Autotransplantation of teeth (ATT) is a surgical technique that involves transplanting a non-functional tooth (donor tooth) within the oral cavity to an edentulous area (recipient site). This procedure not only demonstrates reliable long-term success and survival rates but also possesses unique osteoinductive capacity and soft tissue preservation advantages, making it particularly suitable for the restoration of dental defects in adolescents. However, ATT is highly technique-sensitive, and its successful implementation depends on the operator’s comprehensive mastery of multidisciplinary knowledge, including alveolar surgery, periodontology, endodontics, prosthodontics, and orthodontics, as well as the precise design and execution of personalized surgical plans. Preoperative systematic evaluation is required to assess the root development stage of the donor tooth, the bone volume condition of the recipient site, and the compatibility between the donor tooth and the recipient site. For teeth with an open apex, pulpal healing through revascularization is often achievable with a high success rate, whereas those with a closed apex typically require root canal treatment 2-4 weeks postoperatively to minimize complications. Utilizing cone beam computed tomography, intraoral scanning, and virtual surgical planning enables accurate assessment of donor-recipient matching and the design of the transplantation plan. Intraoperatively, careful attention must be paid to minimizing tissue trauma through precise planning and gentle manipulation, strictly limiting the extra-oral time of the donor tooth to within 15 min, and maintaining the root surface moist at all times to protect the periodontal ligament and improve surgical outcomes. The application of tools, such as 3D-printed personalized surgical guides, donor tooth replicas, and customized osteotomes, has enhanced the precision of socket preparation. Further, emerging technologies, such as dynamic navigation, surgical robotics, and artificial intelligence, have also demonstrated promising potential in the field of ATT.

The Janus kinase/signal transducers and activators of transcription (JAK-STAT) control natural killer (NK) cells development and cytotoxic functions, however, whether long non-coding RNAs (lncRNAs) are involved in this pathway remains unknown. We found that miR155HG was elevated in activated NK cells and promoted their proliferation and effector functions in both NK92 and induced-pluripotent stem cells (iPSCs)-derived NK (iPSC-NK) cells, without reliance on its derived miR-155 and micropeptide P155. Mechanistically, miR155HG bound to miR-6756 and relieved its repression of JAK3 expression, thereby promoting the JAK-STAT pathway and enhancing NK cell proliferation and function. Further investigations disclosed that upon cytokine stimulation, STAT3 directly interacts with miR155HG promoter and induces miR155HG transcription. Collectively, we identify a miR155HG-mediated positive feedback loop of the JAK-STAT signaling. Our study will also provide a power target regarding miR155HG for improving NK cell generation and effector function in the field of NK cell adoptive transfer therapy against cancer, especially iPSC-derived NK cells.

Glioma represents the most prevalent malignant tumor of the central nervous system, with chemotherapy serving as an essential adjunctive treatment. However, most chemotherapeutic agents exhibit limited ability to penetrate the blood-brain barrier (BBB). This study introduced a novel dual-targeting strategy for glioma therapy by modulating the formation of nanobody-driven protein coronas to enhance the brain and tumor-targeting efficiency of hydrophobic cisplatin prodrug-loaded lipid nanoparticles (C8Pt-Ls). Specifically, nanobodies (Nbs) with fibrinogen-binding capabilities were conjugated to the surface of C8Pt-Ls, resulting in the generation of Nb-C8Pt-Ls. Within the bloodstream, Nb-C8Pt-Ls could bound more fibrinogen, forming the protein corona that specifically interacted with LRP-1, a receptor highly expressed on the BBB. This interaction enabled a "Hitchhiking Effect" mechanism, facilitating efficient trans-BBB transport and promoting effective brain targeting. Additionally, the protein corona interacted with LRP-1, which is also overexpressed in glioma cells, achieving precise tumor targeting. Computational simulations and SPR detection clarified the molecular interaction mechanism of the Nb-fibrinogen-(LRP-1) complex, confirming its binding specificity and stability. Our results demonstrated that this strategy significantly enhanced C8Pt accumulation in brain tissues and tumors, induced apoptosis in glioma cells, and improved therapeutic efficacy. This study provides a novel framework for glioma therapy and underscores the potential of protein corona modulation-based dual-targeting strategies in advancing treatments for brain tumors.

OBJECTIVES: To investigate the mechanism underlying the inhibitory effect of Buyang Huanwu Decoction (BYHWD) on vascular aging. METHODS: Eighteen male SD rats were randomized into young group, intraperitoneal D-galactose injection-induced aging group, and BYHWD gavage group. The changes in pulse wave velocity (PWV), vascular SA-β-gal activity, and expressions of p16, p21 and SA‑β‑gal of the rats were examined. Serum exosomes were isolated from the rats, and after characterization using NTA and TEM and for surface markers and vascular cell markers, were examined for miR-590-5p expression using qRT-PCR. The M1/M2 macrophage ratio and cytokine levels were evaluated using immunofluorescence staining and qRT-PCR. Bioinformatics analysis and dual-luciferase reporter assays were carried out to predict the potential target genes of miR-590-5p and validate its targeting relationship with SLC8A3, whose expressions were detected in the vascular tissues of the rats by Western blotting. RESULTS: Compared with the young rats, the aging rats exhibited significantly increased PWV in the abdominal aorta with elevated vascular expressions of p16, p21 and SA-β-gal, which were all reversed by BYHWD treatment. The isolated serum exosomes were positive for CD63, CD81, CD31 and SM-22, and the exosomes from aging rats showed significantly downregulated expression of miR-590-5p, which was upregulated after BYHWD treatment. The aging rat vessels showed an increased M1/M2 macrophage ratio with elevated M1-specific cytokines and reduced M2-specific cytokines, and BYHWD treatment effectively inhibited M1 polarization of the macrophages. Pearson analysis revealed a negative correlation between exosomal miR-590-5p upregulation and the M1/M2 ratio. Bioinformatics analysis and dual-luciferase assays confirmed that miR-590-5p targets SLC8A3. Western blotting demonstrated increased SLC8A3 expression in aging rat vessels, which was downregulated after BYHWD treatment. CONCLUSIONS BYHWD attenuates vascular aging in rats by modulating macrophage M1 polarization and suppressing vascular inflammation via exosomal miR-590-5p-mediated downregulation of SLC8A3.
Animals ; MicroRNAs/genetics* ; Rats, Sprague-Dawley ; Drugs, Chinese Herbal/pharmacology* ; Male ; Macrophages/drug effects* ; Rats ; Exosomes/metabolism* ; Aging/drug effects* ; Signal Transduction

Extensive epigenetic reprogramming involves in memory CD8+ T-cell differentiation. The elaborate epigenetic rewiring underlying the heterogeneous functional states of CD8+ T cells remains hidden. Here, we profile single-cell chromatin accessibility and map enhancer-promoter interactomes to characterize the differentiation trajectory of memory CD8+ T cells. We reveal that under distinct epigenetic regulations, the early activated CD8+ T cells divergently originated for short-lived effector and memory precursor effector cells. We also uncover a defined epigenetic rewiring leading to the conversion from effector memory to central memory cells during memory formation. Additionally, we illustrate chromatin regulatory mechanisms underlying long-lasting versus transient transcription regulation during memory differentiation. Finally, we confirm the essential roles of Sox4 and Nrf2 in developing memory precursor effector and effector memory cells, respectively, and validate cell state-specific enhancers in regulating Il7r using CRISPR-Cas9. Our data pave the way for understanding the mechanism underlying epigenetic memory formation in CD8+ T-cell differentiation.
CD8-Positive T-Lymphocytes/metabolism* ; Cell Differentiation ; Chromatin/immunology* ; Animals ; Mice ; Immunologic Memory ; Epigenesis, Genetic ; SOXC Transcription Factors/immunology* ; NF-E2-Related Factor 2/immunology* ; Mice, Inbred C57BL ; Gene Regulatory Networks ; Enhancer Elements, Genetic

This research study focuses on addressing the limitations of current neuropathic pain (NP) treatments by developing a novel dual-target modulator, E0199, targeting both Na_V1.7, Na_V1.8, and Na_V1.9 and K_V7 channels, a crucial regulator in controlling NP symptoms. The objective of the study was to synthesize a compound capable of modulating these channels to alleviate NP. Through an experimental design involving both in vitro and in vivo methods, E0199 was tested for its efficacy on ion channels and its therapeutic potential in a chronic constriction injury (CCI) mouse model. The results demonstrated that E0199 significantly inhibited Na_V1.7, Na_V1.8, and Na_V1.9 channels with a particularly low half maximal inhibitory concentration (IC₅₀) for Na_V1.9 by promoting sodium channel inactivation, and also effectively increased K_V7.2/7.3, K_V7.2, and K_V7.5 channels, excluding K_V7.1 by promoting potassium channel activation. This dual action significantly reduced the excitability of dorsal root ganglion neurons and alleviated pain hypersensitivity in mice at low doses, indicating a potent analgesic effect without affecting heart and skeletal muscle ion channels critically. The safety of E0199 was supported by neurobehavioral evaluations. Conclusively, E0199 represents a ground-breaking approach in NP treatment, showcasing the potential of dual-target small-molecule compounds in providing a more effective and safe therapeutic option for NP. This study introduces a promising direction for the future development of NP therapeutics.

Objective To investigate the mechanism underlying the inhibitory effect of Buyang Huanwu Decoction(BYHWD)on vascular aging.Methods Eighteen male SD rats were randomized into young group,intraperitoneal D-galactose injection-induced aging group,and BYHWD gavage group.The changes in pulse wave velocity(PWV),vascular SA-β-gal activity,and expressions of p16,p21 and SA-β-gal of the rats were examined.Serum exosomes were isolated from the rats,and after characterization using NTA and TEM and for surface markers and vascular cell markers,were examined for miR-590-5p expression using qRT-PCR.The M1/M2 macrophage ratio and cytokine levels were evaluated using immunofluorescence staining and qRT-PCR.Bioinformatics analysis and dual-luciferase reporter assays were carried out to predict the potential target genes of miR-590-5p and validate its targeting relationship with SLC8A3,whose expressions were detected in the vascular tissues of the rats by Western blotting.Results Compared with the young rats,the aging rats exhibited significantly increased PWV in the abdominal aorta with elevated vascular expressions of p16,p21 and SA-β-gal,which were all reversed by BYHWD treatment.The isolated serum exosomes were positive for CD63,CD81,CD31 and SM-22,and the exosomes from aging rats showed significantly downregulated expression of miR-590-5p,which was upregulated after BYHWD treatment.The aging rat vessels showed an increased M1/M2 macrophage ratio with elevated M1-specific cytokines and reduced M2-specific cytokines,and BYHWD treatment effectively inhibited M1 polarization of the macrophages.Pearson analysis revealed a negative correlation between exosomal miR-590-5p upregulation and the M1/M2 ratio.Bioinformatics analysis and dual-luciferase assays confirmed that miR-590-5p targets SLC8A3.Western blotting demonstrated increased SLC8A3 expression in aging rat vessels,which was downregulated after BYHWD treatment.Conclusion BYHWD attenuates vascular aging in rats by modulating macrophage M1 polarization and suppressing vascular inflammation via exosomal miR-590-5p-mediated downregulation of SLC8A3.