Ketamine has a rapid, obvious, and persistent antidepressant effect, but its underlying molecular mechanisms remain unknown. Recently, microRNAs (miRNAs) have emerged as important modulators of ketamine’s antidepressant effect. We investigated the alteration in miR-29b-3p in the brain of rats subjected to ketamine administration and chronic unpredictable mild stress (CUMS), and a sucrose preference test and forced swimming test were used to evaluate the rats’ depressive-like state. We used recombination adeno-associated virus (rAAV) or lentivirus-expressing miR-29b-3p to observe the change in metabotropic glutamate receptor 4 (GRM4). Cell culture and electrophysiological recordings were used to evaluate the function of miR-29b-3p. Ketamine dramatically increased miR-29b-3p expression in the prefrontal cortex of the normal rats. The dual luciferase reporter test confirmed that GRM4 was the target of miR-29b-3p. The miR-29b-3p levels were downregulated, while the GRM4 levels were upregulated in the prefrontal cortex of the depressive-like rats. The ketamine treatment increased miR-29b-3p expression and decreased GRM4 expression in the prefrontal cortex of the depressive-like rats and primary neurons. By overexpressing and silencing miR-29b-3p, we further validated that miR-29b-3p could negatively regulate GRM4. The silencing of miR-29b-3p suppressed the Ca2+ influx in the prefrontal cortex neurons. The miR-29b-3p overexpression contributed to cell survival, cytodendrite growth, increases in extracellular glutamate concentration, and cell apoptosis inhibition. The overexpression of miR-29b-3p by rAAV resulted in a noticeable relief of the depressive behaviors of the CUMS rats and a lower expression of GRM4. The miR-29b-3p/GRM4 pathway acts as a critical mediator of ketamine’s antidepressant effect in depressive-like rats and could be considered a potential therapeutic target for treating major depression disorder.
Post-operative cognitive dysfunction (POCD) is a complication of the central nervous system characterized by mental disorders, anxiety, personality changes and impaired memory. POCD occurs frequently after coronary artery bypass grafting (CABG) and can severely affect quality of life for patients. To date, the development of POCD biomarkers remains a challenge. Alterations in the expression of non-coding RNAs from brain tissue and peripheral blood have been linked to POCD. The present study aimed to detect the differential circular RNAs (circRNAs) in plasma exosomes of patients with POCD after CABG. The relative expression levels of circRNAs were analyzed using circRNA microarray analysis in the plasma exosomes of patients with POCD. Differentially altered circRNAs (P<0.05, fold change >1.5) were validated by reverse transcription-quantitative PCR in the plasma exosomes of patients with POCD. The target genes of the microRNAs were predicted using bioinformatics analysis. The functions and signaling pathways of these target genes were investigated by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes analyses. The microarray results indicated that the levels of nine circRNAs in patients with POCD were higher than those in the control subjects; and six circRNAs were at a lower level than those in control subjects. The RT-qPCR results from patients with POCD showed that only circRNA_089763 of the 15 circRNAs identified was significantly increased compared with control subjects. circRNA target gene prediction and functional annotation analysis showed significant enrichment in several GO terms and pathways associated with POCD. The present study provides evidence for the abnormal expression of POCD-induced circRNA_089763 in human plasma exosomes, as well as the involvement of POCD.
In our previous experiment, we found that there were abnormal levels of circRNA-089763 in the plasma exosomes of patients with postoperative cognitive dysfunction (POCD) after cardiac surgery. Therefore, the aim of this study was to further investigate the relationship between plasma circRNA-089763 level and POCD in elderly patients after non-cardiac surgery. A prospective cohort study was conducted to select elderly patients undergoing elective non-cardiac surgery. A total of 72 patients were enrolled in this study, and cognitive functions were assessed 1 day before and 3 days after surgery by a series of neuropsychological measurements. Next, patients were divided into POCD and non-POCD (NPOCD) groups according to the Z score method. Blood was collected the day before and 3 days after surgery, and the plasma circRNA-089763 level was detected by quantitative real-time polymerase chain reaction (qRT-PCR). Then, the difference and correlation in plasma circRNA-089763 levels between the POCD and NPOCD groups were analyzed. On the third day after surgery, the incidence of POCD was 30.56%. The relative level of circRNA-089763 in the POCD group was 2.41 times higher than that in the NPOCD group ( t = 4.711, p < 0.001), patients in POCD group had higher age ( t = 5.971, p < 0.001), higher American Society of Anesthesiologists classification (χ 2 = 14.726, p < 0.001), less years of education ( t = 2.449, p = 0.017), more intraoperative blood loss ( t = 3.196, p = 0.002), and higher visual analog scale (VAS) scores ( t = 10.45, p < 0.001). The binary logistic regression analysis showed that the circRNA-089763 level, age, and intraoperative blood loss were independently associated with POCD (OR: 2.75, 95% CI: 1.261–5.999, p = 0.011; OR: 1.32, 95% CI: 1.114–1.565, p = 0.001; OR: 1.017, 95% CI: 1.004–1.03, p = 0.011). These results demonstrated that the circRNA-089763 plasma level was related to POCD after non-cardiac surgery in elderly patients.
Background To evaluate the early prognosis and management of acute coronary involvement (ACI) in type A aortic dissection (ATAAD) patients without myocardial ischemia (MI). Methods We conducted a retrospective cohort study on a multicenter database. A total of 931 ATAAD patients without MI underwent thoracic aortic surgery between 2018 and 2019 in the Acute Aortic Syndrome Cooperation Network (AASCN) and were enrolled in our study. Patients were divided into two groups: ACI group and non-ACI group. Results There were 139 ACI patients (14.9%) and 792 non-ACI patients (85.1%) in our cohort. ACI group had higher 30-day mortality after surgery than non-ACI group (log-rank test: P = 0.028,Cox regression: hazard ratio [HR], 2.3; 95% confidence interval [95% CI], 1.1–5.39; P = 0.047), especially in sub-group of advanced age (53–80 years; HR, 4.0; 95% CI, 1.3–12.8; P = 0.017), low diastolic blood pressure (29-69 mmHg, HR, 3.8; 95% CI, 1.3–11.2; P = 0.018), low systolic blood pressure (51–119 mmHg, HR, 3.6; 95% CI, 1.1–12.4; P = 0.040), high body mass index (BMI;27.25–47.52 kg/m2; HR, 3.7; 95% CI, 1.3–10.7; P = 0.015) and high hemoglobin (>145 g/L; HR, 4.3; 95% CI, 1.2–16.0; P = 0.030). Acute renal failure was significant more in ACI group than non-ACI group (24.5% vs. 15.9%; P = 0.014). Conclusions ACI increases the short-term postoperative mortality and acute renal failure in ATAAD patients without MI. ATAAD patients with ACI may need a narrower control range of blood pressure even if without myocardial ischemia. Trial registration ChiCTR1900022637. Retrospectively registered 19 April 2019.
Our previous studies have revealed that long noncoding RNAs (lncRNAs), microRNAs (miRNAs), and genes were abnormally expressed in the pulmonary artery tissues of the chronic thromboembolic pulmonary hypertension (CTEPH) patients. We aim to establish the CTEPH-related miRNA-gene-lncRNA network for finding the core genes and associated miRNA and lncRNA in CTEPH patients.Firstly, the target genes of differential miRNAs were predicted by searching TargetScan databases, and the predicted target genes were intersected with the mRNAs from the gene chip. Secondly, the intersective genes were analyzed by the Gene Ontology function and Kyoto Encyclopedia of Genes and Genomes pathway software for obtaining differential intersective genes and then establish the miRNA-gene networks. Thirdly, the possible genes regulated by the differential lncRNAs from the gene chip were intersected with the above-screened mRNA to build the lncRNA-mRNA networks. Subsequently, the miRNA-gene-lncRNA networks were constructed according to the two networks above(miRNA-gene networks and lncRNA-mRNA networks). Finally, the core genes of the networks in the experimental group were screened according to Diffk > 0.6 and used to construct the miRNA-core gene-lncRNA networks of CTEPH.The pathway network, miRNA-mRNA network, lncRNA-mRNA networks, and miRNA-gene-lncRNA networks were successfully constructed. The core genes of the miRNA-gene-lncRNA networks (Diffk > 0.6) were the human Beta-type platelet-derived growth factor receptor (PDGFRB) and hypoxia-inducible factor-1a (HIF-1 A), the miRNAs-PDGFRB-lncRNAs and miRNAs-HIF1A-lncRNAs networks were constructed. Finally, miRNA-149-5p-PDGFRB-TCONS_l2_00020587-XLOC_l2_010723 and miRNA-338-5p/miRNA-199b-5p-HIF1 A-TCONS_l2_00020587-XLOC_l2_010723 were found in the analysis of the network.miRNA-149-5p-PDGFRB-lncRNA CTEPH-associated 1 (CTEPHA1) (TCONS_l2_00020587-XLOC_l2_ 010723) and miRNA-338-5p/miRNA-199b-5p-HIF1A-lncRNA CTEPHA1 are related to the development of CTEPH.(Int Heart J 2019; 60: 924-937)
To investigate the effects of ketamine on glucose uptake and glucose transporter (GLUT) expression in depressive-like mice. After HA1800 cells were treated with ketamine, 2-[N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)Amino]-2-Deoxyglucose (2-NBDG) was added to the cells to test the effects of ketamine on glucose uptake, production of lactate, and expression levels of GLUT, ERK1/2, AKT, and AMPK. Adult female C57BL/6 mice were subjected to chronic unpredictable mild stress (CUMS), 27 CUMS mice were randomly divided into the depression, ketamine (i.p.10 mg/kg), and FR180204 (ERK1/2 inhibitor, i.p.100 mg/kg) + ketamine group. Three mice randomly selected from each group were injected with 18F-FDG at 6 h after treatment. The brain tissue was collected at 6 h after treatment for p-ERK1/2 and GLUTs. Treatment with ketamine significantly increased glucose uptake, extracellular lactic-acid content, expression levels of GLUT3 and p-ERK in astrocytes and glucose uptake in the prefrontal cortex (P < 0.05), and the immobility time was significantly shortened in depressive-like mice (P < 0.01). An ERK1/2 inhibitor significantly inhibited ketamine-induced increases in the glucose uptake in depressive-like mice (P < 0.05), as well as prolonged the immobility time (P < 0.01). The expression levels of p-ERK1/2 and GLUT3 in depressive-like mice were significantly lower than those in normal control mice (P < 0.01). Ketamine treatment in depressive-like mice significantly increased the expression levels of p-ERK1/2 and GLUT3 in the prefrontal cortex (P < 0.01), whereas an ERK1/2 inhibitor significantly inhibited ketamine-induced increases (P < 0.01).Our present findings demonstrate that ketamine mitigated depressive-like behaviors in female mice by activating the ERK/GLUT3 signal pathway, which further increased glucose uptake in the prefrontal cortex.
Objective: To determine the effect of renal artery stenosis (RAS) resulting from acute type B aortic dissection (ATBAD) with thoracic endovascular aortic repair (TEVAR) on early prognosis in patients with ATBAD.Methods: A total of 129 ATBAD patients in the National Acute Aortic Syndrome Database (AASCN) who underwent TEVAR between 2019 and 2020 were enrolled in our study. Patients were divided into two groups: the RAS group and the non-RAS group.Results: There were 21 RAS patients (16.3%) and 108 non-RAS patients (83.7%) in our cohort. No patient in our cohort died during the 1-month follow-up. There was no significant difference in preoperative creatinine clearance rate (CCr) between the two groups (90.6 ± 46.1 μmol/L in the RAS group vs. 78.7 ± 39.2 μmol/L in the non-RAS group, P = 0.303) but the RAS group had a significantly lower estimated glomerular filtration rate (eGFR) than the non-RAS group (83.3 ± 25.0 vs. 101.9 ± 26.9 ml/min, respectively; P = 0.028).One month after TEVAR, CCr was significantly higher (99.0 ± 68.1 vs. 78.5 ± 25.8 ml/min, P = 0.043) and eGFR (81.7 ± 23.8 vs. 96.0 ± 20.0 ml/min, P = 0.017) was significantly lower in the RAS group than in the non-RAS group.Conclusions: In ATBAD, RAS could result in acute kidney injury (AKI) in the early stage after TEVAR. The RAS group had a high incidence of hypertension. These results suggest that patients with RAS may need further treatment.
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