scholarly journals Biliary Epithelial Senescence in Liver Disease: There Will Be SASP

2021 ◽  
Vol 8 ◽  
Author(s):  
Vik Meadows ◽  
Leonardo Baiocchi ◽  
Debjyoti Kundu ◽  
Keisaku Sato ◽  
Yessenia Fuentes ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cellular Senescence ◽  
Liver Diseases ◽  
Acute Stress ◽  
Premature Senescence ◽  
Liver Size ◽  
Stress Signals ◽  
End Stage ◽  
And Function ◽  
The Impact

Cellular senescence is a pathophysiological phenomenon in which proliferative cells enter cell cycle arrest following DNA damage and other stress signals. Natural, permanent DNA damage can occur after repetitive cell division; however, acute stress or other injuries can push cells into premature senescence and eventually a senescence-associated secretory phenotype (SASP). In recent years, there has been increased evidence for the role of premature senescence in disease progression including diabetes, cardiac diseases, and end-stage liver diseases including cholestasis. Liver size and function change with aging, and presumably with increasing cellular senescence, so it is important to understand the mechanisms by which cellular senescence affects the functional nature of the liver in health and disease. As well, cells in a SASP state secrete a multitude of inflammatory and pro-fibrogenic factors that modulate the microenvironment. Cellular SASP and the associated, secreted factors have been implicated in the progression of liver diseases, such as cholestatic injury that target the biliary epithelial cells (i.e., cholangiocytes) lining the bile ducts. Indeed, cholangiocyte senescence/SASP is proposed to be a driver of disease phenotypes in a variety of liver injuries. Within this review, we will discuss the impact of cholangiocyte senescence and SASP in the pathogenesis of cholestatic disorders.

scholarly journals The Role of B Cells in Adult and Paediatric Liver Injury

2021 ◽  
Vol 12 ◽  
Author(s):  
Arzoo M. Patel ◽  
Yuxin S. Liu ◽  
Scott P. Davies ◽  
Rachel M. Brown ◽  
Deirdre A. Kelly ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
T Cell Activation ◽  
Cell Biology ◽  
Liver Diseases ◽  
Cell Activation ◽  
Persistent Inflammation ◽  
Stage Disease ◽  
End Stage ◽  
The Impact

B lymphocytes are multitasking cells that direct the immune response by producing pro- or anti-inflammatory cytokines, by presenting processed antigen for T cell activation and co-stimulation, and by turning into antibody-secreting cells. These functions are important to control infection in the liver but can also exacerbate tissue damage and fibrosis as part of persistent inflammation that can lead to end stage disease requiring a transplant. In transplantation, immunosuppression increases the incidence of lymphoma and often this is of B cell origin. In this review we bring together information on liver B cell biology from different liver diseases, including alcohol-related and metabolic fatty liver disease, autoimmune hepatitis, primary biliary and primary sclerosing cholangitis, viral hepatitis and, in infants, biliary atresia. We also discuss the impact of B cell depletion therapy in the liver setting. Taken together, our analysis shows that B cells are important in the pathogenesis of liver diseases and that further research is necessary to fully characterise the human liver B cell compartment.

scholarly journals Mechanical shear stress and leukocyte phenotype and function: Implications for ventricular assist device development and use

2018 ◽  
Vol 42 (3) ◽  
pp. 133-142 ◽  
Author(s):  
Gemma Radley ◽  
Sabrina Ali ◽  
Ina Laura Pieper ◽  
Catherine A Thornton
Keyword(s):  
Heart Failure ◽  
Shear Stress ◽  
Mechanical Circulatory Support ◽  
Circulatory Support ◽  
Modern World ◽  
Mechanical Trauma ◽  
Ventricular Assist ◽  
End Stage ◽  
And Function ◽  
The Impact

Heart failure remains a disease of ever increasing prevalence in the modern world. Patients with end-stage heart failure are being referred increasingly for mechanical circulatory support. Mechanical circulatory support can assist patients who are ineligible for transplant and stabilise eligible patients prior to transplantation. It is also used during cardiopulmonary bypass surgery to maintain circulation while operating on the heart. While mechanical circulatory support can stabilise heart failure and improve quality of life, complications such as infection and thrombosis remain a common risk. Leukocytes can contribute to both of these complications. Contact with foreign surfaces and the introduction of artificial mechanical shear stress can lead to the activation of leukocytes, reduced functionality and the release of pro-inflammatory and pro-thrombogenic microparticles. Assessing the impact of mechanical trauma to leukocytes is largely overlooked in comparison to red blood cells and platelets. This review provides an overview of the available literature on the effects of mechanical circulatory support systems on leukocyte phenotype and function. One purpose of this review is to emphasise the importance of studying mechanical trauma to leukocytes to better understand the occurrence of adverse events during mechanical circulatory support.

scholarly journals Sustained Activation of TNFα-Induced DNA Damage Response in Newly Differentiated Adipocytes

2021 ◽  
Vol 22 (19) ◽  
pp. 10548
Author(s):  
Mahara Valverde ◽  
Aarón Sánchez-Brito
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Oxidative Dna Damage ◽  
Human Adipose Tissue ◽  
Repair Capacity ◽  
Disease States ◽  
Gradual Loss ◽  
Damage Response ◽  
Stress Signals ◽  
The Impact

The response to DNA damage is the mechanism that allows the interaction between stress signals, inflammatory secretions, DNA repair, and maintenance of cell and tissue homeostasis. Adipocyte dysfunction is the cellular trigger for various disease states such as insulin resistance, diabetes, and obesity, among many others. Previously, our group demonstrated that adipogenesis per se, from mesenchymal/stromal stem cells derived from human adipose tissue (hASCs), involves an accumulation of DNA damage and a gradual loss of the repair capacity of oxidative DNA damage. Therefore, our objective was to identify whether healthy adipocytes differentiated for the first time from hASCs, when receiving inflammatory signals induced with TNFα, were able to persistently activate the DNA Damage Response and thus trigger adipocyte dysfunction. We found that TNFα at similar levels circulating in obese humans induce a sustained response to DNA damage response as part of the Senescence-Associated Secretory Phenotype. This mechanism shows the impact of inflammatory environment early affect adipocyte function, independently of aging.

scholarly journals Centrosome Aberrations Associated with Cellular Senescence and p53 Localization at Supernumerary Centrosomes

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Susumu Ohshima
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Cellular Senescence ◽  
Replicative Senescence ◽  
P53 Protein ◽  
Human Fibroblasts ◽  
Immunohistochemical Analysis ◽  
Premature Senescence ◽  
Damage Response ◽  
Mitotic Cells

Centrosome overduplication or amplification has been observed in many human cancers and in premalignant tissue, but the mechanisms leading to such centrosome aberrations are not fully understood. We previously showed that abnormal mitotic cells with supernumerary centrosomes increase with replicative senescence in human fibroblasts, especially in a polyploid subpopulation. This study examines localization of p53 protein at centrosomes in mitotic cells, which is often observed in association with DNA damage response, to investigate a possible association between p53 localization and numerical centrosome aberrations induced by cellular senescence. Cultures at later passages or the 4th day after exposure to H2O2showed increased frequencies of mitotic cells with supernumerary centrosomes, especially in a polyploid subpopulation. Immunohistochemical analysis frequently showed p53-positive foci in mitotic cells, and some were localized at centrosomes. The number of p53-positive foci in mitotic cells and its localization to centrosomes increased with replicative and premature senescence. Supernumerary centrosomes showed higher frequencies of p53 localization compared to normally duplicated centrosomes. Centrosome-associated p53 protein was phosphorylated at Ser15. These data suggest a possible association between localization of p53 protein and numerical centrosome aberrations in replicatively or prematurely senescent cells.

scholarly journals The impact of cellular senescence and DNA damage on colorectal tumour progression

2013 ◽  
Vol 1 (S1) ◽  
Author(s):  
Helen K Angell ◽  
Marie Tosolini ◽  
Bernhard Mlecnik ◽  
Gabriela Bindea ◽  
Tessa Fredriksen ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cellular Senescence ◽  
Tumour Progression ◽  
Colorectal Tumour ◽  
The Impact

scholarly journals Targeted polyubiquitylation of RASSF1C by the Mule and SCFβ-TrCP ligases in response to DNA damage

2011 ◽  
Vol 441 (1) ◽  
pp. 227-236 ◽  
Author(s):  
Xin Zhou ◽  
Ting-Ting Li ◽  
Xu Feng ◽  
Esther Hsiang ◽  
Yue Xiong ◽  
...  
Keyword(s):  
Dna Damage ◽  
Uv Irradiation ◽  
Glycogen Synthase ◽  
E3 Ligase ◽  
Cycle Arrest ◽  
Microtubule Stability ◽  
C Terminus ◽  
Stress Signals ◽  
Phosphoinositide 3 Kinase ◽  
And Function

RASSF1A [Ras association (RalGDS/AF-6) domain family member 1A] and RASSF1C are two ubiquitously expressed isoforms of the RASSF1 gene. The promoter of RASSF1A is frequently hypermethylated, resulting in inactivation in various human cancers. RASSF1A is implicated in the regulation of apoptosis, microtubule stability and cell cycle arrest. However, little is known about the regulation and function of RASSF1C. In the present study we show that exogenously expressed RASSF1C is a very unstable protein that is highly polyubiquitylated and degraded via the proteasome. Furthermore, RASSF1C degradation is enhanced when cells are exposed to stress signals, such as UV irradiation. Mule, a HECT (homologous with E6-associated protein C-terminus) family E3 ligase, but not SCFβ-TrCP [where SCF is Skp1 (S-phase kinase-associated protein 1)/cullin/F-box and β-TrCP is β-bransducin repeat-containing protein] or CUL4 (cullin 4)-DDB1 (damage-specific DNA-binding protein 1), is the E3 ligase for RASSF1C under normal conditions, whereas both Mule and SCFβ-TrCP target RASSF1C degradation in response to UV irradiation. GSK3 (glycogen synthase kinase 3) phosphorylates RASSF1C to promote RASSF1C degradation subsequently, which is negatively regulated by the PI3K (phosphoinositide 3-kinase)/Akt pathway. Thus the present study reveals a novel regulation of RASSF1C and the potentially important role of RASSF1C in DNA damage responses.

scholarly journals Regulation and Modulation of Human DNA Polymerase δ Activity and Function

2017 ◽  
Author(s):  
Mariettta Y.W.T. Lee ◽  
Xiaoxiao Wang ◽  
Sufang Zhang ◽  
Zhongtao Zhang ◽  
Ernest Y.C. Lee.
Keyword(s):  
Dna Damage ◽  
Dna Replication ◽  
Dna Polymerase ◽  
Dna Polymerase Delta ◽  
Cellular Functions ◽  
Human Dna ◽  
Delta Activity ◽  
Dna Replication And Repair ◽  
And Function ◽  
The Impact

This review focuses on the regulation and modulation of human DNA polymerase δ (Pol δ). The emphasis is on mechanisms that regulate the activity and properties of Pol δ in DNA repair and replication. The areas covered are the degradation of the p12 subunit of Pol δ, which converts it from a heterotetramer (Pol δ4) to a heterotrimer (Pol δ3), in response to DNA damage and also during the cell cycle. The biochemical mechanisms that lead to degradation of p12 are reviewed, as well as the properties of Pol δ4 and Pol δ3 that provide insights into their functions in DNA replication and repair. The second focus of the review involves the functions of two Pol δ binding proteins, PDIP46 and PDIP38, both of which are multi-functional proteins. PDIP46 is a novel activator of Pol δ4, and the impact of this function is discussed in relation to its potential roles in DNA replication. Several new models for the roles of Pol δ3 and Pol δ4 in leading and lagging strand DNA synthesis that integrate a role for PDIP46 are presented. PDIP38 has multiple cellular localizations including the mitochondria, the splicesosomes and the nucleus. It has been implicated in a number of cellular functions, including the regulation of specialized DNA polymerases, mitosis, the DNA damage response, Mdm2 alternative splicing and the regulation of the Nox4 NADPH oxidase.

scholarly journals Human skin aging is associated with increased expression of the histone variant H2A.J in the epidermis

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Claudia E. Rübe ◽  
Caroline Bäumert ◽  
Nadine Schuler ◽  
Anna Isermann ◽  
Zoé Schmal ◽  
...  
Keyword(s):  
Dna Damage ◽  
Human Skin ◽  
Cellular Senescence ◽  
Skin Aging ◽  
Histone Variant ◽  
Epidermal Keratinocytes ◽  
Basal Cells ◽  
Telomere Attrition ◽  
Age Related ◽  
And Function

AbstractCellular senescence is an irreversible growth arrest that occurs as a result of damaging stimuli, including DNA damage and/or telomere shortening. Here, we investigate histone variant H2A.J as a new biomarker to detect senescent cells during human skin aging. Skin biopsies from healthy volunteers of different ages (18–90 years) were analyzed for H2A.J expression and other parameters involved in triggering and/or maintaining cellular senescence. In the epidermis, the proportions of H2A.J-expressing keratinocytes increased from ≈20% in young to ≈60% in aged skin. Inverse correlations between Ki67- and H2A.J staining in germinative layers may reflect that H2A.J-expressing cells having lost their capacity to divide. As cellular senescence is triggered by DNA-damage signals, persistent 53BP1-foci, telomere lengths, and telomere-associated damage foci were analyzed in epidermal keratinocytes. Only slight age-related telomere attrition and few persistent nuclear 53BP1-foci, occasionally colocalizing with telomeres, suggest that unprotected telomeres are not a significant cause of senescence during skin aging. Quantification of integrin-α6+ basal cells suggests that the number and function of stem/progenitor cells decreased during aging and their altered proliferation capacities resulted in diminished tissue renewal with epidermal thinning. Collectively, our findings suggest that H2A.J is a sensitive marker of epidermal aging in human skin.

scholarly journals Small-molecule cocktails induce the differentiation of human adipose-derived mesenchymal stem cells into hepatocyte-like cells

2021 ◽  
Author(s):  
Kan Yin ◽  
Yang Xu ◽  
Di Wu ◽  
Weiyan Yang ◽  
Naijun Dong ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Small Molecule ◽  
Liver Diseases ◽  
Liver Cells ◽  
Easy Access ◽  
Adipose Mesenchymal Stem Cells ◽  
End Stage ◽  
And Function

At present, liver transplantation and hepatocyte therapy are common methods for the treatment of end-stage liver diseases, but they are restricted due to the shortage of liver donors and the safety and effectiveness of hepatocyte sources. Human adipose-derived mesenchymal stem cells (HAD-MSCs) have been applied to efficiently and stably induce phenotypic and functional liver cells or tissues in vitro due to their advantages such as wide sources and easy access to materials. In this study, the HAD-MSCs liver differentiation induction system was established and optimized based on the "cocktail method" of chemical small molecule compounds. We used HAD-MSCs as seed cells and gradually obtained mature hepatoid cells with normal phenotype and function after induction with small molecule compounds and growth factor system in vitro. The hepatoid cells induced by the two groups showed high similarity in phenotype and functional characteristics of mature hepatocytes. The differentiation system of human adipose mesenchymal stem cells into hepatocytes induced by small-molecule compounds in vitro was successfully constructed. This study will lay a foundation for the optimization of liver differentiation strategies and provide a reliable source of functional liver cells for clinical studies of liver diseases.

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