The oxysterome and its receptors as pharmacological targets in inflammatory diseases

Alarmins are endogenous mediators released by cells following insults or cell death to alert the host’s innate immune system of a situation of danger or harm. Many of these, such as high-mobility group box-1 and 2 (HMGB1, HMGB2) and S100 (calgranulin proteins), act through RAGE (receptor for advanced glycation end products), whereas the IL-1 and IL-33 cytokines bind the IL-1 receptors type I and II, and the cellular receptor ST2, respectively. The alarmin family and their signal pathways share many similarities of cellular and tissue localization, functions, and involvement in various physiological processes and inflammatory diseases including osteoporosis. The aim of the review was to evaluate the role of alarmins in osteoporosis. A bibliographic search of the published scientific literature regarding the role of alarmins in osteoporosis was organized independently by two researchers in the following scientific databases: Pubmed, Scopus, and Web of Science. The keywords used were combined as follows: “alarmins and osteoporosis”, “RAGE and osteoporosis”, “HMGB1 and osteoporosis”, “IL-1 and osteoporosis”, “IL 33 and osteopororsis”, “S100s protein and osteoporosis”. The information was summarized and organized in the present review. We highlight the emerging roles of alarmins in various bone remodeling processes involved in the onset and development of osteoporosis, as well as their potential role as biomarkers of osteoporosis severity and progression. Findings of the research suggest a potential use of alarmins as pharmacological targets in future therapeutic strategies aimed at preventing bone loss and fragility fractures induced by aging and inflammatory diseases.

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Molecular Structure and Function of Janus Kinases: Implications for the Development of Inhibitors

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjz206 ◽

2019 ◽

Vol 14 (Supplement_2) ◽

pp. S713-S724 ◽

Cited By ~ 2

Author(s):

Alba Garrido-Trigo ◽

Azucena Salas

Keyword(s):

Tyrosine Kinases ◽

Inflammatory Diseases ◽

Gene Promoters ◽

Signal Transducers ◽

Stat Proteins ◽

Cytoplasmic Proteins ◽

Pharmacological Targets ◽

And Function ◽

Molecular Structure And Function

Abstract Cytokines can trigger multiple signalling pathways, including Janus tyrosine kinases [JAK] and signal transducers and activators of transcription [STATS] pathways. JAKs are cytoplasmic proteins that, following the binding of cytokines to their receptors, transduce the signal by phosphorylating STAT proteins which enter the nuclei and rapidly target gene promoters to regulate gene transcription. Due to the critical involvement of JAK proteins in mediating innate and adaptive immune responses, these family of kinases have become desirable pharmacological targets in inflammatory diseases, including ulcerative colitis and Crohn’s disease. In this review we provide an overview of the main cytokines that signal through the JAK/STAT pathway and the available in vivo evidence on mutant or deleted JAK proteins, and discuss the implications of pharmacologically targeting this kinase family in the context of inflammatory diseases.

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Lysyl-tRNA synthetase produces diadenosine tetraphosphate to curb STING-dependent inflammation

Science Advances ◽

10.1126/sciadv.aax3333 ◽

2020 ◽

Vol 6 (21) ◽

pp. eaax3333 ◽

Cited By ~ 3

Author(s):

J. Guerra ◽

A.-L. Valadao ◽

D. Vlachakis ◽

K. Polak ◽

I. K. Vila ◽

...

Keyword(s):

Cyclic Gmp ◽

Inflammatory Responses ◽

Inflammatory Diseases ◽

Trna Synthetase ◽

Diadenosine Tetraphosphate ◽

Pharmacological Targets ◽

Rna:Dna Hybrids ◽

Subsequent Activation

Inflammation is an essential part of immunity against pathogens and tumors but can promote disease if not tightly regulated. Self and non-self-nucleic acids can trigger inflammation, through recognition by the cyclic GMP-AMP (cGAMP) synthetase (cGAS) and subsequent activation of the stimulator of interferon genes (STING) protein. Here, we show that RNA:DNA hybrids can be detected by cGAS and that the Lysyl-tRNA synthetase (LysRS) inhibits STING activation through two complementary mechanisms. First, LysRS interacts with RNA:DNA hybrids, delaying recognition by cGAS and impeding cGAMP production. Second, RNA:DNA hybrids stimulate LysRS-dependent production of diadenosine tetraphosphate (Ap4A) that in turn attenuates STING-dependent signaling. We propose a model whereby these mechanisms cooperate to buffer STING activation. Consequently, modulation of the LysRS-Ap4A axis in vitro or in vivo interferes with inflammatory responses. Thus, altogether, we establish LysRS and Ap4A as pharmacological targets to control STING signaling and treat inflammatory diseases.

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Unveiling the potential of purinergic signaling in schistosomiasis treatment

Current Topics in Medicinal Chemistry ◽

10.2174/1568026620666200924115113 ◽

2020 ◽

Vol 20 ◽

Author(s):

Nathália Ferreira Oliveira ◽

Claudia Lucia Martins Silva

Keyword(s):

Inflammatory Diseases ◽

Purinergic Signaling ◽

P2y Receptors ◽

Current Data ◽

Global Public Health ◽

P2x7 Receptors ◽

Pharmacological Targets ◽

Target Organs ◽

Paracrine Actions ◽

Molecular Patterns

: Schistosomiasis is a neglected tropical disease. It is related to long-lasting granulomatous fibrosis and inflammation of target organs, and current sub-optimal pharmacological treatment awakens global public health concerns. Intravascular worms and eggs release antigens and extracellular vesicles that target host endothelial cells, modulate the immune system, and stimulate the release of damage-associated molecular patterns (DAMPs). ATP, one of the most studied DAMP, triggers a cascade of autocrine and paracrine actions through purinergic P2X and P2Y receptors, which are shaped by ectonucleotidases (CD39). Both P2 receptor families, and in particular P2Y1, P2Y2, P2Y12, and P2X7 receptors, have been attracting increasing interest in several inflammatory diseases and drug development. Current data obtained in the murine model unveil a CD39-ADP-P2Y1/P2Y12 receptors signaling pathway linked to liver and mesenteric exacerbations of schistosomal inflammation. Therefore, we propose that members of this purinergic signaling could be putative pharmacological targets to reduce schistosomal morbidity.

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