Objective To explore the functional impact of A-to-I editing in the seed region of miR-411 during post-myocardial infarction (MI) fibrosis and elucidate its therapeutic potential. Methods Integrating GEO database with myocardial RNA-seq data from MI mouse models, we identified dynamic A-to-I RNA editing in small noncoding RNAs across MI progression (1 day to 8 weeks post-MI). Four miRNAs exhibited differential editing rates between MI and controls, with miR-411 showing progressive editing enhancement at seed region position 4 (P＜0.01). This editing event was validated in both murine MI models and human heart failure specimens. Results The A-to-I editing ratio change of the 4th nucleotide in the seed region of miR-411 mainly occurs in cardiac fibroblasts rather than cardiomyocytes, and the editing at this site depends on ADAR2 rather than ADAR1. Edited miR-411 (ED-miR-411) diverged from wild-type miR-411 (WT-miR-411) in suppressing collagen-related pathways (extracellular matrix [ECM]-receptor interaction, collagen-containing ECM, ECM organization; P＜0.01) in cardiac fibroblasts. Mechanistically, dual-luciferase assays confirmed ED-miR-411 directly targeted the 3′UTR and suppressed expression of type Ⅱ transforming growth factor (TGF)-beta receptor (TGFBR2) and CD44, which were key drivers of TGF-β-mediated fibroblast activation. ED-miR-411 overexpression blunted TGF-β-induced collagen synthesis and myofibroblast proliferation (P＜0.05). In vivo, intramyocardial delivery of ED-miR-411 mimics at 1 week post-MI reduced fibrosis by 40% and improved ejection fraction by 15% (P＜0.01 vs controls), whereas WT-miR-411 showed no therapeutic effect. Conclusions A-to-I editing of miR-411 emerges as an endogenous anti-fibrotic mechanism by repressing TGFBR2 and CD44, thereby disrupting TGF-β signaling and ECM dysregulation. Our findings highlight ED-miR-411 as a novel RNA-based therapeutic candidate to mitigate post-infarction cardiac remodeling.

Myocardial fibrosis is a serious cause of heart failure and even sudden cardiac death. However, the mechanisms underlying myocardial ischemia-induced cardiac fibrosis remain unclear. Here, we identified that the expression of sterile alpha and TIR motif containing 1 (SARM1), was increased significantly in the ischemic cardiomyopathy patients, dilated cardiomyopathy patients (GSE116250) and fibrotic heart tissues of mice. Additionally, inhibition or knockdown of SARM1 can improve myocardial fibrosis and cardiac function of myocardial infarction (MI) mice. Moreover, SARM1 fibroblasts-specific knock-in mice had increased deposition of extracellular matrix and impaired cardiac function. Mechanically, elevated expression of SARM1 promotes the deposition of extracellular matrix by directly modulating P4HA1. Notably, by using the Click-iT reaction, we identified that the increased expression of ZDHHC17 promotes the palmitoylation levels of SARM1, thereby accelerating the fibrosis process. Based on the fibrosis-promoting effect of SARM1, we screened several drugs with anti-myocardial fibrosis activity. In conclusion, we have unveiled that palmitoylated SARM1 targeting P4HA1 promotes collagen deposition and myocardial fibrosis. Inhibition of SARM1 is a potential strategy for the treatment of myocardial fibrosis. The sites where SARM1 interacts with P4HA1 and the palmitoylation modification sites of SARM1 may be the active targets for anti-fibrosis drugs.

Objective:To investigate the efficacy and safety of separated R-CHOP in older patients with newly diagnosed diffuse large B-cell lymphoma(DLBCL).Methods:A total of 137 patients aged 65-80 years newly diagnosed with DLBCL between April 2013 and September 2022 at The First Affiliated Hospital of Zhengzhou University were enrolled.The patients were assigned into separated R-CHOP,full-dose R-CHOP,and reduced R-CHOP-like groups based on their different chemotherapy regimens.All individuals were treated in 21-day cycles for 4-8 cycles.The short-term and long-term efficacies and adverse reactions of the treatments were compared among the three groups,and factors influencing progression-free survival(PFS)and overall survival(OS)were analyzed.Results:The overall response rates(ORR)of patients in the separated R-CHOP,full-dose R-CHOP,and reduced R-CHOP-like groups were 89.7%,90.3%,and 86.1%,respectively,with no significant differences among them.The complete respond rate(CRR)of the separated R-CHOP group(64.1%)was significantly higher than that of the reduced R-CHOP-like group(33.3%)(P=0.008)but not significantly different from that of the full-dose R-CHOP group(66.1%).Survival curve analysis revealed no significant differences in PFS and OS between the separated and full-dose R-CHOP groups.Although the separated R-CHOP group showed improved PFS compared with the reduced R-CHOP-like group(P=0.036),there was no statistical difference in OS between these two groups.Multivariate analysis revealed that the international prognostic index(IPI)and separated R-CHOP had significant effects on PFS in patients with DLBCL(all P<0.05),whereas only IPI had a significant effect on OS(P<0.001).The incidence of leukopenia and grade 3-4 leukopenia in the separated R-CHOP group was significantly lower than that in the full-dose R-CHOP group(P=0.007,P=0.012),but there was no significant difference with the reduced R-CHOP-like group in this regard.Conclusions:In older patients with newly diagnosed DLBCL,separated R-CHOP showed good efficacy both in the short and long terms and had acceptable safety and tolerability profiles.

Objective To investigate the clinical features of Menkes disease(MD)caused by ATP7A gene mutation.Methods Clinical data of one MD patient was retrospectively analyzed,and the literature on the MD cases was reviewed.Results The patient was a 7-month-old male.The initial symptoms were epilepsy,feeding difficulties and psychomotor retardation,followed by distinctive facial appearance,hair abnormality,pectus excavatum and hypotonia.Biochemical tests revealed reduced serum ceruloplasmin and copper.Brain MRI showed diffuse cerebral atrophy,cerebral dysplasia and subdural effusion.Genetic testing showed that there was a new hemizygous mutation c.2916+2(IVS14)T＞C in the ATP7A gene splicing site on the X chromosome,which verified that the mother was a heterozygous carrier with a normal phenotype.Conclusions MD often starts in infancy and childhood.MD may involve multi-system such as the nervous system and connective tissues,and should be diagnosed with genetic testing.

Objective:To improve the therapeutic regimen for mantle cell lymphoma,we investigated the efficacy and safety of adding a BTK inhibitor to a regimen including rituximab,bendamustine,cytarabine,and prednisone to treat patients with mantle cell lymphoma(MCL).Methods:Twenty-six patients newly diagnosed with MCL who were admitted to The First Affiliated Hospital of Zhengzhou University from March 2021 to November 2023 were treated with a regimen of rituximab,bendamustine,cytarabine and prednisone combined with a BTK inhibitor,and the efficacy and adverse effects of this regiment were retrospectively analyzed.Results:The median age of the 26 newly dia-gnosed MCL patients was 59(41-72)years.The cohort included 22 males and 4 females,and the median follow-up time was 12(3-28)months.The overall response rate(ORR)was 92.3%and the complete response rate(CRR)was 88.5%.Median progression-free survival(PFS)and median overall survival(OS)endpoints were not achieved,with a 1-year PFS rate of 81.25%and a 1-year OS rate of 92.3%.A bet-ter PFS was achieved in the low mantle cell lymphoma International Prognostic Index(MIPI)score(0-3 points)group than in the high MIPI score(4-11 points)group(P=0.020).PFS was better in the group without B symptoms than in the group with B symptoms(P=0.002).PFS was better in the classical group than in the pleomorphic-blastoid subtype group(P=0.009).The main adverse effects were lymphopenia and thrombocytopenia.No treatment-related serious adverse events were observed during the follow-up period.Conclusions:The regimen of rituximab,bendamustine,cytarabine,and prednisone in combination with BTK inhibitors is safe and effective for the treatment of newly dia-gnosed patients with MCL.

Objective To explore clinical effects and operative experience of transanal pull-through procedure for Hirschsprung's disease (HD).Methods The clinical data of 126 children aged from 13 days to 14 years with HD were reviewed.There were 30 cases of short-segment type,85 of common type,and 11 of long-segment type.A total of 95 cases was operated with modified Soave and the other 31 cases were operated with modified Swenson.Results Except two-stage resection in 7(5.6％) cases who already underwent transanal Soave procedure early,one-stage transanal pull-through procedure was performed in the other cases.Laparotomy assisted operation was used for 5 cases and laparoscope assisted operation for 12 cases.The complications were occurred in 35 (27.8％) cases post-operation,including 15 perianatitis,9 enterocolitis,5 anastomotic stenosis,2 soiling,and 4 reoperation.The statistical analysis indicated no difference between two procedures and postoperative complications could be noted between different types (P ＞0.05).A total of 103 patients were followed up from 1 to 10 (mean 2) years.Of all patients,96 (93.2％) were cured,5 (4.9％) symptoms were improved and 2(1.9％) were failed.There were no significant differences in two procedure and the excellent rate of defecation function(P ＞ 0.05).Conclusions Two transanal procedures for HD both had a good efficacy and similar complications.By comparison,transanal Swenson procedure was simpler than Soave procedure,and did not need to enlarge anus post-operation as well.