This paper aimed to probe the role of the LINC00641/miR-323a-3p/EIF4G2 axis in regulating behavioral and brain monoamine neurotransmitter levels in a mouse model of depression induced by chronic unpredictable mild stress (CUMS).

A CUMS-induced depression model was established in mice. A series of behavioral tests, comprising the sucrose preference, tail suspension, as well as forced swimming tests, were conducted. Levels of LINC00641, miR-323a-3p, and EIF4G2 in hippocampal tissues were measured. Biochemical indices, including 5-HT, NE, and DA, were analyzed. Hippocampal neuron structure and apoptosis were evaluated. The targeting relationship among LINC00641, miR-323a-3p, and EIF4G2 was validated experimentally.

CUMS mice exhibited reduced sucrose preference, prolonged immobilization time in behavioral tests, decreased 5-HT, NE, and DA levels, and increased hippocampal neuron apoptosis. Overexpression of LINC00641 or knockdown of miR-323a-3p significantly alleviated depression-like behaviors and restored monoamine neurotransmitter levels. LINC00641 regulated EIF4G2 expression by targeting miR-323a-3p, while miR-323a-3p and EIF4G2 also modulated depression through LINC00641.

Upregulation of LINC00641 improves depression-like behaviors and enhances monoamine neurotransmission in CUMS mice via the miR-323a-3p/EIF4G2 axis, underscoring its potent as a therapeutic target for depression.

Major depressive disorder (MDD) is a severe psychiatric disorder with a complex and poorly understood pathogenesis. Epigenetics, a rapidly advancing field of biology, has been implicated in various psychiatric conditions, including schizophrenia, anxiety, substance addiction, and autism. Furthermore, substantial research indicates that epigenetic modifications play a crucial role in the etiology of depression. Early life stress (ELS) refers to adverse experiences occurring during prenatal development (e.g., maternal physical and mental health complications during pregnancy) and/or postnatal life (e.g., abuse, neglect, poverty, parental loss, family conflict, violence, and malnutrition). These early-life adversities can lead to epigenetic modifications, which, in turn, influence key biological processes and contribute to the pathogenesis of MDD. This review provides an overview of the regulatory mechanisms and functions of various epigenetic modifications, including non-coding RNAs, DNA methylation, and histone modifications. We then examine ELS-induced epigenetic alterations and their biological consequences, such as dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, neurogenesis, and neuroplasticity. Finally, we explore their potential implications for both the pathogenesis and treatment of MDD. We hypothesize that ELS-induced epigenetic changes may serve as biomarkers for MDD diagnosis and offer novel therapeutic targets for its treatment.

Depression is of great concern because of the huge burden, and it is impacted by various epigenetic modifications, e.g., histone modification, covalent modifications in DNA, and silencing mechanisms of non-coding protein genes, e.g., microRNAs (miRNAs). MiRNAs are a class of endogenous non-coding RNAs. Alternations in specific miRNAs have been observed both in depressive patients and experimental animals. Also, miRNAs are highly expressed in the central nervous system and can be delivered to different tissues via tissue-specific exosomes. However, the mechanism of miRNAs' involvement in the pathological process of depression is not well understood. Therefore, we summarized and discussed the role of miRNAs in depression. Conclusively, miRNAs are involved in the pathology of depression by causing structural and functional changes in synapses, mediating neuronal regeneration, differentiation, and apoptosis, regulating the gut microbes and the expression of various neurotransmitters and BDNF, and mediating inflammatory and immune responses. Moreover, miRNAs can predict the efficacy of antidepressant medications and explain the mechanism of action of antidepressant drugs and aerobic exercise to prevent and assist in treating depression.

The prevalence of psychiatric disorders and neurodegenerative diseases is steadily increasing, placing a significant burden on both society and individuals. Given the intricate and multifaceted nature of these diseases, the precise underlying mechanisms remain elusive. Consequently, there is an increasing imperative to investigate the mechanisms, identify specific target sites for effective treatment, and provide for accurate diagnosis of patients with these diseases. Numerous studies have revealed significant alterations in the expression of long non-coding RNAs (lncRNAs) in psychiatric disorders and neurodegenerative diseases, suggesting their potential to increase the probability of these diseases. Moreover, these findings propose that lncRNAs could be used as highly valuable biomarkers in diagnosing and treating these diseases, thereby offering novel insights for future clinical interventions. The review presents a comprehensive summary of the origin, biological functions, and action mechanisms of lncRNAs, while exploring their implications in the pathogenesis of psychiatric disorders and neurodegenerative diseases and their potential utility as biomarkers.

MicroRNAs can interfere with protein function by suppressing their messenger RNA translation or the synthesis of its related factors. The function of brain-derived neurotrophic factor (BDNF) is essential to the proper formation and function of the nervous system and is seen to be regulated by many microRNAs. However, understanding how microRNAs influence BDNF actions within cells requires a wider comprehension of their integrative regulatory mechanisms. Aim: In this literature review, we have synthesized the evidence of microRNA regulation on BDNF in cells and tissues, and provided an analytical discussion about direct and indirect mechanisms that appeared to be involved in BDNF regulation by microRNAs. Methods: Searches were conducted on PubMed.gov using the terms "BDNF" AND "MicroRNA" and "brain-derived neurotrophic factor" AND "MicroRNA", updated on 1 September 2023. Papers without open access were requested from the authors. One hundred and seventy-one papers were included for review and discussion. Results and Discussion: The local regulation of BDNF by microRNAs involves a complex interaction between a series of microRNAs with target proteins that can either inhibit or enhance BDNF expression, at the core of cell metabolism. Therefore, understanding this homeostatic balance provides resources for the future development of vector-delivery-based therapies for the neuroprotective effects of BDNF.

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.

Curcumin (CUR) exhibits a definite curative effect in the treatment of depression. To identify potential antidepressant targets and mechanisms of action of CUR. This study used network pharmacology to explore the signaling pathways and CUR-related targets in depression. C57BL/6 J mice (male,12-14 weeks old) were randomly divided into four groups (n = 8): saline-treated (control mice), lipopolysaccharide (LPS, 2 mg/kg/day, intraperitoneally), LPS + CUR (50 mg/kg/day, intragastrically), and LPS + CUR + LY294002 (7.5 mg/kg/day, intraperitoneally). After 1 week, behavioral tests were performed. Then, neuronal damage in the prefrontal cortex of mice was evaluated by hematoxylin-eosin (HE) staining. We uncovered the main active mechanism of CUR against depression using Western blotting and enzyme-linked immunosorbent assay (ELISA). Gene set enrichment analysis (GSEA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways showed that the most significantly enriched pathway in CUR against depression was the PI3K-Akt pathway. Moreover, 52 targets were significantly correlated with the PI3K-Akt signaling pathway and CUR-related targets. In addition, among the top 50 targets ranked by degree in the protein-protein interaction (PPI) network, there were 23 targets involved in the 52 intersection targets. Administration of LPS alone extended immobility time in the open field test (OFT) and tail suspension test (TST) and decreased sucrose consumption in the sucrose preference test (SPT). Pretreatment with CUR relieved LPS-induced changes in the behavioral tests, activity of the PI3K-Akt signaling pathway, neuronal damage in the prefrontal cortex (PFC), and inflammatory response. Moreover, inhibition of the PI3K-Akt signaling pathway by LY294002 blocked the therapeutic effects of CUR. Our study indicates that CUR may be an effective antidepressant agent in an LPS-induced mouse model, partly because of its anti-inflammatory action through the PI3K-Akt signaling pathway.

Our previous study reported that the single-nucleotide polymorphism (SNP) rs155979 GC in the promoter region of long-chain non-coding RNA (lncRNA) NONHSAT102891 affects depression susceptibility in a Chinese population.

To explored associations of two SNPs and haplotypes in the lncRNA NONHSAT102891 promoter region with depression susceptibility in Chinese population.

This this case-control association study was approved by the Ethics Committee of Chengdu Medical College (approval number: 201815). Patient diagnosis was based on DSM-IV criteria. We selected a total of 480 patients with depression and 329 healthy controls with no history of psychopathology, and performed genotyping of two SNPs by extracting peripheral venous blood samples from the subjects. The function of the two lncRNA NONHSAT102891 promoter G/C and A/T haplotypes was detected by dual-luciferase reporter assays of human embryonic kidney 293T transfected cells.

Stratified analysis of clinical and genotypic characteristics of our cohort showed that the degree of mild depressive episodes associated with the rs6230 TC/CC genotype increased by 1.59 times [TC/CC vs TT: odds ratio (OR) = 1.59, 95% confidence interval (CI): 1.08-2.35, P = 0.019]. The haploid analysis revealed linkage disequilibrium between rs3792747 and rs6230, and the double SNP CG haplotype was more common in the control group compared to case group, indicating that this haplotype significantly reduced the risk of depression (C/G vs T/A: OR = 0.42, 95%CI: 0.21-0.83, P = 0.01). There was no significant difference in the dual-luciferase reporter activity of the G/C and A/T haplotypes compared with the control group (P > 0.05), indicating that the double SNP haplotype has no transcriptional activity.

The rs3792747 and rs6230 CG haplotypes of the lncRNA NONHSA T102891 promoter may be related to a reduced risk of depression in the Han Chinese population.

Perinatal depression (PND) is the most common complication of childbirth and negatively affects the mother. Long noncoding RNA (lncRNA) NONHSAG045500 inhibits the expression of 5-hydroxytryptamine (5-HT) transporter (i.e. serotonin transporter [SERT]) and produces an antidepressant effect. This study aimed to identify a link between the lncRNA NONHSAG045500 and the pathogenesis of PND.

Female C57BL/6 J mice were divided into normal control group (control group, n = 15), chronic unpredictable stress (CUS) model group (PND group, n = 15), lncRNA NONHSAG045500-overexpressed group (LNC group, sublingual intravenous injection of NONHSAG045500 overexpression cells for 7 days, n = 15), and escitalopram treatment group (i.e. the selective serotonin reuptake inhibitor [SSRI] group, with escitalopram administered from the 10th day after pregnancy to the 10th day after delivery, n = 15). Control group mice were conceived normally, whereas, in the other groups, a CUS model was established before mice were conceived. Depressive-like behaviour was assessed via sucrose preference, forced swimming, and open-field tests. The expression levels of 5-HT, SERT, and cAMP-PKA-CREB pathway-related proteins in the prefrontal cortex were detected on the 10th day after delivery.

Mice in the PND group exhibited significant depressive-like behaviours compared with those in the control group, indicating that the PND model was successfully established. The expression of lncRNA NONHSAG045500 was markedly decreased in the PND group compared with that in the control group. After treatment, both LNC and SSRI groups showed a significant improvement in depression-like behaviour, and the expression of 5-HT in the prefrontal cortex was increased in these groups compared with that in the PND group. In addition, the LNC group displayed lower expression of SERT and higher expression of cAMP, PKA, and CREB when in comparison to PND group.

NONHSAG045500 mediates the development of PND mainly by activating the cAMP-PKA-CREB pathway, increasing the level of 5-HT, and decreasing the expression of SERT.

Depression is a common mental illness. Ferroptosis is a form of cell death that may be responsible for neurological disease, but the role of ferroptosis in depression remains unclear. tRNA-derived small RNA (tsRNA) is an emerging non-coding small RNA, making it an important medium for studying neurological diseases. Chronic unpredictable mild stress (CUMS) was used to construct the depression model in mice, which was treated with ferrostatin-1 (Fer-1). Classical behavioral test, immunofluorescence and small RNA sequencing were used to detect depression-like behaviors, neuronal proliferation and the expression profile of tsRNAs in mice, respectively. The primary neuronal cell damage model was constructed by corticosterone (CORT), and the function of key tsRNA was investigated by quantitative real-time PCR, western blot and CCK-8 assays. Here, Fer-1 reduced the depression-like behavior of CUMS-induced mice and promoted neuronal growth. In addition, CUMS caused the disorder of tsRNA expression profile in hippocampal tissues of mice, and Fer-1 alleviated the abnormal tsRNA expression, among which tsRNA-3029b was an effective target. In vitro experiments manifested that ROS accumulation and decreased expression of SLC7A11 and GPX4 were found in CORT-induced depression-like cell model, suggesting that ferroptosis was involved in neuronal injury. However, inhibition of tsRNA-3029b suppressed neuronal cell ferroptosis and facilitated neuronal regeneration. In conclusion, Fer-1 showed an antidepressant effect in CUMS-induced mice and alleviated the abnormal expression profile of tsRNA. tsRNA-3029b was a key target in depression, and silencing of tsRNA-3029b reduced the occurrence of ferroptosis and protected neurons from injury, which may provide novel target for the treatment of depression.

Depression is one of the most common mental illnesses, affecting more than 350 million people worldwide. However, the occurrence of depression is a complex process involving genetic, physiological, psychological, and social factors, and the underlying mechanisms of its pathogenesis remain unclear. With advances in sequencing technology and epigenetic studies, increasing research evidence suggests that long noncoding RNAs (lncRNAs) play nonnegligible roles in the development of depression and may be involved in the pathogenesis of depression through multiple pathways, including regulating neurotrophic factors and other growth factors and affecting synaptic function. In addition, significant alterations in lncRNA expression profiles in peripheral blood and different brain regions of patients and model animals with depression suggest that lncRNAs may function as biomarkers for the differential diagnosis of depression and other psychiatric disorders and may also be potential therapeutic targets. In this paper, the biological functions of lncRNAs are briefly described, and the functional roles and abnormal expression of lncRNAs in the development, diagnosis and treatment of depression are reviewed.

Abnormal expression of long non-coding RNAs (lncRNAs) has been correlated with depressive disorders, but limited data are available on the lncRNA-microRNA (miRNA/miR)-messenger RNA (mRNA) competitive endogenous RNA (ceRNA) mechanism in depression. Herein, we address this issue based on transcriptome sequencing and in vitro experiments. Mouse hippocampus tissues were obtained from chronic unpredictable mild stress (CUMS)-induced mice to screen out differentially expressed mRNAs and lncRNAs based on the transcriptome sequencing. Next, the depression-related differentially expressed genes (DEGs) were obtained, followed by Gene Ontology (GO) and Kyoto Encylopedia of Genes and Genomes (KEGG) enrichment analysis. A total of 1018 differentially expressed mRNAs, 239 differentially expressed lncRNAs, and 58 DEGs related to depression were acquired. The miRNAs targeting Harvey rat sarcoma virus oncogene (Hras) and miRNAs sponged by Hras-related lncRNA were intersected to identify the ceRNA regulatory network. In addition, the synapse-related genes related to depression were acquired by bioinformatics analysis. Hras was identified as the core gene related to depression, mainly related to neuronal excitation. We also found that 2210408F21Rik competitively bound to miR-1968-5p that targeted Hras. The effects of 2210408F21Rik/miR-1968-5p/Hras axis on neuronal excitation were verified in primary hippocampal neurons. The experimental data indicated that the downregulation of 2210408F21Rik increased the level of miR-1968-5p to diminish Hras expression, thereby affecting neuronal excitation in CUMS mice. In conclusion, the 2210408F21Rik/miR-1968-5p/Hras ceRNA network can potentially affect the expression of synapsia-related proteins and is a promising target for preventing and treating depression.

Chronic pain is frequently comorbid with depression. However, the mechanisms underlying chronic pain-induced depression remain unclear. Here, we found that DNA methyltransferase 1 (DNMT1) was upregulated in the central amygdala (CeA) of spared nerve injury (SNI)-induced chronic pain-depression rats, and knockdown of DNMT1 could improve the depression-like behaviors in SNI rats. Additionally, a panel of differentially expressed lncRNAs, including 38 upregulated and 12 downregulated lncRNAs, were identified by microarray analysis. Bioinformatics analysis suggested that the upregulated lncRNA XR_351665 was the upstream molecule to regulate DNMT1 expression. The knockdown of XR_351665 significantly alleviated the depression-like behaviors in SNI rats, whereas overexpression of XR_351665 induced the depression-like behaviors in naïve rats. Further mechanism-related researches uncovered that XR_351665 functioned as a competing endogenous RNA (ceRNA) to upregulate DNMT1 by competitively sponging miR-152-3p, and subsequently promoted the development of chronic pain-induced depression. Our findings suggest that lncRNA XR_351665 is involved in the development of chronic pain-induced depression by upregulating DNMT1 via sponging miR-152-3p. These data provide novel insight into understanding the pathogenesis of chronic pain-induced depression and identify a potential therapeutic target. PERSPECTIVE: LncRNA XR_351665 in CeA functions as a ceRNA to block the inhibitory effect of miR-152-3p on DNMT1 and contributes to the development of chronic pain-induced depression. These data suggest that manipulation of XR_351665/miR-152-3p/DNMT1 axis may be a potential method to attenuate chronic pain-induced depression.

Inflammatory bowel disease (IBD), classified primarily between Crohn's disease and ulcerative colitis, is a collection of chronic gastrointestinal inflammatory conditions that cause multiple complications because of systemic alterations in the immune response. One major player is microRNA (miRNA), which is found to be associated with multiple pathways in mediating inflammation, especially those of a chronic nature in IBD, as well as irritable bowel syndrome. Although there have been studies linking miRNA alterations in IBD, even differentiating Crohn's disease and ulcerative colitis, this review focuses mainly on how miRNAs cause and mechanistically influence the pathologic complications of IBD. In addition to its role in the well-known progression towards colorectal cancer, we also emphasize how miRNA manifests the many extraintestinal complications in IBD such as cardiovascular diseases; neuropsychiatric conditions such as depression and anxiety disorders; and others, including various musculoskeletal, dermatologic, ocular, and hepatobiliary complications. We conclude through a description of its potential use in bettering diagnostics and the future treatment of IBD and its systemic symptoms.

Baihe Dihuang Decoction is a well-known traditional Chinese medicine prescription (Also known as Lilium Henryi Baker and Rehmannia Glutinosa Decoction, LBRD) composed of Lilium Henryi Baker bulb and raw juice from Rehmannia Glutinosa (Gaertn) DC with the curative efficacy of nourishing yin and clearing heat based on the Chinese herbal medicine theory. It has been used as routine medication in treating depression combined with conventional western medicine in China for years.

LBRD can attenuates GABAergic deficits in the medial prefrontal cortex (mPFC) of depression. This study aimed to investigate the mechanism of antidepressive properties of LBRD in the prefrontal GABAergic interneuron subtypes, including parvalbumin (PV), somatostatin (SST), vasoactive intestinal peptide (VIP)-positive neuron.

In this project, chronic unpredicted mild stress paradigm was adopted to construct depression model. After treated with LBRD standard decoction and behaviors test, the level of GABA associated miRNA/mRNA and GABAergic subtype-specific markers were detected by qRT-PCR and Western blot. The lncRNAs/miRNAs/GABA regulatory axis was verified by luciferase reporter assay, RNA immunoprecipitation, RNA pull-down assay, and theses changes were measured in LBRD administration with the use of immunofluorescence staining and RNA-fluorescence in situ hybridization.

In the current study, we found that LBRD exhibited high efficacy based on the results of behavioral tests. Meanwhile, LBRD also improved the reduced GABA levels in depression by increasing the expression of lncRNA Neat1 and Malat1, as well as decreasing miRNA-144-3p and miRNA-15b-5p. Moreover, the level of Sst mRNA and protein that were harvested from the mPFC tissues of depression group was significantly lower than those in the control mice. While, these changes can be reverted by LBRD standard decoction administration. Whereas, neither chronic stress nor treatment can change the level of PV and VIP mRNAs and protein expression. In the SST-positive neuron of mPFC tissues, treatment with LBRD standard decoction resulted in the elevation of Gad-67, VGAT, GAT-3 and a reduction of miRNA-144-3p expression.

These findings suggested that LBRD antidepressant activities may be related to ameliorating the SST-positive neuron deficits via regulating the miRNA-144-3p mediated GABA synthesis and release.

Depression is the second most common psychiatric disorder, affecting more than 340 million people of all ages worldwide. However, the mechanisms underlying the development of depression remain unclear, and existing antidepressants may cause clinical dependence and toxic side effects. Recently, emerging evidence from the fields of neuroscience, genetics, and genomics supports the modulatory role of long non-coding RNA (lncRNA) in depression. LncRNAs may mediate the pathogenesis of depression through multiple pathways, including regulating neurotransmitters and neurotrophic factors, affecting synaptic conduction, and regulating the ventriculo-olfactory neurogenic system. In addition, relying on genome-wide association study and molecular biological experiment, the possibility of lncRNA as a potential biomarker for the differential diagnosis of depression and other mental illnesses, including schizophrenia and anxiety disorders, is gradually being revealed. Thus, it is important to explore whether lncRNAs are potential therapeutic targets and diagnostic biomarkers for depression. Here, we summarize the genesis and function of lncRNAs and discuss the aberrant expression and functional roles of lncRNAs in the development, diagnosis, and therapy of depression, as well as the deficiencies and limitations of these studies. Moreover, we established a lncRNA-miRNA-mRNA-pathway-drug network of depression through bioinformatics analysis methods to deepen our understanding of the relationship between lncRNA and depression, promoting the clinical application of epigenetic research.

Depression is characterized by persistent depressed mood and cognitive dysfunction, severely impacting human health. In the present study, we aimed to explore the role and mechanism of microRNA (miR)-212 in depression in vivo. Chronic unpredictable mild stress (CUMS) mice were established, and depression-like behaviors were confirmed using the forced swimming test (FST), sucrose preference test (SPT), and the tail suspension test (TST). Next, the expression of miR-212 and its potential target, i.e., nuclear factor I-A (NFIA), was verified using quantitative reverse transcription (qRT)-PCR analysis and Western blotting in CUMS mice. The effects of miR-212 and NFIA on depression-like behaviors, inflammatory response, and neuronal apoptosis were examined using FST, TST, SPT, enzyme-linked immunosorbent assay (ELISA) assay, and flow cytometry analysis. Finally, the relationship between miR-212 and NFIA was examined using a dual-luciferase reporter assay. Based on our findings, miR-212 was significantly upregulated, while NFIA was downregulated in CUMS mice. miR-212 overexpression could suppress the CUMS-induced weight loss, immobility time in FST and TST, and increased hippocampal neuronal apoptosis and pro-inflammatory cytokines levels. In addition, NFIA upregulation could partially reverse the effects of miR-212 mimic in CUMS mice. Accordingly, miR-212 could ameliorate CUMS-induced depression-like behavior in mice by targeting NFIA, indicating its protective role in depression.

Constipation and depression are tightly related and often co-occur and coexist in clinic. Yet, the relationships and the underlying mechanisms are still unclear. Fecal metabolomics and network pharmacology were, for the first time, applied to investigate the potential correlations from multiple levels including classic behaviors, metabolomics, and gene targets. The behavioral indicators were analyzed, providing behavioral correlations at a macrolevel. Besides, fecal samples were analyzed by nuclear magnetic resonance spectroscopy to screen the shared and the unique metabolites and pathways, revealing correlations from a metabolic perspective. Finally, the disease targets and the functional pathways were obtained via network pharmacology, demonstrating correlations at the molecular level. The correlations between constipation and depression were demonstrated and supported by four-level evidence: (1) general behaviors, (2) gastrointestinal functions, (3) fecal metabolites and pathways, and (4) common gene targets and functional pathways. Especially, the correlations of behaviors and common metabolites showed that metabolites, including choline, betaine, and glycine, were significantly associated with constipation and depression. Besides, inflammation and immune abnormalities and energy metabolism were significantly involved in the mechanisms. The current findings prove the correlations between constipation and depression, and provide a basis for deeply understanding the comorbidities of constipation and depression.