Depression is a prevalent mental disorder that affects numerous individuals, manifesting as persistent anhedonia, sadness, and hopelessness. Despite extensive research, the exact causes and optimal treatment approaches for depression remain unclear. Extracellular vesicles (EVs), which carry biological molecules such as proteins, lipids, nucleic acids, and metabolites, have emerged as crucial players in both pathological and physiological processes. EVs derived from various sources exert distinct effects on depression. Specifically, EVs released by neurons, astrocytes, microglia, oligodendrocytes, immune cells, stem cells, and even bacteria contribute to the pathogenesis of depression. Moreover, there is growing interest in potential of EVs as diagnostic and therapeutic tools for depression. This review provides a comprehensive overview of recent research on EVs from different sources, their roles in depression, and their potential clinical applications.

Unsuccessful response to several courses of antidepressants is a core feature of treatment-resistant depression (TRD), a severe condition that affects a third of patients with depression treated with conventional pharmacotherapy. However, the molecular mechanisms underlying TRD remain poorly understood. Here, we assessed the successful vs. unsuccessful response to ketamine (KET) in chronically stressed mice that failed to respond to initial treatment with fluoxetine (FLX) as a rodent model of TRD and characterized the associated transcriptional profiles in the nucleus accumbens (NAc) using RNA-sequencing. We observed that failed treatment with FLX exerts a priming effect that promotes behavioral and transcriptional responses to subsequent ketamine treatment. We also identified specific gene networks that are linked to both susceptibility to stress and resistance to antidepressant response. Collectively, these findings offer valuable insights into the molecular mechanisms underlying antidepressant resistance and help address a critical gap in preclinical models of TRD.

The clinical presentations of dry eye disease (DED) and depression (DEP) often comanifest. However, the robustness and the mechanisms underlying this association were undetermined.

To this end, we set up a three-segment study that employed multimodality results (meta-analysis, genome-wide association study [GWAS] and Mendelian randomization [MR]) to elucidate the association, common pathways and causality between DED and DEP.

A meta-analysis comprising 26 case-control studies was first conducted to confirm the DED-DEP association. Next, we performed a linkage disequilibrium (LD)-adjusted GWAS and targeted phenotype association study (PheWAS) in East Asian TW Biobank (TWB) and European UK Biobank (UKB) populations. Single-nucleotide polymorphisms (SNPs) were further screened for molecular interactions and common pathways at the functional gene level. To further elucidate the activated pathways in DED and DEP, a systemic transcriptome review was conducted on RNA sequencing samples from the Gene Expression Omnibus. Finally, 48 MR experiments were implemented to examine the bidirectional causation between DED and DEP.

Our meta-analysis showed that DED patients are associated with an increased DEP prevalence (OR = 1.83), while DEP patients have a concurrent higher risk of DED (OR = 2.34). Notably, cross-disease GWAS analysis revealed that similar genetic architecture (rG = 0.19) and pleiotropic functional genes contributed to phenotypes in both diseases. Through protein-protein interaction and ontology convergence, we summarized the pleiotropic functional genes under the ontology of immune activation, which was further validated by a transcriptome systemic review. Importantly, the inverse variance-weighted (IVW)-MR experiments in both TWB and UKB populations (p value <0.001) supported the bidirectional exposure-outcome causation for DED-to-DEP and DEP-to-DED. Despite stringent LD-corrected instrumental variable re-selection, the bidirectional causation between DED and DEP remained.

With the multi-modal evidence combined, we consolidated the association and causation between DED and DEP.

Major depressive disorder (MDD) is a severe mental illness characterized by a lack of objective biomarkers. Mounting evidence suggests there are extensive transcriptional molecular changes in the prefrontal cortex (PFC) of individuals with MDD. However, it remains unclear whether there are specific genes that are consistently altered and possess diagnostic power. In this study, we conducted a systematic search of PFC datasets of MDD patients from the Gene Expression Omnibus database. We calculated the differential expression of genes (DEGs) and identified robust DEGs using the RRA and MetaDE methods. Furthermore, we validated the consistently altered genes and assessed their diagnostic power through enzyme-linked immunosorbent assay experiments in our clinical blood cohort. Additionally, we evaluated the diagnostic power of hub DEGs in independent public blood datasets. We obtained eight PFC datasets, comprising 158 MDD patients and 263 healthy controls, and identified a total of 1468 unique DEGs. Through integrated analysis, we identified 290 robustly altered DEGs. Among these, seven hub DEGs (SLC1A3, PON2, AQP1, EFEMP1, GJA1, CENPD, HSD11B1) were significantly down-regulated at the protein level in our clinical blood cohort. Moreover, these hub DEGs exhibited a negative correlation with the Hamilton Depression Scale score (P < 0.05). Furthermore, these hub DEGs formed a panel with promising diagnostic power in three independent public blood datasets (average AUCs of 0.85) and our clinical blood cohort (AUC of 0.92). The biomarker panel composed of these genes demonstrated promising diagnostic efficacy for MDD and serves as a useful tool for its diagnosis.

MicroRNAs (miRNAs) are emerging as crucial elements in the regulation of gene expression, playing a significant role in the underlying neurobiology of a wide range of neuropsychiatric disorders. This review examines the intricate involvement of miRNAs in neuropsychiatric disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Fragile X syndrome (FXS), autism spectrum disorder (ASD), attention-deficit hyperactivity disorder (ADHD), Tourette syndrome (TS), schizophrenia (SCZ), and mood disorders. This review highlights how miRNA dysregulation can illuminate the molecular pathways of these diseases and potentially serve as biomarkers for early diagnosis and prognosis. Specifically, miRNAs' ability to target genes critical to the pathology of neurodegenerative diseases, their role in the development of trinucleotide repeat and neurodevelopmental disorders, and their distinctive patterns in SCZ and mood disorders are discussed. The review also stresses the value of miRNAs in precision neuropsychiatry, where they could predict treatment outcomes and aid in disease management. Furthermore, the study of conserved miRNAs in model organisms like Drosophila underscores their broad utility and provides deeper mechanistic insights into their biological functions. This comprehensive examination of miRNAs across various conditions advocates for their integration into clinical practice, promising advancements in personalized healthcare for neurological and psychiatric conditions.

GATA binding protein 3 (GATA3) is a transcription factor that plays a critical role in the differentiation and function of luminal epithelial cells in the breast. MicroRNAs (miRNAs) are small non-coding RNAs that modulate gene expression and their dysregulation has been implicated in cancer. The purpose of this study was to investigate the expression of GATA3 and its corresponding targeting miRNAs in breast cancer.

In this study, we used bioinformatic tools, including the miRWalk database and RNA Hybrid online tool, to identify potential miRNAs that target the GATA3 mRNA. Then, we collected frozen tissue specimens from 67 breast cancer patients and 67 adjacent normal breast tissue samples and evaluated the expression levels of GATA3, hsa-miR-433-3p, and hsa-miR-144-3p using quantitative RT-PCR.

We found that hsa-miR-433-3p and hsa-miR-144-3p are potential miRNAs that target the GATA3 mRNA, and we found that both were significantly downregulated in breast cancer tissues relative to adjacent normal breast tissues (P < 0.0001). We also observed a significant upregulation of the GATA3 mRNA in breast cancer tissues (P < 0.0001). Additionally, we found that their dysregulation was associated with clinicopathological features such as invasive carcinoma and carcinoma in situ subtypes, tumor grade, estrogen receptor status, progesterone receptor status, and HER2 status.

Our study represents the first attempt to investigate the expression of GATA3 and its targeting miRNAs simultaneously in breast cancer. Our findings suggest that dysregulation of these genes may contribute to breast cancer development and progression.

Depression accounts for a high proportion of neuropsychiatric disorders and is associated with abnormal states of neurons in specific brain regions. Microglia play a pivotal role in the inflammatory state during depression development; however, the exact mechanism underlying chronic mood states remains unknown. Thus, the present study aimed to determine whether microRNAs (miRNAs) alleviate stress-induced depression-like behavior in mice by regulating the expression levels of their target genes, explore the role of neuroinflammation induced by microglial activation in the pathogenesis and progression of depression, and determine whether the role of the miR-29a-5p/transmembrane protein 33 (TMEM33) axis.

In this study, chronic unpredictable mild stress (CUMS) mouse depression model, various behavioral tests, western blotting, dual-luciferase reporter assay, enzyme-linked immunosorbent assay, real-time quantitative reverse transcription PCR, immunofluorescence and lentivirus-mediated gene transfer were used.

After exposure to the CUMS paradigm, miR-29a-5p was significantly down-regulated. This downregulation subsequently promoted the polarization of microglia M1 by upregulating the expression of TMEM33, resulting in enhanced inflammatory chemokines affecting neurons. Conversely, the upregulation of miR-29a-5p within the prefrontal cortex (PFC) suppressed TMEM33 expression, facilitated microglia M2-polarization, and ameliorated depressive-like behavior.

Only rodent models of depression were used, and human samples were not included.

The results of this study suggest that miR-29a-5p deficits within the PFC mediate microglial anomalies and contribute to depressive-like behaviors. miR-29a-5p and TMEM33 may, therefore, serve as potential therapeutic targets for the treatment of depression.

Depression is one of the most common mental disorders and is mainly characterized by low mood or lack of interest and pleasure. It can be accompanied by varying degrees of cognitive and behavioral changes and may lead to suicide risk in severe cases. Due to the subjectivity of diagnostic methods and the complexity of patients' conditions, the diagnosis of major depressive disorder (MDD) has always been a difficult problem in psychiatry. With the discovery of more diagnostic biomarkers associated with MDD in recent years, especially emerging non-coding RNAs (ncRNAs), it is possible to quantify the condition of patients with mental illness based on biomarker levels. Point-of-care biosensors have emerged due to their advantages of convenient sampling, rapid detection, miniaturization, and portability. After summarizing the pathogenesis of MDD, representative biomarkers, including proteins, hormones, and RNAs, are discussed. Furthermore, we analyzed recent advances in biosensors for detecting various types of biomarkers of MDD, highlighting representative electrochemical sensors. Future trends in terms of new biomarkers, new sample processing methods, and new detection modalities are expected to provide a complete reference for psychiatrists and biomedical engineers.

A majority of humans faced with severe stress maintain normal physiological and behavioral function, a process referred to as resilience. Such stress resilience has been modeled in laboratory animals and, over the past 15 years, has transformed our understanding of stress responses and how to approach the treatment of human stress disorders such as depression, post-traumatic stress disorder (PTSD), and anxiety disorders. Work in rodents has demonstrated that resilience to chronic stress is an active process that involves much more than simply avoiding the deleterious effects of the stress. Rather, resilience is mediated largely by the induction of adaptations that are associated uniquely with resilience. Such mechanisms of natural resilience in rodents are being characterized at the molecular, cellular, and circuit levels, with an increasing number being validated in human investigations. Such discoveries raise the novel possibility that treatments for human stress disorders, in addition to being geared toward reversing the damaging effects of stress, can also be based on inducing mechanisms of natural resilience in individuals who are inherently more susceptible. This review provides a progress report on this evolving field.

Physical exercise is a robust lifestyle intervention known for its enhancement of cognitive abilities. Nevertheless, the extent to which these benefits can be transmitted across generations (intergenerational inheritance to F1, and transgenerational to F2 and beyond) remains a topic of limited comprehension. We have already shown that cognitive improvements resulting from physical exercise can be inherited from parents to their offspring, proving intergenerational effects. So, we set out to explore whether these enhancements might extend transgenerationally, impacting the F2 generation. In this study, we initially examined the behavioral traits of second generation (F2) male mice, whose grandfathers (F0) had an exercise intervention. Our findings revealed that F2 mice with physically active grandpaternal F0 progenitors displayed significantly improved memory recall, encompassing both spatial and non-spatial information when compared to their counterparts from sedentary F0 progenitors, and proving for the first time the transgenerational inheritance of physical exercise induced cognitive enhancement. Surprisingly, while F2 memory improved (as was the case with F1), adult hippocampal neurogenesis remained unchanged between experimental and control groups (unlike in F1). Additionally, our analysis of small RNA sequences in the hippocampus identified 35 differentially expressed miRNAs linked to important brain function categories. Notably, two of these miRNAs, miRNA-144 and miRNA-298, displayed a robust negative correlation with cognitive performance. These findings highlight the enduring transgenerational transmission of cognitive benefits associated with exercise, even after two generations, suggesting that moderate exercise training can have lasting positive effects, possibly orchestrated by a specific set of miRNAs that exert their influence across multiple generations.

Major depressive disorder (MDD) was involved in widely transcriptional changes in central and peripheral tissues. While, previous studies focused on single tissues, making it difficult to represent systemic molecular changes throughout the body. Thus, there is an urgent need to explore the central and peripheral biomarkers with intrinsic correlation.

We systematically retrieved gene expression profiles of blood and anterior cingulate cortex (ACC). 3 blood datatsets (84 MDD and 88 controls) and 6 ACC datasets (100 MDD and 100 controls) were obtained. Differential expression analysis, RobustRankAggreg (RRA) analysis, functional enrichment analysis, immune associated analysis and protein-protein interaction networks (PPI) were integrated. Furthermore, the key genes were validated in an independent ACC dataset (12 MDD and 15 controls) and a cohort with 120 MDD and 117 controls.

Differential expression analysis identified 2211 and 2021 differential expressed genes (DEGs) in blood and ACC, respectively. RRA identified 45 and 25 robust DEGs in blood and ACC based on DEGs, and all of them were closely associated with immune cells. Functional enrichment results showed both the robust DEGs in blood and ACC were enriched in humoral immune response. Furthermore, PPI identified 8 hub DEGs (CD79A, CD79B, CD19, MS4A1, PLP1, CLDN11, MOG, MAG) in blood and ACC. Independent ACC dataset showed the area under the curve (AUC) based on these hub DEGs was 0.77. Meanwhile, these hub DEGs were validated in the serum of MDD patients, and also showed a promising diagnostic power.

The biomarker panel based on hub DEGs yield a promising diagnostic efficacy, and all of these hub DEGs were strongly correlated with immunity. Humoral immune response may be the key link between the brain and blood in MDD, and our results may provide further understanding for MDD.

The risk of depression is influenced by both genetic and environmental factors. It has been suggested that epigenetic mechanisms may mediate the risk of depression following exposure to adverse life events. Epigenetics encompasses stable alterations in gene expression that are controlled through transcriptional, post-transcriptional, translational, or post-translational processes, including DNA modifications, chromatin remodeling, histone modifications, RNA modifications, and non-coding RNA (ncRNA) regulation, without any changes in the DNA sequence. In this review, we explore recent research advancements in the realm of epigenetics concerning depression. Furthermore, we evaluate the potential of epigenetic changes as diagnostic and therapeutic biomarkers for depression.

Depressive disorders have a significant impact on public health, and depression have an unsatisfactory recurrence rate and are challenging to treat. Non-coding RNAs (ncRNAs) are RNAs that do not code protein, which have been shown to be crucial for transcriptional regulation. NcRNAs are important to the onset, progress and treatment of depression because they regulate various physiological functions. This makes them distinctively useful as biomarkers for diagnosing and tracking responses to therapy among individuals with depression. It is important to seek out and summarize the research findings on the impact of ncRNAs on depression since significant advancements have been made in this area recently. Hence, we methodically outlined the findings of published researches on ncRNAs and depression, focusing on microRNAs. Above all, this review aims to improve our understanding of ncRNAs and provide new insights of the diagnosis and treatment of depression.

The eight biological hallmarks of health that we initially postulated (Cell. 2021 Jan 7;184(1):33-63) include features of spatial compartmentalization (integrity of barriers, containment of local perturbations), maintenance of homeostasis over time (recycling & turnover, integration of circuitries, rhythmic oscillations) and an array of adequate responses to stress (homeostatic resilience, hormetic regulation, repair & regeneration). These hallmarks affect all eight somatic strata of the human body (molecules, organelles, cells, supracellular units, organs, organ systems, systemic circuitries and meta-organism). Here we postulate that mental and socioeconomic factors must be added to this 8×8 matrix as an additional hallmark of health ("psychosocial adaptation") and as an additional stratum ("psychosocial interactions"), hence building a 9×9 matrix. Potentially, perturbation of each of the somatic hallmarks and strata affects psychosocial factors and vice versa. Finally, we discuss the (patho)physiological bases of these interactions and their implications for mental health improvement.

Depression is a major contributor to the overall global burden of disease. The discovery of biomarkers for diagnosis or prediction of treatment responses and as therapeutic agents is a current priority. Previous studies have demonstrated the importance of short RNA molecules in the etiology of depression. The most extensively researched of these are microRNAs, a major component of cellular gene regulation and function. MicroRNAs function in a temporal and tissue-specific manner to regulate and modify the post-transcriptional expression of target mRNAs. They can also be shuttled as cargo of extracellular vesicles between the brain and the blood, thus informing about relevant mechanisms in the CNS through the periphery. In fact, studies have already shown that microRNAs identified peripherally are dysregulated in the pathological phenotypes seen in depression. Our article aims to review the existing evidence on microRNA dysregulation in depression and to summarize and evaluate the growing body of evidence for the use of microRNAs as a target for diagnostics and RNA-based therapies.

The prevalence of depression is higher in heart failure (HF) patients. Early screening of depressive symptoms in HF patients and timely intervention can help to improve patients' quality of life and prognosis. This study aims to explore diagnostic biomarkers by examining the expression profile of serum exosomal miRNAs in HF patients with depressive symptoms.

Serum exosomal RNA was isolated and extracted from 6 HF patients with depressive symptoms (HF-DS) and 6 HF patients without depressive symptoms (HF-NDS). High-throughput sequencing was performed to obtain miRNA expression profiles and target genes were predicted for the screened differentially expressed miRNAs. Biological functions of the target genes were analyzed through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Subsequently, we collected serum exosomal RNAs from HF-DS (n = 20) and HF-NDS (n = 20). The differentially expressed miRNAs selected from the sequencing results were validated using reverse transcription quantitative polymerase chain reaction (RT-qPCR). Finally, the diagnostic efficacy of the differentially expressed exosomal miRNAs for HF-DS was evaluated by using receiver operating characteristic (ROC) curves.

A total of 19 significantly differentially expressed exosomal miRNAs were screened by high-throughput sequencing, consisting of 12 up-regulated and 7 down-regulated exosomal miRNAs. RT-qPCR validation demonstrated that the expression level of exo-miR-144-3p was significantly down-regulated in the HF-DS group, and the expression levels of exo-miR-625-3p and exo-miR-7856-5p were significantly up-regulated. In addition, the expression level of exo-miR-144-3p was negatively correlated with the severity of depressive symptoms in HF patients, and that the area under the curve (AUC) of exo-miR-144-3p for diagnosing HF-DS was 0.763.

In this study, we examined the serum exosomal miRNA expression profiles of HF patients with depressive symptoms and found that lower level of exo-miR-144-3p was associated with more severe depressive symptoms. Exo-miR-144-3p is a potential biomarker for the diagnosis of HF-DS.

MicroRNAs (miRNAs) play a crucial role in the regulation of gene expression levels and have been implicated in the pathogenesis of autism spectrum disorder (ASD) and schizophrenia (SCZ). In this study, we examined the adult expression profiles of specific miRNAs in the prefrontal cortex (PFC) of a neurodevelopmental mouse model for ASD and SCZ that mimics perinatal pathology, such as NMDA receptor hypofunction, and exhibits behavioral and neurophysiological phenotypes related to these disorders during adulthood. To model the early neuropathogenesis of the disorders, mouse pups were administered subcutaneously with ketamine (30 mg/Kg) at postnatal days 7, 9, and 11. We focused on a set of miRNAs most frequently altered in ASD (miR-451a and miR-486-3p) and in SCZ (miR-132-3p and miR-137-3p) according to human studies. Additionally, we explored miRNAs whose alterations have been identified in both disorders (miR-21-5p, miR-92a-2-5p, miR-144-3p, and miR-146a-5p). We placed particular emphasis on studying the sexual dimorphism in the dynamics of these miRNAs. Our findings revealed significant alterations in the PFC of this ASD- and SCZ-like mouse model. Specifically, we observed upregulated miR-451a and downregulated miR-137-3p. Furthermore, we identified sexual dimorphism in the expression of miR-132-3p, miR-137-3p, and miR-92a-2-5p. From a translational perspective, our results emphasize the potential involvement of miR-92a-2-5p, miR-132-3p, miR-137-3p, and miR-451a in the pathophysiology of ASD and SCZ and strengthen their potential as biomarkers and therapeutic targets of such disorders.

Detecting and addressing depression symptoms at their outset can reduce the burden on individuals and society; however, it has a limitation in that such evaluations mainly rely on self-reports. Several studies have demonstrated a strong association between motor symptoms and early depression. We aimed to associate body balance measured by the Lower Quarter Y Balance Test (YBT-LQ) with depressive symptoms among young adults in the community, to confirm the current evidence that depression negatively influences body balance.

Is the YBT-LQ an objective tool for measuring and evaluating young adults' depression risks, as well as assessing whether depression negatively influences body balance?

Our participants comprised 36 young adults. We assessed their depressive symptoms using the Center for Epidemiological Studies Depression Scale (CES-D) via a Google survey, measured their body balance with the YBT-LQ, and analyzed data with Spearman's rank-order correlation coefficient test, using SPSS version 27.0.

We found that the right leg's anterior, posteromedial, and posterolateral scores- Z = -2.129, p = .033; Z = -2.181, p = .029; and Z = -2.250, p = .024, respectively-and composite scores-Z = 73.00, p = .027 -were significantly lower in the group with risk for clinical depression compared to the normal group. The CES-D total score had a negative association with all YBT-LQ scores, except for the anterior score of the left leg. Among the CES-D sub-factors, somatic and retarded activity showed negative correlations with all the YBT-LQ scores.

Our findings revealed that depressive symptoms have a negative association with balance, and that the YBT-LQ can be a reliable tool for measuring motor symptoms of depression, specifically among young adults.

Neuropsychiatric disorders, which are associated with stress hormone dysregulation, occur at different rates in men and women. Moreover, nowadays, preclinical and clinical evidence demonstrates that sex and gender can lead to differences in stress responses that predispose males and females to different expressions of similar pathologies. In this curated review, we focus on what is known about sex differences in classic mechanisms of stress response, such as glucocorticoid hormones and corticotrophin-releasing factor (CRF), which are components of the hypothalamicpituitary- adrenal (HPA) axis. Then, we present sex differences in neurotransmitter levels, such as serotonin, dopamine, glutamate and GABA, as well as indices of neurodegeneration, such as amyloid β and Tau. Gonadal hormone effects, such as estrogens and testosterone, are also discussed throughout the review. We also review in detail preclinical data investigating sex differences caused by recentlyrecognized regulators of stress and disease, such as the immune system, genetic and epigenetic mechanisms, as well neurosteroids. Finally, we discuss how understanding sex differences in stress responses, as well as in pharmacology, can be leveraged into novel, more efficacious therapeutics for all. Based on the supporting evidence, it is obvious that incorporating sex as a biological variable into preclinical research is imperative for the understanding and treatment of stress-related neuropsychiatric disorders, such as depression, anxiety and Alzheimer's disease.

More than two-thirds of suicides occur during a major depressive episode. Acting out prevention measures and therapeutic options to manage the suicidal crisis are limited. The impulsive-aggressive dimensions are vulnerability factors associated with suicide in patients suffering from a characterized depressive episode: this can be a dimension involved in animals. Impulsive and aggressive rodent models can help analyze, at least in part, the neurobiology of suicide and the beneficial effects of treatments. Ketamine, a glutamatergic antagonist, by rapidly improving the symptoms of depressive episodes, would help reduce suicidal thoughts in the short term. Animal models share with humans impulsive and aggressive endophenotypes modulated by the serotonergic system (5-HTB receptor, MAO-A enzyme), neuroinflammation or the hypothalamic-pituitary-adrenal axis and stress. Significant effects of ketamine on these endophenotypes remain to be demonstrated.

The purpose of this study was to explore the expression level of SNHG4 in patients with COPD and its diagnostic value in COPD, to probe the biological function of SNHG4 in COPD at the cellular level, and to reveal the interaction between SNHG4 and miR-144-3p/EZH2 axis.

The serum levels of SNHG4, miR-144-3p and EZH2 in healthy people and patients with COPD were detected by RT-qPCR. The diagnostic value of SNHG4 in COPD was evaluated by ROC curve. Pearson method was chosen to estimate the correlation between SNHG4 and clinical indicators in patients with COPD. Cigarette smoke extract (CSE) was obtained, and Beas-2B cells were exposed with 2% CSE to establish an inflammatory cell model of COPD in vitro. MTT assay was used to detect cell viability, flow cytometry was used to evaluate cell apoptosis, and ELISA was performed to detect inflammatory cytokines. Dual-luciferase reporting assay was carried out to verify the targeting of lncRNA-miRNA or miRNA-mRNA.

(1) The expression of SNHG4 is decreased in patients with COPD, and the expression level in acute exacerbation COPD was lower than that in stable COPD. SNHG4 demonstrated high diagnostic accuracy in distinguishing between stable and acute exacerbation COPD. (2) The expression of SNHG4 was decreased in CSE-induced Beas-2B cells, and overexpression of SNHG4 was beneficial to alleviate CSE-induced apoptosis and inflammation. (3) The expression of miR-144-3p is up-regulated in patients with COPD and CSE-induced Beas-2B cells. MiR-144-3p has a targeting relationship with SNHG4, which is negatively regulated by SNHG4. Overexpression of miR-144-3p could counteract the beneficial effects of increased SNHG4 on CSE-induced cells. (4) The expression of EZH2 is reduced in patients with COPD and CSE-induced Beas-2B cells. Bioinformatics analysis and luciferase reporter gene confirmed that EZH2 is the downstream target gene of miR-144-3p and is negatively regulated by miR-144-3p.

The expression of SNHG4 decreased in patients with COPD, and it may promote the progression of COPD by inhibiting the viability, promoting apoptosis and inflammatory response of bronchial epithelial cells via regulating the miR-144-3p/EZH2 axis.

Stress is a major risk factor for psychiatric disorders. During and after exposure to stressors, the stress response may have pro- or maladaptive consequences, depending on several factors related to the individual response and nature of the stressor. However, the mechanisms mediating the long-term effects of exposure to stress, which may ultimately lead to the development of stress-related disorders, are still largely unknown. Epigenetic mechanisms have been shown to mediate the effects of the environment on brain gene expression and behavior. MicroRNAs, small non-coding RNAs estimated to control the expression of about 60% of all genes by post-transcriptional regulation, are a fundamental epigenetic mechanism. Many microRNAs are expressed in the brain, where they work as fine-tuners of gene expression, with a key role in the regulation of homeostatic balance, and a likely influence on pro- or maladaptive brain changes. Here we have selected a number of microRNAs, which have been strongly implicated as mediators of the effects of stress in the brain and in the development of stress-related psychiatric disorders. For all of them recent evidence is reported, obtained from rodent stress models, manipulation of microRNAs levels with related behavioral changes, and clinical studies of stress-related psychiatric disorders. Moreover, we have performed a bioinformatic analysis of the predicted brain-expressed target genes of the microRNAs discussed, and found a central role for mechanisms involved in the regulation of synaptic function. The complex regulatory role of microRNAs has suggested their use as biomarkers for diagnosis and treatment response, as well as possible therapeutic drugs. While, microRNA-based diagnostics have registered advancements, particularly in oncology and other fields, and many biotech companies have launched miRNA therapeutics in their development pipeline, the development of microRNA-based tests and drugs for brain disorders is comparatively slower.

Major depressive disorder (MDD) is a chronic, generally episodic and debilitating disease that affects an estimated 300 million people worldwide, but its pathogenesis is poorly understood. The heritability estimate of MDD is 30-40%, suggesting that genetics alone do not account for most of the risk of major depression. Another factor known to associate with MDD involves environmental stressors such as childhood adversity and recent life stress. Recent studies have emerged to show that the biological impact of environmental factors in MDD and other stress-related disorders is mediated by a variety of epigenetic modifications. These epigenetic modification alterations contribute to abnormal neuroendocrine responses, neuroplasticity impairment, neurotransmission and neuroglia dysfunction, which are involved in the pathophysiology of MDD. Furthermore, epigenetic marks have been associated with the diagnosis and treatment of MDD. The evaluation of epigenetic modifications holds promise for further understanding of the heterogeneous etiology and complex phenotypes of MDD, and may identify new therapeutic targets. Here, we review preclinical and clinical epigenetic findings, including DNA methylation, histone modification, noncoding RNA, RNA modification, and chromatin remodeling factor in MDD. In addition, we elaborate on the contribution of these epigenetic mechanisms to the pathological trait variability in depression and discuss how such mechanisms can be exploited for therapeutic purposes.

Fetal restriction (FR) alters insulin sensitivity, but it is unknown how the metabolic profile associated with restriction affects development of the dopamine (DA) system and DA-related behaviors. The Netrin-1/DCC guidance cue system participates in maturation of the mesocorticolimbic DA circuitry. Therefore, our objective was to identify if FR modifies Netrin-1/DCC receptor protein expression in the prefrontal cortex (PFC) at birth and mRNA in adulthood in rodent males. We used cultured HEK293 cells to assess if levels of miR-218, microRNA regulator of DCC, are sensitive to insulin. To assess this, pregnant dams were subjected to a 50% FR diet from gestational day 10 until birth. Medial PFC (mPFC) DCC/Netrin-1 protein expression was measured at P0 at baseline and Dcc/Netrin-1 mRNA levels were quantified in adults 15 min after a saline/insulin injection. miR-218 levels in HEK-293 cells were measured in response to insulin exposure. At P0, Netrin-1 levels are downregulated in FR animals in comparison to controls. In adult rodents, insulin administration results in an increase in Dcc mRNA levels in control but not FR rats. In HEK293 cells, there is a positive correlation between insulin concentration and miR-218 levels. Since miR-218 is a Dcc gene expression regulator and our in vitro results show that insulin regulates miR-218 levels, we suggest that FR-induced changes in insulin sensitivity could be affecting Dcc expression via miR-218, impacting DA system maturation and organization. As fetal adversity is linked to nonadaptive behaviors later in life, this may contribute to early identification of vulnerability to chronic diseases associated with fetal adversity.

Post-traumatic stress disorder (PTSD) is usually considered a psychiatric disorder upon emotional trauma. However, with the rising number of conflicts and traffic accidents around the world, the incidence of PTSD has skyrocketed along with traumatic brain injury (TBI), a complex neuropathological disease due to external physical force and is also the most common concurrent disease of PTSD. Recently, the overlap between PTSD and TBI is increasingly attracting attention, as it has the potential to stimulate the emergence of novel treatments for both conditions. Of note, treatments exploiting the microRNAs (miRNAs), a well-known class of small non-coding RNAs (ncRNAs), have rapidly gained momentum in many nervous system disorders, given the miRNAs' multitudinous and key regulatory role in various biological processes, including neural development and normal functioning of the nervous system. Currently, a wealth of studies has elucidated the similarities of PTSD and TBI in pathophysiology and symptoms; however, there is a dearth of discussion with respect to miRNAs in both PTSD and TBI. In this review, we summarize the recent available studies of miRNAs in PTSD and TBI and discuss and highlight promising miRNAs therapeutics for both conditions in the future.

Emerging evidence suggests that brain derived extracellular vesicles (EVs) and particles (EPs) can cross blood-brain barrier and mediate communication among neurons, astrocytes, microglial, and other cells of the central nervous system (CNS). Yet, a complete understanding of the molecular landscape and function of circulating EVs & EPs (EVPs) remain a major gap in knowledge. This is mainly due to the lack of technologies to isolate and separate all EVPs of heterogeneous dimensions and low buoyant density. In this review, we aim to provide a comprehensive understanding of the neurosecretome, including the extracellular vesicles that carry the molecular signature of the brain in both its microenvironment and the systemic circulation. We discuss the biogenesis of EVPs, their function, cell-to-cell communication, past and emerging isolation technologies, therapeutics, and liquid-biopsy applications. It is important to highlight that the landscape of EVPs is in a constant state of evolution; hence, we not only discuss the past literature and current landscape of the EVPs, but we also speculate as to how novel EVPs may contribute to the etiology of addiction, depression, psychiatric, neurodegenerative diseases, and aid in the real time monitoring of the "living brain". Overall, the neurosecretome is a concept we introduce here to embody the compendium of circulating particles of the brain for their function and disease pathogenesis. Finally, for the purpose of inclusion of all extracellular particles, we have used the term EVPs as defined by the International Society of Extracellular Vesicles (ISEV).

Mood disorders are the most prevalent psychiatric disorders associated with significant disability, morbidity, and mortality. The risk of suicide is associated with severe or mixed depressive episodes in patients with mood disorders. However, the risk of suicide increases with the severity of depressive episodes and is often presented with higher incidences in bipolar disorder (BD) patients than in patients with major depression (MDD). Biomarker study in neuropsychiatric disorders is critical for developing better treatment plans by facilitating more accurate diagnosis. At the same time, biomarker discovery also provides more objectivity to develop state-of-the-art personalized medicine with increased accuracy through clinical interventions. Recently, colinear changes in miRNA expression between brain and systemic circulation have added great interest in examining their potential as molecular markers in mental disorders, including MDD, BD, and suicidality. A present understanding of circulating miRNAs in body fluids implicates their role in managing neuropsychiatric conditions. Most notably, their use as prognostic and diagnostic markers and their potential role in treatment response have significantly advanced our knowledge base. The present review discusses circulatory miRNAs and their underlying possibilities to be used as a screening tool for assessing major psychiatric conditions, including MDD, BD, and suicidal behavior.

Stress is a key risk factor in the onset of neuropsychiatric disorders. The study of the mechanisms underlying stress response is important to understand the etiopathogenetic mechanisms and identify new putative therapeutic targets. In this context, microRNAs (miRNAs) have emerged as key regulators of the complex patterns of gene/protein expression changes in the brain, where they have a crucial role in the regulation of neuroplasticity, neurogenesis, and neuronal differentiation. Among them, miR-135a-5p has been associated with stress response, synaptic plasticity, and the antidepressant effect in different brain areas. Here, we used acute unavoidable foot-shock stress (FS) and chronic mild stress (CMS) on male rats to study whether miR-135a-5p was involved in stress-induced changes in the prefrontal cortex (PFC). Both acute and chronic stress decreased miR-135a-5p levels in the PFC, although after CMS the reduction was induced only in animals vulnerable to CMS, according to a sucrose preference test. MiR-135a-5p downregulation in the primary neurons reduced dendritic spine density, while its overexpression exerted the opposite effect. Two bioinformatically predicted target genes, Kif5c and Cplx1/2, were increased in FS rats 24 h after stress. Altogether, we found that miR-135a-5p might play a role in stress response in PFC involving synaptic mechanisms.

Women suffer from depression at twice the rate of men, but the underlying molecular mechanisms are poorly understood. Here, we identify marked baseline sex differences in the expression of long noncoding RNAs (lncRNAs), a class of regulatory transcripts, in human postmortem brain tissue that are profoundly lost in depression. One such human lncRNA, RP11-298D21.1 (which we termed FEDORA), is enriched in oligodendrocytes and neurons and up-regulated in the prefrontal cortex (PFC) of depressed females only. We found that virally expressing FEDORA selectively either in neurons or in oligodendrocytes of PFC promoted depression-like behavioral abnormalities in female mice only, changes associated with cell type-specific regulation of synaptic properties, myelin thickness, and gene expression. We also found that blood FEDORA levels have diagnostic implications for depressed women and are associated with clinical response to ketamine. These findings demonstrate the important role played by lncRNAs, and FEDORA in particular, in shaping the sex-specific landscape of the brain and contributing to sex differences in depression.

Identification of early biomarkers of stress is important for preventing mood and anxiety disorders. Saliva is an easy-to-collect and non-invasive diagnostic target. The aim of this study was to characterize the changes in salivary whole microRNAs (miRNAs) and metabolites in mice subjected to subchronic and mild social defeat stress (sCSDS). In this study, we identified seven upregulated and one downregulated miRNAs/PIWI-interacting RNA (piRNA) in the saliva of sCSDS mice. One of them, miR-208b-3p, which is reported as a reliable marker for myocardial infarction, was upregulated in the saliva of sCSDS mice. Histological analysis showed frequent myocardial interstitial fibrosis in the heart of such mice. In addition, gene ontology and pathway analyses suggested that the pathways related to energy metabolism, such as the oxidative phosphorylation and the pentose phosphate pathway, were significantly related to the miRNAs affected by sCSDS in saliva. In contrast, salivary metabolites were not significantly changed in the sCSDS mice, which is consistent with our previous metabolomic study on the plasma of sCSDS mice. Taken in the light of previous studies, the present study provides novel potential stress biomarkers for future diagnosis using saliva.

(R,S)-ketamine is known to elicit persistent prophylactic effects in rodent models of depression. However, the precise molecular mechanisms underlying its action remain elusive. Using RNA-sequencing analysis, we searched for novel molecular target(s) that contribute to the prophylactic effects of (R)-ketamine, a more potent enantiomer of (R,S)-ketamine in chronic restraint stress (CRS) model. Pretreatment with (R)-ketamine (10 mg/kg, 1 day before CRS) significantly ameliorated body weight loss, increased immobility time of forced swimming test, and decreased sucrose preference of sucrose preference test in CRS-exposed mice. RNA-sequencing analysis of prefrontal cortex (PFC) revealed that several miRNAs such as miR-132-5p might contribute to sustained prophylactic effects of (R)-ketamine. Methyl CpG binding protein 2 (MeCP2) is known to regulate brain-derived neurotrophic factor (BDNF) expression. Quantitative RT-PCR confirmed that (R)-ketamine significantly attenuated altered expression of miR-132-5p and its regulated genes (Bdnf, Mecp2, Tgfb1, Tgfbr2) in the PFC of CRS-exposed mice. Furthermore, (R)-ketamine significantly attenuated altered expression of BDNF, MeCP2, TGF-β1 (transforming growth factor β1), and synaptic proteins (PSD-95, and GluA1) in the PFC of CRS-exposed mice. Administration of agomiR-132-5p decreased the expression of Bdnf and Tgfb1 in the PFC, resulting in depression-like behaviors. In contrast, administration of antagomiR-132-5p blocked the increased expression of miR-132-5p and decreased expression of Bdnf in the PFC of CRS-exposed mice, resulting in antidepressant-like effects. In conclusion, our data show a novel role of miR-132-5p in the PFC underlying depression-like phenotypes in CRS model and the sustained prophylactic effects of (R)-ketamine.

The N-methyl-d-aspartate receptor (NMDAR) antagonist (R,S)-ketamine causes rapid onset and sustained antidepressant actions in treatment-resistant patients with major depressive disorder (MDD) and other psychiatric disorders, such as bipolar disorder and post-traumatic stress disorder. (R,S)-ketamine is a racemic mixture consisting of (R)-ketamine (or arketamine) and (S)-ketamine (or esketamine), with (S)-enantiomer having greater affinity for the NMDAR. In 2019, an esketamine nasal spray by Johnson & Johnson was approved in the USA and Europe for treatment-resistant depression. In contrast, an increasing number of preclinical studies show that arketamine has greater potency and longer-lasting antidepressant-like effects than esketamine in rodents, despite the lower binding affinity of arketamine for the NMDAR. Importantly, the side effects, i.e., psychotomimetic and dissociative effects and abuse liability, of arketamine are less than those of (R,S)-ketamine and esketamine in animals and humans. An open-label study demonstrated the rapid and sustained antidepressant effects of arketamine in treatment-resistant patients with MDD. A phase 2 clinical trial of arketamine in treatment-resistant patients with MDD is underway. This study was designed to review the brief history of the novel antidepressant arketamine, the molecular mechanisms underlying its antidepressant actions, and future directions.