The Role of Nuclear Factor of Activated T Cells 5 in Hyperosmotic Stress-Exposed Human Lens Epithelial Cells

We investigated the role of nuclear factor of activated T cells 5 (NFAT5) under hyperosmotic conditions in human lens epithelial cells (HLECs). Hyperosmotic stress decreased the viability of human lens epithelial B-3 cells and significantly increased NFAT5 expression. Hyperosmotic stress-induced cell death occurred to a greater extent in NFAT5-knockout (KO) cells than in NFAT5 wild-type (NFAT5 WT) cells. Bcl-2 and Bcl-xl expression was down-regulated in NFAT5 WT cells and NFAT5 KO cells under hyperosmotic stress. Pre-treatment with a necroptosis inhibitor (necrostatin-1) significantly blocked hyperosmotic stress-induced death of NFAT5 KO cells, but not of NFAT5 WT cells. The phosphorylation levels of receptor-interacting protein kinase 1 (RIP1) and RIP3, which indicate the occurrence of necroptosis, were up-regulated in NFAT5 KO cells, suggesting that death of these cells is predominantly related to the necroptosis pathway. This finding is the first to report that necroptosis occurs when lens epithelial cells are exposed to hyperosmolar conditions, and that NFAT5 is involved in this process.     

An Update on the Role of Leptin in the Immuno-Metabolism of Cartilage

Since its discovery in 1994, leptin has been considered as an adipokine with pleiotropic effects. In this review, we summarize the actual information about the impact of this hormone on cartilage metabolism and pathology. Leptin signalling depends on the interaction with leptin receptor LEPR, being the long isoform of the receptor (LEPRb) the one with more efficient intracellular signalling. Chondrocytes express the long isoform of the leptin receptor and in these cells, leptin signalling, alone or in combination with other molecules, induces the expression of pro-inflammatory molecules and cartilage degenerative enzymes. Leptin has been shown to increase the proliferation and activation of immune cells, increasing the severity of immune degenerative cartilage diseases. Leptin expression in serum and synovial fluid are related to degenerative diseases such as osteoarthritis (OA), rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Inhibition of leptin signalling showed to have protective effects in these diseases showing the key role of leptin in cartilage degeneration.     

Nuclear Envelope Integrity in Health and Disease: Consequences on Genome Instability and Inflammation

The dynamic nature of the nuclear envelope (NE) is often underestimated. The NE protects, regulates, and organizes the eukaryote genome and adapts to epigenetic changes and to its environment. The NE morphology is characterized by a wide range of diversity and abnormality such as invagination and blebbing, and it is a diagnostic factor for pathologies such as cancer. Recently, the micronuclei, a small nucleus that contains a full chromosome or a fragment thereof, has gained much attention. The NE of micronuclei is prone to collapse, leading to DNA release into the cytoplasm with consequences ranging from the activation of the cGAS/STING pathway, an innate immune response, to the creation of chromosomal instability. The discovery of those mechanisms has revolutionized the understanding of some inflammation-related diseases and the origin of complex chromosomal rearrangements, as observed during the initiation of tumorigenesis. Herein, we will highlight the complexity of the NE biology and discuss the clinical symptoms observed in NE-related diseases. The interplay between innate immunity, genomic instability, and nuclear envelope leakage could be a major focus in future years to explain a wide range of diseases and could lead to new classes of therapeutics.     

TRPV1 Channel: A Noxious Signal Transducer That Affects Mitochondrial Function

The Transient Receptor Vanilloid 1 (TRPV1) or capsaicin receptor is a nonselective cation channel, which is abundantly expressed in nociceptors. This channel is an important transducer of several noxious stimuli, having a pivotal role in pain development. Several TRPV1 studies have focused on understanding its structure and function, as well as on the identification of compounds that regulate its activity. The intracellular roles of these channels have also been explored, highlighting TRPV1′s actions in the homeostasis of Ca²⁺ in organelles such as the mitochondria. These studies have evidenced how the activation of TRPV1 affects mitochondrial functions and how this organelle can regulate TRPV1-mediated nociception. The close relationship between this channel and mitochondria has been determined in neuronal and non-neuronal cells, demonstrating that TRPV1 activation strongly impacts on cell physiology. This review focuses on describing experimental evidence showing that TRPV1 influences mitochondrial function.     

The MEK5/ERK5 Pathway in Health and Disease

The MEK5/ERK5 mitogen-activated protein kinases (MAPK) cascade is a unique signaling module activated by both mitogens and stress stimuli, including cytokines, fluid shear stress, high osmolarity, and oxidative stress. Physiologically, it is mainly known as a mechanoreceptive pathway in the endothelium, where it transduces the various vasoprotective effects of laminar blood flow. However, it also maintains integrity in other tissues exposed to mechanical stress, including bone, cartilage, and muscle, where it exerts a key function as a survival and differentiation pathway. Beyond its diverse physiological roles, the MEK5/ERK5 pathway has also been implicated in various diseases, including cancer, where it has recently emerged as a major escape route, sustaining tumor cell survival and proliferation under drug stress. In addition, MEK5/ERK5 dysfunction may foster cardiovascular diseases such as atherosclerosis. Here, we highlight the importance of the MEK5/ERK5 pathway in health and disease, focusing on its role as a protective cascade in mechanical stress-exposed healthy tissues and its function as a therapy resistance pathway in cancers. We discuss the perspective of targeting this cascade for cancer treatment and weigh its chances and potential risks when considering its emerging role as a protective stress response pathway.     

NLRP3 and Infections: β-Amyloid in Inflammasome beyond Neurodegeneration

Amyloid beta (Aβ)-induced abnormal neuroinflammation is recognized as a major pathological feature of Alzheimer’s disease (AD), which results in memory impairment. Research exploring low-grade systemic inflammation and its impact on the development and progression of neurodegenerative disease has increased. A particular research focus has been whether systemic inflammation arises only as a secondary effect of disease, or it is also a cause of pathology. The inflammasomes, and more specifically the NLRP3 inflammasome, are crucial components of the innate immune system and are usually activated in response to infection or tissue damage. Although inflammasome activation plays critical roles against various pathogens in host defense, overactivation of inflammasome contributes to the pathogenesis of inflammatory diseases, including acute central nervous system (CNS) injuries and chronic neurodegenerative diseases, such as AD. This review summarizes the current literature on the role of the NLRP3 inflammasome in the pathogenesis of AD, and its involvement in infections, particularly SARS-CoV-2. NLRP3 might represent the crossroad between the hypothesized neurodegeneration and the primary COVID-19 infection.     

Heme Burden and Ensuing Mechanisms That Protect the Kidney: Insights from Bench and Bedside

With iron at its core, the tetrapyrrole heme ring is a cardinal prosthetic group made up of many proteins that participate in a wide array of cellular functions and metabolism. Once released, due to its pro-oxidant properties, free heme in sufficient amounts can result in injurious effects to the kidney and other organs. Heme oxygenase-1 (HO-1) has evolved to promptly attend to such injurious potential by facilitating degradation of heme into equimolar amounts of carbon monoxide, iron, and biliverdin. HO-1 induction is a beneficial response to tissue injury in diverse animal models of diseases, including those that affect the kidney. These protective attributes are mainly due to: (i) prompt degradation of heme leading to restraining potential hazardous effects of free heme, and (ii) generation of byproducts that along with induction of ferritin have proven beneficial in a number of pathological conditions. This review will focus on describing clinical aspects of some of the conditions with the unifying end-result of increased heme burden and will discuss the molecular mechanisms that ensue to protect the kidneys.     

Osteoblast Dysfunction in Non-Hereditary Sclerosing Bone Diseases

A review of the available literature was performed in order to summarize the existing evidence between osteoblast dysfunction and clinical features in non-hereditary sclerosing bone diseases. It has been known that proliferation and migration of osteoblasts are concerted by soluble factors such as fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), transforming growth factor (TGF), bone morphogenetic protein (BMP) but also by signal transduction cascades such as Wnt signaling pathway. Protein kinases play also a leading role in triggering the activation of osteoblasts in this group of diseases. Post-zygotic changes in mitogen-activated protein kinase (MAPK) have been shown to be associated with sporadic cases of Melorheostosis. Serum levels of FGF and PDGF have been shown to be increased in myelofibrosis, although studies focusing on Sphingosine-1-phosphate receptor was shown to be strongly expressed in Paget disease of the bone, which may partially explain the osteoblastic hyperactivity during this condition. Pathophysiological mechanisms of osteoblasts in osteoblastic metastases have been studied much more thoroughly than in rare sclerosing syndromes: striking cellular mechanisms such as osteomimicry or complex intercellular signaling alterations have been described. Further research is needed to describe pathological mechanisms by which rare sclerosing non hereditary diseases lead to osteoblast dysfunction.     

Signals and Mechanisms Regulating Monocyte and Macrophage Activation in the Pathogenesis of Juvenile Idiopathic Arthritis

Monocytes (Mos) and macrophages (Mφs) are key players in the innate immune system and are critical in coordinating the initiation, expansion, and regression of many autoimmune diseases. In addition, they display immunoregulatory effects that impact inflammation and are essential in tissue repair and regeneration. Juvenile idiopathic arthritis (JIA) is an umbrella term describing inflammatory joint diseases in children. Accumulated evidence suggests a link between Mo and Mφ activation and JIA pathogenesis. Accordingly, topics regarding the signals and mechanisms regulating Mo and Mφ activation leading to pathologies in patients with JIA are of great interest. In this review, we critically summarize recent advances in the understanding of how Mo and Mφ activation is involved in JIA pathogenesis and focus on the signaling pathways and mechanisms participating in the related cell activation processes.     

Description of a Novel Mechanism Possibly Explaining the Antiproliferative Properties of Glucocorticoids in Duchenne Muscular Dystrophy Fibroblasts Based on Glucocorticoid Receptor GR and NFAT5

Glucocorticoids are drugs of choice in Duchenne muscular dystrophy (DMD), prolonging patients’ ambulation. Their mode of action at the protein level is not completely understood. In DMD, muscle tissue is replaced by fibrotic tissue produced by fibroblasts, reducing mobility. Nuclear factor of activated T-cells 5 (NFAT5) is involved in fibroblast proliferation. By treating one DMD fibroblast cell culture and one of unaffected skeletal muscle fibroblasts with methylprednisolone (MP) or hydrocortisone (HC) for 24 h or 12 d, the antiproliferative properties of glucocorticoids could be unraveled. NFAT5 localization and expression was explored by immunocytochemistry (ICC), Western blotting (WB) and RT-qPCR. NFAT5 and glucocorticoid receptor (GR) colocalization was measured by ImageJ. GR siRNA was used, evaluating GR’s influence on NFAT5 expression during MP and HC treatment. Cell proliferation was monitored by IncuCyte ZOOM. In DMD fibroblasts, treatment with MP for 24 h induced dots (ICC) positive for NFAT5 and colocalizing with GR. After 12 d of MP or HC in DMD fibroblasts, NFAT5 expression was decreased (RT-qPCR and WB) and growth arrest was observed (Incucyte ZOOM), whereas NFAT5 expression and cell growth remained unchanged in unaffected skeletal muscle fibroblasts. This study may help understand the antiproliferative properties of glucocorticoids in DMD fibroblasts.     

An Overview of Adipose Tissue ACE2 Modulation by Diet and Obesity. Potential Implications in COVID-19 Infection and Severity

The present review is aimed at analysing the current evidence concerning the potential modulation of obesity and/or diet in adipose tissue ACE2. Additionally, the potential implications of these effects on COVID-19 are also addressed. The results published show that diet and obesity are two factors that effectively influence the expression of Ace2 gene in adipose tissue. However, the shifts in this gene do not always occur in the same direction, nor with the same intensity. Additionally, there is no consensus regarding the implications of increased adipose tissue ACE2 expression in health. Thus, while in some studies a protective role is attributed to ACE2 overexpression, other studies suggest otherwise. Similarly, there is much debate regarding the role played by ACE2 in COVID-19 in terms of degree of infection and disease outcomes. The greater risk of infection that may hypothetically derive from enhanced ACE2 expression is not clear since the functionality of the enzyme seems to be as important as the abundance. Thus, the greater abundance of ACE2 in adipose tissue of obese subjects may be counterbalanced by its lower activation. In addition, a protective role of ACE2 overexpression has also been suggested, associated with the increase in anti-inflammatory factors that it may produce.     

Aberrant NLRP3 Inflammasome Activation Ignites the Fire of Inflammation in Neuromuscular Diseases

Inflammasomes are molecular hubs that are assembled and activated by a host in response to various microbial and non-microbial stimuli and play a pivotal role in maintaining tissue homeostasis. The NLRP3 is a highly promiscuous inflammasome that is activated by a wide variety of sterile triggers, including misfolded protein aggregates, and drives chronic inflammation via caspase-1-mediated proteolytic cleavage and secretion of proinflammatory cytokines, interleukin-1β and interleukin-18. These cytokines further amplify inflammatory responses by activating various signaling cascades, leading to the recruitment of immune cells and overproduction of proinflammatory cytokines and chemokines, resulting in a vicious cycle of chronic inflammation and tissue damage. Neuromuscular diseases are a heterogeneous group of muscle disorders that involve injury or dysfunction of peripheral nerves, neuromuscular junctions and muscles. A growing body of evidence suggests that dysregulation, impairment or aberrant NLRP3 inflammasome signaling leads to the initiation and exacerbation of pathological processes associated with neuromuscular diseases. In this review, we summarize the available knowledge about the NLRP3 inflammasome in neuromuscular diseases that affect the peripheral nervous system and amyotrophic lateral sclerosis, which affects the central nervous system. In addition, we also examine whether therapeutic targeting of the NLRP3 inflammasome components is a viable approach to alleviating the detrimental phenotype of neuromuscular diseases and improving clinical outcomes.