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Despite considerable progress in our understanding of systemic lupus erythematosus (SLE) pathophysiology, patient diagnosis is often deficient and late, and this has an impact on disease progression. The aim of this study was to analyze non-coding RNA (ncRNA) packaged into exosomes by next-generation sequencing to assess the molecular profile associated with renal damage, one of the most serious complications of SLE, to identify new potential targets to improve disease diagnosis and management using Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. The plasma exosomes had a specific ncRNA profile associated with lupus nephritis (LN). The three ncRNA types with the highest number of differentially expressed transcripts were microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and piwi-interacting RNAs (piRNAs). We identified an exosomal 29-ncRNA molecular signature, of which 15 were associated only with LN presence; piRNAs were the most representative, followed by lncRNAs and miRNAs. The transcriptional regulatory network showed a significant role for four lncRNAs (LINC01015, LINC01986, AC087257.1 and AC022596.1) and two miRNAs (miR-16-5p and miR-101-3p) in network organization, targeting critical pathways implicated in inflammation, fibrosis, epithelial–mesenchymal transition and actin cytoskeleton. From these, a handful of potential targets, such as transforming growth factor-β (TGF-β) superfamily binding proteins (activin-A, TGFB receptors, etc.), WNT/β-catenin and fibroblast growth factors (FGFs) have been identified for use as therapeutic targets of renal damage in SLE. [ABSTRACT FROM AUTHOR]

Background: Severe coronavirus disease 2019 (COVID-19) is characterized, in part, by an excessive inflammatory response. Evidence from animal and human studies suggests that vagus nerve stimulation can lead to reduced levels of various biomarkers of inflammation. We conducted a prospective randomized controlled study (SAVIOR-I) to assess the feasibility, efficacy, and safety of non-invasive vagus nerve stimulation (nVNS) for the treatment of respiratory symptoms and inflammatory markers among patients who were hospitalized for COVID-19 (ClinicalTrials.gov identifier: NCT04368156). Methods: Participants were randomly assigned in a 1:1 allocation to receive either the standard of care (SoC) alone or nVNS therapy plus the SoC. The nVNS group received 2 consecutive 2-min doses of nVNS 3 times daily as prophylaxis. Efficacy and safety were evaluated via the incidence of specific clinical events, inflammatory biomarker levels, and the occurrence of adverse events. Results: Of the 110 participants who were enrolled and randomly assigned, 97 (nVNS, n = 47; SoC, n = 50) had sufficient available data and comprised the evaluable population. C-reactive protein (CRP) levels decreased from baseline to a significantly greater degree in the nVNS group than in the SoC group at day 5 and overall (i.e., all postbaseline data points collected through day 5, combined). Procalcitonin level also showed significantly greater decreases from baseline to day 5 in the nVNS group than in the SoC group. D-dimer levels were decreased from baseline for the nVNS group and increased from baseline for the SoC group at day 5 and overall, although the difference between the treatment groups did not reach statistical significance. No significant treatment differences were seen for clinical respiratory outcomes or any of the other biochemical markers evaluated. No serious nVNS-related adverse events occurred during the study. Conclusions: nVNS therapy led to significant reductions in levels of inflammatory markers, specifically CRP and procalcitonin. Because nVNS has multiple mechanisms of action that may be relevant to COVID-19, additional research into its potential use earlier in the course of COVID-19 and its potential to mitigate some of the symptoms associated with post-acute sequelae of COVID-19 is warranted. [ABSTRACT FROM AUTHOR]

Autoimmune diseases (ADs) are characterized by the activation of the immune system against self-antigens. More common in women than in men and with an early onset, their incidence is increasing worldwide, and this, combined with their chronic nature, is contributing to an enlarged medical and economic burden. Conventional immunosuppressive agents are designed to alleviate symptoms but do not constitute an effective therapy, highlighting a need to develop new alternatives. In this regard, mesenchymal stem cells (MSCs) have demonstrated powerful immunosuppressive and regenerative effects. MSC-derived extracellular vesicles (MSC-EVs) have shown some advantages, such as less immunogenicity, and are proposed as novel therapies for ADs. In this review, we summarize current perspectives on therapeutic options for ADs based on MSCs and MSC-EVs, focusing particularly on their mechanism of action exerted through their non-coding RNA (ncRNA) cargo. A complete state-of-the-art review was performed, centralized on some of the most severe ADs (rheumatoid arthritis, autoimmune type 1 diabetes mellitus, and systemic lupus erythematosus), giving evidence that a promising field is evolving to overcome the current knowledge and provide new therapeutic possibilities centered on MSC-EVs and their role as ncRNA delivery vehicles for AD gene therapy. [ABSTRACT FROM AUTHOR]

Circular RNAs (circRNAs) are a class of non-coding RNAs that regulate gene expression by acting as competitive endogenous RNAs (ceRNAs) and modulating gene transcription. Several studies support the implication of circRNAs in a variety of human diseases, but research on the role of circRNAs in systemic lupus erythematosus (SLE) is lacking. In a study recently published in Clinical Science (2018), Zhang et al. identified hsa circ 0012919 as a potential biomarker of disease activity in SLE patients. The authors observed different circRNA expression between SLE patients and healthy controls, an association with clinical variables and with the abnormal DNA methylation present in SLE CD4+ T cells. Finally, Zhang et al. demonstrated that hsa circ 0012919 acts as a miRNA sponge for miR-125a-3p, regulating the gene expression of targets RANTES and KLF13 that are involved in the physiology and pathophysiology of acute and chronic inflammatory processes. These findings support the role of circRNAs in the pathophysiology of SLE. [ABSTRACT FROM AUTHOR]

Identifying new markers of disease flares in lupus nephritis (LN) that facilitate patient stratification and prognosis is important. Therefore, the aim of the present study was to analyze whether urinary SIRT1 expression was altered in LN and whether SIRT1 values in urine could be valuable biomarker of disease activity. In a cohort study, urinary pellets from 40 patients diagnosed with systemic lupus erythematosus (SLE) were analyzed. Clinical measures of lupus activity were assessed. The expression of SIRT1 was quantified by quantitative PCR (qRT-PCR) and immunoblot, then compared between patients with active lupus nephritis, in remission and healthy controls. Association with lupus activity and renal histological features was also analyzed. A significant increase in SIRT1 mRNA levels in patients with active LN was observed compared with those in remission (P=0.02) or healthy controls (P=0.009). In addition, SIRT-1 protein levels were also augmented in LN group than remission (P=0.029) and controls (P=0.001). A strong association was found between SIRT1 expression with anti-dsDNA in SLE and in patients with LN. In addition, histological features in LN biopsies were related with SIRT1, increasing its expression in proliferative forms. Finally, SIRT1 expression values showed a strong discriminatory power of renal injury in SLE. Our study demonstrated an altered urinary expression of SIRT1 and a strong association with disease activity in LN patients, being a valuable marker of renal injury. These results showed the role of the SIRT1 pathway in the SLE pathogenesis. [ABSTRACT FROM AUTHOR]

There is increased interest in using microRNAs (miRNAs) as biomarkers in different diseases. Present in body fluids, it is controversial whether or not they are mainly enclosed in exosomes, thus we studied if urinary miRNAs are concentrated inside exosomes and if the presence of systemic lupus erythematosus with or without lupus nephritis modifies their distribution pattern. We quantified specific miRNAs in urine of patients with systemic lupus erythematosus (n = 38) and healthy controls (n = 12) by quantitative reverse-transcription PCR in cell-free urine, exosome-depleted supernatant and exosome pellet obtained by ultracentrifugation. In control group, miR-335* and miR-302d were consistently higher in exosomes than in exosome-depleted supernatant, and miR-200c and miR-146a were higher in cell-free fraction. In lupus patients, all urinary miRNAs tested were mainly in exosomes with lower levels outside them (p<0.05 and p<0.01, respectively). This pattern is especially relevant in patients with active lupus nephritis compared to the control group or to the SLE patients in absence of lupus nephritis, with miR-146a being the most augmented (100-fold change, p<0.001). Among the exosomal miRNAs tested, only the miR-146a discriminates the presence of active lupus nephritis. In conclusion, urinary miRNAs are contained primarily in exosomes in systemic lupus erythematosus, and the main increment was found in the presence of active lupus nephritis. These findings underscore the attractiveness of exosomal miRNAs in urine, a non-invasive method, as potential renal disease markers. [ABSTRACT FROM AUTHOR]

Exosomes, nanometer-sized lipid-bilayer-enclosed extracellular vesicles (EVs), have attracted increasing attention due to their inherent ability to shuttle proteins, lipids and genes between cells and their natural affinity to target cells. Their intrinsic features such as stability, biocompatibility, low immunogenicity and ability to overcome biological barriers, have prompted interest in using exosomes as drug delivery vehicles, especially for gene therapy. Evidence indicates that exosomes play roles in both immune stimulation and tolerance, regulating immune signaling and inflammation. To date, exosome-based nanocarriers delivering small molecule drugs have been developed to treat many prevalent autoimmune diseases. This review highlights the key features of exosomes as drug delivery vehicles, such as therapeutic cargo, use of targeting peptide, loading method and administration route with a broad focus. In addition, we outline the current state of evidence in the field of exosome-based drug delivery systems in systemic lupus erythematosus (SLE), evaluating exosomes derived from various cell types and engineered exosomes. [ABSTRACT FROM AUTHOR]

This study aimed to assess the time course of circulating neutrophil and lymphocyte counts and their ratio (NLR) in ST-segment elevation myocardial infarction (STEMI) and coronavirus disease (COVID)-19 and explore their associations with clinical events and structural damage. Circulating neutrophil, lymphocyte and NLR were sequentially measured in 659 patients admitted for STEMI and in 103 COVID-19 patients. The dynamics detected in STEMI (within a few hours) were replicated in COVID-19 (within a few days). In both entities patients with events and with severe structural damage displayed higher neutrophil and lower lymphocyte counts. In both scenarios, higher maximum neutrophil and lower minimum lymphocyte counts were associated with more events and more severe organ damage. NLR was higher in STEMI and COVID-19 patients with the worst clinical and structural outcomes. A canonical deregulation of the immune response occurs in STEMI and COVID-19 patients. Boosted circulating innate (neutrophilia) and depressed circulating adaptive immunity (lymphopenia) is associated with more events and severe organ damage. A greater understanding of these critical illnesses is pivotal to explore novel alternative therapies. [ABSTRACT FROM AUTHOR]

Background and Hypothesis: Assess incidence of Acute Kidney Diseas and Disorders (AKD) and Acute Kidney Injury (AKI) episodes and impact on progression of renal dysfunction and risk of all-cause mortality in the community., Methods: Community of 1 863 731 aged > 23 years with at least two serum creatinine measurements. eGFR was calculated using CKD-EPI formula. CKD, AKD and AKI were defined according to the harmonized KDIGO criteria (Lameire 2021). The sCr values and RIFLE scale was used to classify episodes. Progression of renal dysfunction and mortality were evaluated., Results: 56 850 episodes of AKD in 47 972 patients in 4.8 years were identified. AKD incidence of AKD was 3.51 and 12.56/1000 patients/year in non-CKD and CKD, respectively. One AKD episode was observed in 87.3% patients, two in 9.3% and three or more in 3.4%. A second episode was less common in patients without CKD (10.3%) compared to those with CKD (18.4%). Among patients without CKD a total of 43.8% progressed to CKD, and those with previous CKD 63.1% had eGFR decline of > 50%. The risk of progression to CKD was higher in women, older, overweight-obesity and heart failure, as was the risk of eGFR decline > 50% in CKD patients, although the number of AKD episodes was also a risk factor. AKI episodes were observed in 5646 patients with or without CKD. Of these, 12.7% progressed to CKD and of those with pre-existing CKD, 43.2% had an eGFR decline of > 20%. In the toal population mortality within 3 months of detection of AKD episode occurred in 7% patients, and was even higher in patients with AKI, 30.1%., Conclusion: Acute elevations in serum creatinine in the community may pose a health risk and contribute to the development of CKD. Identification of therapeutic targets and provision of appropriate follow-up for those who survive an episode is warranted., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Exosomes, nanometer-sized lipid-bilayer-enclosed extracellular vesicles (EVs), have attracted increasing attention due to their inherent ability to shuttle proteins, lipids and genes between cells and their natural affinity to target cells. Their intrinsic features such as stability, biocompatibility, low immunogenicity and ability to overcome biological barriers, have prompted interest in using exosomes as drug delivery vehicles, especially for gene therapy. Evidence indicates that exosomes play roles in both immune stimulation and tolerance, regulating immune signaling and inflammation. To date, exosome-based nanocarriers delivering small molecule drugs have been developed to treat many prevalent autoimmune diseases. This review highlights the key features of exosomes as drug delivery vehicles, such as therapeutic cargo, use of targeting peptide, loading method and administration route with a broad focus. In addition, we outline the current state of evidence in the field of exosome-based drug delivery systems in systemic lupus erythematosus (SLE), evaluating exosomes derived from various cell types and engineered exosomes.