Search results for " senes"

Chemotherapy accelerates immune-senescence and functional impairments of Vδ2pos T cells in elderly patients affected by liver metastatic colorectal c…

2019

Abstract Human (gamma delta) γδ T cells are unconventional innate-like lymphocytes displaying a broad array of anti-tumor activities with promising perspectives in cancer immunotherapy. In this context, Vδ2pos T cells represent the preferential target of several immunotherapy protocols against solid tumors. However, the impact of both aging and chemotherapy (CHT) on Vδ2pos T cells is still unknown. The present study evaluates with multi-parametric flow cytometry the frequencies, terminal differentiation, senescence and effector-functions of peripheral blood and tumor infiltrating Vδ2pos T cells purified from liver metastases (CLM) of patients affected by colorectal cancer (CRC) compared to …

2020

Cellular senescence is a cell state involved in both physiological and pathological processes such as age-related diseases and cancer. While the mechanism of senescence is now well known, its role in tumorigenesis still remains very controversial. The positive and negative effects of senescence on tumorigenesis depend largely on the diversity of the senescent phenotypes and, more precisely, on the senescence-associated secretory phenotype (SASP). In this review, we discuss the modulatory effect of nitric oxide (NO) in SASP and the possible benefits of the use of NO donors or iNOS inducers in combination with senotherapy in cancer treatment.

Oxidative stress, autophagy, epigenetic changes and regulation by miRNAs as potential therapeutic targets in osteoarthritis

2015

Aging is a natural process characterized by the declining ability of the different organs and tissues to respond to stress, increasing homeostatic imbalance and risk of disease. Osteoarthritis (OA) is a multifactorial disease in which cartilage degradation is a central feature. Aging is the main risk factor for OA. In OA cartilage, a decrease in the number of chondrocytes and in their ability to regenerate the extracellular matrix and adequately respond to stress has been described. OA chondrocytes show a senescence secretory phenotype (SSP) consisting on the overproduction of cytokines (interleukins 1 and 6), growth factors (e.g., epidermal growth factor) and matrix metalloproteinases (MMP…

On the origin of BAG(3) and its consequences for an expansion of BAG3's role in protein homeostasis

2021

The B-cell CLL 2-associated athanogene (BAG) protein family in general and BAG3, in particular, are pivotal elements of cellular protein homeostasis, with BAG3 playing a major role in macroautophagy. In particular, in the contexts of senescence and degeneration, BAG3 has exhibited an essential role often related to its capabilities to organize and remove aggregated proteins. Exciting studies in different species ranging from human, murine, zebrafish, and plant samples have delivered vital insights into BAG3s' (and other BAG proteins') functions and their regulations. However, so far no studies have addressed neither BAG3's evolution nor its phylogenetic position in the BAG family.

Telomeres and telomerase in risk assessment of cardiovascular diseases

2020

Telomeres are repetitive nucleoprotein structures located at the ends of chromosomes. Reduction in the number of repetitions causes cell senescence. Cells with high proliferative potential age with each replication cycle. Post- mitotic cells (e.g. cardiovascular cells) have a different aging mechanism. During the aging of cardiovascular system cells, permanent DNA damage occurs in the telomeric regions caused by mitochondrial dysfunction, which is a phenomenon independent of cell proliferation and telomere length. Mitochondrial dysfunction is accompanied by increased production of reactive oxygen species and development of inflammation. This phe-nomenon in the cells of blood vessels can lea…

Telomere Length Determines TERRA and R-Loop Regulation through the Cell Cycle

2017

Maintenance of a minimal telomere length is essential to prevent cellular senescence. When critically short telomeres arise in the absence of telomerase, they can be repaired by homology-directed repair (HDR) to prevent premature senescence onset. It is unclear why specifically the shortest telomeres are targeted for HDR. We demonstrate that the non-coding RNA TERRA accumulates as HDR-promoting RNA-DNA hybrids (R-loops) preferentially at very short telomeres. The increased level of TERRA and R-loops, exclusively at short telomeres, is due to a local defect in RNA degradation by the Rat1 and RNase H2 nucleases, respectively. Consequently, the coordination of TERRA degradation with telomere r…

Ageing: from inflammation to cancer.

2018

Abstract Ageing is the major risk factor for cancer development. Hallmark of the ageing process is represented by inflammaging, which is a chronic and systemic low-grade inflammatory process. Inflammation is also a hallmark of cancer and is widely recognized to influence all cancer stages from cell transformation to metastasis. Therefore, inflammaging may represent the biological phenomena able to couple ageing process with cancer development. Here we review the molecular and cellular pathway involved in age-related chronic inflammation along with its potential triggers and their connection with cancer development.

BAG2 Interferes with CHIP-Mediated Ubiquitination of HSP72

2016

The maintenance of cellular proteostasis is dependent on molecular chaperones and protein degradation pathways. Chaperones facilitate protein folding, maturation, and degradation, and the particular fate of a misfolded protein is determined by the interaction of chaperones with co-chaperones. The co-factor CHIP (C-terminus of HSP70-inteacting protein, STUB1) ubiquitinates chaperone substrates and directs proteins to the cellular degradation systems. The activity of CHIP is regulated by two co-chaperones, BAG2 and HSPBP1, which are potent inhibitors of the E3 ubiquitin ligase activity. Here, we examined the functional correlation of HSP72, CHIP, and BAG2, employing human primary fibroblasts.…

Cytomics of Oxidative Stress: Probes and Problems

2017

Oxidative stress has been implicated in cellular senescence and aging, as well as in the onset and progression of many diverse genetic and acquired diseases and conditions. However, reactive oxygen (ROS) and nitrogen (RNS) species initiating oxidative stress also serve important regulatory roles, mediated by intercellular and intracellular signaling, adaptation to endogenous and exogenous stress, and destruction of invading pathogens. Fluorescence-based analysis of oxidative stress and related processes is an important cytomic application; almost 4000 papers were published between 1989 and 2016. To ascertain the specific role of ROS and RNS in oxidative stress studies by cytomic methodologi…

RNase H2 Loss in Murine Astrocytes Results in Cellular Defects Reminiscent of Nucleic Acid-Mediated Autoinflammation

2018

Aicardi-Goutières syndrome (AGS) is a rare early onset childhood encephalopathy caused by persistent neuroinflammation of autoimmune origin. AGS is a genetic disorder and >50% of affected individuals bear hypomorphic mutations in ribonuclease H2 (RNase H2). All available RNase H2 mouse models so far fail to mimic the prominent CNS involvement seen in AGS. To establish a mouse model recapitulating the human disease, we deleted RNase H2 specifically in the brain, the most severely affected organ in AGS. Although RNase H2δGFAPmice lacked the nuclease in astrocytes and a majority of neurons, no disease signs were apparent in these animals. We additionally confirmed these results…