Novel Therapeutic Approaches in Rheumatoid Arthritis: Role of Janus Kinases Inhibitors.

Rheumatoid Arthritis (RA) is a chronic inflammatory disease characterized by synovial inflammation and hyperplasia, autoantibody production, cartilage and bone destruction and several systemic features. Cardiovascular, pulmonary, psychological, and muscle involvement are the main comorbidities of RA and are responsible for the severity of the disease and long-term prognosis. Pharmacological treatment of rheumatic diseases has evolved remarkably over the past years. In addition, the widespread adoption of treat to target and tight control strategies has led to a substantial improvement of outcomes, so that drug-free remission is nowadays a realistic goal in the treatment of RA. However, despite the availability of multiple therapeutic options, up to 40% of patients do not respond to current treatments, including biologics. Small-molecule therapies offer an alternative to biological therapies for the treatment of inflammatory diseases. In the past 5 years, a number of small-molecule compounds targeting Janus Kinases (JAKs) have been developed. Since JAKs are essential for cell signaling in immune cells, in particular controlling the response to many cytokines, their inhibitors quickly became a promising class of oral therapeutics that proved effective in the treatment of RA. Tofacitinib is the first Janus Kinase (JAK) inhibitor approved for the treatment of RA, followed more recently by baricitinib. Several other JAK inhibitors, are currently being tested in phase II and III trials for the treatment of a different autoimmune diseases. Most of these compounds exhibit an overall acceptable safety profile similar to that of biologic agents, with infections being the most frequent adverse event. Apart from tofacitinib, safety data on other JAK inhibitors are still limited. Long-term follow-up and further research are needed to evaluate the general safety profile and the global risk of malignancy of these small molecules, although no clear association with malignancy has been reported to date. Here, we will review the main characteristics of JAK inhibitors, including details on their molecular targets and on the clinical evidences obtained so far in the treatment of RA

Lipid profile changes during the development of <i>Artemia franciscana</i>, from cysts to the first two naupliar stages

The brine shrimp Artemia is an interesting experimental system for studies of developmental processes. Hatching of dormant cysts gives rise to shrimp larvae called nauplii, characterized by numerous naupliar stages representing the first forms of brine shrimp life cycle. Here combined Thin Layer Chromatography (TLC) and Matrix-Assisted Laser Desorption Ionization-Time-of-Flight/Mass Spectrometry (MALDI-TOF/MS) analyses have been performed to gain information on the lipid profiles of cysts and two naupliar stages. Lipid bands isolated after preparative TLC of the lipid extracts have been analyzed to detect various species of each lipid class; in addition Post-Source Decay (PSD) analyses allowed the identification of phospholipid chains. We compared the relative abundance of various polar and neutral lipid species in the lipid extracts, proving for the first time that during the development of nauplii there is an increase of cardiolipin (CL) and lysophospholipid levels; in parallel, the amount of phosphatidylcholine (PC) decreases. In addition, as regards neutral lipids, we found an increase of diacylglycerols (DAGs) in correspondence of the decrease of triacylglycerols (TAGs). Data reflect the fact that naupliar stages, being an active form of life, are more metabolically active and offer a platform to develop further studies on the importance of lipid metabolic pathways and bioactive lipids during the development

Morphological and Structural Aspects of the Extremely Halophilic Archaeon Haloquadratum walsbyi

Ultrathin square cell Haloquadratum walsbyi from the Archaea domain are the most abundant microorganisms in the hypersaline water of coastal salterns and continental salt lakes. In this work, we explore the cell surface of these microorganisms using amplitude-modulation atomic-force microscopy in nearly physiological conditions. We demonstrate the presence of a regular corrugation with a periodicity of 16–20 nm attributed to the surface layer (S-layer) protein lattice, striped domains asymmetrically distributed on the cell faces and peculiar bulges correlated with the presence of intracellular granules. Besides, subsequent images of cell evolution during the drying process indicate the presence of an external capsule that might correspond to the giant protein halomucin, predicted by the genome but never before observed by other microscopy studies

Editorial: The multifaceted roles of lipids in physiological and pathophysiological states

Lipids have been first described during 18th century and since then they have been described in all living tissues. The chemistry of lipids started when the French chemist Poultier de la Salle (1719–1788) for the first time isolated cholesterol crystals from bile. Although Poultier’s work was never published, his disciples had quoted it later. Recently, the advance in technology further improved the ability to characterize their highly variable structure and function. Almost 250 years later, this special volume of Frontiers in Physiology entitled “The multifaceted roles of lipids in physiological and pathophysiological states” aims to cover the last advances in lipid physiology. Because the human lipidome is made of thousands of lipid molecules, it is no wonder that their different chemical structures may exert an enormous variety of biological functions. These include energy production and membrane structural scaffold, sorting and regulation of membrane proteins, cellular signaling and vesicle trafficking. Lipidomics has been developed to study qualitatively and quantitatively these multifaceted molecules. This OMICS technology is a relatively young branch of analytical chemistry as well as an interdisciplinary field of study involving biochemistry and biophysics, applied mass spectrometry, complex statistical analyses, and miniaturization of the assays, which needs increased analytical standardization, especially in the quantification of individual lipid species. In addition, fine alterations of lipid composition can lead to a wide spectrum of human pathologies, ranging from cancer to metabolic, cardiovascular and neurodegenerative diseases. Enlightening this complexity, the various articles pinpoint some of these facts. The readers will thus find a Research Topic of articles on lipid functions ranging from oxysterols to cardiolipin, from fatty acids derivatives to protein lipidation and beyond. Indeed, Wiley et al. describe new methods to assess activity of enzymes responsible for biosynthesis and degradation of endocannabinoid and related lipids in various mouse mucosal tissues. Griffiths and Wang suggest that oxysterols could rapidly act as a paracrine version of free cholesterol, mainly for resistance to microbial pathogens. Bozelli et al. enlighten the links between plasmalogens, common glycerophospholipids, and chronic inflammatory pathologies, and how they can be used to prevent inflammation. Engel et al. stress that determination of lipid biomarkers such as lysophosphatidylcholine needs a solid expertise. This point is crucial especially whether this biomarker is used to define pathological processes such as infertility, metabolic disorders, and cancers. Elkes et al. point out that diet supplementation with linoleic acid could ameliorate the effects of tafazzin deficiency in an animal model of the cardiomyopathy Barth syndrome. The link between lipids and immune cell physiology is ascertain by Zhang et al. work. It describes the lipid droplets as a “central hub” connecting metabolism and inflammation, and not only as lipid “bags”. Lobasso et al. report a comprehensive lipid analysis of exosomes secreted from melanoma cells having different metastatic behavior by a lipidomic approach. Hamsanathan and Gurkar review the current knowledge on lipid metabolism and cellular lipids during senescence. They clearly identify specific lipids such as 15d-PGJ2 as a biomarker of senescent cell removal (senolysis). The authors also define C16:0 ceramide level as a prognosis marker of functional decline. Likewise, Dai et al. describe that lifespan could be regulated by phosphatidylethanolamine, phosphatidylserine and cardiolipin levels, even though the precise mechanism is still unknown. Lipids may also be associated to proteins to modify their activity. This point is exemplified by Thomas et al. with Ghrelin, an orexigenic hormone that presents a unique octanoyl modification within its peptide sequence. The authors discuss the role of Ghrelin acylation for the brain physiology and the possible consequences of the acylation for cognition and neuropathology. Ralph-Epps et al. summarise the important role of cardiolipin in Barth syndrome using the yeast model Saccharomyces cerevisiae. Beside an understandable alteration of the mitochondrial bioenergetics, the authors highlight that tafazzin defects also impair iron and calcium metabolism. Altogether, this Research Topic, even though not exhaustive, offers various examples of successful strategies for dissecting out the multifaceted roles of lipids in physiology and pathology. We believe that this volume could be a springboard for other Research Topics that focus on lipid measurements, lipid homeostasis and their role in pathologies