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In comparison to human immunoglobulin (Ig) G, antibodies of IgA class are not well investigated. In line with this, the functional role of the IgA component in IgM/IgA-enriched immunoglobulin preparations is also largely unknown. In recent years, powerful anti-pathogenic and immunomodulatory properties of human serum IgA especially on neutrophil function were unraveled. Therefore, the aim of our work is to investigate functional aspects of the trimodulin IgA component, a new plasma-derived polyvalent immunoglobulin preparation containing ~56% IgG, ~23% IgM and ~21% IgA. The functional role of IgA was investigated by analyzing the interaction of IgA with FcαRI, comparing trimodulin with standard intravenous IgG (IVIG) preparation and investigating Fc receptor (FcR)-dependent functions by excluding IgM-mediated effects. Trimodulin demonstrated potent immunomodulatory, as well as anti-pathogenic effects in our neutrophil model (neutrophil-like HL-60 cells). The IgA component of trimodulin was shown to induce a strong FcαRI-dependent inhibitory immunoreceptor tyrosine-based activation motif (ITAMi) signaling, counteract lipopolysaccharide-induced inflammation and mediate phagocytosis of Staphylococcus aureus. The fine-tuned balance between immunomodulatory and anti-pathogenic effects of trimodulin were shown to be dose-dependent. Summarized, our data demonstrate the functional role of IgA in trimodulin, highlighting the importance of this immunoglobulin class in immunoglobulin therapy.Spinal cord injury (SCI) is an incurable condition in which the brain is disconnected partially or completely from the periphery. Mainly, SCIs are traumatic and are due to traffic, domestic or sport accidents. To date, SCIs are incurable and, most of the time, leave the patients with a permanent loss of sensitive and motor functions. Therefore, for several decades, researchers have tried to develop treatments to cure SCI. Among them, recently, our lab has demonstrated that, in mice, repetitive trans-spinal magnetic stimulation (rTSMS) can, after SCI, modulate the lesion scar and can induce functional locomotor recovery non-invasively. These results are promising; however, before we can translate them to humans, it is important to reproduce them in a more clinically relevant model. Indeed, SCIs do not lead to the same cellular events in mice and humans. In particular, SCIs in humans induce the formation of cystic cavities. That is why we propose here to validate the effects of rTSMS in a rat animal model in which SCI leads to the formation of cystic cavities after penetrating and contusive SCI. To do so, several techniques, including immunohistochemical, behavioral and MRI, were performed. Our results demonstrate that rTSMS, in both SCI models, modulates the lesion scar by decreasing the formation of cystic cavities and by improving axonal survival. Moreover, rTSMS, in both models, enhances functional locomotor recovery. Altogether, our study describes that rTSMS exerts positive effects after SCI in rats. This study is a further step towards the use of this treatment in humans.Large bone fractures with segmental defects are a vital phase to accelerate bone integration. The present study examined the role of supercritical carbon dioxide (scCO2) decellularized bone matrix (scDBM) seeded with allogeneic adipose-derived mesenchymal stem cells (ADSC) as bio-scaffold for bone regeneration. Bio-scaffold produced by seeding ADSC to scDBM was evaluated by scanning electron microscopy (SEM). Rat segmental femoral defect model was used as a non-union model to investigate the callus formation in vivo. Histological analysis and osteotomy gap closure in the defect area were analyzed at 12 and 24 weeks post-surgery. Immunohistochemical expression of Ki-67, BMP-2 and osteocalcin was evaluated to assess the ability of new bone formation scDBM. ADSC was found to attach firmly to scDBM bioscaffold as evidenced from SEM images in a dose-dependent manner. Callus formation was observed using X-ray bone imaging in the group with scDBM seeded with 2 × 106 and 5 × 106 ASCs group at the same time-periods. H&E staining revealed ASCs accelerated bone formation. IHC staining depicted the expression of Ki-67, BMP-2, and osteocalcin was elevated in scDBM seeded with 5 × 106 ASCs group at 12 weeks after surgery, relative to other experimental groups. To conclude, scDBM is an excellent scaffold that enhanced the attachment and recruitment of mesenchymal stem cells. scDBM seeded with ASCs accelerated new bone formation.The accumulation of saturated very long-chain fatty acids (VLCFA, ≥C220) due to peroxisomal impairment leads to oxidative stress and neurodegeneration in X-linked adrenoleukodystrophy (ALD). Among the neural supporting cells, myelin-producing oligodendrocytes are the most sensitive to the detrimental effect of VLCFA. Here, we characterized the mitochondrial dysfunction and cell death induced by VLFCA, and examined whether N-acetylcysteine (NAC), an antioxidant, prevents the cytotoxicity. We exposed murine oligodendrocytes (158 N) to hexacosanoic acid (C260, 1-100 µM) for 24 h and measured reactive oxygen species (ROS) and cell death. Low concentrations of C260 (≤25 µM) induced a mild effect on cell survival with no alterations in ROS or total glutathione (GSH) concentrations. However, analysis of the mitochondrial status of cells treated with C260 (25 µM) revealed depletion in mitochondrial GSH (mtGSH) and a decrease in the inner membrane potential. These results indicate that VLCFA disturbs the mitochondrial membrane potential causing ROS accumulation, oxidative stress, and cell death. We further tested whether NAC (500 µM) can prevent the mitochondria-specific effects of VLCFA in C260-treated oligodendrocytes. Our results demonstrate that NAC improves mtGSH levels and mitochondrial function in oligodendrocytes, indicating that it has potential use in the treatment of ALD and related disorders.Diabetes is a chronic metabolic disease affecting over 400 million people worldwide and one of the leading causes of death, especially in developing nations. The disease is characterized by chronic hyperglycemia, caused by defects in the insulin secretion or action pathway. Current diagnostic methods measure metabolic byproducts of the disease such as glucose level, glycated hemoglobin (HbA1c), insulin or C-peptide levels, which are indicators of the beta-cell function. However, they inaccurately reflect the disease progression and provide poor longitudinal information. Beta-cell mass has been suggested as an alternative approach to study disease progression in correlation to beta-cell function, as it behaves differently in the diabetes physiopathology. Study of the beta-cell mass, however, requires highly invasive and potentially harmful procedures such as pancreatic biopsies, making diagnosis and monitoring of the disease tedious. Nuclear medical imaging techniques using radiation emitting tracers have been suggested as strong non-invasive tools for beta-cell mass. A highly sensitive and high-resolution technique, such as positron emission tomography, provides an ideal solution for the visualization of beta-cell mass, which is particularly essential for better characterization of a disease such as diabetes, and for estimating treatment effects towards regeneration of the beta-cell mass. Bemnifosbuvir Development of novel, validated biomarkers that are aimed at beta-cell mass imaging are thus highly necessary and would contribute to invaluable breakthroughs in the field of diabetes research and therapies. This review aims to describe the various biomarkers and radioactive probes currently available for positron emission tomography imaging of beta-cell mass, as well as highlight the need for precise quantification and visualization of the beta-cell mass for designing new therapy strategies and monitoring changes in the beta-cell mass during the progression of diabetes.Mortality and morbidity associated with COVID-19 continue to be significantly high worldwide, owing to the absence of effective treatment strategies. The emergence of different variants of SARS-CoV-2 is also a considerable source of concern and has led to challenges in the development of better prevention and treatment strategies, including vaccines. Immune dysregulation due to pro-inflammatory mediators has worsened the situation in COVID-19 patients. Inflammasomes play a critical role in modulating pro-inflammatory cytokines in the pathogenesis of COVID-19 and their activation is associated with poor clinical outcomes. Numerous preclinical and clinical trials for COVID-19 treatment using different approaches are currently underway. Targeting different inflammasomes to reduce the cytokine storm, and its associated complications, in COVID-19 patients is a new area of research. Non-coding RNAs, targeting inflammasome activation, may serve as an effective treatment strategy. However, the efficacy of these therapeutic agents is highly dependent on the delivery system. MicroRNAs and long non-coding RNAs, in conjunction with an efficient delivery vehicle, present a potential strategy for regulating NLRP3 activity through various RNA interference (RNAi) mechanisms. In this regard, the use of nanomaterials and other vehicle types for the delivery of RNAi-based therapeutic molecules for COVID-19 may serve as a novel approach for enhancing drug efficacy. The present review briefly summarizes immune dysregulation and its consequences, the roles of different non-coding RNAs in regulating the NLRP3 inflammasome, distinct types of vectors for their delivery, and potential therapeutic targets of microRNA for treatment of COVID-19.
The wide availability of monoclonal antibodies for the add-on therapy of severe asthma currently allows for the personalization of biologic treatment by selecting the most appropriate drug for each patient. However, subjects with overlapping allergic and eosinophilic phenotypes can be often eligible to more than one biologic, so that the first pharmacologic choice can be quite challenging for clinicians. Within such a context, the aim of our real-life investigation was to verify whether allergic patients with severe eosinophilic asthma, not adequately controlled by an initial biologic treatment with omalizumab, could experience better therapeutic results from a pharmacologic shift to benralizumab.

Twenty allergic patients with severe eosinophilic asthma, unsuccessfully treated with omalizumab and then switched to benralizumab, were assessed for at least 1 year in order to detect eventual changes in disease exacerbations, symptom control, oral corticosteroid intake, lung function, and blood eosinophils.

ot adequately controlled by anti-IgE treatment.To elucidate the effects of switching a PGF2α agonist, bimatoprost acid (BIM-A), to an EP2 agonist (Omidenepag-OMD; butaprost-Buta) or reversing the switching on adipose tissue, two-dimensional (2D) and three-dimensional (3D) cultures of 3T3-L1 cells were analyzed by lipid staining and according to the mRNA expression of adipogenesis-related genes (Pparγ, Ap2, and Leptin), components of the extracellular matrix (ECM; collagen1 (Col1), Col4, Col6, and fibronectin (Fn)), and the sizes and stiffness of the 3D spheroids. Switching from BIM-A to EP2 agonists caused (1) suppression of lipid staining and downregulation of most adipogenesis-related genes, (2) smaller and stiffer 3D spheroids, and (3) upregulation of Col1 and Fn, downregulation of Col4 (2D), or up-regulation of all ECM genes (3D, BIM-A to OMD), as well as downregulation of Col6 (3D, BIM-A to Buta). In contrast, reversing the switching resulted in (1) an enhancement in lipid staining (2D) and a significant upregulation of adipogenesis-related genes (2D, 3D Buta to BIM-A), (2) larger and slightly stiffer 3D spheroids, and (3) upregulation of Col1 and Fn (2D).
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