Pro-Resolving Lipid Mediators (SPMs) and Their Actions in Regulating miRNA in Novel Resolution Circuits in Inflammation

Unresolved inflammation is associated with several widely occurring diseases such as arthritis, periodontal diseases, cancer, and atherosclerosis. Endogenous mechanisms that curtail excessive inflammation and prompt its timely resolution are of considerable interest. In recent years, previously unrecognized chemical mediators derived from polyunsaturated fatty acids were identified that control the acute inflammatory response by activating local resolution programs. Among these are the so-called specialized pro-resolving lipid mediators (SPMs) that include lipoxins (LX), resolvins (Rv), protectins (PD), and maresins (MaR), because they are enzymatically biosynthesized during resolution of self-limited inflammation. They each possess distinct chemical structures and regulate cellular pathways by their ability to activate pro-resolving G-protein coupled receptors (GPCRs) in a stereospecific manner. For instance, RvD1 controls several miRNAs of interest in self-limited acute inflammation that counter-regulate the mediators and proteins that are involved in inflammation. Here, we overview some of the biosynthesis and mechanisms of SPM actions with focus on the recently reported miR involved in their pro-resolving responses that underscore their beneficial actions in the regulation of acute inflammation and its timely resolution. The elucidation of these mechanisms operating in vivo to keep acute inflammation within physiologic boundaries as well as stimulate resolution have opened resolution pharmacology and many new opportunities to target inflammation-related human pathologies via activating resolution mechanisms

Lipoxin Receptors

Lipoxins (LXs) represent a class of arachidonic acid (AA) metabolites that carry potent immunoregulatory and anti-inflammatory properties, LXA4 and LXB4 being the main components of this series. LXs are generated by cooperation between 5-lipoxygenase (LO) and 12- or 15-LO during cell-cell interactions or by single cell types. LX epimers at carbon 15, the 15-epi-LXs, are formed by aspirin-acetylated cyclooxygenase-2 (COX-2) in cooperation with 5-LO. 15-epi-LXA4 is also termed aspirin-triggered LX (ATL). In vivo studies with stable LX and ATL analogs have established that these eicosanoids possess potent anti-inflammatory activities. A LXA4 receptor has been cloned. It belongs to the family of chemotactic receptors and clusters with formyl peptide receptors on chromosome 19. Therefore, it was initially denominated formyl peptide receptor like 1 (FPRL1). This receptor binds with high affinity and stereoselectivity LXA4 and ATL. It also recognizes a variety of peptides, synthetic, endogenously generated, or disease associated, but with lower affinity compared to LXA4. For this reason, this receptor has been renamed ALX. This review summarizes the current knowledge on ALX expression, signaling, and potential pathophysiological role. The involvement of additional recognition sites in LX bioactions is also discussed

Roles, Actions, and Therapeutic Potential of Specialized Pro-resolving Lipid Mediators for the Treatment of Inflammation in Cystic Fibrosis

Non-resolving inflammation is the main mechanism of morbidity and mortality among patients suffering from cystic fibrosis (CF), the most common life-threatening human genetic disease. Resolution of inflammation is an active process timely controlled by endogenous specialized pro-resolving lipid mediators (SPMs) produced locally in inflammatory loci to restrain this innate response, prevent further damages to the host, and permit return to homeostasis. Lipoxins, resolvins, protectins, and maresins are SPM derived from polyunsaturated fatty acids that limit excessive leukocyte infiltration and pro-inflammatory signals, stimulate innate microbial killing, and enhance resolution. Their unique chemical structures, receptors, and bioactions are being elucidated. Accruing data indicate that SPMs carry protective functions against unrelenting inflammation and infections in preclinical models and human CF systems. Here, we reviewed their roles and actions in controlling resolution of inflammation, evidence for their impairment in CF, and proofs of principle for their exploitation as innovative, non-immunosuppressive drugs to address inflammation and infections in CF

Impaired pro‐resolving mechanisms promote abnormal NETosis , fueling autoimmunity in sickle cell disease

Sickle cell disease (SCD) is a worldwide distributed hereditary red cell disorders with still high mortality and morbidity and limited therapeutic options. SCD is characterized by anemia, chronic hemolysis, and acute vaso-occlusive painful crises. The biocomplexity of SCD goes beyond red cells, involving neutrophils and soluble factors such as cytokines or alternative complement pathway intensively cross-talking with vascular endothelial cells. In addition, in SCD, the overactivation of neutrophils contributes to the production of neutrophil extracellular traps (NETs) (1, 2). This might trigger endothelial vascular injury, promoting acute sickle cell related events and increasing the risk of infections in patients with SC

Mechanisms of endothelial cell dysfunction in cystic fibrosis

Although cystic fibrosis (CF) patients exhibit signs of endothelial perturbation, the functions of the cystic fibrosis conductance regulator (CFTR) in vascular endothelial cells (EC) are poorly defined. We sought to uncover biological activities of endothelial CFTR, relevant for vascular homeostasis and inflammation. We examined cells from human umbilical cords (HUVEC) and pulmonary artery isolated from non-cystic fibrosis (PAEC) and CF human lungs (CF-PAEC), under static conditions or physiological shear. CFTR activity, clearly detected in HUVEC and PAEC, was markedly reduced in CF-PAEC. CFTR blockade increased endothelial permeability to macromolecules and reduced trans‑endothelial electrical resistance (TEER). Consistent with this, CF-PAEC displayed lower TEER compared to PAEC. Under shear, CFTR blockade reduced VE-cadherin and p120 catenin membrane expression and triggered the formation of paxillin- and vinculin-enriched membrane blebs that evolved in shrinking of the cell body and disruption of cell-cell contacts. These changes were accompanied by enhanced release of microvesicles, which displayed reduced capability to stimulate proliferation in recipient EC. CFTR blockade also suppressed insulin-induced NO generation by EC, likely by inhibiting eNOS and AKT phosphorylation, whereas it enhanced IL-8 release. Remarkably, phosphodiesterase inhibitors in combination with a β2 adrenergic receptor agonist corrected functional and morphological changes triggered by CFTR dysfunction in EC. Our results uncover regulatory functions of CFTR in EC, suggesting a physiological role of CFTR in the maintenance EC homeostasis and its involvement in pathogenetic aspects of CF. Moreover, our findings open avenues for novel pharmacology to control endothelial dysfunction and its consequences in CF

Lesions of hypertrophic osteopathy in the forelimbs of a dog associated with pulmonary metastasis from a periosteal osteosarcoma

Hypertrophic osteopathy is commonly associated with primary lung neoplasms. It may also be secondary to intrathoracic lesions such as pulmonary metastasis, granulomatous pleurisy and chronic pneumonia, among others. It is characterized by progressive proliferation of sub periosteal bone tissue in limb bones. Clinically, patient usually exhibits lameness. It is a rare disease most frequently observed in dogs among domestic animals. A case of a dog with pulmonary hypertrophic osteopathy associated with pulmonary metastases coming from an appendicular periosteal osteosarcoma is reported.Facultad de Ciencias Veterinaria

The LiberAction Project: Implementation of a Pediatric Liberation Bundle to Screen Delirium, Reduce Benzodiazepine Sedation, and Provide Early Mobilization in a Human Resource-Limited Pediatric Intensive Care Unit

Background: Delirium, bed immobilization, and heavy sedation are among the major contributors of pediatric post-intensive care syndrome. Recently, the Society of Critical Care Medicine has proposed the implementation of daily interventions to minimize the incidence of these morbidities and optimize children functional outcomes and quality of life. Unfortunately, these interventions require important clinical and economical efforts which prevent their use in many pediatric intensive care units (PICU). Aim: First, to evaluate the feasibility and safety of a PICU bundle implementation prioritizing delirium screening and treatment, early mobilization (<72 h from PICU admission) and benzodiazepine-limited sedation in a human resource-limited PICU. Second, to evaluate the incidence of delirium and describe the early mobilization practices and sedative drugs used during the pre- and post-implementation periods. Third, to describe the barriers and adverse events encountered during early mobilization. Methods: This observational study was structured in a pre- (15th November 2019-30th June 2020) and post-implementation period (1st July 2020-31st December 2020). All patients admitted in PICU for more than 72 h during the pre and post-implementation period were included in the study. Patients were excluded if early mobilization was contraindicated. During the pre-implementation period, a rehabilitation program including delirium screening and treatment, early mobilization and benzodiazepine-sparing sedation guidelines was developed and all PICU staff trained. During the post-implementation period, delirium screening with the Connell Assessment of Pediatric Delirium scale was implemented at bedside. Early mobilization was performed using a structured tiered protocol and a new sedation protocol, limiting the use of benzodiazepine, was adopted. Results: Two hundred and twenty-five children were enrolled in the study, 137 in the pre-implementation period and 88 in the post-implementation period. Adherence to delirium screening, benzodiazepine-limited sedation and early mobilization was 90.9, 81.1, and 70.4%, respectively. Incidence of delirium was 23% in the post-implementation period. The median cumulative dose of benzodiazepines corrected for the total number of sedation days (mg/kg/sedation days) was significantly lower in the post-implementation period compared with the pre-implementation period: [0.83 (IQR: 0.53-1.31) vs. 0.74 (IQR: 0.55-1.16), p = 0.0001]. The median cumulative doses of fentanyl, remifentanil, and morphine corrected for the total number of sedation days were lower in the post-implementation period, but these differences were not significant. The median number of mobilizations per patient and the duration of each mobilization significantly increased in the post-implementation period [3.00 (IQR: 2.0-4.0) vs. 7.00 (IQR: 3.0-12.0); p = 0.004 and 4 min (IQR: 3.50-4.50) vs. 5.50 min (IQR: 5.25-6.5); p < 0.0001, respectively]. Barriers to early mobilization were: disease severity and bed rest orders (55%), lack of physicians' order (20%), lack of human resources (20%), and lack of adequate devices for patient mobilization (5%). No adverse events related to early mobilization were reported in both periods. Duration of mechanical ventilation and PICU length of stay was significantly lower in the post-implementation period as well as the occurrence of iatrogenic withdrawal syndrome. Conclusion: This study showed that the implementation of a PICU liberation bundle prioritizing delirium screening and treatment, benzodiazepine-limited sedation and early mobilization was feasible and safe even in a human resource-limited PICU. Further pediatric studies are needed to evaluate the clinical impact of delirium, benzodiazepine-limited sedation and early mobilization protocols on patients' long-term functional outcomes and on hospital finances

On the magnetosphere-ionosphere coupling during the May 2021 geomagnetic storm

On 12 May 2021 the interplanetary doppelganger of the 9 May 2021 coronal mass ejection impacted the Earth's magnetosphere, giving rise to a strong geomagnetic storm. This paper discusses the evolution of the various events linking the solar activity to the Earth's ionosphere with special focus on the effects observed in the circumterrestrial environment. We investigate the propagation of the interplanetary coronal mass ejection and its interaction with the magnetosphere-ionosphere system in terms of both magnetospheric current systems and particle redistribution, by jointly analyzing data from interplanetary, magnetospheric, and low Earth orbiting satellites. The principal magnetospheric current system activated during the different phases of the geomagnetic storm was correctly identified through the direct comparison between geosynchronous orbit observations and model predictions. From the particle point of view, we have found that the primary impact of the storm development is a net and rapid loss of relativistic electrons from the entire outer radiation belt. Our analysis shows no evidence for any short-term recovery to pre-storm levels during the days following the main phase. Storm effects also included a small Forbush decrease driven by the interplay between the interplanetary shock and subsequent magnetic cloud arrival

Mitapivat, a pyruvate kinase activator, improves transfusion burden and reduces iron overload in M-thalassemic mice

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