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Cited by 41Circular RNAs in diseasesTreatment of Major DepressionCancer-related molecular mechanisms research

The DOI matches its Crossref record; 106 of the 106 references it cites were found in a registry or an index; none of the 112 sources its claims cite is checked for support yet.

Circular RNAs in depression: Biogenesis, function, expression, and therapeutic potential

Open access
Gan, Hua, Lei, Yuhe, Yuan, Naijun, Tang, Kairui, Hao, Wenzhi, Ma, Qingyu, Wu, Mansi, Zhou, Xuan, Li, Xiaojuan, Huang, Junqing, Deng, Lijuan, Chen, Jiaxu·2021·Biomedicine & Pharmacotherapy
DOI 10.1016/j.biopha.2021.111244
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Abstract

Depression is the second most common disease burden worldwide that threatens human health; however, mechanisms underlying the development of depression remain unclear. A family of non-coding RNAs, circular RNAs (circRNAs), has been shown to play a critical role in the development of depression by competitively binding to certain microRNAs (miRNA) and regulating the expression of target genes. Behavioral symptoms of depression may be ameliorated by knockdown or overexpression of depression-associated circRNAs. In this review, we summarized important functions of circRNAs and analyzed the most recent findings regarding the expression and biological function of circRNAs in depression. We discussed novel circRNA-based strategies to illuminate potential therapeutic targets that may aid in the development of new treatments for depression.

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

This review summarizes circRNA biogenesis, molecular functions, and evidence linking circRNAs to depression, including altered expression in patients and animal models and potential as diagnostic/therapeutic targets. It highlights circDYM, circHIPK2, circSTAG1, and hsa_circRNA_103636 among candidate circRNAs, while noting the field is in its infancy.

Key findings

  • circRNAs are covalently closed non-coding RNAs produced by back-splicing; more than 10,000 have been identified across organisms, with three reported types: ciRNAs, EIciRNAs, and intergenic circRNAs. They can act as miRNA sponges, bind RBPs/proteins, regulate transcription, and some may be translated.
  • Differential circRNA expression is reported in depression: Cui et al. identified four differentially expressed circRNAs between depression patients and controls using a human circRNA array including 13,617 circRNAs, and hsa_circRNA_103636 recovered to normal levels after 4-week and 8-week antidepressant regimens. Zheng et al. identified 20 significantly over-expressed and 17 significantly under-expressed circRNAs in the PFC of maternal separation rats. An et al. found 75 upregulated and 32 downregulated circRNAs in T2DM patients with depression; Jiang et al. found 183 upregulated and 64 downregulated circRNAs in T2DM patients with depression.
  • Mechanistic candidates include circDYM, which was significantly lower in peripheral blood of depression patients and in CUS/LPS mouse models; restoring circDYM attenuated depressive-like behaviors via an endogenous miR-9 sponge and decreased microglial activation through HSP90 ubiquitination. circSTAG1 and circHIPK2 were linked to astrocyte activation, and a gut microbiota-circHIPK2-astrocyte axis was implicated in depression.
  • Intervention studies reported circRNA changes: ketamine treatment identified rno_circRNA_014900 and rno_circRNA_005442 in rat hippocampus; SLPN treatment up-regulated mmu_circ_0001223 in CUMS mice; a 12-week Baduanjin intervention identified 266 differentially expressed circRNAs (170 down-regulated and 96 up-regulated); electroacupuncture at GV20 and GV29 identified three circRNAs derived from LOC102555866, Npepo, and Cdh12.

Methods

  • Narrative review based on PubMed literature retrieval using “circRNA,” “depression,” and “major depressive disorder (MDD)” as keywords.
  • Summarizes explorations of circRNAs in patients or animal models with depression over the past 20 years, including transcriptome analyses, qRT-PCR findings, and animal models such as CUS, CUMS, LPS, and maternal separation.
  • Includes a summary table of circRNAs in depression; no primary experimental data are reported.

Limitations

  • The paper states the field is in its infancy and is limited by a paucity of literature on corroborations between circRNA and depression; safety concerns exist for modulating circRNA to combat depression; and whether circRNA changes are specific to depressed patients remains unknown because circRNA levels may be affected by age, smoking, or drug abuse.
  • Evident from the text: this is a narrative review without a reported systematic search strategy, quality assessment, or meta-analysis, and it synthesizes heterogeneous human blood and animal brain/tissue findings.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.biopha.2021.111244

Cites

106 of 106 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

0 of 112 cited sources checked · 0 supported · 0 flagged

  • Premisenone given

    Aberrant expressions of circRNAs have been found through transcriptome analyses in the peripheral blood of humans and animal models with depression.

    “The participation of circRNAs in pathogenesis of depression has attracted considerable attention because aberrant expressions of circRNAs have been found through transcriptome analyses in the peripheral blood of humans and animal models with depression.”
    Quote in the paperSubstantial claim
  • Premisecitation

    CircRNAs participate in the development of diseases by regulating gene expression at several levels, such as regulating mRNA splicing and transcription, interacting with RNA-binding proteins (RBPs), and acting as miRNA sponges.

    “Independent of the mechanism of synthesis, circRNAs participate in the development of diseases by regulating gene expression at several levels, such as regulating mRNA splicing and transcription, interacting with RNA-binding proteins (RBPs), and acting as miRNA sponges [14].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [14] source
  • Premisecitation

    Three types of circRNAs have been reported: circular intronic RNAs (ciRNAs), retained-intron or exon-intron circRNAs (EIciRNAs), and intergenic circRNAs.

    “Three types of circRNAs have been reported, which are produced via different molecular processes, including circular intronic RNAs (ciR-NAs), retained-intron or exon-intron circRNAs (EIciRNAs), and intergenic circRNAs [40,41] (Fig. 1).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [40] source
    • cites [41] source
  • Premisecitation

    The role of circRNAs as novel therapeutic targets to ameliorate depression-like symptoms has been demonstrated in various animal models.

    “Likewise, the role of circRNAs as novel therapeutic targets to ameliorate depression-like symptoms has been demonstrated in various animal models [21][22][23][24].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [21] source
    • cites [22] source
    • cites [23] source
  • Interpretationreasoning

    CircRNAs play prominent roles in brain health and neurological diseases, including neuropsychiatric disorders.

    “CircRNAs are abundantly expressed in the brain and are highly active at neuronal synapses [21,28,[47][48][49][50], suggesting that circRNAs play prominent roles in brain health and neurological diseases, including neuropsychiatric disorders.”
    Quote in the paperSubstantial claim
  • It may state two separate claims as one. 36
  • Probably not a substantial claim. 8
  • The quote only partly states this claim. 6

  • It may state two separate claims as one.

    Premisecitation

    CircRNAs act as miRNA sponges by binding and inhibiting miRNAs, thereby regulating target gene expression at transcriptional and post-transcriptional levels.

    “Similar to competitive endogenous RNA (ceRNA), circRNAs act as sponges to bind and inhibit the activity of miRNAs [14], thus regulating the expression of target genes at the transcriptional and post-transcriptional levels through destabilization and translational silencing of mRNAs [15].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [14] source
    • cites [15] source

  • It may state two separate claims as one.

    Premisecitation

    CircRNAs are synthesized by the back-splicing of protein-coding precursor mRNAs, primarily in eukaryotes.

    “Originating from various genomic regions, circRNAs are synthesized by the back-splicing of protein-coding precursor mRNAs (primarily in eukaryotes) [25,26].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [25] source
    • cites [26] source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Two models of circRNA formation have been proposed: Lariat-Driven Circularization and Intron-Pairing-Driven Circularization.

    “Two different models of circRNA formation have been proposed: an exon-skipping process known as “Lariat-Driven Circularization” and a nonsequential donor-acceptor pairing process called “Intron-Pairing-Driven Circularization” or “direct back splicing” [28].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [28] source

  • It may state two separate claims as one.

    Premisecitation

    CircRNAs may act as miRNA sponges by interacting with RBPs, and regulating mRNA transcription, splicing, and translation.

    “CircRNAs may act as miRNA sponges by interacting with RBPs, and regulating mRNA transcription, splicing, and translation [14,41,51].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [14] source
    • cites [41] source
    • cites [51] source

  • It may state two separate claims as one.

    Premisereasoning

    Many circRNAs appear to be particularly enriched in the cerebellum, indicating possible involvement of circRNAs in the regulation of the nervous system.

    “Many circRNAs appear to be particularly enriched in the cerebellum, a brain area rich in neuronal spines, synapses, and neurons, indicating possible involvement of circRNAs in the regulation of the nervous system.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation

    CircRNAs are abundantly expressed in the brain and are highly active at neuronal synapses.

    “CircRNAs are abundantly expressed in the brain and are highly active at neuronal synapses [21,28,[47][48][49][50], suggesting that circRNAs play prominent roles in brain health and neurological diseases, including neuropsychiatric disorders.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21,28,[47][48][49][50]

  • It may state two separate claims as one.

    Premisecitation

    CDR1as circRNA acts as a miR-7 sponge and is named ciRS-7; ciRS-7 contains more than 70 selectively conserved miRNA target sites.

    “Hansen et al. have shown that the human cerebellar degeneration-related protein 1 antisense (CDR1as) circRNA acts as a miR-7 sponge and named this circular transcript circular RNA sponge for miR-7 (ciRS-7).CiRS-7 contains more than 70 selectively conserved miRNA target sites [14].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [14] source

  • It may state two separate claims as one.

    Premisecitation

    CircRNAs are pseudogenes that can be translated into peptides.

    “Recent studies have shown that circRNAs are pseudogenes that can be translated into peptides [52][53][54][55][56] (Fig. 2).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [52][53][54][55][56]

  • It may state two separate claims as one.

    Premisecitation

    CircRNAs play essential roles in neurological disorders because they back-splice from neural genes and many circRNAs originate from genes with pivotal regulatory functions in neurons and in brain development.

    “CircRNAs are believed to play essential roles in neurological disorders because they back-splice from neural genes and many circRNAs originate from genes with pivotal regulatory functions in neurons and in brain development [67].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [67] source

  • It may state two separate claims as one.

    Premisecitation

    CiRS-7 is abundantly expressed in the mammalian brain, where it increases the translation of the miR-7 target mRNA.

    “CiRS-7 is abundantly expressed in the mammalian brain [49,62], where it increases the translation of the miR-7 target mRNA [14,49].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [49] source
    • cites [62] source
    • cites [14] source

  • Probably not a substantial claim. The paper may give no reason why it holds. It may state two separate claims as one.

    Interpretationreasoning

    CircRNAs appear to play a vital role in the pathogenesis of mental diseases, which may make circRNAs a potential target of therapeutic drugs for mental diseases.

    “Regardless of inhibiting cell proliferation or blocking the cell cycle, circRNAs appear to play a vital role in the pathogenesis of mental diseases, which may make circRNAs a potential target of therapeutic drugs for mental diseases.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation

    CircRNAs maintain specificity and conservatism in dynamic expression and are highly enriched in the mammalian brain, independent of linear transcripts.

    “CircRNAs maintain specificity and conservatism in the process of dynamic expression and are highly enriched in the mammalian brain, independent of linear transcripts [62].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [62] source

  • It may state two separate claims as one.

    Premisecitation

    circFoxo3 produces anti-proliferative effects and blocks cell cycle progression by weakening CDK2 activity through formation of the circFoxo3-p21-CDK2 ternary complex.

    “CircFoxo3 produces anti-proliferative effects and blocks cell cycle progression by weakening the activity of cyclin-dependent kinase 2 (CDK2) through formation of the circFoxo3-p21-CDK2 ternary complex [15].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [15] source

  • It may state two separate claims as one.

    Premisecitation

    circPABPN1 inhibits linear splicing by binding to the HuR protein to reduce HeLa cell proliferation and PABPN1 translation.

    “Additionally, circular PABPN1 (circPABPN1) has been reported to inhibit linear splicing by binding to the HuR protein to reduce HeLa cell proliferation and PABPN1 translation [66].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [66] source

  • It may state two separate claims as one.

    Premisecitation

    Compared with other cytoplasmic RNAs, circRNAs seem to be more prone to being localized in synapses and their expression is correlated with neural plasticity.

    “Compared with other cytoplasmic RNAs, circRNAs seem to be more prone to being localized in synapses and their expression is correlated with neural plasticity, which further supports an important function of circRNAs in synaptic transmission [50,62].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [50] source
    • cites [62] source

  • It may state two separate claims as one.

    Premisecitation

    CircMBL contains conserved MBL/MBNL1 RNA binding sites derived from the second exon of the MBL mRNA; specific binding of circMBL to MBL mRNA regulates gene expression by inhibiting linear splicing of the MBL mRNA.

    “Circular MBL (circMBL) contains conserved muscleblind (MBL/MBNL1) RNA binding sites, which are derived from the second exon of the MBL mRNA.The specific binding of circMBL to MBL mRNA regulates gene expression by inhibiting the linear splicing of the MBL mRNA [65].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [65] source

  • It may state two separate claims as one.

    Premisecitation

    Dysregulation of ciRS-7 has been found in zebrafish with an impaired midbrain and in the hippocampus of AD patients.

    “In addition, dysregulation of ciRS-7 has been found in zebrafish with an impaired midbrain [71] and in the hippocampus of AD patients [45].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [71] source
    • cites [45] source

  • It may state two separate claims as one.

    Premisecitation

    Transcriptome analysis has been used to identify thousands of circRNAs expressed in peripheral blood mononuclear cells (PBMCs), and circRNAs are expressed at significantly higher levels than corresponding linear mRNAs.

    “Transcriptome analysis has been used to identify thousands of circRNAs that are expressed in peripheral blood mononuclear cells (PBMCs), and has shown that circRNAs are expressed at significantly higher levels than corresponding linear mRNAs [33].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [33] source

  • It may state two separate claims as one.

    Premisecitation

    CDR1as-deficient mice displayed a strongly impaired sensorimotor gating deficiency in which the animals were unable to filter out unnecessary information; a similar deficiency has been associated with neuropsychiatric disorders in humans.

    “In an animal model where the CR1as locus was removed from the mouse genome, CDR1as-deficient mice displayed a strongly impaired sensorimotor gating deficiency in which the animals were unable to filter out unnecessary information.A similar deficiency has been associated with neuropsychiatric disorders in humans [49].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [49] source

  • It may state two separate claims as one.

    Premisecitation

    Knockdown of circHIPK2 and overexpression of circSTAG1 have been shown to induce an inhibitory effect on the progression of depression.

    “Knockdown of circHIPK2 and overexpression of circSTAG1 have been shown to induce an inhibitory effect on the progression of depression, due to the binding mechanism between circSTAG1 and human AlkB homolog 5 (ALKBH5) and the miR-9 sponge function of circHIPK2.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [16] source
    • cites [22] source

  • It may state two separate claims as one.

    Premisecitation

    circDYM acts as an endogenous miR-9 sponge to inhibit miR-9 activity, resulting in a decrease of microglial activation via HSP90 ubiquitination.

    “Restoration of circDYM expression significantly attenuated depressive-like behaviors, which may have been mediated by circDYM acting as an endogenous miR-9 sponge to inhibit miR-9 activity, resulting in a decrease of microglial activation via heat shock protein 90 (HSP90) ubiquitination [21] (Fig. 3B).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [21] source

  • It may state two separate claims as one.

    Premisecitation

    The circRNA of human CDR1as/ciRS-7 is a miR-7 sponge, harbors 74 binding sites for miR-7, and binds to the argonaute (AGO) protein in a miR-7-dependent manner; this allows it to participate in the initiation and progression of PD.

    “Interestingly, the circRNA of human CDR1as/ciRS-7 is a miR-7 sponge, which harbors 74 binding sites for miR-7 and is able to bind to the argonaute (AGO) protein in a miR-7-dependent manner.Binding to the AGO protein allows the circRNA of human CDR1as/ciRS-7 to participate in the initiation and progression of PD [14,70].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [14] source
    • cites [70] source

  • It may state two separate claims as one.

    Interpretationreasoning

    CircRNAs may be involved in the onset and progression of depression, and thus may be potentially useful for diagnosis and treatment of depression.

    “CircRNAs may be involved in the onset and progression of depression, and thus may be potentially useful for diagnosis and treatment of depression.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationcitation

    circDYM is a biomarker for the diagnosis and treatment of depression.

    “Therefore, visual cortical repetitive transcranial magnetic stimulation (rTMS), a noninvasive intervention in depression, may up-regulate circDYM expression to produce anti-depressive effects, further confirming the significant role of circDYM as a biomarker for the diagnosis and treatment of depression [95].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [95] source

  • It may state two separate claims as one.

    Premisecitation

    Antidepressants and psychotherapy are currently the main clinical treatments for depression, but patients often become drug dependent or show poor compliance because of long-term continuous treatment, which are major limitations.

    “Although antidepressants and psychotherapy are currently the main clinical treatments for depression, patients often become drug dependent or show poor compliance because of long term continuous treatment, which are major limitations of current treatment options [85][86][87][88].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [85][86][87][88]

  • It may state two separate claims as one.

    Premisecitation

    mmu_circ_0001223 was significantly down-regulated in CUMS mice, but was significantly up-regulated by SLPN treatment.

    “Among them, mmu_circ_0001223 was significantly down-regulated in CUMS mice, but was significantly up-regulated by SLPN treatment, indicating that mmu_circ_0001223 may be an important mediator of SLPN's anti-depression effects [90].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [90] source

  • It may state two separate claims as one. The quote only partly states this claim.

    Premisecitation

    circTFRC and circTNIK were significantly upregulated in the depression group, suggesting that the function of TFRC and TNIK may be related to the pathogenesis of depression.

    “Circular TFRC (circTFRC) and circular TNIK (circTNIK) were significantly upregulated in the depression group, suggesting that the function of TFRC and TNIK may be related to the pathogenesis of depression [82].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [82] source

  • It may state two separate claims as one. The quote only partly states this claim.

    Interpretationcitation

    Baduanjin may ameliorate the symptoms of depression and alter blood glucose levels in depression patients via changes in circRNA expression.

    “This study provided valuable insights into potential mechanisms by which Baduanjin may ameliorate the symptoms of depression and alter blood glucose levels in depression patients [94].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [94] source

  • It may state two separate claims as one.

    Premisecitation

    Two circRNAs showed increased expression in depression rats compared with EA rats, and one circRNA showed decreased expression in the depression group compared with the EA group.

    “Two circRNAs that showed increased expression in depression rats compared with EA rats, and one circRNA that showed decreased expression in the depression group compared with the EA group, were identified.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [79] source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    The microbiota-gut-brain axis is believed to regulate various central processes through microbial metabolites.

    “The participation of gut microbiome in bidirectional communication pathway with the central nervous system (CNS) was named the microbiota-gut-brain axis, which is believed to regulate various central processes through microbial metabolites [98].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [98] source

  • It may state two separate claims as one.

    Interpretationcitation

    hsa_circRNA_003251 and hsa_circRNA_015115 may function as miR-761 sponges and participate in the circRNA-miRNA-mRNA network associated with depression.

    “Among them, hsa_circRNA_003251 and hsa_circRNA_015115 may function as miR-761 sponges and participate in the circRNA-miRNA-mRNA network associated with depression [80].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [80] source

  • It may state two separate claims as one.

    Premisereasoning

    This process increases degradation of FAAH in astrocytes and attenuates astrocyte dysfunction induced by CUS and corticosterone.

    “This process increases degradation of FAAH in astrocytes, and finally attenuates astrocyte dysfunction induced by CUS and corticosterone.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [16] source

  • It may state two separate claims as one.

    Interpretationreasoning

    Several key circRNAs, such as circDYM and circHIPK2, are associated with depression, providing translational evidence that circRNAs may represent novel therapeutic targets for depression.

    “Most recently, several key circRNAs have been associated with depression, such as circDYM and circHIPK2, providing translational evidence that circRNAs may represent novel therapeutic targets for depression.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Premisecitation

    CircHECTD1 and circHIPK2 activate astrocytes via autophagic processes that target miR142-TIPARP and miR124-2HG, respectively.

    “Circular HECTD1 (CircHECTD1) and circHIPK2 activate astrocytes via autophagic processes that target miR142-TIPARP and miR124-2HG, respectively [108,109].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [108] source
    • cites [109] source

  • The quote only partly states this claim.

    Premisecitation

    mmu_circRNA010860 (STAG1) is downregulated in human and mouse blood, hippocampus, plasma, heart, liver, spleen, lung, and kidney.

    “| 1 | mmu_circRNA010860 | STAG1 | Human & | | √ | Blood, Hippocampus, Plasma, Heart, Liver, Spleen, Lung, | [16] |”
    • Also stated in: § 5. Future perspectives · plain
      “| | | | Mouse | | | Kidney | |”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16] source

  • Probably not a substantial claim.

    Interpretationreasoning

    Autophagy and circRNA activity may act synergistically to modulate depression.

    “Autophagy and circRNA activity may act synergistically to modulate depression.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper may give no reason why it holds.

    Interpretationnone given

    The molecular mechanisms related to the onset and progression of depression likely involve circRNAs that function through multiple complex signal transduction pathways.

    “The molecular mechanisms related to the onset and progression of depression likely involve circRNAs that function through multiple complex signal transduction pathways.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation

    Transplantation of the NLRP3 KO gut microbiota decreases the expression of circHIPK2 and reverses astrocyte dysfunction in the CUS model mouse.

    “(C) Transplantation of the NLRP3 KO gut microbiota decreases the expression of circHIPK2 and reverses astrocyte dysfunction in the CUS model mouse.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [22] source

  • It may state two separate claims as one.

    Premisecitation

    CircSTAG1 binding to ALKBH5 inhibits the translocation of cytoplasmic ALKBH5 into the nucleus and promotes up-regulation of m6A methylation of FAAH mRNA.

    “(D) The binding of CircSTAG1 and ALKBH5 inhibits the translocation of cytoplasmic ALKBH5 into the nucleus, and promotes the up-regulation of m 6 A methylation of fatty acid amide hydrolase (FAAH) messenger RNA.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16] source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    PPP1R13B regulated by mmu_circ_012091 contributes to the proliferation and migration of lung fibroblasts that rely on endoplasmic reticulum stress (ERS) and autophagy.

    “According to recent research, protein phosphatase 1 regulatory subunit 13B (PPP1R13B) regulated by mmu_circ_012091 contributes to the proliferation and migration of lung fibroblasts that rely on endoplasmic reticulum stress (ERS) and autophagy [107].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [107] source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.

    Interpretationnone given

    CircRNAs may block autophagosome formation, maturation, selection, expansion, and degradation by regulating the expression or function of autophagy-related proteins and interfering with the normal internal environment of human cells.

    “CircRNAs may block autophagosome formation, maturation, selection, expansion, and degradation by regulating the expression of, or the function of, autophagy-related proteins and interfering with the normal internal environment of human cells.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation

    Autophagy is closely related to depression and many antidepressants induce the autophagy pathway.

    “Numerous studies have shown that autophagy is closely related to depression and that many antidepressants induce the autophagy pathway [101][102][103][104][105][106].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [101][102][103][104][105][106]

  • It may state two separate claims as one.

    Premisecitation

    CircDYM (DYM) is downregulated in human and mouse plasma and hippocampus.

    “| 23 | CircDYM | DYM | Human & | | √ | Plasma, Hippocampus | [21] |”
    • Also stated in: § 5. Future perspectives · plain
      “| | | | Mouse | | | | |”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21] source

  • The quote only partly states this claim.

    Premisecitation

    mmu_circ_0001223 (Bnc2) is downregulated in mouse ventral medial prefrontal cortex.

    “| 20 | mmu_circ_0001223 | Bnc2 | Mouse | | √ | ventral medial prefrontal cortex | [23] |”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [23] source

  • The quote only partly states this claim.

    Premisecitation

    rno_circRNA_005442 is downregulated in rat hippocampus.

    “| 22 | rno_circRNA_005442 | - | Rat | | √ | Hippocampus | [81] |”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [81] source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. The quote only partly states this claim.

    Premisecitation

    chr3:195781950-195782172 (TFRC) is upregulated in human blood.

    “| 24 | chr3:195781950- | TFRC | Human | √ | | Blood | [82] |”
    • Also stated in: § 5. Future perspectives · plain
      “| | 195782172 | | | | | | |”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [82] source
46 of 46

  • The paper relies on this without support.

    CircRNA dysregulation observed in animal models of depression is relevant to human depression.

    “The participation of circRNAs in pathogenesis of depression has attracted considerable attention because aberrant expressions of circRNAs have been found through transcriptome analyses in the peripheral blood of humans and animal models with depression.”

  • The paper relies on this without support.

    Differential expression of circRNAs in depression indicates a causal role in the pathogenesis of depression.

    “These results suggest that circRNAs play an important role in depression; however, whether depression leads to the differential expression of circRNAs or changes in circRNA expression cause abnormal behavior requires further investigation.”
2 of 2

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • circRNAs are covalently closed circular RNA molecules that typically contain exons, formed by direct splicing of 3′ and 5′ terminal ends generated from precursor mRNA.

    “circRNAs are covalently closed circular RNA molecules that typically contain exons, formed by direct splicing 3′ and 5′ terminal ends generated from precursor mRNA.220,287”

    From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [287]

    Section 2 (Biogenesis of circRNAs; page unavailable) describes circRNAs as covalently closed loops, says most are formed from exons, and attributes their synthesis to back-splicing of precursor mRNAs. It does not describe formation as direct splicing of 3′ and 5′ terminal ends; it presents direct back-splicing as one of two proposed formation models. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • circRNAs regulate the expression levels of downstream genes at several levels, including mRNA transcription, splicing, and translation.

    “circRNAs regulate the expression levels of downstream genes at several levels, including mRNA transcription, splicing, and translation287.”

    From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [287]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • The three circRNA types differ between the text and Figure 1

    Minor

    The text names intergenic circRNAs as one of the three types, whereas Figure 1 names exonic circRNAs alongside ciRNAs and EIciRNAs. The two lists do not describe the same three types.

1 of 1

Citations

Cites

Flagged first, then by citations

Research works printed but not linked: 3

  1. Salmanidis, 2014, Direct transcriptional regulation by nuclear microRNAs, Int. J. Biochem. Cell Biol., 54, 304, 10.1016/j.biocel.2014.03.010 · DOI · Paper page
  2. Zheng, 2019, Transcriptome analysis on maternal separation rats with depression-related manifestations ameliorated by electroacupuncture, Front. Neurosci., 13, 314, 10.3389/fnins.2019.00314 · DOI · Paper page
  3. Zhang, 2018, Total saponins from the leaves of Panax notoginseng inhibit depression on mouse chronic unpredictable mild stress model by regulating circRNA expression, Brain Behav., 8, 10.1002/brb3.1127 · DOI · Paper page

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Metadata

Authors
Gan, H., Lei, Y., Yuan, N., Tang, K., Hao, W., Ma, Q., Wu, M., Zhou, X., Li, X., Huang, J., Deng, L., & Chen, J.
Affiliations
  • Jinan University (CN)
  • Guangzhou University of Chinese Medicine (CN)
Corresponding author
  • Deng, Lijuan
  • Chen, Jiaxu
ORCID
Venue
Biomedicine & Pharmacotherapy
Publisher
Elsevier BV
Published
2021-05
Volume
137
Pages
111244
ISSN
0753-3322 (ISSN-L)
DOI
10.1016/j.biopha.2021.111244
OpenAlex
W3122526457
Semantic Scholar
d57d33404cf6292b7250da074edb3dcd82800d93
Cited by
41
References
106
Citations by year
2026: 3 · 2025: 5 · 2024: 16 · 2023: 6 · 2022: 7 · 2021: 4
FWCI
0.89
Type
journal article
Language
en
Open access
Licence
Locations
  • Biomedicine & Pharmacotherapy (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Natural Science Foundation of China
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Circular RNAs in diseases
  • Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
Keywords
circular RNA, depression, circRNA biogenesis, microRNA sponging, non-coding RNA, circRNA expression, therapeutic target, depression mechanisms
MeSH terms
RNA, Circular, Affect, Animals, Antidepressive Agents, Brain, Depression, Gene Expression Regulation, Humans, MicroRNAs

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

A language model drew the claims from the paper on 2026-10-09, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).

A second model labelled each claim on 2026-10-09 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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