Diagnostic and Therapeutic Roles of Extracellular Vesicles and Their Enwrapped ncRNAs in Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a systemic inflammatory disease whose precise pathogenesis remains mysterious. The involvement of epigenetic regulation in the pathogenesis of RA is one of the most anticipated findings, among which non-coding RNAs (ncRNAs) hold great application promise as diagnostic and therapeutic biomarkers for RA. Extracellular vesicles (EVs) are a heterogeneous group of nano-sized, membrane-enclosed vesicles that mediate intercellular communication and substance exchange, especially the transfer of ncRNAs from donor cells, thereby regulating the functional activities and biological processes of recipient cells. In light of the significant correlation between EVs, ncRNAs, and RA, we first documented expression levels of EVs and their-encapsulated ncRNAs in RA individuals, and methodically discussed their-implicated signaling pathways and phenotypic changes. The last but not least, we paied special attention to the therapeutic benefits of gene therapy reagents specifically imitating or silencing candidate ncRNAs with exosomes as carriers on RA animal models, and briefly highlighted their clinical application advantage and foreground. In conclusion, the present review may be conducive to a deeper comprehension of the diagnostic and therapeutic roles of EVs-enwrapped ncRNAs in RA, with special emphasis on exosomal ncRNAs, which may offer hints for the monitoring and treatment of RA.

Clinical features and prognosis of patients with anti-GBM disease combined with mesangial IgA deposition.

Introduction: Anti-GBM diseases with IgA deposition in the mesangial region are rarely described.The factors influencing renal prognosis in patients with anti-GBM disease combined with mesangial IgA deposition are unknown. Methods: We searched the pathological reports of the First Affiliated Hospital of Zhengzhou University from 2015 to 2023 and found that a total of 72 patients with the anti-GBM disease and 25 patients combined with mesangial IgA deposition. We studied the clinical and pathological features, renal prognosis, and the factors affecting renal prognosis in patients with anti-GBM disease combined with mesangial IgA deposition. Results: Their median age was 44 years, and their age distribution was unimodal. The proportion of oliguria or anuria in patients with anti-GBM disease combined with mesangial IgA deposition was significantly lower than that in patients with classic anti-GBM disease (13.04 vs. 42.31%, p=0.030). Their 24-hour urinary protein excretion was significantly higher [median:3.25 vs. 1.12g/24h, Interquartile range(IQR):1.032~3.945 vs. 0.63~1.79g/24h, p=0.020], serum creatinine (SCr) level at the initial diagnosis was lower(median:456.0 vs. 825.5µmol/L, IQR:270.0~702.0 vs. 515.8~1231.2µmol/L, p=0.002), peak SCr level was lower (median: 601.0 vs. 907.2µmol/L, IQR: 376.5~937.0 vs. 607.0~1361.2µmol/L, p=0.007), and their serum complement 3(C3) level was higher(median: 1.275 vs. 1.015g/L, IQR:1.097~1.462 vs. 0.850~1.220g/L, p=0.027). They had better renal outcomes during follow-up (p<0.001). After adjustment for hypertension, oliguria or anuria, and crescents%, IgA deposition in the mesangial region was still an independent protective factor (p=0.003) for ESRD in anti-GBM patients. Hypertension (p=0.026) and SCr levels at initial diagnosis (p=0.004) were risk factors for renal prognosis in patients with anti-GBM disease combined with mesangial IgA deposition. Discussion: Patients with anti-GBM disease combined with mesangial IgA deposition have less severe renal impairment and better renal prognosis than patients with classic anti-GBM disease.

[Rapid Start-up of Continuous Autotrophic Nitrogen Removal Reactor by Hybrid-inoculating PN and PN/A Granular Sludges].

The rapid cultivation of partial nitritation/ANAMMOX （PN/A） granular sludge in a continuous-flow mode is one of the key technologies for efficient biological nitrogen removal in domestic wastewater treatment. Compared with that in PN/A granular sludge, PN granular sludge demonstrates a shorter incubation period and suitability for batch culture. It is also a good carrier for enriching ANAMMOX （AMX） bacteria. In this study, we established a continuous-flow autotrophic nitrogen removal process in three continuously stirred tank reactors （CSTR） （R1-R3） by hybrid-inoculating PN/A and PN granular sludge at the mass ratios of 3∶1, 1∶1, and 1∶3, respectively. By implementing high ammonium nitrogen loading and short hydraulic retention time, continuous autotrophic nitrogen removal processes were successfully started up in the three CSTRs. The results showed that compared with that of R1 and R2, R3 had a longer start-up time but a similar steady-state nitrogen removal performance. The total nitrogen removal load of R3 could be more than 2.6 kg·ï¼ˆm3·d）-1. Intriguingly, the inoculated PN granular sludge served as a precursor for PN/A granular sludge cultivation. This approach facilitated the enrichment of anaerobic ammonia-oxidizing bacteria （AMX） by introducing abundant ammonium-oxidizing bacteria （AOB） and nitrite nitrogen substrates into the CSTR. According to the results of high-throughput sequencing, the microbial abundance and diversity of the mature granules in R1-R3 were significantly higher than those of the inoculation sludge. AOB （genus Nitrosomonas）, AMX （genera Candidatus Kuenenia and Candidatus Brocadia）, and symbiotic heterotrophs, such as Chloroflexi, Bacteroidetes, and Chlorobi, drove the autotrophic nitrogen removal process and maintained the stability of the granular structure. In summary, a novel start-up strategy of hybrid-inoculating granular sludge was provided for a continuous-flow autotrophic nitrogen removal in engineering application.

Evaluation of plasma-derived extracellular vesicles miRNAs and their connection with hippocampal mRNAs in alcohol use disorder.

Alcohol use disorder (AUD) is a common mental illness with high morbidity and disability. The discovery of laboratory biomarkers has progressed slowly, resulting in suboptimal diagnosis and treatment of AUD. This study aimed to identify promising biomarkers, as well as the potential miRNA-mRNA networks associated with AUD pathogenesis. RNA sequencing was performed on plasma-derived small extracellular vesicles (sEVs) from AUD patients and healthy controls (HCs) to harvest miRNAs expression profiles. Machine learning (ML) models were built to screen characteristic miRNAs, whose target mRNAs were analyzed using TargetScan, miRanda and miRDB databases. Gene Expression Omnibus (GEO) datasets (GSE181804 and GSE180722) providing postmortem hippocampal gene expression profiles of AUD subjects were mined. A total of 247 differentially expressed (DE) plasma-derived sEVs miRNAs and 122 DE hippocampal mRNAs were obtained. Then, 22 overlapping sEVs miRNAs with high importance scores were gained by intersecting 5 ML models. As a result, we established a putative sEVs miRNA-hippocampal mRNA network that can effectively distinguish AUD patients from HCs. In conclusion, we proposed 5 AUD-representative sEVs miRNAs (hsa-miR-144-5p, hsa-miR-182-5p, hsa-miR-142-5p, hsa-miR-7-5p, and hsa-miR-15b-5p) that may participate in the pathogenesis of AUD by modulating downstream target hippocampal genes. These findings may provide novel insights into the diagnosis and treatment of AUD.

[Liujunzi Decoction treats 4NQO-induced esophageal cancer in mice: a study based on serum metabolomics].

This study aims to explore the mechanism of Liujunzi Decoction in the treatment of 4-nitroquinoline-N-oxide(4NQO)-induced esophageal cancer in mice. One hundred mice of 35-45 days were randomized into blank, model, and low-, medium-, and high-concentration(18.2, 36.4, and 54.6 g·kg~(-1), respectively) Liujunzi Decoction groups. The mice in other groups except the blank group had free access to the water containing 100 µg·mL~(-1) 4NQO for 16 weeks for the modeling of esophageal cancer. The mice in the Liujunzi Decoction groups were fed with the diets supplemented with corresponding concentrations of Liujunzi Decoction. The body weight and organ weights were weighed for the calculation of organ indexes. The pathological changes of the esophageal tissue were observed by hematoxylin-eosin(HE) staining. Ultra performance liquid chromatography-mass spectrometry(UPLC-MS/MS) was employed to collect metabolites from mouse serum samples, screen out potential biomarkers, and predict related metabolic pathways. Compared with the blank group, the model group showed decreased spleen and stomach indexes and increased lung, esophagus, and kidney indexes. Compared with the model group, Liujunzi Decoction groups had no significant changes in the organ indexes. The HE staining results showed that Liujunzi Decoction inhibited the invasive growth and cancerization of the esophageal cancer cells. A total of 9 potential biomarkers of Liujunzi Decoction in treating esophageal cancer were screened out in this study, which were urocanic acid, 1-oleoylglycerophosphoserine, 11-deoxy prostaglandin E1, Leu-Glu-Lys-Glu,(±) 4-hydroxy-5E,7Z,10Z,13Z,16Z,19Z-docosahexaenoic acid, ureidosuccinic acid,(2R)-2,4-dihydroxy-3,3-dimethylbutanoic acid, kynurenic acid, and bicyclo prostaglandin E2, which were mainly involved in histidine, pyrimidine, alanine, aspartate, glutamate, pantothenate and tryptophan metabolism and coenzyme A biosynthesis. In summary, Liujunzi Decoction may exert the therapeutic effect on the 4NQO-induced esophageal cancer in mice by regu-lating the amino acid metabolism, inflammation, and immune function.