The Role of Omalizumab in NSAID-Exacerbated Respiratory Disease: A Narrative Review.

Nonsteroidal anti-inflammatory drug-exacerbated respiratory disease (N-ERD) is a condition characterized by the triad of chronic rhinosinusitis with nasal polyps, bronchial asthma, and hypersensitivity to nonsteroidal anti-inflammatory drugs. This article explores the current knowledge on the various pathological mechanism(s) of N-ERD-such as arachidonic acid metabolism, cysteinyl leukotrienes, prostaglandins, platelets, IgE, mast cells, eosinophils, basophils, and innate immune system-and the role of omalizumab in its management. The authors dive deep into the role of IgE in N-ERD and its potential as a therapeutic target. IgE plays a significant role in mediating allergic reactions, is intricately linked with mast cells, interacts with multiple immunopathological pathways involved in N-ERD, and tends to be elevated in patients with N-ERD. Multiple real-world studies, observational studies, and case series, as well as 2 phase III trials, have demonstrated the effectiveness of omalizumab in the management of N-ERD. For a disease with such a well-documented history, the pathophysiology of N-ERD and the most effective ways to manage it remain a mystery. With this background, the authors ask-is IgE a missing piece of the N-ERD puzzle, thus explaining the efficacy of omalizumab in the treatment of the disease?

Mechanistic aspects of carotenoid health benefits - where are we now?

Dietary intake and tissue levels of carotenoids have been associated with a reduced risk of several chronic diseases, including cardiovascular diseases, type 2 diabetes, obesity, brain-related diseases and some types of cancer. However, intervention trials with isolated carotenoid supplements have mostly failed to confirm the postulated health benefits. It has thereby been speculated that dosing, matrix and synergistic effects, as well as underlying health and the individual nutritional status plus genetic background do play a role. It appears that our knowledge on carotenoid-mediated health benefits may still be incomplete, as the underlying mechanisms of action are poorly understood in relation to human relevance. Antioxidant mechanisms - direct or via transcription factors such as NRF2 and NF-κB - and activation of nuclear hormone receptor pathways such as of RAR, RXR or also PPARs, via carotenoid metabolites, are the basic principles which we try to connect with carotenoid-transmitted health benefits as exemplified with described common diseases including obesity/diabetes and cancer. Depending on the targeted diseases, single or multiple mechanisms of actions may play a role. In this review and position paper, we try to highlight our present knowledge on carotenoid metabolism and mechanisms translatable into health benefits related to several chronic diseases.

Handling wine pomace: The importance of drying to preserve phenolic profile and antioxidant capacity for product valorization.

Four different wine grape pomaces (GP) (Vitis vinifera) varieties, Auxerrois, Pinot Blanc, Gamay and Pinot Noir, and obtained from white, rosé or red wine vinification, were considered for possible valorization in food supplement industry. Stabilization of GP by drying is paramount prior to further processing in the valorization chain, as GP might suffer spoilage over time. The objectives of this work were therefore to: evaluate the effect of microbiological spoilage and drying on the polyphenol profile and antioxidant capacity of GP; define a drying procedure by comparing kinetics of freeze-drying (FD) and vacuum oven (VO) (at 60 °C and 40 °C). Microbiological spoilage led to significant losses (P < 0.01) of antioxidant capacity (40% to 87%) and total phenolic content (70% to 90%), while drying had no significant effect. FD and VO at 60 °C drying kinetics exhibited similar drying curves, and a dry weight (DW) plateau was reached by 48 hr. In contrast VO at 40 °C required 170 hr to reach similar DW values, pointing out the importance of temperature when opting for VO technology. Antioxidant capacity of GP extracts did not differ between drying methods. Interestingly, GPs from white and rosé wines (AUX, PB, and GAM) had up to 3.5 times higher content (P < 0.001) of total polyphenols compared to PN, obtained from red wine. These results reinforce the importance of drying of GP as a pretreatment, which otherwise could result in significant product degradation. Additionally, we propose white and rosé GP as more interesting sources for valorization, with higher phenolic content, compared to red wine GP.

miR-148a controls metabolic programming and survival of mature CD19-negative plasma cells in mice.

Long-lived antibody-secreting plasma cells are essential to establish humoral memory against pathogens. While a regulatory transcription factor network has been established in plasma cell differentiation, the regulatory role of miRNAs remains enigmatic. We have recently identified miR-148a as the most abundant miRNA in primary mouse and human plasma cells. To determine whether this plasma cell signature miRNA controls the in vivo development of B cells into long-lived plasma cells, we established mice with genomic, conditional, and inducible deletions of miR-148a. The analysis of miR-148a-deficient mice revealed reduced serum Ig, decreased numbers of newly formed plasmablasts and reduced CD19-negative, CD93-positive long-lived plasma cells. Transcriptome and metabolic analysis revealed an impaired glucose uptake, a reduced oxidative phosphorylation-based energy metabolism, and an altered abundance of homing receptors CXCR3 (increase) and CXCR4 (reduction) in miR-148a-deficient plasma cells. These findings support the role of miR-148a as a positive regulator of the maintenance of long-lived plasma cells.

A new staining protocol for detection of murine antibody-secreting plasma cell subsets by flow cytometry.

We provide a robust four-color fluorescence-based flow cytometry protocol that distinguishes viable dividing plasmablasts from nondividing plasma cells and, based on CD19 surface abundance, identifies two mature plasma cell populations in the spleen and the bone marrow of mice.

miR-148a promotes plasma cell differentiation and targets the germinal center transcription factors Mitf and Bach2.

B cells undergo affinity maturation and class switch recombination of their immunoglobulin receptors during a germinal center (GC) reaction, before they differentiate into long-lived antibody-secreting plasma cells (PCs). Transcription factors such as Bach2 and Mitf are essential during this process, as they delay premature differentiation of GC B cells by repressing Blimp-1 and IRF4, two transcription factors required for terminal PC differentiation. Therefore, Bach2 and Mitf expression must be attenuated in activated B cells to allow terminal PC differentiation, but the precise mechanism remains enigmatic. Here, we provide evidence that miR-148a, a small noncoding microRNA, fosters PC differentiation and survival. Next-generation sequencing revealed that miR-148a is the most abundant microRNA in primary human and murine PCs, and its expression is upregulated in activated murine B cells and coincides with Blimp-1 synthesis. miR-148a targets Bach2, Mitf and proapoptotic factors such as PTEN and Bim. When prematurely expressed, miR-148a promotes the differentiation and survival of plasmablasts and reduces frequencies of IgG1(+) cells in primary B-cell cultures. In summary, we propose that miR-148a is a new player in the regulatory network controlling terminal PC differentiation and could, therefore, be a therapeutic target for interfering with PC differentiation and survival.

Autoimmunity triggers in the NOD mouse: a role for natural auto-antibody reactivities in type 1 diabetes.

The nonobese diabetic mouse (NOD) is widely used as a model to study human type 1 diabetes (T1D). In the NOD mouse T1D is a T cell-mediated autoimmune disease of complex etiology in which B cells play an essential role. One of the major unresolved issues in T1D is the genetic and/or environmental factors that trigger the autoimmune reaction. In the NOD mouse, as in humans, auto-antibodies to pancreatic islets are present at early ages and are highly correlated to diabetes progression, but their etiological role has long been disputed. NOD auto-antibodies have the characteristics of a natural repertoire, and B1 cells, the main natural antibody producers, exhibit functional differences in this strain that could have consequences for disease determination. Using a genetic approach, we propose to test if the NOD natural auto-antibody repertoire includes innate reactivities that participate in diabetes pathogenesis by promoting insulitis initiation.