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Alternative splicing (AS) is a complex coordinated transcriptional regulatory mechanism. It affects nearly 95% of all protein-coding genes and occurs in nearly all human organs. Aberrant alternative splicing can lead to various neurological diseases and cancers and is responsible for aging, infection, inflammation, immune and metabolic disorders, and so on. Though aberrant alternative splicing events and their regulatory mechanisms are widely recognized, the association between autoimmune disease and alternative splicing has not been extensively examined. Autoimmune diseases are characterized by the loss of tolerance of the immune system towards self-antigens and organ-specific or systemic inflammation and subsequent tissue damage. In the present review, we summarized the most recent reports on splicing events that occur in the immunopathogenesis of systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) and attempted to clarify the role that splicing events play in regulating autoimmune disease progression. We also identified the changes that occur in splicing factor expression. The foregoing information might improve our understanding of autoimmune diseases and help develop new diagnostic and therapeutic tools for them.

Background: The efficacy and safety of potassium-competitive acid blockers (P-CABs) in the eradication of Helicobacter pylori (Hp) remains controversial when compared with proton pump inhibitors (PPIs). Objectives: The current study set out to compare the differences in the eradication rate and adverse reactions between eradication regimens based on P-CAB or PPI drugs and the differences between the vonoprazan-based and the tegoprazan-based regimens to explore the efficacy and safety of different Hp eradication regimens. Data sources and methods: Databases including PubMed, EMBASE, Cochrane Library, and WOS were searched from the inception of these databases up to July 2023, and eligible randomized controlled trials (RCTs) were included. The outcome measures were the eradication rate and the incidence of adverse reactions of different regimens in treating Hp. The results were estimated as relative risk (RR) and its 95% confidence interval (CI), and R 4.2.1 software was used to perform the network meta-analysis (NMA). Results: A total of 20 studies were included in the analysis, involving 5815 patients with Hp. In terms of eradication rate, the 2-week vonoprazan-based triple regimen (V-Tri-2w) was the best, which was superior to the 2-week PPI-based quadruple regimen [P-Qua-2w, RR = 0.9, 95% CI: (0.85–0.95)] and the 1-week tegoprazan-based triple regimen [T-Tri-1w, RR = 0.79, 95% CI: (0.64–0.97)]; the 2-week tegoprazan-based quadruple regimen (T-Qua-2w) was superior to the 1-week PPI-based triple regimen [P-Tri-1w, RR = 0.82, 95% CI: (0.67–0.99)], and there was no difference between the remaining tegoprazan-based regimens and the PPI-based or vonoprazan-based regimens. In terms of the incidence of adverse reactions, the 2-week vonoprazan-based binary regimen (V-Bi-2w) was lower than that of the 2-week PPI-based quadruple regimen [P-Qua-2w, RR = 1.98, 95% CI: (1.57–2.52)]; there was no significant difference between 1 and 2 weeks for each regimen, such as the vonoprazan-based triple regimen [RR = 1.11, 95% CI: (0.82–1.52)]. Conclusion: In the eradication treatment of Hp, the efficacy and safety of vonoprazan-based regimens are generally better than those of PPI-based regimens. Among them, the V-Tri-2w regimen has the highest eradication rate and may be the preferred choice for Hp eradication.

[This corrects the article DOI: 10.3389/fimmu.2021.713540.].

Sporadic aortic aneurysm and dissections (AADs) are common vascular diseases that carry a high mortality rate. ADAMTS-4 (a disintegrin-like and metalloproteinase with thrombospondin motifs-4) is a secreted proteinase involved in inflammation and matrix degradation. We previously showed ADAMTS-4 levels were increased in human sporadic descending thoracic AAD (TAAD) samples. Here, we provide evidence that ADAMTS-4 contributes to aortic destruction and sporadic AAD development. In a mouse model of sporadic AAD induced by a high-fat diet and angiotensin II infusion, ADAMTS-4 deficiency ( Adamts-4−/− ) significantly reduced challenge-induced aortic diameter enlargement, aneurysm formation, dissection and aortic rupture. Aortas in Adamts-4−/− mice showed reduced elastic fibre destruction, versican degradation, macrophage infiltration, and apoptosis. Interestingly, ADAMTS-4 was directly involved in smooth muscle cell (SMC) apoptosis. Under stress, ADAMTS-4 translocated to the nucleus in SMCs, especially in apoptotic SMCs. ADAMTS-4 directly cleaved and degraded poly ADP ribose polymerase-1 (a key molecule in DNA repair and cell survival), leading to SMC apoptosis. Finally, we showed significant ADAMTS-4 expression in aortic tissues from patients with sporadic ascending TAAD, particularly in SMCs. Our findings indicate that ADAMTS-4 induces SMC apoptosis, degrades versican, promotes inflammatory cell infiltration, and thus contributes to sporadic AAD development.

Background Henoch-Schönlein purpura nephritis (HSPN) shares many similarities with IgA nephropathy. We aimed to analyze the predictive value of the International Study of Kidney Disease in Children (ISKDC) classification and the updated Oxford classification for IgA nephropathy in HSPN patients. Methods Data of 275 HSPN patients (aged≥14 years) were retrieved, and all of them underwent a renal biopsy. We re-classified the biopsies according to the ISKDC classification and the updated Oxford classification to analyze their correlations with clinical features and renal outcomes. The renal endpoints were defined as ≥30% reduction in baseline estimated glomerular filtration rate (eGFR) in 2 years, doubling of serum creatinine (Scr) or end stage renal disease. Results During follow-up period of 56(30,86) months, 30(10.9%) patients reached renal endpoints. Segmental sclerosis was the only pathological feature independently associated with renal endpoints (HR 4.086, 95%CI 1.111–15.026, P  = 0.034). Tubular atrophy/ interstitial fibrosis was associated with eGFR and Scr levels, and its correlation with renal endpoints was found by univariate analysis. Endocapillary hypercellularity was associated with 24 h urine protein and is of prognostic value in univariate analysis. Mesangial hypercellularity was not associated with clinical features or renal endpoints. Crescents were associated with 24 h urine protein, Scr and eGFR levels, but both ISKDC and updated Oxford classifications of crescents were not associated with renal endpoints by multivariate analysis. Conclusions The updated Oxford classification can help in disease management and renal outcome prediction of HSPN.

Recent studies have suggested a protective effect of finerenone on renal function and reduced the risk of cardiovascular events in patients with CKD and type 2 diabetes. However, its role in IgA nephropathy remains unknown. This study aimed to evaluate its efficacy against IgA nephropathy. A total of 18 IgAN patients with full supportive therapy, including RAS blockade as much as allowed or tolerated, blood pressure control and steroids and/or other immunosuppressive agents. Analyzed at 2, 4, 6 and 8 months after finerenone therapy. Eighteen IgA nephropathy patients were enrolled in this study, after 6.78 ± 3.47 months follow-up, a significant reduction was observed in protein-to-creatinine ratio with a 28.48% (  = 0.003), 13.12% (  = 0.17), 31.33% (  = 0.003), 39.69% (  = 0.02), respectively, at 2, 4, 6 and 8 months of treatment with finerenone compared to baseline. The eGFR was relatively stable during follow-up. The protein-to-creatinine ratio was significantly reduced after finerenone treatment in IgA nephropathy patients with full supportive therapy, and the eGFR was stable during follow-up.

Objective Refractory focal segmental glomerulosclerosis (FSGS) poses significant therapeutic challenges under conventional immunosuppressants. Although rituximab (RTX), an anti-CD20 monoclonal antibody, has demonstrated efficacy in nephrotic syndrome, its real-world effectiveness in adults with refractory FSGS remains unproven. Study design We retrospectively included 34 adults with biopsy-proven FSGS that was refractory to immunosuppressive regimens involving corticosteroids or calcineurin inhibitors, defined by persistent proteinuria > 3.5 g/day with < 50% reduction from baseline despite at least 4 months of therapy. Patients were grouped into either RTX combined with prednisone (RTX group, n  = 16) or conventional non-RTX regimens (including prednisone, calcineurin inhibitors, cyclophosphamide, or their combinations; Conv group, n  = 18). Rituximab was dosed to achieve peripheral B-cell depletion (CD19⁺ cell = 0/µL). Endpoints comprised complete remission (CR), overall response, relapse in initial responders, and relapse-free survival. Results The patients were 44.4 ± 21.8 years old, with a median follow-up duration of 18.0 (10.6, 41.1) months. The baseline characteristics were comparable between groups, except that RTX group had a longer disease duration than Conv group (median 10.7 vs. 4.0 months, p  = 0.046). The CR rate was 62.5% in RTX group and 33.3% in Conv group ( p  = 0.168), while the overall response rate was 75.0% in RTX group and 50.0% in Conv-group ( p  = 0.172). Among the responders, the median follow-up was 33.6 months in the Conv group and 36.1 months in the RTX group ( p  = 0.557). Responders in RTX group had a lower relapse rate compared to those in Conv group (25.0% vs. 77.8%, p  = 0.030), and had a prolonged relapse-free survival (log-rank χ²=3.827, p  = 0.050). There were 3 patients in RTX group relapsed, who achieved CR after repeat RTX therapy. No severe infusion reactions or opportunistic infections were observed in RTX group. Conclusions RTX combining with prednisone was comparable in inducing remission for refractory FSGS patients and was associated with a significantly lower relapse rate and a strong trend towards prolonged relapse-free survival than conventional therapy. While heterogeneity exists, RTX may be a valuable therapeutic strategy for maintaining long-term disease control in responsive patients. Clinical trail number Not applicable.

Background To compare the efficacy and safety of rituximab (RTX), calcineurin inhibitor (CNI) and cyclophosphamide (CTX) plus glucocorticoids in the treatment of primary membranous nephropathy (PMN). Methods Totally 478 biopsy-proven PMN patients in single center were retrospectively included. After 1:1 propensity score matching (PSM), 258 patients were included in RTX, CNI or CTX group (86 patients in each group). Results After PSM, there were no differences on serum creatinine, eGFR, serum albumin, urine protein, anti-PLA2R antibody levels among groups. The follow-up duration was 12 (10.5, 18) months in CNI group, 12 (12, 18) months in CTX group and 12 (12, 18) months in RTX group. Throughout entire follow-up period, 39 patients (45.3%) in CNI group, 47 patients (54.7%) in CTX group, and 59 patients (68.6%) in RTX group achieved total remission (TR, either complete remission or partial remission). The survival curve showed a higher rate of TR in RTX group than CNI group ( p  = 0.018). A relapse occurred in 15 of 39 (38.5%) patients in CNI group, significantly higher than CTX group (4.3%, p  < 0.001) and RTX group (3.4%, p  < 0.001). In CNI group, 36% patients had a ≥ 25% decline in eGFR. Conclusions RTX may be more effective than CNI in inducing remission in PMN and showed similar efficacy to CTX. CNI may have a high risk of proteinuria relapse and eGFR decline.

Background Focal segmental glomerulosclerosis (FSGS) constituted one of the most common causes of end-stage kidney disease. We aimed to compare the presentation and prognosis for FSGS patients based on whether they met the criteria of nephrotic syndrome (NS) at disease onset. Methods Retrospective analysis of 291 treatment-naïve adult FSGS patients managed per clinical guidelines. Patients were categorized into non-NS-FSGS ( n  = 158) and NS-FSGS ( n  = 133) groups based on NS criteria. Immunosuppressants were administered based on KDIGO 2021 Guideline and disease progression. Kidney outcomes were analyzed in 144 patients followed up for more than 1 year. Results A total of 291 FSGS patients were included, with 158 patients in the non-NS-FSGS group and 133 patients in NS-FSGS group. Patients in the non-NS-FSGS group exhibited higher prevalences of hypertension, along with higher body mass index, hemoglobin level, eGFR, serum albumin and immunoglobulin levels, and more severe chronic pathological changes compared to those in NS-FSGS group. Among patients followed up for more than 1 year, the annual eGFR decline rate (ADR) was 5.0 (2.4, 10.1) % in the non-NS-FSGS group and 2.1 (0.6, 6.1) % in NS-FSGS group ( P  = 0.922); ADR > 5% was more common in non-NS-FSGS patients than in NS-FSGS patients (49.3% vs. 29.0%, P  = 0.017), especially than treatment-responsive patients in the NS-FSGS group (49.3% vs. 17.2%, P  < 0.001). For the non-NS-FSGS group, multivariate Cox regression revealed that persistent urinary protein-creatinine ratio (uPCR) ≥ 0.5 during follow-up (HR 2.455, 95% CI 1.105–5.454, P  = 0.027) was an independent risk factor for ADR > 5%. Conclusions FSGS patients without NS at onset experienced a faster decline in kidney function compared to those with NS, particularly those with treatment-responsive NS.

Arginine plays an important role regulating nutrient metabolism, but the underlying mechanisms are largely unknown. This study was conducted to determine the effect of dietary arginine supplementation on the metabolome in serum of growing pigs using 1H nuclear magnetic resonance spectroscopy. Sixteen 120-day-old pigs (48 ± 1 kg) were randomly assigned to one of two groups, representing supplementation with 0 or 1.0% l-arginine to corn- and soybean meal-based diets. Serum was collected after a 46-day period of treatment. Dietary arginine supplementation decreased fat deposition and increased protein accretion in the body. Principal component analysis showed that serum concentrations of low density lipoprotein, very low density lipoprotein, and urea were lower, but concentrations of creatinine, tricarboxylic acid cycle metabolites, ornithine, lysine and tyrosine were greater in arginine-supplemented than in control pigs. Additionally, the arginine treatment affected serum concentrations of nitrogenous and lipid signaling molecules (glycerophosphorylcholine and myo-inositol) and intestinal bacterial metabolites (formate, ethanol, methylamine, dimethylamine, acetate, and propionate). These novel findings suggest that dietary arginine supplementation alters the catabolism of fat and amino acids in the whole body, enhances protein synthesis in skeletal muscle, and modulates intestinal microbial metabolism in growing pigs.