Neurogenesis and Neuronal Driven Alternative Splicing Sound Like Suspects in Tumor Growth and Dissemination.

During development, as tissues expand and grow, they require circulatory, lymphatic, and nervous system expansion for proper function and support. Similarly, as tumors arise and develop, they also require the expansion of these systems to support them. While the contribution of blood and lymphatic systems to the development and progression of cancer is well known and is targeted with anticancer drugs, the contribution of the nervous system is less well studied and understood. Recent studies have shown that the interaction between neurons and a tumor are bilateral and promote metastasis on one hand, and the formation of new nerve structures (neoneurogenesis) on the other. Substances such as neurotransmitters and neurotrophins being the main actors in such interplay, it seems reasonable to expect that alternative splicing and the different populations of protein isoforms can affect tumor-derived neurogenesis. Here, we report the different, documented ways in which neurons contribute to the development and progression of cancer and investigate what is currently known regarding cancer-neuronal interaction in several specific cancer types. Furthermore, we discuss the incidence of alternative splicing that have been identified as playing a role in tumor-induced neoneurogenesis, cancer development and progression. Several examples of changes in alternative splicing that give rise to different isoforms in nerve tissue that support cancer progression, growth and development have also been investigated. Finally, we discuss the potential of our knowledge in alternative splicing to improve tumor diagnosis and treatment.

Tumour-induced neoneurogenesis and perineural tumour growth: a mathematical approach.

It is well-known that tumours induce the formation of a lymphatic and a blood vasculature around themselves. A similar but far less studied process occurs in relation to the nervous system and is referred to as neoneurogenesis. The relationship between tumour progression and the nervous system is still poorly understood and is likely to involve a multitude of factors. It is therefore relevant to study tumour-nerve interactions through mathematical modelling: this may reveal the most significant factors of the plethora of interacting elements regulating neoneurogenesis. The present work is a first attempt to model the neurobiological aspect of cancer development through a system of differential equations. The model confirms the experimental observations that a tumour is able to promote nerve formation/elongation around itself, and that high levels of nerve growth factor and axon guidance molecules are recorded in the presence of a tumour. Our results also reflect the observation that high stress levels (represented by higher norepinephrine release by sympathetic nerves) contribute to tumour development and spread, indicating a mutually beneficial relationship between tumour cells and neurons. The model predictions suggest novel therapeutic strategies, aimed at blocking the stress effects on tumour growth and dissemination.