ABSTRACT
RNA modifications, including N6-methyladenosine (m6A), critically modulate protein expression programs in a range of cellular processes. Although the transcriptomes of cells undergoing senescence are strongly regulated, the landscape and impact of m6A modifications during senescence are poorly understood. Here, we report a robust m6A modification of PTCHD4 mRNA, encoding Patched Domain-Containing Protein 4, in senescent cells. The METTL3/METTL14 complex was found to incorporate the m6A modification on PTCHD4 mRNA; addition of m6A rendered PTCHD4 mRNA more stable and increased PTCHD4 production. MeRIP RT-qPCR and eCLIP analyses were used to map this m6A modification to the last exon of PTCHD4 mRNA. Further investigation identified IGF2BP1, but not other m6A readers, as responsible for the stabilization and increased abundance of m6A-modified PTCHD4 mRNA. Silencing PTCHD4, a transmembrane protein, enhanced growth arrest and DNA damage in pre-senescent cells and sensitized them to senolysis and apoptosis. Our results indicate that m6A modification of PTCHD4 mRNA increases the production of PTCHD4, a protein associated with senescent cell survival, supporting the notion that regulating m6A modification on specific mRNAs could be exploited to eliminate senescent cells for therapeutic benefit.
Subject(s)
Adenosine , Cell Survival , Cellular Senescence , Methyltransferases , RNA, Messenger , RNA-Binding Proteins , Humans , Cellular Senescence/genetics , Adenosine/analogs & derivatives , Adenosine/metabolism , RNA, Messenger/metabolism , RNA, Messenger/genetics , Methyltransferases/metabolism , Methyltransferases/genetics , RNA-Binding Proteins/metabolism , RNA-Binding Proteins/genetics , Cell Survival/genetics , Apoptosis/genetics , Membrane Proteins/genetics , Membrane Proteins/metabolism , DNA DamageABSTRACT
The senescence-associated secretory phenotype (SASP) is a major trait of senescent cells, but the molecular regulators of SASP factor secretion are poorly understood. Mass spectrometry analysis revealed that secretory carrier membrane protein 4 (SCAMP4) levels were strikingly elevated on the surface of senescent cells compared with proliferating cells. Interestingly, silencing SCAMP4 in senescent fibroblasts reduced the secretion of SASP factors, including interleukin 6 (IL6), IL8, growth differentiation factor 15 (GDF-15), C-X-C motif chemokine ligand 1 (CXCL1), and IL7, while, conversely, SCAMP4 overexpression in proliferating fibroblasts increased SASP factor secretion. Our results indicate that SCAMP4 accumulates on the surface of senescent cells, promotes SASP factor secretion, and critically enhances the SASP phenotype.
Subject(s)
Carrier Proteins/metabolism , Cellular Senescence/genetics , Fibroblasts/metabolism , Membrane Proteins/metabolism , Carrier Proteins/genetics , Cell Line , Cell Proliferation/physiology , Fibroblasts/cytology , Gene Silencing , Humans , Membrane Proteins/genetics , Proteasome Endopeptidase Complex/metabolism , Ubiquitin/metabolismABSTRACT
Senescent cell accumulation in aging tissues is linked to age-associated diseases and declining function, prompting efforts to eliminate them. Mass spectrometry analysis revealed that DPP4 (dipeptidyl peptidase 4) was selectively expressed on the surface of senescent, but not proliferating, human diploid fibroblasts. Importantly, the differential presence of DPP4 allowed flow cytometry-mediated isolation of senescent cells using anti-DPP4 antibodies. Moreover, antibody-dependent cell-mediated cytotoxicity (ADCC) assays revealed that the cell surface DPP4 preferentially sensitized senescent, but not dividing, fibroblasts to cytotoxicity by natural killer cells. In sum, the selective expression of DPP4 on the surface of senescent cells enables their preferential elimination.
Subject(s)
Cellular Senescence/physiology , Dipeptidyl Peptidase 4/metabolism , Membrane Proteins/metabolism , Adult , Aged , Aged, 80 and over , Antibody-Dependent Cell Cytotoxicity , Cells, Cultured , Cyclin-Dependent Kinase Inhibitor p16/genetics , Diploidy , Fibroblasts/metabolism , Flow Cytometry , Humans , Killer Cells, Natural/metabolism , Lymphocyte Subsets/enzymology , Mass Spectrometry , RNA, Messenger/metabolism , RNA, Ribosomal/metabolismABSTRACT
We summarize the copy number variations (CNVs) and phenotype spectrum of infantile epileptic spasms syndrome (IESS) in a Chinese cohort. The CNVs were identified by genomic copy number variation sequencing. The CNVs and clinical data were analyzed. 74 IESS children with CNVs were enrolled. 35 kinds of CNVs were identified. There were 11 deletions and 5 duplications not reported previously in IESS, including 2 CNVs not reported in epilepsy. 87.8% were de novo, 9.5% were inherited from mother and 2.7% from father. Mosaicism occurred in one patient with Xq21.31q25 duplication. 16.2% (12/74) were 1p36 deletion, and 20.3% (15/74) were 15q11-q13 duplication. The age of seizure onset ranged from 17 days to 24 months. Seizure types included epileptic spasms, focal seizures, tonic seizures, and myoclonic seizures. All patients displayed developmental delay. Additional features included craniofacial anomaly, microcephaly, congenital heart defects, and hemangioma. 29.7% of patients were seizure-free for more than 12 months, and 70.3% still had seizures after trying 2 or more anti-seizure medications. In conclusion, CNVs is a prominent etiology of IESS. 1p36 deletion and 15q duplication occurred most frequently. CNV detection should be performed in patients with IESS of unknown causes, especially in children with craniofacial anomalies and microcephaly.
Subject(s)
DNA Copy Number Variations , Phenotype , Spasms, Infantile , Humans , DNA Copy Number Variations/genetics , Spasms, Infantile/genetics , Female , Male , Infant , Chromosome Duplication/genetics , Chromosomes, Human, Pair 15/genetics , Child, Preschool , Infant, Newborn , Chromosome Deletion , Mosaicism , Chromosome Aberrations , Intellectual DisabilityABSTRACT
In this study, a ratiometric fluorescence nanoprobe is developed for the analysis of hydrogen peroxide (H2O2). Silver nanoclusters (AgNCs) were synthesized by chemical reduction method using sodium borohydride (NaBH4) as reducing agent, and were coupled with CdSe/ZnS quantum dots (QDs) to form the ratiometric fluorescence nanoprobe silver nanoclusters-quantum dots (AgNCs-QDs). The effect of the volume ratio of CdSe/ZnS QDs to AgNCs on the fluorescence ratio of AgNCs-QDs was investigated. The fluorescence characterization results show that two emission peaks of AgNCs-QDs are located at 473 nm and 661 nm, respectively. Transmission electron microscope (TEM) and X-ray photoelectron spectroscopy (XPS) results show that H2O2 can cause the fluorescence probe to aggregate, while etching AgNCs to produce silver ions, which together cause the fluorescence of the QDs in the ratiometric fluorescent probe to be quenched. Based on this strategy, the fluorescence intensity ratio of the two emission peaks F473/F661 exhibits a strong linear correlation with the concentration of H2O2. The detection range is 3.32 µM ~ 2.65 mM with a detection limit of 3.32 µM. In addition, the ratiometric fluorescence probe can specifically recognize H2O2 and has excellent anti-interference performance and good fluorescence stability. Importantly, the probe was utilized for the detection of H2O2 in serum, showing the possibility of the probe in clinical detection applications.
ABSTRACT
Long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) modulate gene expression programs in physiology and disease. Here, we report a noncoding RNA regulatory network that modulates myoblast fusion into multinucleated myotubes, a process that occurs during muscle development and muscle regeneration after injury. In early stages of human myogenesis, the levels of lncRNA OIP5-AS1 increased, while the levels of miR-7 decreased. Moreover, OIP5-AS1 bound and induced miR-7 decay via target RNA-directed miRNA decay; accordingly, loss of OIP5-AS1 attenuated, while antagonizing miR-7 accelerated, myotube formation. We found that the OIP5-AS1-mediated miR-7 degradation promoted myoblast fusion, as it derepressed the miR-7 target MYMX mRNA, which encodes the fusogenic protein myomixer (MYMX). Remarkably, an oligonucleotide site blocker interfered with the OIP5-AS1-directed miR-7 degradation, allowing miR-7 to accumulate, lowering MYMX production and suppressing myotube formation. These results highlight a mechanism whereby lncRNA OIP5-AS1-mediated miR-7 decay promotes myotube formation by stimulating a myogenic fusion program.
Subject(s)
MicroRNAs , RNA, Long Noncoding , Humans , RNA, Long Noncoding/genetics , MicroRNAs/genetics , Muscle Development/geneticsABSTRACT
The mammalian transcriptome comprises a vast family of long noncoding (lnc)RNAs implicated in physiologic processes such as myogenesis, through which muscle forms during embryonic development and regenerates in the adult. However, the specific molecular mechanisms by which lncRNAs regulate human myogenesis are poorly understood. Here, we identified a novel muscle-specific lncRNA, lncFAM71E1-2:2 (lncFAM), which increased robustly during early human myogenesis. Overexpression of lncFAM promoted differentiation of human myoblasts into myotubes, while silencing lncFAM suppressed this process. As lncFAM resides in the nucleus, chromatin isolation by RNA purification followed by mass spectrometry (ChIRP-MS) analysis was employed to identify the molecular mechanisms whereby it might promote myogenesis. Analysis of lncFAM-interacting proteins revealed that lncFAM recruited the RNA-binding protein HNRNPL to the promoter of MYBPC2, in turn increasing MYBPC2 mRNA transcription and enhancing production of the myogenic protein MYBPC2. These results highlight a mechanism whereby a novel ribonucleoprotein complex, lncFAM-HNRNPL, elevates MYBPC2 expression transcriptionally to promote myogenesis.
Subject(s)
Heterogeneous-Nuclear Ribonucleoprotein L , Muscle Development , Promoter Regions, Genetic , RNA, Long Noncoding , Transcription, Genetic , Humans , Heterogeneous-Nuclear Ribonucleoprotein L/genetics , Heterogeneous-Nuclear Ribonucleoprotein L/metabolism , Muscle Development/genetics , Muscle Fibers, Skeletal/metabolism , Myoblasts/cytology , Myoblasts/metabolism , RNA, Long Noncoding/genetics , RNA, Long Noncoding/metabolism , Transcription, Genetic/genetics , Gene Silencing , Protein Transport/geneticsABSTRACT
Myocardial ischemia/reperfusion (I/R) injury is a classic type of cardiovascular disease characterized by injury to cardiomyocytes leading to different types of cell death. The degree of irreversible myocardial damage is closely related to age, and ferroptosis is involved in cardiomyocyte damage. However, the mechanisms underlying ferroptosis regulation in aging myocardial I/R injury are still unclear. The present study aims to explore the underlying mechanism of piRNA regulation in ferroptosis. Using left anterior descending coronary artery ligation in an aging rat model and a D-galactose-induced rat cardiomyocyte line (H9C2) to construct an aging cardiomyocyte model, we investigate whether ferroptosis occurs after reperfusion injury in vitro and in vivo. This study focuses on the upregulation of piR-000699 after hypoxia/reoxygenation treatment in aging cardiomyocytes by observing hypoxia/reoxygenation (H/R) injury indicators and ferroptosis-related indicators and clarifying the role of piR-000699 in H/R injury caused by ferroptosis in aging cardiomyocytes. Bioinformatics analysis reveals that SLC39A14 is a gene that binds to piR-000699. Our data show that ferroptosis plays an important role in I/R injury both in vivo and in vitro. Furthermore, the results show the potential role of piR-000699 in regulating SLC39A14 in ferroptosis in aging cardiomyocytes under hypoxia/reoxygenation conditions. Together, our results reveal that the mechanism by which piR-000699 binds to SLC39A14 regulates ferroptosis in aging myocardial I/R injury.
ABSTRACT
BACKGROUND: Previous studies have shown that intravenous normal saline (NS) may be associated with the incidence of acute kidney injury (AKI). This study aimed to evaluate the association between the volume of NS infusion and AKI in heat stroke (HS) patients. METHODS: This multicenter retrospective cohort study included 138 patients with HS. The primary outcome was the incidence of AKI. Secondary outcomes included the need for continuous renal replacement therapy (CRRT), admission to the intensive care unit (ICU), length of stay in the ICU and hospital, and in-hospital mortality. Multivariate regression models, random forest imputation, and genetic and propensity score matching were used to explore the relationship between NS infusion and outcomes. RESULTS: The mean volume of NS infusion in the emergency department (ED) was 3.02 ± 1.45 L. During hospitalization, 33 patients (23.91%) suffered from AKI. In the multivariate model, as a continuous variable (per 1 L), the volume of NS infusion was associated with the incidence of AKI (OR, 2.51; 95% CI, 1.43-4.40; p = .001), admission to the ICU (OR, 3.46; 95% CI 1.58-7.54; p = .002), and length of stay in the ICU (ß, 1.00 days; 95% CI, 0.44-1.56; p < .001) and hospital (ß, 1.41 days; 95% CI, 0.37-2.45; p = .008). These relationships also existed in the forest imputation cohort and matching cohort. There were no differences in the use of CRRT or in-hospital mortality. CONCLUSIONS: The volume of NS infusion was associated with a significant increase in the incidence of AKI, admission to the ICU, and length of stay in the ICU and hospital among patients with HS.
Subject(s)
Acute Kidney Injury , Heat Stroke , Humans , Acute Kidney Injury/epidemiology , Acute Kidney Injury/etiology , Acute Kidney Injury/therapy , Emergency Service, Hospital , Intensive Care Units , Retrospective Studies , Saline SolutionABSTRACT
Some mitochondrial long noncoding RNAs (lncRNAs) are encoded by nuclear DNA, but the mechanisms that mediate their transport to mitochondria are poorly characterized. Using affinity RNA pull-down followed by mass spectrometry analysis, we found two RNA-binding proteins (RBPs), HuR (human antigen R) and GRSF1 (G-rich RNA sequence-binding factor 1), that associated with the nuclear DNA-encoded lncRNA RMRP and mobilized it to mitochondria. In cultured human cells, HuR bound RMRP in the nucleus and mediated its CRM1 (chromosome region maintenance 1)-dependent export to the cytosol. After RMRP was imported into mitochondria, GRSF1 bound RMRP and increased its abundance in the matrix. Loss of GRSF1 lowered the mitochondrial levels of RMRP, in turn suppressing oxygen consumption rates and modestly reducing mitochondrial DNA replication priming. Our findings indicate that RBPs HuR and GRSF1 govern the cytoplasmic and mitochondrial localization of the lncRNA RMRP, which is encoded by nuclear DNA but has key functions in mitochondria.
Subject(s)
Cell Nucleus/metabolism , ELAV-Like Protein 1/metabolism , Mitochondria/metabolism , Poly(A)-Binding Proteins/metabolism , RNA, Long Noncoding/metabolism , Active Transport, Cell Nucleus , HEK293 Cells , HeLa Cells , Humans , Protein Binding , Protein TransportABSTRACT
AIM: To investigate the occurrence of mosaicism in epilepsy probands and their parents using amplicon-based deep sequencing (ADS). METHODS: Patients were recruited from the outpatient of Peking University First Hospital. Two hundred and sixty-four probands with pathogenic variants tested by next-generation sequencing (NGS) were enrolled. RESULTS: Mosaic variants were detected in seventeen disease-associated genes from 20 probands, 5 paternal, and 6 maternal parents. The frequency of mosaicism was 11.74% (31/264). Mosaicism in 11 genes was identified from 20 probands with the mutant allelic fractions (MAFs) of 12.95-38.00% in autosomal dominant genes. Five paternal mosaicisms were identified in genes with a MAF of 6.30-20.99%, and six maternal mosaic individuals with a MAF of 2.07-21.90%. Only four mosaic parents had milder seizure history. The affected sibling had the same phenotype consistent with that of the proband, who inherited the variant of SLC1A2 or STXBP1 from their unaffected mosaic mothers, respectively. INTERPRETATION: Mosaic phenomenon is not rare in families with epilepsy. Phenotypes of mosaic parents were milder or normal. Mosaicism detection is helpful to identify the mutation origin and it provides a theoretical basis for prenatal diagnosis of family reproduction. ADS is a reliable way of mosaicism detection for clinical application.
Subject(s)
Epilepsy , Mosaicism , Humans , Epilepsy/genetics , Mutation , Genomics , High-Throughput Nucleotide SequencingABSTRACT
Data sets of colorectal cancer (CRC) were obtained from The Cancer Genome Atlas (TCGA), three N6-methyladenosine (m6A) subtypes were identified using 21 m6A-related long noncoding RNAs (lncRNAs) and differential m6A subtypes of different CRC tumors were determined in this study to evaluate the m6A expression and the prognosis of patients with CRC. Subsequently, eight key lncRNAs were identified based on co-expression with 21 m6A-related genes in CRC tumors using the single-factor Cox and least absolute shrinkage and selection operator. Finally, an m6A-related lncRNA risk score model of CRC tumor was established using multifactor Cox regression based on the eight important lncRNAs and found to have a better performance in evaluating the prognosis of patients in the TCGA-CRC data set. TCGA-CRC tumor samples were divided based on the risk scores: high and low. Then, the clinical characteristics, tumor mutation load, and tumor immune cell infiltration difference between the high- and low-risk-score groups were explored, and the predictive ability of the risk score was assessed for immunotherapeutic benefits. We found that the risk score model can determine the overall survival, be a relatively independent prognostic indicator, and better evaluate the immunotherapeutic benefits for patients with CRC. This study provides data support for accurate immunotherapy in CRC.
Subject(s)
Colorectal Neoplasms , Methyltransferases , RNA, Long Noncoding , Humans , Colorectal Neoplasms/genetics , Immunotherapy , Mutation , Prognosis , RNA, Long Noncoding/genetics , Methyltransferases/geneticsABSTRACT
AIM: To explore the phenotypic spectrum and refine the genotype-phenotype correlation of DYNC1H1-related epilepsy. METHOD: The clinical data of 15 patients with epilepsy in our cohort and 50 patients with epilepsy from 24 published studies with the DYNC1H1 variants were evaluated. RESULTS: In our cohort, 13 variants were identified from 15 patients (seven males, eight females). Twelve variants were de novo and seven were new. Age at seizure onset ranged from 3 months to 4 years 5 months (median age 1 year). Common seizure types were epileptic spasms, focal seizures, tonic seizures, and myoclonic seizures. Mild-to-severe developmental delay was present in all patients. Six patients were diagnosed with West syndrome and one was diagnosed with epileptic encephalopathy with continuous spikes and waves during slow sleep (CSWS). Collectively, in our cohort and published studies, 17% had ophthalmic diseases, 31% of variants were located in the stalk domain, and 92% patients with epilepsy had a malformation of cortical development (MCD). INTERPRETATION: The phenotypes of DYNC1H1-related epilepsy included multiple seizure types; the most common epileptic syndrome was West syndrome. CSWS is a new phenotype of DYNC1H1-related epilepsy. One-third of the variants in patients with epilepsy were located in the stalk domain. Most patients had a MCD and developmental delay. WHAT THIS PAPER ADDS: Nearly 40% of patients with DYNC1H1 variants had epilepsy. Ninety-two percent of patients with DYNC1H1-related epilepsy had malformation of cortical development. More than 10% of patients with DYNC1H1-related epilepsy were diagnosed with West syndrome. Continuous spikes and waves during slow sleep could be a new phenotype of DYNC1H1 variants. One-third of the variants in patients with epilepsy were located in the stalk domain.
Subject(s)
Epilepsy , Spasms, Infantile , Male , Female , Humans , Spasms, Infantile/genetics , Mutation , Epilepsy/genetics , Seizures/genetics , Genetic Association Studies , Electroencephalography , Cytoplasmic Dyneins/geneticsABSTRACT
This study aimed to evaluate the antibacterial activities of α-terpineol against common foodborne pathogenic bacteria by agar well diffusion, broth microdilution, and colony counting assay. Propulsive research was conducted to reveal the antibacterial mechanisms, including morphology, infrared spectroscopy, membrane fluidity, membrane permeability, proton motive force, and oxidative phosphorylation. Results indicated that the antibacterial activity of α-terpineol decreased in the following order: Escherichia coli O157:H7, Salmonella typhimurium, Listeria monocytogenes, and Staphylococcus aureus. With an initial cell count of 8 log CFU/mL, α-terpineol at 0.8% (v/v) reduced E. coli O157:H7 and S. aureus by approximately 5.6 and 3.9 log CFU/mL within 1 h, respectively. Remarkable destruction in cell envelopes and intracellular organizations was observed. The hydroxyl of α-terpineol might form glycosidic bonds with carbohydrates and hydrogen bonds with PO2- and COO- via infrared spectroscopy analysis. Generalized polarization of Laurdan revealed that the polar head groups of phospholipids transformed into close packed. The anisotropy variations of trimethyl amino-diphenylhexatriene (TMA-DPH) and DPH suggested membrane fluidity decreased. The N-phenyl-1-naphthylamine intake assay indicated that α-terpineol impaired the cell wall. Propidium iodide staining was indicative of damaged plasma membranes. Electron transport in the cytoplasmic membrane was impaired, inducing reactive oxygen species accumulation. Both membrane electrical potential and membrane pH gradient collapsed. The disruption of proton motive force and the leakage of ATP resulted in a deficit of intracellular ATP. Our research revealed the interaction between the hydroxyl group of α-terpineol and bacteria affects membrane function contributing to the bacteria's death. KEY POINTS: ⢠α-Terpineol hydroxy formed glycosidic bonds and hydrogen bonds with bacteria ⢠α-Terpineol increased the membrane gelation and reduced the membrane fluidity ⢠Proton motive force and oxidative phosphorylation were impaired.
Subject(s)
Escherichia coli O157 , Listeria monocytogenes , Food Microbiology , Staphylococcus aureus , Colony Count, Microbial , Anti-Bacterial Agents/pharmacology , Adenosine TriphosphateABSTRACT
Hb variants prevalent in China are different from those in other countries. We aimed to assess the interference from Hb variants found in China on HbA1c measurement. All Hb variants were confirmed using Sanger sequencing. HbA1c was measured using a capillary electrophoresis method (Capillarys 3 OCTA), two cation-exchange high-performance liquid chromatography methods (ADAMS HA-8180V and HLC-723 G8 standard mode), an immunoassay (Cobas c501), and a boronate affinity chromatography method (Premier Hb9210). Premier Hb9210 was used as a comparative method. A total of 16 species of Hb variants were identified in 102 variant carriers. The most common variant was Hb E, followed by Hb Q-Thailand, Hb New York and Hb J-Bangkok. Clinically significant interference was observed for the Capillarys 3 OCTA (two Hb variants), ADAMS HA-8180V (seven Hb variants), HLC-723 G8 (14 Hb variants), and Cobas c501 (two Hb variants). The proportion of unacceptable HbA1c results was 13.7% for Capillarys 3 OCTA, 52.9% for HA-8180V, 83.3% for HLC-723 G8, and 3.9% for Cobas c501. Hb variants in China severely affect the accuracy of some commonly used HbA1c methods.
Subject(s)
Hematologic Tests , Hemoglobins, Abnormal , Humans , Chromatography, High Pressure Liquid/methods , Electrophoresis, Capillary , Glycated Hemoglobin/genetics , Hematologic Tests/methods , Hemoglobins, Abnormal/genetics , Hemoglobins, Abnormal/analysisABSTRACT
OBJECTIVES: Standard base excess (SBE) is a quick and effective tool to identify acid-base disorders in critically ill patients, independent of respiratory factors. The predictive value of SBE for adverse outcomes in patients with heat stroke (HS) is still unclear. This study aimed to explore the prognostic significance of SBE for in-hospital mortality and other adverse outcomes in patients with HS. METHODS: A retrospective, observational multicenter cohort study with consecutive patients between 2021 and 2022 was conducted. The SBE was performed upon emergency department (ED) admission. The primary outcome was in-hospital mortality. Secondary outcomes included the use of vasoactive drugs in the ED, admission to the ICU, acute kidney failure, acute heart failure, acute respiratory failure, sepsis, and coagulation impairment. Logistic regression models and receiver operating characteristic (ROC) curves were used to estimate the association of SBE with outcomes in HS patients. Interaction and stratified analyses were also conducted. RESULTS: The median level of SBE was -4.70 (-8.05- -1.55) mmol/L. Overall hospital mortality in these 151 HS patients was 12.58%. SBE was independently associated with hospital mortality (OR 0.81, 95% CI 0.70-0.95, P = 0.011). Age and HS type played interactive roles in the relationship between SBE and in-hospital mortality. The OR between SBE and hospital mortality was 0.5 (95% CI, 0.3-0.9; p < 0.018) in classic HS participants and 0.62 (95% CI, 0.45-0.87; p = 0.005) in participants aged >65 years. The AUC of SBE to predict in-hospital mortality was 0.868 (95% CI: 0.704-0.962) and 0.883 (95% CI: 0.750-0.951) in these two groups, respectively. SBE was significantly associated with admission to the ICU, acute kidney failure, acute respiratory failure, sepsis, and coagulation impairment. CONCLUSION: SBE upon emergency admission was significantly associated with adverse outcomes in patients with HS.
Subject(s)
Acute Kidney Injury , Heat Stroke , Respiratory Insufficiency , Sepsis , Humans , Retrospective Studies , Cohort Studies , Prognosis , Hospital Mortality , Heat Stroke/complications , Heat Stroke/therapy , ROC Curve , Emergency Service, Hospital , Intensive Care UnitsABSTRACT
A major stress response influenced by microRNAs (miRNAs) is senescence, a state of indefinite growth arrest triggered by sublethal cell damage. Here, through bioinformatic analysis and experimental validation, we identified miR-340-5p as a novel miRNA that foments cellular senescence. miR-340-5p was highly abundant in diverse senescence models, and miR-340-5p overexpression in proliferating cells rendered them senescent. Among the target mRNAs, miR-340-5p prominently reduced the levels of LBR mRNA, encoding lamin B receptor (LBR). Loss of LBR by ectopic overexpression of miR-340-5p derepressed heterochromatin in lamina-associated domains, promoting the expression of DNA repetitive elements characteristic of senescence. Importantly, overexpressing miR-340-5p enhanced cellular sensitivity to senolytic compounds, while antagonization of miR-340-5p reduced senescent cell markers and engendered resistance to senolytic-induced cell death. We propose that miR-340-5p can be exploited for removing senescent cells to restore tissue homeostasis and mitigate damage by senescent cells in pathologies of human aging.
Subject(s)
Cellular Senescence/genetics , MicroRNAs/metabolism , Receptors, Cytoplasmic and Nuclear/genetics , Cell Line , Cell Proliferation , Cells, Cultured , Cellular Senescence/drug effects , Gene Expression Regulation , Heterochromatin , Humans , Receptors, Cytoplasmic and Nuclear/metabolism , Lamin B ReceptorABSTRACT
Mammalian circRNAs can influence different cellular processes by interacting with proteins and other nucleic acids. Here, we used ribonucleoprotein immunoprecipitation (RIP) analysis to identify systematically the circRNAs associated with the cancer-related protein AUF1. Among the circRNAs interacting with AUF1 in HeLa (human cervical carcinoma) cells, we focused on hsa_circ_0032434 (circPCNX), an abundant target of AUF1. Overexpression of circPCNX specifically interfered with the binding of AUF1 to p21 (CDKN1A) mRNA, thereby promoting p21 mRNA stability and elevating the production of p21, a major inhibitor of cell proliferation. Conversely, silencing circPCNX increased AUF1 binding to p21 mRNA, reducing p21 production and promoting cell division. Importantly, eliminating the AUF1-binding region of circPCNX abrogated the rise in p21 levels and rescued proliferation. Therefore, we propose that the interaction of circPCNX with AUF1 selectively prevents AUF1 binding to p21 mRNA, leading to enhanced p21 mRNA stability and p21 protein production, thereby suppressing cell growth.
Subject(s)
Cell Proliferation/genetics , Cyclin-Dependent Kinase Inhibitor p21/genetics , Heterogeneous Nuclear Ribonucleoprotein D0/metabolism , RNA, Circular/metabolism , 3' Untranslated Regions , Binding Sites , Cyclin-Dependent Kinase Inhibitor p21/biosynthesis , Cyclin-Dependent Kinase Inhibitor p21/metabolism , HeLa Cells , Humans , RNA, Circular/chemistry , RNA, Messenger/metabolismABSTRACT
BACKGROUND: As previous studies reported, gadolinium deposits in globus pallidus (GP) and dentate nucleus (DN) after repeated administrations of gadolinium-based contrast agents (GBCAs) and a signal intensity (SI) increase on T1-weighted images were related to linear GBCAs, not macrocyclic GBCAs. PURPOSE: To identify whether quantitative susceptibility mapping (QSM) could measure a subtle increase in magnetic susceptibility in DN and GP in patients after repeated administrations of gadoteric acid meglumine (Gd-DOTA). MATERIAL AND METHODS: In this study, 50 patients with cerebral tumors who had received at least three injections of Gd-DOTA (GBCA group) and 50 individuals without a history of GBCA injections (non-GBCA group) were included. The image data for QSM and T1-weighted images were reviewed. Spearman rank correlation was used to estimate the associations between the values (magnetic susceptibility of QSM and SI ratios of T1-weighted images) and the number of Gd-DOTA injections. RESULTS: The mean magnetic susceptibility of GP in GBCA group was 0.136 ± 0.031 ppm, which was significantly higher than that in control group (0.114 ± 0.030 ppm) (P = 0.001). In the GBCA group (n = 50), we found a substantial positive correlation between magnetic susceptibility of GP and the number of Gd-DOTA injections according to Spearman rank correlation coefficient (ρ = 0.673, P = 0.0001). There was a modest but significant correlation between magnetic susceptibility of DN and the number of Gd-DOTA injections (ρ = 0.311, P = 0.028). CONCLUSION: In comparison to the control group, the magnetic susceptibility of GP in the GBCA group was significantly higher and had a substantial positive association with the number of Gd-DOTA injections.