Effects of esketamine and fluoxetine on depression-like behaviors in chronic variable stress: a role of plasma inflammatory factors.

Mounting evidence has identified the rapid and sustained antidepressive and anxiolytic-like effects of esketamine. However, the underlying mechanism of this no-monoamine target rapid-onset antidepressant is still underexplored. Immune-inflammatory pathways and cell-mediated immune activation, mainly including inflammatory cytokines in plasma, play a pivotal role in the pathogenesis of major depressive disorder and are also a potential therapeutic target for MDD. The current study was designed to clarify the role of esketamine on the expression of plasma cytokines in a depressive-like model introduced by chronic variable stress (CVS). In this study, a 21-day consecutive CVS protocol was applied to produce depressive- and anxiety-like behaviors. After the single dose or 7-day repeated administration of esketamine or fluoxetine, the depressive- and anxiety-like behaviors and the expression of inflammatory cytokines in plasma were examined. Both a single dose of esketamine and 7-days repeated fluoxetine administration elicited anti-depressive and anxiolytic effects in mice exposed to CVS. Additionally, CVS produced significant changes in the plasma inflammatory factors, notably increasing the expression of IL-1ß, IL-6, IL-8, IL-17A, TNFα, IL-4, IL-9, IL-24, IL-37, IFN-ß, and CXCL12, while reducing IL-10 and IL-33. With the administration of esketamine and fluoxetine, CVS-produced inflammatory disturbances were partially normalized. Together, our findings provide a novel insight that acute esketamine treatment could rescue CVS-produced depressive-like and anxiety-like behaviors in mice by normalizing the expression of inflammatory cytokines; this effect was similar to the repeated administration of fluoxetine. These results contributed to the understating of rapid anti-depressant effects elicited by esketamine.

Electroacupuncture treatment ameliorates depressive-like behavior and cognitive dysfunction via CB1R dependent mitochondria biogenesis after experimental global cerebral ischemic stroke.

Introduction: This study aimed to identify the effect of electroacupuncture (EA) treatment on post-stroke depression (PSD) and explore whether cannabinoid receptor 1 (CB1R)-mediated mitochondrial biogenesis accounts for the treatment effect of EA. Methods: The PSD mouse model was induced by a consecutive 14-day chronic unpredictable stress operation after 7 days of recovery from the bilateral common carotid artery occlusion surgery. Either EA treatment or sham stimulation was performed for 14 consecutive days from Day 7 after the BCCAO operation. Subjects' PSD-like behaviors were tested via open field test, sucrose preference test, novelty suppressed feeding test, tail suspension test, and forced swim test, and subjects' cognitive function was examined using Y-maze and novelty object recognition test. In addition, the levels of CB1R, mitochondrial biogenesis-related proteins (nuclear transcription factor 1, NRF1; mitochondrial transcription factor A, TFAM), proteins related to mitochondrial function (Cytochrome C, Cyto C; AIF, COX IV), and mitochondrial DNA were measured. To elucidate the role of CB1R in EA treatment, CB1R antagonists AM251 and CB1R-shRNA were given to mice before EA treatment. Likewise, subjects' depressive-like behaviors, cognitive function, mitochondrial function, and mitochondrial biogenesis were examined after the PSD procedure. Results: It has been showed that EA successfully ameliorated depressive-like behaviors, improved cognitive dysfunctions, and upregulated CB1R, NRF1 and TFAM expressions. However, the supplementation of AM251 and CB1R-shRNA blocked the antidepressant-like effects generated by EA, and EA failed to improve cognitive dysfunction, upregulate CB1R protein expression, and increase mitochondrial function and biogenesis. Conclusion: Altogether, these results indicated that EA ameliorated PSD-like behaviors in mice, improved cognitive dysfunctions after PSD, and promoted mitochondrial biogenesis by activating CB1R, a novel mechanism underlying EA's antidepressant-like effects in treating PSD.

Integrating multiple machine learning algorithms for prognostic prediction of gastric cancer based on immune-related lncRNAs.

Background: Long non-coding RNAs (lncRNAs) play an important role in the immune regulation of gastric cancer (GC). However, the clinical application value of immune-related lncRNAs has not been fully developed. It is of great significance to overcome the challenges of prognostic prediction and classification of gastric cancer patients based on the current study. Methods: In this study, the R package ImmLnc was used to obtain immune-related lncRNAs of The Cancer Genome Atlas Stomach Adenocarcinoma (TCGA-STAD) project, and univariate Cox regression analysis was performed to find prognostic immune-related lncRNAs. A total of 117 combinations based on 10 algorithms were integrated to determine the immune-related lncRNA prognostic model (ILPM). According to the ILPM, the least absolute shrinkage and selection operator (LASSO) regression was employed to find the major lncRNAs and develop the risk model. ssGSEA, CIBERSORT algorithm, the R package maftools, pRRophetic, and clusterProfiler were employed for measuring the proportion of immune cells among risk groups, genomic mutation difference, drug sensitivity analysis, and pathway enrichment score. Results: A total of 321 immune-related lncRNAs were found, and there were 26 prognostic immune-related lncRNAs. According to the ILPM, 18 of 26 lncRNAs were selected and the risk score (RS) developed by the 18-lncRNA signature had good strength in the TCGA training set and Gene Expression Omnibus (GEO) validation datasets. Patients were divided into high- and low-risk groups according to the median RS, and the low-risk group had a better prognosis, tumor immune microenvironment, and tumor signature enrichment score and a higher metabolism, frequency of genomic mutations, proportion of immune cell infiltration, and antitumor drug resistance. Furthermore, 86 differentially expressed genes (DEGs) between high- and low-risk groups were mainly enriched in immune-related pathways. Conclusion: The ILPM developed based on 26 prognostic immune-related lncRNAs can help in predicting the prognosis of patients suffering from gastric cancer. Precision medicine can be effectively carried out by dividing patients into high- and low-risk groups according to the RS.

Effects of (S)-ketamine on depression-like behaviors in a chronic variable stress model: a role of brain lipidome.

Introduction: Compelling evidence indicates that a single sub-anesthetic dose of (S)-ketamine elicits rapid and robust antidepressant effects. However, the underlying mechanisms behind the antidepressant effects of (S)-ketamine remain unclear. Methods: Here, using a chronic variable stress (CVS) model in mice, we analyzed changes inthe lipid compositions of the hippocampus and prefrontal cortex (PFC) with a mass spectrometry-based lipidomic approach. Results: Similar to previous research outcomes, the current study also showed that (S)-ketamine reversed depressive-like behaviors in mice produced by CVS procedures. Moreover, CVS induced changes inthe lipid compositions of the hippocampus and PFC, notably in the contents of sphingolipids, glycerolipids, and fatty acyls. With the administration of (S)-ketamine, CVS-induced lipid disturbances were partially normalized, particularly in the hippocampus. Conclusion: Altogether, our results indicated that (S)-ketamine could rescue CVS-induced depressive-like behaviors in mice through region-specific modulation of the brain lipidome, contributing to the understanding of (S)-ketamine's antidepressant effects.

Emotional Blunting in Patients With Major Depressive Disorder: A Brief Non-systematic Review of Current Research.

Emotional blunting is frequently reported by patients with major depressive disorder (MDD) and has been identified as one of the most prominent side effects of antidepressants leading to medication discontinuation. However, antidepressant-induced emotional blunting remains largely unexplored-there lacks a clinical definition of this condition, and no agreeing conclusion has been reached regarding its etiology. Current research suggests that the onset of diminished emotional response may be related to antidepressant dose, with higher doses being more likely to induce emotional blunting. Consequently, most clinicians either reduce the dose or switch to another drug when treating this symptom. Overall, more comprehensive clinical assessments or interviews specifically designed to evaluate antidepressant-induced emotional blunting in MDD patients are in need to elucidate the neuropsychological mechanisms behind this increasingly prevalent symptom.

miR-137 and its target T-type CaV 3.1 channel modulate dedifferentiation and proliferation of cerebrovascular smooth muscle cells in simulated microgravity rats by regulating calcineurin/NFAT pathway.

OBJECTIVES: Postflight orthostatic intolerance has been regarded as a major adverse effect after microgravity exposure, in which cerebrovascular adaptation plays a critical role. Our previous finding suggested that dedifferentiation of vascular smooth muscle cells (VSMCs) might be one of the key contributors to cerebrovascular adaptation under simulated microgravity. This study was aimed to confirm this concept and elucidate the underlying mechanisms. MATERIALS AND METHODS: Sprague Dawley rats were subjected to 28-day hindlimb-unloading to simulate microgravity exposure. VSMC dedifferentiation was evaluated by ultrastructural analysis and contractile/synthetic maker detection. The role of T-type CaV 3.1 channel was revealed by assessing its blocking effects. MiR-137 was identified as the upstream of CaV 3.1 channel by luciferase assay and investigated by gain/loss-of-function approaches. Calcineurin/nuclear factor of activated T lymphocytes (NFAT) pathway, the downstream of CaV 3.1 channel, was investigated by detecting calcineurin activity and NFAT nuclear translocation. RESULTS: Simulated microgravity induced the dedifferentiation and proliferation in rat cerebral VSMCs. T-type CaV 3.1 channel promoted the dedifferentiation and proliferation of VSMC. MiR-137 and calcineurin/NFATc3 pathway were the upstream and downstream signalling of T-type CaV 3.1 channel in modulating the dedifferentiation and proliferation of VSMCs, respectively. CONCLUSIONS: The present work demonstrated that miR-137 and its target T-type CaV 3.1 channel modulate the dedifferentiation and proliferation of rat cerebral VSMCs under simulated microgravity by regulating calcineurin/NFATc3 pathway.

BMAL1 Disrupted Intrinsic Diurnal Oscillation in Rat Cerebrovascular Contractility of Simulated Microgravity Rats by Altering Circadian Regulation of miR-103/CaV1.2 Signal Pathway.

The functional and structural adaptations in cerebral arteries could be one of the fundamental causes in the occurrence of orthostatic intolerance after space flight. In addition, emerging studies have found that many cardiovascular functions exhibit circadian rhythm. Several lines of evidence suggest that space flight might increase an astronaut's cardiovascular risks by disrupting circadian rhythm. However, it remains unknown whether microgravity disrupts the diurnal variation in vascular contractility and whether microgravity impacts on circadian clock system. Sprague-Dawley rats were subjected to 28-day hindlimb-unweighting to simulate the effects of microgravity on vasculature. Cerebrovascular contractility was estimated by investigating vasoconstrictor responsiveness and myogenic tone. The circadian regulation of CaV1.2 channel was determined by recording whole-cell currents, evaluating protein and mRNA expressions. Then the candidate miRNA in relation with Ca2+ signal was screened. Lastly, the underlying pathway involved in circadian regulation of cerebrovascular contractility was determined. The major findings of this study are: (1) The clock gene BMAL1 could induce the expression of miR-103, and in turn modulate the circadian regulation of CaV1.2 channel in rat cerebral arteries at post-transcriptional level; and (2) simulated microgravity disrupted intrinsic diurnal oscillation in rat cerebrovascular contractility by altering circadian regulation of BMAL1/miR-103/CaV1.2 signal pathway.

Optogenetic Stimulation Enhanced Neuronal Plasticities in Motor Recovery after Ischemic Stroke.

Motor capability recovery after ischemic stroke involves dynamic remodeling processes of neural connectomes in the nervous system. Various neuromodulatory strategies combining direct stimulating interventions with behavioral trainings for motor recovery after ischemic stroke have been developed. However, the effectiveness of these interventions varies widely due to unspecific activation or inhibition of undefined neuronal subtypes. Optogenetics is a functional and structural connection-based approach that can selectively activate or inhibit specific subtype neurons with a higher precision, and it has been widely applied to build up neuronal plasticities of the nervous system, which shows a great potential in restoring motor functions in stroke animal models. Here, we reviewed neurobiological mechanisms of enhanced brain plasticities underlying motor recovery through the optogenetic stimulation after ischemic stroke. Several brain sites and neural circuits that have been previously proven effective for motor function rehabilitation were identified, which would be helpful for a more schematic understanding of effective neuronal connectomes in the motor function recovery after ischemic stroke.

Acid sphingomyelinase mediates the noise-induced liver disorder in mice.

Noise-induced structural and functional disorder of the liver has been realized, but the underlying mechanism remains to be characterized, which has limited the introduction of precautious measures. Over-activation of acid sphingomyelinase (ASM)/ceramide (Cer) pathway takes centre stage in hepatocyte injury entailed by various stimulus. We aimed to investigate whether it mediated the noise elicited liver disorder on infrastructure, lipid metabolism, apoptosis, and oxidative stress. Mice were exposed to broad band noise (20-20k Hz, 90-110 dB) for 1, 3, 5 or 7 days by 3 hr/d. Doxepin hydrochloride (DOX), an ASM inhibitor was given by 5 mg/kg/d gavage. We showed that 5 or 7 days intense, broad band noise exposure caused significant infrastructure derangement and lipid droplets storage in hepatocytes. The content of cholesterol, free fatty acids or triglyceride was increased significantly in liver tissue upon noise stimulation. Moreover, the noise promoted apoptosis and superoxide generation in hepatocytes significantly, enhancing activity of aspartate aminotransferase (AST) or alanine amino transferase (ALT) in serum. Acid sphingomyelinase activity and Cer generation in liver tissue were elevated by noise exposure, which was normalized with DOX administrated. Accordingly, DOX alleviated steatosis, apoptosis, oxidative stress and enzymatic change in hepatocytes or serum of noise exposed mice substantially. In summary, our results suggest the ASM/Cer pathway contributes to the broad band noise elicited liver damage in mice.

Large-Scale Analysis of Drug Side Effects via Complex Regulatory Modules Composed of microRNAs, Transcription Factors and Gene Sets.

Identifying the occurrence mechanism of drug-induced side effects (SEs) is critical for design of drug target and new drug development. The expression of genes in biological processes is regulated by transcription factors(TFs) and/or microRNAs. Most of previous studies were focused on a single level of gene or gene sets, while studies about regulatory relationships of TFs, miRNAs and biological processes are very rare. Discovering the complex regulating relations among TFs, gene sets and miRNAs will be helpful for researchers to get a more comprehensive understanding about the mechanism of side reaction. In this study, a framework was proposed to construct the relationship network of gene sets, miRNAs and TFs involved in side effects. Through the construction of this network, the potential complex regulatory relationship in the occurrence process of the side effects was reproduced. The SE-gene set network was employed to characterize the significant regulatory SE-gene set interaction and molecular basis of accompanied side effects. A total of 117 side effects complex modules including four types of regulating patterns were obtained from the SE-gene sets-miRNA/TF complex regulatory network. In addition, two cases were used to validate the complex regulatory modules which could more comprehensively interpret occurrence mechanism of side effects.

IGSA: Individual Gene Sets Analysis, including Enrichment and Clustering.

Analysis of gene sets has been widely applied in various high-throughput biological studies. One weakness in the traditional methods is that they neglect the heterogeneity of genes expressions in samples which may lead to the omission of some specific and important gene sets. It is also difficult for them to reflect the severities of disease and provide expression profiles of gene sets for individuals. We developed an application software called IGSA that leverages a powerful analytical capacity in gene sets enrichment and samples clustering. IGSA calculates gene sets expression scores for each sample and takes an accumulating clustering strategy to let the samples gather into the set according to the progress of disease from mild to severe. We focus on gastric, pancreatic and ovarian cancer data sets for the performance of IGSA. We also compared the results of IGSA in KEGG pathways enrichment with David, GSEA, SPIA, ssGSEA and analyzed the results of IGSA clustering and different similarity measurement methods. Notably, IGSA is proved to be more sensitive and specific in finding significant pathways, and can indicate related changes in pathways with the severity of disease. In addition, IGSA provides with significant gene sets profile for each sample.

28-Day hindlimb unweighting reduces expression of Rho kinase and inhibits its effects in femoral artery of rat

Previous studies have demonstrated inconsistent roles of Rho kinase (ROCK) in the decreased vasoconstriction of rat hindquarter vessels induced by hindlimb unweighting (HU). The present study was designed to determine the unclear role of ROCK in the mediation of HU-induced decreased femoral arterial vasoconstriction. 28-day HU rat was adopted as the animal model. With or without Y-27632, a ROCK inhibitor, isometric force of femoral artery was measured. The expression of ROCK and its effects on downstream targets were also examined. Results showed that (1) HU caused a significant decrease of the phenylephrine (PE)-evoked and potassium chloride (KCl)-evoked femoral arterial vasoconstriction (P < 0.05), confirming the functional findings by previous studies. (2) Inhibition of ROCK with Y-27632 produced an equal reduction of the vasoconstriction in CON and HU. (3) HU significantly decreased ROCK II expression and the effects of ROCK on myosin light-chain phosphatase (MLCP) and MLC (P < 0.05), but increased p65 nuclear translocation (P < 0.05) and inducible nitric oxide synthase (iNOS) expression (P < 0.05). (4) HU significantly (P < 0.05) increased NO production in femoral arteries, with Y-27632 significantly (P < 0.01) amplifying this effect. These findings have revealed that 28-day HU reduced the expression and effects of ROCK on downstream targets both directly (MLCP and MLC) and possibly indirectly (NF-κB/iNOS/NO pathway) related to vasoconstriction in femoral arteries

Identifying the causative proteins of similar side effect pairs to explore the common molecular basis of these side effects.

Drug side effects, or adverse drug reactions (ADRs), have become a major public health concern and often cause drug development failure and withdrawal. Some ADRs always occur concomitantly. Therefore, identifying these ADRs and their common molecular basis can better promote their prevention and treatment. In this paper we predicted the potential proteins for ADR pairs with similar mechanisms based on three layers of information: (i) the drug co-occurrence between a pair of ADRs; (ii) the correlation between a protein and an ADR pair based on the co-occurrence of drugs and (iii) the interaction between these proteins within the protein-protein interaction (PPI) network. The methods of randomization and functional annotation are used to investigate and analyze the relation between causative proteins and similar ADR pairs. The prediction accuracy of the relation between similar ADR pairs and related proteins reached 80%, and it increases with the number of drugs shared by the ADR pairs. From the ADR network made of single ADRs from predicted similar ADR pairs, we found that some ADRs are involved in multiple ADR pairs. The functional analysis of these ADR-related proteins suggests that a similar molecular basis is shared by multiple ADR pairs containing the same ADR, and these ADR pairs are almost caused by the same drug sets. The results of this study are reliable and provide a theoretical basis for the better prevention and treatment of ADRs that always occur concomitantly.

28-Day hindlimb unweighting reduces expression of Rho kinase and inhibits its effects in femoral artery of rat.

Previous studies have demonstrated inconsistent roles of Rho kinase (ROCK) in the decreased vasoconstriction of rat hindquarter vessels induced by hindlimb unweighting (HU). The present study was designed to determine the unclear role of ROCK in the mediation of HU-induced decreased femoral arterial vasoconstriction. 28-day HU rat was adopted as the animal model. With or without Y-27632, a ROCK inhibitor, isometric force of femoral artery was measured. The expression of ROCK and its effects on downstream targets were also examined. Results showed that (1) HU caused a significant decrease of the phenylephrine (PE)-evoked and potassium chloride (KCl)-evoked femoral arterial vasoconstriction (P < 0.05), confirming the functional findings by previous studies. (2) Inhibition of ROCK with Y-27632 produced an equal reduction of the vasoconstriction in CON and HU. (3) HU significantly decreased ROCK II expression and the effects of ROCK on myosin light-chain phosphatase (MLCP) and MLC (P < 0.05), but increased p65 nuclear translocation (P < 0.05) and inducible nitric oxide synthase (iNOS) expression (P < 0.05). (4) HU significantly (P < 0.05) increased NO production in femoral arteries, with Y-27632 significantly (P < 0.01) amplifying this effect. These findings have revealed that 28-day HU reduced the expression and effects of ROCK on downstream targets both directly (MLCP and MLC) and possibly indirectly (NF-κB/iNOS/NO pathway) related to vasoconstriction in femoral arteries.

Drug repositioning by applying 'expression profiles' generated by integrating chemical structure similarity and gene semantic similarity.

Drug repositioning, also known as drug repurposing or reprofiling, is the process of finding new indications for established drugs. Because drug repositioning can reduce costs and enhance the efficiency of drug development, it is of paramount importance in medical research. Here, we present a systematic computational method to identify potential novel indications for a given drug. This method utilizes some prior knowledge such as 3D drug chemical structure information, drug-target interactions and gene semantic similarity information. Its prediction is based on another form of 'expression profile', which contains scores ranging from -1 to 1, reflecting the consensus response scores (CRSs) between each drug of 965 and 1560 proteins. The CRS integrates chemical structure similarity and gene semantic similarity information. We define the degree of similarity between two drugs as the absolute value of their correlation coefficients. Finally, we establish a drug similarity network (DSN) and obtain 33 modules of drugs with similar modes of action, determining their common indications. Using these modules, we predict new indications for 143 drugs and identify previously unknown indications for 42 drugs without ATC codes. This method overcomes the instability of gene expression profiling derived from experiments due to experimental conditions, and predicts indications for a new compound feasibly, requiring only the 3D structure of the compound. In addition, the high literature validation rate of 71.8% also suggests that our method has the potential to discover novel drug indications for existing drugs.

A sensitive method for computing GO-based functional similarities among genes with 'shallow annotation'.

Methods for computing similarities among genes have attracted increasing attention for their applications in gene clustering, gene expression data analysis, protein interaction prediction and evaluation. To address the need for automatically computing functional similarities of genes, an important class of methods that computes functional similarities by comparing Gene Ontology (GO) annotations of genes has been developed. However, all of the currently available methods have some drawbacks; for example, they either ignore the specificity of the GO terms or do not consider the information contained within the GO structure. As a result, the existing methods perform weakly when the genes are annotated with 'shallow annotations'. Here, we propose a new method to compute functional similarities among genes based on their GO annotations and compare it with the widely-used G-SESAME method. The results show that the new method reliably distinguishes functional similarities among genes and demonstrate that the method is especially sensitive to genes with 'shallow annotations'. Moreover, our method has high correlations with sequence and EC similarities.