Aging-related diseases such as cancer can be traced to the accumulation of molecular disorder including increased DNA mutations and epigenetic drift. We provide a comprehensive review of recent results in mice and humans on modifications of DNA methylation and histone variants during aging and in cancer. Accumulated errors in DNA methylation maintenance lead to global decreases in DNA methylation with

The assessment of DNA damage can be a significant diagnostic for precision medicine. DNA double strand break (DSBs) pathways in cancer are the primary targets in a majority of anticancer therapies, yet the molecular vulnerabilities that underlie each tumor can vary widely making the application of precision medicine challenging. Identifying and understanding these interindividual vulnerabilities enables

Genomic instability and metabolic reprogramming are among the key hallmarks discriminating cancer cells from normal cells. The two phenomena contribute to the robust and evasive nature of cancer, particularly when cancer cells are exposed to chemotherapeutic agents. Genomic instability is defined as the increased frequency of mutations within the genome, while metabolic reprogramming is the alteration

Glucotoxicity-induced β-cell dysfunction in type 2 diabetes is associated with alterations of mitochondria and the endoplasmic reticulum (ER). Mitochondria and ER form a network in cells that controls cell function and fate. Mitochondria of the pancreatic β cell play a central role in the secretion of insulin in response to glucose through their ability to produce ATP. Both organelles interact at contact

Hematopoiesis is based on the existence of hematopoietic stem cells (HSC) with the capacity to self-proliferate and self-renew or to differentiate into specialized cells. The hematopoietic niche is the essential microenvironment where stem cells reside and integrate various stimuli to determine their fate. Recent studies have identified niche containing high level of calcium (Ca2 +) suggesting that

Skeletal muscle mitochondria are placed in close proximity of the sarcoplasmic reticulum (SR), the main intracellular Ca2 + store. During muscle activity, excitation of sarcolemma and of T-tubule triggers the release of Ca2 + from the SR initiating myofiber contraction. The rise in cytosolic Ca2 + determines the opening of the mitochondrial calcium uniporter (MCU), the highly selective channel of the

Calreticulin (CALR) is a chaperone present in the endoplasmic reticulum, which is involved in the quality control of N-glycosylated proteins and storage of calcium ions. In 2013, the C-terminal mutation in CALR was identified in half of the patients with essential thrombocythemia and primary myelofibrosis who did not have a JAK2 or MPL mutation. The results of 8 years of intensive research are changing

Transcription is an essential cellular process but also a major threat to genome integrity. Transcription-associated DNA breaks are particularly detrimental as their defective repair can induce gene mutations and oncogenic chromosomal translocations, which are hallmarks of cancer. The past few years have revealed that transcriptional breaks mainly originate from DNA topological problems generated by

Oxidative and alkylating DNA damage occurs under normal physiological conditions and exogenous exposure to DNA damaging agents. To counteract DNA base damage, cells have evolved several defense mechanisms that act at different levels to prevent or repair DNA base damage. Cells combat genomic lesions like these including base modifications, abasic sites, as well as single-strand breaks, via the base

The Janus kinase (JAK), signal transducer of activation (STAT) pathway, discovered by investigating interferon gene induction, is now recognized as an evolutionary conserved signaling pathway employed by diverse cytokines, interferons, growth factors, and related molecules. Since its discovery, this pathway has become a paradigm for membrane-to-nucleus signaling and explains how a broad range of soluble

Three structurally related tyrosine receptor cell surface kinases, Tyro3, Axl, and Mertk (TAM) have been recognized to modulate immune function, tissue homeostasis, cardiovasculature, and cancer. The TAM receptor family appears to operate in adult mammals across multiple cell types, suggesting both widespread and specific regulation of cell functions and immune niches. TAM family members regulate tissue

Cellular homeostasis is essential for healthy functioning of cells and tissues as well as proper organ development and maintenance. A disruption in cellular homeostasis triggers stress responses including the unfolded protein response (UPR), an endoplasmic reticulum (ER) stress coping response. There is increasing evidence that Ca2 + signaling plays a pivotal role in stress responses, as Ca2 + is involved

Invadopodia are actin-rich membrane protrusions that facilitate cancer cell dissemination by focusing on proteolytic activity and clearing paths for migration through physical barriers, such as basement membranes, dense extracellular matrices, and endothelial cell junctions. Invadopodium formation and activity require spatially and temporally regulated changes in actin filament organization and dynamics

Actins form a strongly conserved family of proteins that are central to the functioning of the actin cytoskeleton partaking in natural processes such as cell division, adhesion, contraction and migration. These processes, however, also occur during the various phases of cancer progression. Yet, surprisingly, alterations in the six human actin genes in cancer studies have received little attention and

An increase in intracellular Ca2 + concentration ([Ca2 +]i) regulates a plethora of functions in the cardiovascular (CV) system, including contraction in cardiomyocytes and vascular smooth muscle cells (VSMCs), and angiogenesis in vascular endothelial cells and endothelial colony forming cells. The sarco/endoplasmic reticulum (SR/ER) represents the largest endogenous Ca2 + store, which releases Ca2 +

Compared with normal cells, cancer cells often have an increase in reactive oxygen species (ROS) level. This high level of ROS allows the activation of different pathways essential for cellular transformation and tumorigenesis development. Increase of ROS can be due to increase of production or decrease of detoxification, both situations being well described in various cancers. Oxidative stress is

Lysosomal calcium is emerging as a modulator of autophagy and lysosomal compartment, an obligatory partner to complete the autophagic pathway. A variety of specific signals such as nutrient deprivation or oxidative stress can trigger lysosomal calcium-mediated nuclear translocation of the transcription factor EB (TFEB), a master regulator of global lysosomal function. Also, lysosomal calcium can promote

Cancer is a leading cause of death worldwide. All major tumor suppressors and oncogenes are now recognized to have fundamental connections with metabolic pathways. A hallmark feature of cancer cells is a reprogramming of their metabolism even when nutrients are available. Increasing evidence indicates that most cancer cells rely on mitochondrial metabolism to sustain their energetic and biosynthetic

Glial cells exploit calcium (Ca2+) signals to perceive the information about the activity of the nervous tissue and the tissue environment to translate this information into an array of homeostatic, signaling and defensive reactions. Astrocytes, the best studied glial cells, use several Ca2+ signaling generation pathways that include Ca2+ entry through plasma membrane, release from endoplasmic reticulum

Over the past decades, a variety of MPN mouse models have been developed to express in HSC the main mutations identified in patients: JAK2V617F, CALRdel52 or ins5 and MPLW515L. These models mimic quite faithfully human PV or ET with their natural evolutions into MF and their hemostasis complications, demonstrating the driver function of these mutations in MPN. Here, we review these models and show

It has been demonstrated for more than 40 years that intracellular calcium (Ca2 +) controls a variety of cellular functions, including mitochondrial metabolism and cell proliferation. Cytosolic Ca2 + fluctuation during key stages of the cell cycle can lead to mitochondrial Ca2 + uptake and subsequent activation of mitochondrial oxidative phosphorylation and a range of signaling. However, the relationship

Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by pancreatic islet inflammation (insulitis) and specific pancreatic β-cell destruction by an immune attack. Although the precise underlying mechanisms leading to the autoimmune assault remain poorly understood, it is well accepted that insulitis takes place in the context of a conflicting dialogue between pancreatic β-cells and the

Diabetes is one of the most prevalent metabolic diseases and its incidence is increasing throughout the world. Data from World Health Organization (WHO) point-out that diabetes is a major cause of blindness, kidney failure, heart attacks, stroke and lower limb amputation and estimated 1.6 million deaths were directly caused by it in 2016. Population studies show that the incidence of this disease increases

Monogenetic forms of diabetes represent 1%–5% of all diabetes cases and are caused by mutations in a single gene. These mutations, that affect genes involved in pancreatic β-cell development, function and survival, or insulin regulation, may be dominant or recessive, inherited or de novo. Most patients with monogenic diabetes are very commonly misdiagnosed as having type 1 or type 2 diabetes. The severity

MicroRNA (miRNAs) are small non-coding RNA involved in gene expression regulation. Emerging evidences identify miRNAs as key regulators of beta cell physiology. Their role in fine-tuned gene expression regulation is crucial in the differentiation of insulin-producing cells and contributes to the acquisition and management of their unique phenotype. Dysregulation of miRNA expression causes beta cell

The human and mouse islet of Langerhans is an endocrine organ composed of five different cells types; insulin-secreting β-cells, glucagon-producing α-cells, somatostatin-producing δ-cells, pancreatic polypeptide-secreting PP cells and ɛ-cells that secretes ghrelin. The most important cells are the pancreatic β-cells that comprise around 45–50% of human islets and 75–80% in the mouse. Pancreatic β-cells

Long non-coding RNAs (lncRNAs) are transcripts of more than 200 nucleotides that have not coding potential, but act as gene expression regulators through several molecular mechanisms. Several studies have identified tons of lncRNAs that are expressed in pancreatic β cells and many of them have been shown to have β cell-specific expression, suggesting a potential role in the regulation of basal β cell

Type 2 diabetes (T2D), a heterogeneous disorder derived from metabolic dysfunctions, leads to a glucose overflow in the circulation due to both defective insulin secretion and peripheral insulin resistance. One of the critical risk factor for T2D is obesity, which represents a global epidemic that has nearly tripled since 1975. Obesity is characterized by chronically elevated free fatty acid (FFA)

Molecular laboratory investigations for myeloproliferative neoplasm (MPN) can ideally be divided into two distincts groups, those for the detection of the BCR-ABL rearrangement (suspect of chronic myeloid leukemia) and those for the variants determination of the driver genes of the negative Philadelphia forms (MPN Ph neg). The BCR-ABL detection is based on RT-Polymerase Chain Reaction techniques and

Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disease without appropriate cure. One of the main reasons for the lack of a proper pharmacotherapy in ALS is the narrow knowledge on the molecular causes of the disease. In this respect, the identification of dysfunctional pathways in ALS is now considered a critical medical need. Among the causative factors involved in ALS, Ca2 +

In recent decades cancer emerged as one of the leading causes of death in the developed countries, with some types of cancer contributing to the top 10 causes of death on the list of the World Health Organization. Carcinogenesis, a malignant transformation causing formation of tumors in normal tissues, is associated with changes in the cell cycle caused by suppression of signaling pathways leading

Refractory celiac disease (RCD) encompasses biologically heterogeneous disorders that develop in a small proportion (0.3%) of individuals with celiac disease that are associated with high morbidity. Two broad categories are currently recognized, type I (RCD I) and type II (RCD II), based on immunophenotypic and molecular features of the intraepithelial lymphocytes (IELs). RCD I is characterized by

Toll-like receptor (TLR) signaling induces substantial changes in the phosphoproteome of innate immune cells, mainly in the form of increased phosphorylation of signaling intermediaries. Loss of constitutive phosphorylation occurs simultaneously, but these transitions from a stable, phosphorylated state in resting cells to a sustained underphosphorylated state in activated cells have received far less

The human endeavor to venture beyond the orbit of Earth is challenged by both continuous space radiation and microgravity-induced immune dysfunction. If cancers were to develop in astronauts, it is unclear how these abnormal cells would grow and progress in the microgravity environment. It is unknown if the astronaut's immune response would be able to control or eradicate cancer. A better molecular

Mitochondrial calcium ion (Ca2+) uptake is important for buffering cytosolic Ca2+ levels, for regulating cell bioenergetics, and for cell death and autophagy. Ca2+ uptake is mediated by a mitochondrial Ca2+ uniporter (MCU) and the discovery of this channel in trypanosomes has been critical for the identification of the molecular nature of the channel in all eukaryotes. However, the trypanosome uniporter

Blood brain barrier (BBB) is formed by the brain microvascular endothelial cells (BMVECs) lining the wall of brain capillaries. Its integrity is regulated by multiple mechanisms, including up/downregulation of tight junction proteins or adhesion molecules, altered Ca2 + homeostasis, remodeling of cytoskeleton, that are confined at the level of BMVECs. Beside the contribution of BMVECs to BBB permeability

The cAMP-dependent protein kinase, more commonly referred to as protein kinase A (PKA), is one of the most-studied enzymes in biology. PKA is ubiquitously expressed in mammalian cells, can be activated in response to a plethora of biological stimuli, and phosphorylates more than 250 known substrates. Indeed, PKA is of central importance to a wide range of organismal processes, including energy homeostasis

The RAL proteins RALA and RALB belong to the superfamily of small RAS-like GTPases (guanosine triphosphatases). RAL GTPases function as molecular switches in cells by cycling through GDP- and GTP-bound states, a process which is regulated by several guanine exchange factors (GEFs) and two heterodimeric GTPase activating proteins (GAPs). Since their discovery in the 1980s, RALA and RALB have been established

The actin cytoskeleton is a dynamic network that regulates cellular behavior from development to disease. By rearranging the actin cytoskeleton, cells are capable of migrating and invading during developmental processes; however, many of these cellular properties are hijacked by cancer cells to escape primary tumors and disseminate to distant organs in the body. In this review article, we highlight

Evolutionarily conserved highly regulated process of apoptosis has been a major physiological process throughout the entire evolutionary history of living beings that has impacted the process of evolution itself. One of the key features of this highly researched field of science is the process of phosphatidylserine (PS) externalization by the different membrane bound enzymes. The process is a result

TAM family tyrosine kinase receptors including Tyro3, Axl, and MerTK are the key efferocytosis receptors presenting on antigen-presenting cell that mediate the clearance of apoptotic cells. They are thought to regulate inflammatory diseases by modulating inflammatory response and efferocytosis. Recent studies have revealed novel roles of TAM receptors in the biosynthesis of specialized pro-resolving

The Tyro3, Axl, and MerTK (TAM) receptors are three homologous Type I Receptor Tyrosine Kinases that have important homeostatic functions in multicellular organisms by regulating the clearance of apoptotic cells (efferocytosis). Pathologically, TAM receptors are overexpressed in a wide array of human cancers, and often associated with aggressive tumor grade and poor overall survival. In addition to

TAM receptors belong to the family of receptor tyrosine kinases, comprising of Tyro3, Axl and Mertk receptors (TAMs) and are important homeostatic regulators of inflammation in higher eukaryotes. Along with their ligands, Gas6 and ProteinS, TAMs acts as receptors to phosphatidylserine (PtdSer), an anionic phospholipid that becomes externalized on the surface of apoptotic and stressed cells. TAM receptors

Phosphatidylserine (PS) is an anionic phospholipid that is usually localized in the inner leaflets of the plasma membrane. However, the enzyme scramblase catalyzes the externalization of PS on the outer leaflet of the plasma membrane during apoptosis or cellular stress. This event prompts the recognition of PS displaying cells by phagocytes leading to “apoptotic clearance.” Multiple PS receptors (PSRs)

Containment and clearance of invading pathogens, such as viruses, by suppression of viral replication through antiviral mechanisms (e.g. CRISPR, interferon response or programmed cell death) provide examples of evolutionary developed responses by hosts to limit the establishment of infection. Degradation of the cytoplasm en masse provides an ideal cellular response against intruding pathogens. Degradation

Epithelial barriers are essential to maintain multicellular organisms well compartmentalized and protected from external environment. In the intestine, the epithelial layer orchestrates a dynamic balance between nutrient absorption and prevention of microorganisms, and antigen intrusion. Intestinal barrier function has been shown to be altered in coeliac disease but whether it contributes to the pathogenesis

Celiac Disease (CeD) is an immune-mediated complex disease that is triggered by the ingestion of gluten and develops in genetically susceptible individuals. It has been known for a long time that the Human Leucocyte Antigen (HLA) molecules DQ2 and DQ8 are necessary, although not sufficient, for the disease development, and therefore other susceptibility genes and (epi)genetic events must participate

Celiac disease (CD) is an immune-mediated disease that develops in genetically susceptible individuals upon gluten exposure. Human Leukocyte Antigen (HLA) genes in the Major Histocompatibility Complex (MHC) have been described to represent the 40% of the genetic risk to develop CD. Aiming to gain understanding of the genetic involvement in CD, high throughput studies have been performed, revealing

The Human Leukocyte Antigen (HLA) has a crucial role in the development and pathogenesis of coeliac disease (CD). The genes HLA-DQA1 and HLA-DQB1, both lying in this region and encoding the HLA-DQ heterodimer, are the main genetic predisposing factors to CD. Approximately 90% of CD patients carry the heterodimer HLA-DQ2.5, leaving only a small proportion of patients with lower risk heterodimers (HLA-DQ8

Coeliac disease (CD) is the prototype of an inflammatory chronic disease induced by food. In this context, gliadin p31–43 peptide comes into the spotlight as an important player of the inflammatory/innate immune response to gliadin in CD. The p31–43 peptide is part of the p31–55 peptide from α-gliadins that remains undigested for a long time, and can be present in the small intestine after ingestion

T cells (or T lymphocytes) exhibit a myriad of functions in immune responses, ranging from pathogen clearance to autoimmunity, cancer and even non-lymphoid tissue homeostasis. Therefore, deciphering the molecular mechanisms orchestrating their specification, function and gene expression pattern is critical not only for our comprehension of fundamental biology, but also for the discovery of novel therapeutic

Dendritic cells (DC) and macrophages (Mϕ) constitute the most abundant antigen presenting cells in the human intestinal mucosa. In resting conditions, they are essential to maintain the mechanisms of immune tolerance toward food antigens and commensals, at the time that they keep the capacity to initiate and maintain antigen-specific pro-inflammatory immune responses toward invading pathogens. Nevertheless

The intestinal epithelium limits host-luminal interactions and maintains gut homeostasis. Breakdown of the epithelial barrier and villous atrophy are hallmarks of coeliac disease. Besides the well characterized immune-mediated epithelial damage induced in coeliac mucosa, constitutional changes and early gluten direct effects disturb intestinal epithelial cells. The subsequent modifications in key epithelial

The tumor microenvironment is a complex milieu that dictates the growth, invasion, and metastasis of cancer cells. Both cancer and stromal cells in the tumor tissue encounter and adapt to a variety of extracellular factors, and subsequently contribute and drive the progression of the disease to more advanced stages. As the disease progresses, a small population of cancer cells becomes more invasive

Malignant gliomas including Glioblastoma (GBM) are characterized by extensive diffuse tumor cell infiltration throughout the brain, which represents a major challenge in clinical disease management. While surgical resection is beneficial for patient outcome, it is well recognized that tumor cells at the invasive front or beyond stay behind and constitute a major source of tumor recurrence. Invasive

Actin cytoskeleton remodeling facilitates and fine-tunes diverse cellular processes. Cells have evolved to use the same building blocks of actin monomers to form filaments through the sequential and synchronous use of actin filament regulators. This is best illustrated in immune cells which rely on a highly dynamic cytoskeleton to patrol the body and recognize and respond to cancer cells. Here, we

The immune system protects the body against cancer by recognizing and eliminating neoplastic cells. Immune effector cells physically interact with cancer cells through a specialized membrane interface known as the immunological synapse. Such intimate interaction is necessary for immune cell activation and directional killing of target cells. A vast array of studies has established that actin cytoskeleton

The paxillin family of proteins, including paxillin, Hic-5, and leupaxin, are focal adhesion adaptor/scaffolding proteins which localize to cell-matrix adhesions and are important in cell adhesion and migration of both normal and cancer cells. Historically, the role of these proteins in regulating the actin cytoskeleton through focal adhesion-mediated signaling has been well documented. However, studies