DA.Vra1-congenic rats display increased gene expression and Schwann cell apoptosis but unaffected nerve regeneration compared to parental DA rats after sciatic nerve injury and repair

Frontiers in Cell and Developmental Biology, Journal Year: 2025, Volume and Issue: 13

Published: April 28, 2025

The rat Vra1 locus, containing glutathione S-transferase alpha 4 (Gsta4), regulates the degeneration of central nervous system (CNS) neurons in toxin-, protein-, and injury-based models. We hypothesize that Piebald Virol Glaxo.1AV1 (PVG) alleles confer protection increased axonal outgrowth after peripheral nerve injury repair. DA rats (n = 14) with PVG locus (DA.Vra1, n were subjected to sciatic transection immediate After 6 days, protein gene expression analyzed injured uninjured nerves dorsal root ganglia (DRG). No differences observed between strains, but number apoptotic Schwann cells distal end was higher DA.Vra1 than (p 0.003). In both gene- activating transcription factor 3 (ATF3) 27-kDa heat shock (HSP27, i.e., Hspb1) vs. DRG. rats, Gsta4 lower DRG 0.043) 0.008) 0.008). had Atf3 0.016) caspase 0.032) rats. Results highlight complexity repair, supporting further investigation regeneration.

Language: Английский

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MSC-derived mitochondria promote axonal regeneration via Atf3 gene up-regulation by ROS induced DNA double strand breaks at transcription initiation region

Cell Communication and Signaling, Journal Year: 2024, Volume and Issue: 22(1)

Published: April 25, 2024

Abstract Background The repair of peripheral nerve injury poses a clinical challenge, necessitating further investigation into novel therapeutic approaches. In recent years, bone marrow mesenchymal stromal cell (MSC)-derived mitochondrial transfer has emerged as promising therapy for cellular injury, with reported applications in central injury. However, its potential effect on remains unclear. Methods We established mouse sciatic crush model. Mitochondria extracted from MSCs were intraneurally injected the injured nerves. Axonal regeneration was observed through whole-mount imaging. dorsal root ganglions (DRGs) corresponding to harvested test gene expression, reactive oxygen species (ROS) levels, well degree and location DNA double strand breaks (DSBs). Results vivo experiments showed that injection effectively promoted axon Four days after fluorescently labeled mitochondria nerves, detected DRGs. RNA-seq qPCR results enhanced expression Atf3 other regeneration-associated genes DRG neurons. Knocking down DRGs by siRNA could diminish injection. Subsequent increase levels ROS DSBs injury-associated neurons, this being correlated expression. ChIP Co-IP revealed an elevation DSB within transcription initiation region following therapy, while also demonstrating spatial proximity between mitochondria-induced CTCF binding sites. Conclusion These findings suggest MSC-derived nerves can be retrogradely transferred neuron somas via axoplasmic transport, at regions accumulation, which rapidly release CTCF-mediated topological constraints chromatin interactions. This process may enhance interactions promoter enhancer, ultimately promoting up-regulation induced promotes downstream facilitates regeneration.

Language: Английский

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Transcriptional Regulation and Signaling of Type IV IFN with Identification of the ISG Repertoire in an Amphibian Model, Xenopus laevis

The Journal of Immunology, Journal Year: 2023, Volume and Issue: 210(11), P. 1771 - 1789

Published: April 5, 2023

Abstract The type IV IFN (IFN-υ) is reported in vertebrates from fish to primary mammals with IFN-υR1 and IL-10R2 as receptor subunits. In this study, the proximal promoter of IFN-υ was identified amphibian model, Xenopus laevis, functional IFN-sensitive responsive element NF-κB sites, which can be transcriptionally activated by transcription factors, such regulatory factor (IRF)1, IRF3, IRF7, p65. It further found that signals through classical IFN-stimulated gene (ISG) 3 (ISGF3) induce expression ISGs. seems likely elements amphibians similar III genes, mechanism involved induction very much I IFNs. Using recombinant protein X. laevis A6 cell line, >400 ISGs were transcriptome, including homologous humans. However, many 268 genes unrelated human or zebrafish ISGs, some these expanded families novel TRIM (AMNTR) family. AMNTR50, a member family, induced I, III, IFNs sites promoter, molecule has negative role regulating considered current study contributes understanding transcription, signaling, aspects at least amphibians.

Language: Английский

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CD4 ⁺ T cells drive corneal nerve damage but not epitheliopathy in an acute aqueous-deficient dry eye model

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(48)

Published: Nov. 19, 2024

Dry eye disease (DED) is characterized by a dysfunctional tear film in which the corneal epithelium and its abundant nerves are affected ocular desiccation inflammation. Although adaptive immunity specifically CD4 + T cells play role DED pathogenesis, exact contribution of these to epithelial neural damage remains undetermined. To address this, we explored progression surgical model wild-type (WT) cell-deficient mice. We observed that immune-deficient mice developed all aspects comparably WT except for absence functional morphological nerve changes, damage-associated transcriptomic signature trigeminal ganglia, sustained cytokine levels. Adoptive transfer from reproduced but not epitheliopathy. Conversely, reconstituted solely with naïve impairment epitheliopathy upon induction, thus replicating phenotype. Collectively, our data show while neuropathy driven DED, develops independently immune response. These findings have implications cell-targeting therapies currently use DED.

Language: Английский

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Activation of ATF3 via the Integrated Stress Response Pathway Regulates Innate Immune Response to Restrict Zika Virus

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: July 27, 2023

Zika virus (ZIKV) is a re-emerging mosquito-borne flavivirus that can have devastating health consequences. The developmental and neurological effects from ZIKV infection arise in part the triggering cellular stress pathways perturbing transcriptional programs. To date, underlying mechanisms of control directing viral restriction virus-host interaction are understudied. Activating Transcription Factor 3 (ATF3) stress-induced effector modulates expression genes involved myriad processes, including inflammation antiviral responses, to restore homeostasis. While ATF3 known be upregulated during infection, mode by which activated specific role unknown. In this study, we show via inhibitor RNA interference approaches initiates integrated response pathway activate ATF4 turn induces expression. Additionally, using CRISPR-Cas9 system delete ATF3, found acts limit gene A549 cells. We also determined enhances such as STAT1 other components innate immunity induce an ATF3-dependent anti-ZIKV response. Our study reveals crosstalk between immune highlights important for establishing effect infection.

Language: Английский

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CD4+ T cells drive corneal nerve damage but are dispensable for corneal epitheliopathy development in dry eye disease

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: March 26, 2024

Abstract Dry eye disease (DED) is a disorder characterized by dysfunctional tear film in which the corneal epithelium and its abundant nerves are affected ocular desiccation, inflammation, local immune response. Although adaptive immunity specifically CD4 + T cells play role DED pathogenesis, exact contribution of these to epithelial neural damage remains undetermined. To address this, we explored progression surgical model wild-type (WT) cell-deficient mice. We observed that immune-deficient mice developed all aspects comparably WT except for absence functional morphological nerve changes, damage-associated transcriptomic signature trigeminal ganglia, sustained cytokine levels. Adoptive transfer from reproduced but not epitheliopathy. Conversely, reconstituted solely with naive impairment epitheliopathy upon induction, thus replicating phenotype. Collectively, our data show while neuropathy driven DED, develops independently These findings have implications cell-targeting therapies currently use DED.

Language: Английский

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Molecular mechanisms of spinal cord injury repair across vertebrates: A comparative review

European Journal of Neuroscience, Journal Year: 2024, Volume and Issue: 60(4), P. 4552 - 4568

Published: July 8, 2024

In humans and other adult mammals, axon regeneration is difficult in axotomized neurons. Therefore, spinal cord injury (SCI) a devastating event that can lead to permanent loss of locomotor sensory functions. Moreover, the molecular mechanisms vertebrates are not very well understood, currently, no effective treatment available for SCI. striking contrast many nonmammalian such as reptiles, amphibians, bony fishes lampreys spontaneously resume locomotion even after complete recent years, rapid progress development next-generation sequencing technologies has offered valuable information on this review, we aimed provide comparison process across classical model organisms, focusing crucial genes signalling pathways play significant roles individually identifiable descending neurons Considering special evolutionary location powerful regenerative ability lamprey zebrafish, they will be key organisms ongoing studies regeneration. Detailed study SCI these help elucidation neuron species.

Language: Английский

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Activating Transcription Factor 3 Diminishes Ischemic Cerebral Infarct and Behavioral Deficit by Downregulating Carboxyl-Terminal Modulator Protein

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(3), P. 2306 - 2306

Published: Jan. 24, 2023

Activating transcription factor 3 (ATF3) is a stress-induced and familiar neuronal marker for nerve injury. This has been shown to protect neurons from hypoxic insult in vitro by suppressing carboxyl-terminal modulator protein (CTMP) transcription, indirectly activating the anti-apoptotic Akt/PKB cascade. Despite prior studies vitro, whether this neuroprotective pathway also exists brain vivo after ischemic remains be determined. In present study, we showed rapid marked induction of ATF3 mRNA throughout ischemia-reperfusion middle cerebral artery (MCA) occlusion model. Although level CTMP was quickly induced upon ischemia, its only mild increase reperfusion. With gain-of-function approach, both pre- post-ischemic administration Ad-ATF3 ameliorated infarct neurological deficits. Whereas, with loss-of-function knockout (KO) mice bigger worse functional outcome ischemia. addition, these congenital defects were rescued reintroducing KO mice. overexpression led lower higher p-Akt(473) brain. On contrary, resulted upregulation downregulation instead. Furthermore, siRNA knockdown smaller better behaviors. increased p-Akt(473), but did not alter brain, upholding ATF3→CTMP signal summary, our proof-of-principle experiments support existence cascade regulating results suggest therapeutic potential stroke treatment.

Language: Английский

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Establishment of Ferroptosis-Related Key Gene Signature and Its Validation in Compression-Induced Intervertebral Disc Degeneration Rats

Oxidative Medicine and Cellular Longevity, Journal Year: 2023, Volume and Issue: 2023, P. 1 - 20

Published: Feb. 10, 2023

Cell death and functional loss of nucleus pulposus cell play essential roles in intervertebral disc degeneration (IDD). Ferroptosis is a newly identified type, its role IDD still under investigation. Identifying the key genes ferroptosis helps to identify therapeutic targets IDD. In this study, we downloaded human mRNA microarray data from Gene Expression Omnibus FerrDb, then performed series analyses using strict bioinformatics algorithms. general, obtained 40 ferroptosis-related differential expression (FerrDEGs) six gene signatures, namely, ATF3, EIF2S1, AR, NQO1, TXNIP, AKR1C3. addition, enrichment analysis FerrDEGs was conducted, protein-protein interaction network constructed, correlations between immune infiltrating cells were analyzed, lncRNA-miRNA-mRNA ceRNA constructed. particular, ATF3 EIF2S1 showed strongest correlation with function, which might lead development Finally, expressions verified rat compression-induced conclusion, preliminary study analyzed mechanism IDD, laid foundation for follow-up provided new preventing delaying

Language: Английский

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Development of a Systems Medicine Approach to Spinal Cord Injury

Journal of Neurotrauma, Journal Year: 2023, Volume and Issue: 40(17-18), P. 1849 - 1877

Published: June 19, 2023

Traumatic spinal cord injury (SCI) causes a sudden onset multi-system disease, permanently altering homeostasis with multiple complications. Consequences include aberrant neuronal circuits, organ system dysfunctions, and chronic phenotypes such as neuropathic pain metabolic syndrome. Reductionist approaches are used to classify SCI patients based on residual neurological function. Still, recovery varies due interacting variables, including individual biology, comorbidities, complications, therapeutic side effects, socioeconomic influences for which data integration methods lacking. Infections, pressure sores, heterotopic ossification known modifiers. However, the molecular pathobiology of disease-modifying factors recovery-chronic syndrome trajectory is mainly unknown, significant gaps between intensive early treatment phases. Changes in function gut dysbiosis, adrenal dysregulation, fatty liver, muscle loss, autonomic dysregulation disrupt homeostasis, generating progression-driving allostatic load. Interactions interdependent systems produce emergent resilience, that preclude single mechanism interpretations. Due many variables individuals, substantiating effects treatments improve outcomes difficult. Acute outcome predictors, blood cerebrospinal fluid biomarkers, neuroimaging signal changes, abnormalities, often do not predict phenotypes. In medicine, network analysis bioinformatics derive control modules. To better understand evolution from acute states, we propose topological phenotype framework integrating bioinformatics, physiological data, load tested against accepted established metrics. This form correlational phenotyping may reveal critical nodal points intervention trajectories. study examines limitations current classifications how these can evolve through medicine.

Language: Английский

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