MiR-98-5p plays a critical role in depression and antidepressant effect of ketamine.
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ABSTRACT:
SUBMITTER: Huang C
PROVIDER: S-EPMC8417029 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description: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.
| S-EPMC6204429 | biostudies-literature
Project description:BackgroundIntervertebral disk degeneration (IDD) is a serious public health problem associated with genetic and environmental factors. However, the pathogenic factors involved and the pathological mechanism of this disease still remain enigmatic.MethodsThe associated microarray was downloaded and further analyzed using statistical software R. The competing endogenous RNA (ceRNA) co-expression network was constructed to measure the meaningful correlated expression of differentially expressed genes. We further measured the expression of circARL15/miR-431-5p/DISC1 in IDD tissues. Cell proliferation and apoptosis were detected in NP cells transfected with a circARL15 overexpression plasmid and miR-431-5p mimics. The expression of DISC1 was detected by immunohistochemistry and Western blot analysis.ResultsWithin the ceRNA network, circARL15 is the most differentially expressed circular RNA. circARL15 was down-regulated in IDD and was negatively correlated with miR-431-5p and positively associated with DISC1. miR-431-5p was found to bind directly to circARL15 and DISC1. circARL15 inhibited nucleus pulposus cell apoptosis but promoted nucleus pulposus cell proliferation by targeting the miR-431-5p/DISC1 signaling pathway.ConclusioncircARL15/miR-431-5p/DISC1 is involved in the pathogenesis of IDD, which might be helpful in determining the diagnostic biomarkers and providing potential therapeutic targets for patients with IDD.
| S-EPMC8255806 | biostudies-literature
Project description:BackgroundClinical evidence that ketamine, a nonselective N-methyl-D-aspartate receptor (NMDAR) antagonist, has therapeutic effects within hours in people suffering from depression suggests that modulating glutamatergic neurotransmission is a fundamental step in alleviating the debilitating symptoms of mood disorders. Acutely, ketamine increases extracellular glutamate levels, neuronal excitability, and spontaneous γ oscillations, but it is unknown whether these effects are key to the mechanism of antidepressant action of ketamine.MethodsTwenty drug-free major depressive disorder patients received a single, open-label intravenous infusion of ketamine hydrochloride (.5 mg/kg). Magnetoencephalographic recordings were made approximately 3 days before and approximately 6.5 hours after the infusion, whereas patients passively received tactile stimulation to the right and left index fingers and also while they rested (eyes-closed). Antidepressant response was assessed by percentage change in Montgomery-Åsberg Depression Rating Scale scores.ResultsPatients with robust improvements in depressive symptoms 230 min after infusion (responders) exhibited increased cortical excitability within this antidepressant response window. Specifically, we found that stimulus-evoked somatosensory cortical responses increase after infusion, relative to pretreatment responses in responders but not in treatment nonresponders. Spontaneous somatosensory cortical γ-band activity during rest did not change within the same timeframe after ketamine in either responders or nonresponders.ConclusionsThese findings suggest NMDAR antagonism does not lead directly to increased cortical excitability hours later and thus might not be sufficient for therapeutic effects of ketamine to take hold. Rather, increased cortical excitability as depressive symptoms improve is consistent with the hypothesis that enhanced non-NMDAR-mediated glutamatergic neurotransmission via synaptic potentiation is central to the antidepressant effect of ketamine.
| S-EPMC3408548 | biostudies-literature
Project description:Brucella-caused brucellosis is one of the most widespread worldwide zoonoses. Lipopolysaccharide (LPS) of Brucella, which functions as pathogen-associated molecular patterns (PAMPs), is an important virulence factor that elicits protective antibodies. Per of B. melitensis is involved in the biosynthesis of the O-side chain of LPS. Autophagy is a crucial element of the innate immune response against intracellular pathogens including Brucella. In this study, we observed that autophagy was inhibited in RAW264.7 cells infected with Brucella melitensis ∆per. And, a high-throughput array-based screen and qRT-PCR validation were performed to identify the differentially expressed miRNAs in RAW264.7 cells infected with B. melitensis M5-90 ∆per. The results suggested that mmu-miR-146a-5p, mmu-miR-155-5p, mmu-miR-146b-5p, and mmu-miR-3473a were upregulated and mmu-miR-30c-5p was downregulated. During B. melitensis M5-90 ∆per infection, the increased expression of miR-146b-5p inhibited the autophagy activation in RAW264.7 cells. Using a bioinformatics approach, Tbc1d14 was predicted to be a potential target of miR-146b-5p. The results of a luciferase reporter assay indicated that miR-146b-5p directly targeted the 3'-UTR of Tbc1d14, and the interaction between miR-146b-5p and the 3'-UTR of Tbc1d14 was sequence-specific. High-throughput RNA-Seq-based screening was performed to identify differentially expressed genes in Tbc1d14-expressing RAW264.7 cells, and these were validated by qRT-PCR. Among the differentially expressed genes, four autophagy associated genes, IFNγ-inducible p47 GTPase 1 (IIGP1), nuclear receptor binding protein 2 (Nrbp2), transformation related protein 53 inducible nuclear protein 1 (Trp53inp1), and immunity-related GTPase family M member 1 (Irgm1), were obtained. Our findings provide important insights into the functional mechanism of LPS of B. melitensis.
| S-EPMC6995328 | biostudies-literature
Project description:Rapid diagnosis of pulmonary tuberculosis is an effective measure to prevent the spread of tuberculosis. However, the grim fact is that the new, rapid, and safe methods for clinical diagnosis are lacking. Moreover, although auto-lysosome is critical in clearing Mycobacterium tuberculosis, the pathological significance of microRNAs, as biomarkers of tuberculosis, in autophagosome maturation is unclear. Here, these microRNAs were investigated by Solexa sequencing and qPCR validation, and a potential diagnostic model was established by logistic regression. Besides that, the mechanism of one of the microRNAs involved in the occurrence of tuberculosis was studied. The results showed that the expression of miR-423-5p, miR-17-5p, and miR-20b-5p were significantly increased in the serum of patients with tuberculosis. The combination of these three microRNAs established a model to diagnose tuberculosis with an accuracy of 78.18%, and an area under the curve value of 0.908. Bioinformatics analysis unveiled miR-423-5p as the most likely candidate in regulating autophagosome maturation. The up-regulation of miR-423-5p could inhibit autophagosome maturation through suppressing autophagosome-lysosome fusion in macrophages. Further investigations showed that VPS33A was the direct target of miR-423-5p, and the two CUGCCCCUC domains in VPS33A 3'-UTR were the direct regulatory sites for miR-423-5p. In addition, an inverse correlation between VPS33A and miR-423-5p was found in peripheral blood mononuclear cells of patients with tuberculosis. Since the inhibition of autolysosome formation plays a critical role in tuberculosis occurrence, our findings suggests that miR-423-5p could suppress autophagosome-lysosome fusion by post-transcriptional regulation of VPS33A, which might be important for the occurrence of active tuberculosis.
| S-EPMC6455132 | biostudies-literature
Project description:Non-small cell lung cancer (NSCLC) is the most deadly cancer in the world due to its often delayed diagnosis. Identification of biomarkers with high sensitivity, specificity, and accessibility for early detection, such as circulating microRNAs, is therefore of utmost importance. In the present study, we identified a significantly higher expression of miR-146a-5p in the serum and tissue samples of NSCLC patients than that of the healthy controls. In parallel, miR-146a-5p was also highly expressed in three human NSCLC adenocarcinoma-cell lines (A549, H1299, and H1975) compared to the human bronchial epithelium cell line (HBE). By dual-luciferase reporter assay and manipulation of the expressions of miR-146a-5p and its target gene, tumor necrosis factor receptor-associated factor 6 (TRAF6), we showed that the functional effects of miR-146a-5p on NSCLC cell survival and migration were mediated by direct binding to and suppression of TRAF6. Overexpression of TRAF6 sufficiently reversed miR-146a-5p-induced cancer cell proliferation, migration, and apoptosis resistance. Our data implied that miR-146a-5p/TRAF6/NF-?B-p65 axis could be a promising diagnostic marker and a therapeutic target for NSCLC.
| S-EPMC7493784 | biostudies-literature
Project description:Accumulating evidence underscores the utility of ketamine in treating severely treatment-resistant depressed patients. We investigated the relationship between the rapid antidepressant effects of ketamine and hippocampal volume, a biomarker of antidepressant treatment outcome. We gave 16 medication-free, major depressive disorder (MDD) patients a single, sub-anesthetic dose infusion of ketamine (0.5 mg/kg, over 40 min). We assessed depression severity pre-treatment, and at 24 h post-treatment, with the Montgomery-Åsberg Depression Rating Scale (MADRS). Prior to treatment, patients underwent magnetic resonance imaging (MRI) to estimate their hippocampal volume: We obtained viable MRI data in 13 patients. Delta MADRS (post- minus pre-treatment) was significantly correlated with the pre-treatment volumes of the left hippocampus (r = 0.66; p = 0.01), but not the right hippocampus (r = 0.49; p = 0.09). The correlation between delta MADRS and the left hippocampus remained high (r > 0.6; p = 0.13), after controlling for several demographic and clinical variables, although the p value increased due to the reduced degree of freedom (df = 5). Ketamine exerts enhanced antidepressant effects in patients with a relatively smaller hippocampus, a patient population that has been repeatedly shown to be refractory to traditional antidepressants.
| S-EPMC4852551 | biostudies-literature
Project description:BackgroundMajor depressive disorder (MDD) and treatment-resistant depression (TRD) represent a global source of societal and health burden. To advise proper management of inflammation-related depression among TRD patients, it is important to identify therapeutic clinical treatments. A key factor is related to proinflammatory cytokines such as interleukin- (IL-) 1β, IL-6, and tumor necrosis factor- (TNF-) α which have been implicated in the pathogenesis of depressive symptoms in MDD patients. Ketamine may provide an anti-inflammatory therapeutic strategy by targeting proinflammatory pathways associated with depressive disorders, which may be exacerbated in the ageing population with TRD.ObjectiveDespite a burgeoning body of literature demonstrating that inflammation is linked to TRD, there is still a lack of comprehensive research on the relationship between proinflammatory biomarkers and ketamine's antidepressant effect on TRD patients.MethodThe Cochrane Library and PubMed/MEDLINE databases were systematically searched from inception up to February 1, 2022, adopting broad inclusion criteria to assess clinical topics related to the impact of ketamine on inflammatory cytokines in TRD patients. The present work is in compliance with the World Health Organization Rapid Review Guide.ResultsFive out of the seven studies examined in this review show that ketamine infusion may reduce depressive symptoms with a quick start of effect on TRD patients. Based on the Montgomery-Åsberg Depression Rating Scale (MADRS) and Hamilton Depression Rating Scale (HAM-D) scores, the overall response rate for ketamine was 56%; that is, 56% of those treated with ketamine had MADRS/HAM-D scores decreased by at least 50%.ConclusionsWhile the anti-inflammatory effects of ketamine modulate specific proinflammatory cytokines, its rapid antidepressant effect on TRD patients remains inconsistent. However, our study findings can provide a reliable basis for future research on how to improve systemic inflammatory immune disorders and mental health. We suggest that ketamine infusion may be part of a comprehensive treatment approach in TRD patients with elevated levels of depression-specific inflammatory biomarkers.
| S-EPMC9507757 | biostudies-literature
Project description:Ketamine has rapid and sustained antidepressant effects in patients with treatment resistant depression (TRD). However, the underlying mechanisms of action are not well understood. There is increasing evidence that TRD is associated with a pro-inflammatory state and that ketamine may inhibit inflammatory cytokine production. We investigated whole blood transcriptional profiles related to TRD and gene expression changes associated with treatment response to ketamine. Whole blood was collected at baseline (21 healthy controls [HC], 26 patients with TRD) and then again in patients with TRD 24 hours following a single intravenous infusion of ketamine (0.5 mg/kg). We performed RNA-sequencing and compared a) baseline transcriptional profiles between patients with TRD and HC, b) responders vs. non-responders before ketamine treatment, and c) gene expression signatures associated with clinical improvement. At baseline, patients with TRD compared to HC were characterized by a gene expression signature indicative of interferon signaling pathway activation. Prior to ketamine administration, the metabotropic glutamate receptor gene GRM2 and the ionotropic glutamate receptor gene GRIN2D were upregulated in responders compared to non-responders. Ketamine response was associated with the downregulation of multiple genes coding for pro-inflammatory cytokines, the predicted inhibition of several interferon signaling associated upstream regulators and the downregulation of Indoleamine 2,3-Dioxygenase 1 (IDO1). The current study indicates that response to ketamine may be associated with up-regulation of glutamate receptors at baseline, and linked to transcriptional changes indicative of an anti-inflammatory response following ketamine. One specific anti-inflammatory mechanism might be the downregulation of IDO1 via inhibition of the interferon pathway.
2021-10-13 | GSE185855 | GEO
Project description:BACKGROUND: Pim-1 kinase is a proto-oncogene and its dysregulation contributes to tumorigenesis and progression of a variety of malignancies. Pim-1 was suggested as a therapeutic target of cancers. The functional relevance of Pim-1 and the mechanism underlying its dysregulation in lung tumorigenesis remained unclear. This study aimed to investigate if Pim-1 has important functions in non-small-cell lung cancer (NSCLC) by: 1) evaluating the clinicopathologic significance of Pim-1 through analysing its expression in 101 human NSCLCs tissues using quantitative PCR, Western Blot and immunohistochemical studies, 2) determining its role in NSCLC and drug resistance using in vitro assays, and 3) investigating the regulatory mechanism of Pim-1 dysregulation in lung tumorigenesis. RESULTS: Pim-1 was upregulated in 66.2% of the lung tumor tissues and its expression was significantly related to advanced stage (P?=?0.019) and lymph node metastasis (P?=?0.026). Reduced Pim-1 expression suppressed NSCLC cell growth, cell cycle progression and migration in vitro. Pim-1 was a novel target of miR-486-5p determined by luciferase report assay, and ectopic miR-486-5p expression in cancer cells reduced Pim-1 expression. Furthermore, eukaryotic translation initiation factor 4E (eIF4E) controlled the synthesis of Pim-1 in NSCLC cells, and its expression was positively associated with that of Pim-1 in NSCLC tissue specimens (r?=?0.504, p?<?0.001). The downregulated miR-486-5p and upregulated eIF4E in NSCLC cells led to the overexpression of Pim-1 by relieving the inhibitory effect of the 3'-UTR or 5'-UTR of Pim-1 mRNA, respectively. Moreover, Pim-1 knockdown sensitized NSCLC cells to cisplatin and EGFR tyrosine kinase inhibitor, gefitinib. CONCLUSIONS: Pim-1 kinase could be a critical survival signaling factor in NSCLC, and regulated by miR-486-5p and eIF4E. Pim-1 kinase may provide a potential target for diagnosis and treatment for lung cancer.
| S-EPMC4213487 | biostudies-literature