Casual relationships between circulating metabolites and rheumatoid arthritis: A mendelian randomization study.

Background: Blood metabolites serve as pivotal indicators in identifying and predicting the course of rheumatoid arthritis (RA). However, empirical substantiation of a direct causal link between these serum biomarkers and the development of RA is still lacking comprehensive support. Method: In pursuit of a thorough exploration of the causal links between circulating blood metabolites and RA, we deployed a two-sample Mendelian randomization (MR) approach during our initial investigative phase. This method was utilized to examine the potential connections between 249 distinct circulating metabolites and the prevalence of RA. In the validation phase, we conducted replication analyses with a new metabolic dataset consisting of 123 metabolites. Furthermore, we employed the Mendelian randomization based on Bayesian model averaging (MR-BMA) technique to pinpoint key metabolic characteristics that have significant causal implications. Results: In our primary analysis, we found that acetate, acetoacetate and pyruvate exhibited a consistent protective causal association with rheumatoid arthritis, while lactate demonstrated a positive correlation with rheumatoid arthritis risk. It is also noteworthy that a substantial subset of traits related to both saturated and unsaturated fatty acids showed causal influences. Subsequent secondary analyses substantiated these observations, revealing that traits associated with the average number of methylene groups in a fatty acid chain exhibited protective effects. Ultimately, our MR-BMA analyses unveiled that the ratio of polyunsaturated fatty acids (PUFAs) to total fatty acids assumes a paramount role in increasing the susceptibility to rheumatoid arthritis. Conclusions: By employing systemic MR analyses, our study has successfully generated an all-encompassing atlas elucidating the intricate connections between circulating metabolites and the susceptibility to rheumatoid arthritis. Our results indicate the high unsaturation degree is a dominant risk factors correlated with rheumatoid arthritis.

Ibuprofen promotes p75 neurotrophin receptor expression through modifying promoter methylation and N6-methyladenosine-RNA-methylation in human gastric cancer cells.

It is acknowledged that nonsteroidal anti-inflammatory drugs (NSAIDs) can participate in various signaling pathways, while information about their epigenetic effects are limited. p75NTR (p75 neurotrophin receptor) can inhibit tumor growth by inducing cell cycle arrest and regulating cell cycle arrest and apoptotic cell death. The expression of p75NTR is influenced by epigenetic roles. We explored the effects of ibuprofen on p75NTR expression and investigated whether promoter methylation and N6-methyladenosine (m6A) RNA methylation regulates this process in human gastric cancer cells (SGC7901 and MKN45). Cell lines were treated with ibuprofen 0, 2.5, 5, 10, 20 µM, and then DNA, RNA, and protein were isolated 24 h later. Expression and promoter methylation of p75NTR were detected by RT-qPCR and Western blot. The levels of m6A-p75NTR were measured by RNA immunoprecipitation. We also used RT-qPCR to determine the levels of m6A-related regulators, METTL3, METTL14, ALKBH5, FTO, YTHDC2, and YTHDF1-3. Ibuprofen attenuated p75NTR promoter methylation (p < 0.01) and increased p75NTR level (p < 0.001). Ibuprofen increased m6A-p53 expression (p < 0.01) by promoting the expression of METTL3 (p < 0.01) and METTL14 (p < 0.05); and increased levels of YTHDF1 (p < 0.001), YTHDF3 (p < 0.001), and YTHDC2 (p < 0.01) that finally reinforced p53 translation (p < 0.01). Therefore, our results present that ibuprofen epigenetically increased p75NTR expression by downregulating promoter methylation and upregulating m6A-RNA-methylation in SGC7901 and MKN45 cells. Our study unveils a novel mechanism for p75NTR regulation by NSAIDs and helps the design of treatment targets.

Evaluation of a Novel Laboratory Candiduria Screening Protocol in the Intensive Care Unit.

BACKGROUND: Since urine cultures are only guaranteed for patients with obvious urinary symptoms in most cases, most of candiduria episodes are ignored in clinic. OBJECTIVE: This study aimed to design a screening protocol to improve diagnostic efficiency of candiduria, and provide information of Candida species and drug susceptibility. METHODS: All patients, who were admitted to the intensive care unit (ICU) of our hospital during December 1, 2018 and October 1, 2019, were enrolled in this study. Urinalysis was performed every three days for each subject from the first day of ICU admission. Urine specimens were sampled for fungal culture with either condition: (1) yeast-like cell counting (YLCC) ≥200; (2) positive YLCCs were observed in two consecutive tests, and at least one YLCC ≥100. RESULTS: The screening protocol dramatically improved the candiduria diagnostic rate of ICU patients from 2.28% to 17.27%. However, compared to the historical control, the screening protocol has no time-saving advantage in candiduria diagnosing. Higher percentage of C. albicans in screening protocol-identified candiduria patients was observed, although there was no statistical difference. Our results indicated that female gender, pneumonia, diabetes and infarction/hemorrhage patients were more prone to develop candiduria. Non-candiduria patients showed a better tendency for survival and shorter ICU stay length. Multisite colonization was common in the surveyed candiduria patients, who were up to 70.83% showed Candida positive cultures in sputum. CONCLUSION: The screening protocol established in the study was a convenient and practical tool for early warning and feasible management of candiduria and IC.