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Abstract The peroxisome is a versatile organelle that performs diverse metabolic functions. PEX3, a critical regulator of the peroxisome, participates in various biological processes associated with the peroxisome. Whether PEX3 is involved in peroxisome-related redox homeostasis and myocardial regenerative repair remains elusive. We investigate that cardiomyocyte-specific PEX3 knockout (Pex3-KO) results in an imbalance of redox homeostasis and disrupts the endogenous proliferation/development at different times and spatial locations. Using Pex3-KO mice and myocardium-targeted intervention approaches, the effects of PEX3 on myocardial regenerative repair during both physiological and pathological stages are explored. Mechanistically, lipid metabolomics reveals that PEX3 promotes myocardial regenerative repair by affecting plasmalogen metabolism. Further, we find that PEX3-regulated plasmalogen activates the AKT/GSK3β signaling pathway via the plasma membrane localization of ITGB3. Our study indicates that PEX3 may represent a novel therapeutic target for myocardial regenerative repair following injury.

Background The regenerative capacity of the adult mammalian hearts is limited. Numerous studies have explored mechanisms of adult cardiomyocyte cell‐cycle withdrawal. This translational study evaluated the effects and underlying mechanism of rhCHK1 (recombinant human checkpoint kinase 1) on the survival and proliferation of cardiomyocyte and myocardial repair after ischemia/reperfusion injury in swine. Methods and Results Intramyocardial injection of rhCHK1 protein (1 mg/kg) encapsulated in hydrogel stimulated cardiomyocyte proliferation and reduced cardiac inflammation response at 3 days after ischemia/reperfusion injury, improved cardiac function and attenuated ventricular remodeling, and reduced the infarct area at 28 days after ischemia/reperfusion injury. Mechanistically, multiomics sequencing analysis demonstrated enrichment of glycolysis and mTOR (mammalian target of rapamycin) pathways after rhCHK1 treatment. Co‐Immunoprecipitation (Co‐IP) experiments and protein docking prediction showed that CHK1 (checkpoint kinase 1) directly bound to and activated the Serine 37 (S37) and Tyrosine 105 (Y105) sites of PKM2 (pyruvate kinase isoform M2) to promote metabolic reprogramming. We further constructed plasmids that knocked out different CHK1 and PKM2 amino acid domains and transfected them into Human Embryonic Kidney 293T (HEK293T) cells for CO‐IP experiments. Results showed that the 1–265 domain of CHK1 directly binds to the 157–400 amino acids of PKM2. Furthermore, hiPSC‐CM (human iPS cell‐derived cardiomyocyte) in vitro and in vivo experiments both demonstrated that CHK1 stimulated cardiomyocytes renewal and cardiac repair by activating PKM2 C‐domain‐mediated cardiac metabolic reprogramming. Conclusions This study demonstrates that the 1–265 amino acid domain of CHK1 binds to the 157–400 domain of PKM2 and activates PKM2‐mediated metabolic reprogramming to promote cardiomyocyte proliferation and myocardial repair after ischemia/reperfusion injury in adult pigs.

The potential of circular RNAs (circRNAs) as biomarkers and therapeutic targets is becoming increasingly evident, yet their roles in cardiac regeneration and myocardial renewal remain largely unexplored. Here, we investigated the function of circIGF1R and related mechanisms in cardiac regeneration. Through analysis of circRNA sequencing data from neonatal and adult cardiomyocytes, circRNAs associated with regeneration were identified. Our data showed that circIGF1R expression was high in neonatal hearts, decreased with postnatal maturation, and up-regulated after cardiac injury. The elevation was validated in patients diagnosed with acute myocardial infarction (MI) within 1 week. In human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and myocardial tissue from mice after apical resection and MI, we observed that circIGF1R overexpression enhanced cardiomyocyte proliferation, reduced apoptosis, and mitigated cardiac dysfunction and fibrosis, while circIGF1R knockdown impeded endogenous cardiac renewal. Mechanistically, we identified circIGF1R binding proteins through circRNA precipitation followed by mass spectrometry. RNA pull-down Western blot and RNA immunoprecipitation demonstrated that circIGF1R directly interacted with DDX5 and augmented its protein level by suppressing ubiquitin-dependent degradation. This subsequently triggered the β-catenin signaling pathway, leading to the transcriptional activation of cyclin D1 and c-Myc. The roles of circIGF1R and DDX5 in cardiac regeneration were further substantiated through site-directed mutagenesis and rescue experiments. In conclusion, our study highlights the pivotal role of circIGF1R in facilitating heart regeneration and repair after ischemic insults. The circIGF1R/DDX5/β-catenin axis emerges as a novel therapeutic target for enhancing myocardial repair after MI, offering promising avenues for the development of regenerative therapies.

Background/Aims: Acute rejection (AR) is a major complication post renal transplantation, with no widely-accepted non-invasive biomarker. This study aimed to explore the expression profiles of long non-coding RNAs (lncRNAs) in the peripheral blood (PB) of renal transplant recipients and their potential diagnostic values. Methods: The genome-wide lncRNA expression profiles were analyzed in 150 PB samples from pediatric and adult renal transplant (PRTx and ARTx) cohorts. The diagnostic performance of differentially expressed lncRNA was determined using receiver operator characteristic curve, with area under the curve (AUC) and 95% confidential interval (CI). Finally, a risk score was constructed with logistical regression model. Results: A total of 162 lncRNAs were found differentially expressed in PRTx cohort, while 163 in ARTx cohort. Among these identified lncRNAs, 23 deregulated accordingly in both cohorts, and could distinguish AR recipients from those without AR. Finally, a risk score with two most significant lncRNAs (AF264622 and AB209021) was generated and exhibited excellent diagnostic performance in both PRTx (AUC:0.829, 95% CI:0.735-0.922) and ARTx cohorts (AUC: 0.889, 95% CI: 0.817-0.960). Conclusion: A molecular signature of two lncRNAs in PB could serve as a novel non-invasive biomarker for the diagnosis of AR in both pediatric and adult renal transplant recipients.

[This corrects the article DOI: 10.1371/journal.pone.0170729.].

OBJECTIVE:We conducted this meta-analysis of randomized controlled trials (RCTs) to investigate whether remote ischemic conditioning (RIC) could improve graft functions in kidney transplantation. METHODS:PubMed, Web of Science, and Cochrane Library were comprehensively searched to identify all eligible studies by October 5, 2016. The treatment effects were examined with risk ratio (RR) and weighted mean difference with the corresponding 95% confidence intervals (CI). The statistical significance and heterogeneity were assessed with both Z-test and Q-test. RESULTS:A total of six RCTs including 651 recipients, were eventually identified. Compared to the controls, RIC could reduce the incidence of delayed graft function (DGF) after kidney transplantation (random-effects model: RR = 0.89; fixed-effect model: RR = 0.84). However, the decrease did not reveal statistical significance. The subgroup analysis by RIC type demonstrated no significant difference among the three interventions in protecting renal allografts against DGF. Furthermore, no significant difference could be observed in the incidence of acute rejection, graft loss, 50% fall in serum creatinine, as well as the estimated glomerular filtration rate and hospital stay between the RIC and Control groups. CONCLUSIONS:This meta-analysis suggested that RIC might exert renoprotective functions in human kidney transplantation, and further well-designed RCTs with large sample size are warranted to assess its clinical efficacy.

Bladder cancer (BC) is a common urinary system tumor with high aggressiveness, and it results in relatively high mortality due to a lack of precise and suitable biomarkers. In this study, we applied the weighted gene coexpression network analysis method to miRNA expression data from BC patients, and screened for network modules associated with BC progression. Hub miRNAs were selected, followed by functional enrichment analyses of their target genes for the most closely related module. These hub miRNAs were found to be involved in several functional pathways including pathway in cancer, regulation of actin cytoskeleton, PI3K-Akt signaling pathway, mitogen-activated protein kinase (MAPK) signaling pathway, Wnt signaling pathway, proteoglycans in cancer, focal adhesion and p53 signaling pathway via regulating target genes. Finally, their prognostic significance was tested using analyses of overall survival. A few novel prognostic miRNAs were identified based on expression profiles and related survival data. In conclusion, several miRNAs that were critical in BC initiation and progression have been identified in this study. These miRNAs, which may contribute to a comprehensive understanding of the pathogenesis of BC, could serve as potential biomarkers for BC prognosis or as new therapeutic targets. [ABSTRACT FROM AUTHOR]