Journal: International Journal of Molecular Sciences
Article Title: The Role of Exosomes in the Regulation of Molecular Mechanisms Underlying Treatment Resistance—Linking Cellular Crosstalk to Clinical Implications in Depression
doi: 10.3390/ijms27052449
Figure Lengend Snippet: Exosomes in the pathophysiology of TRD. SIRT2 activates the AKT/GSK-3β pathway, promoting neurogenesis as evidenced by increased expression of DCX + , Nestin + cells, SYP, and PSD95. miR-139-5p inhibits the PI3K/Akt pathway, leading to reduced neuronal differentiation markers (DCX + , MAP2 + , BrdU/NeuN + cells). Sig-1R activates ERK1/2 signaling, enhances BDNF expression, and suppresses microglial activation, thereby reducing pro-inflammatory cytokines (IL-1β, IL-6, TNF-α). miR-207 modulates TLR4/MyD88/NF-κB signaling, thereby contributing to decreased neuroinflammation. miR-409-3p regulates Nr4a2-dependent NF-κB activation, while miR-9-5p influences SOCS2 and the JAK/STAT3 pathway, affecting microglial polarization toward pro-inflammatory M1 phenotype. miR-26a exhibits anti-apoptotic and antioxidant effects by increasing SOD levels and reducing Bax, MDA, LDH, TNF-α, and IL-1β, while upregulating Bcl-2. Collectively, these pathways highlight the interplay between neurogenesis, neuroinflammation, oxidative stress, and apoptosis, which all may underlie TRD pathophysiology. Abbreviations: AKT-Protein kinase B; BDNF-Brain-Derived Neurotrophic Factor; Bax-Bcl-2-Associated X protein; Bcl-2-B-cell lymphoma 2; BrdU-5-Bromo-2′-deoxyuridine; DCX-Doublecortin; ERK1/2-Extracellular Signal-Regulated Kinases 1 and 2; GSK-3β-Glycogen Synthase Kinase 3 beta; IL-1β-Interleukin 1 beta; IL-6-Interleukin 6; JAK-Janus Kinase; LDH-Lactate Dehydrogenase; MAP2-Microtubule-Associated Protein 2; MDA-Malondialdehyde; miR-microRNA; MyD88-Myeloid Differentiation Primary Response 88; Nestin-Neural stem cell marker Nestin; NeuN-Neuronal Nuclei (Neuronal Nuclear Antigen); NF-κB-Nuclear Factor kappa-light-chain-enhancer of activated B cells; Nr4a2-Nuclear Receptor Subfamily 4 Group A Member 2; PI3K-Phosphoinositide 3-Kinase; PSD95-Postsynaptic Density Protein 95; Sig-1R-Sigma-1 Receptor; SOCS2-Suppressor of Cytokine Signaling 2; SIRT2-Sirtuin 2; SOD-Superoxide Dismutase; STAT3-Signal Transducer and Activator of Transcription 3; SYP-Synaptophysin; TLR4-Toll-Like Receptor 4; TNF-α-Tumor Necrosis Factor alpha. (→)—activated; (⊣)—inhibited; (↑)—increase; (↓)—decrease.
Article Snippet: SPF-grade SD pregnant rats (250–300 g); SPF-grade SD female rats (8 weeks old; 300–350 g; n = 32) , Chronic unpredictable mild stress (CUMS; 21 days) + ovariectomy (OVX) Neural stem cell-derived exosomes (NSCs-Exo; 30 μg/rat in 200 μL PBS; 2 weeks; i.c.v.) + electro-acupuncture treatment (EA; 28 days) , n.a. , Hippocampus (HP) , Exosome isolation: ultracentrifugation Exosome characterization: TEM, NTA, markers (Alix, CD9) Western Blot IF , ↑ NeuN+ cells, Nestin+ cells ↑ AMPK, p-AMPK, PGC-1α, NRF1, and TFAM ↑ PSD95, SYN, and GAP43 , [ ] .
Techniques: Expressing, Activation Assay, Derivative Assay, Marker
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