Linyi Chen

Herpes zoster is caused by the reactivation of latent varicella-zoster virus (VZV), primarily affecting middle-aged and older individuals and often accompanied by severe pain and other complications. Vaccination is an effective preventive measure against this disease. In the present study, we evaluated the adjuvant activity of Toll-like receptor (TLR)9 and TLR7 agonists in combination with stimulator of interferon genes (STING) agonists for a VZV-glycoprotein E (gE)-based vaccine. Among the tested combinations, the CpG-2722 (TLR9 agonist) and 2'3'-c-di-AM(PS)2 (STING agonist) pairing exhibited potent immunostimulatory activity in immune cells and superior adjuvant activity for VZV-gE vaccines in a mouse models. Shingrix, a licensed herpes zoster vaccine, is administered intramuscularly. The CpG-2722/2'3'-c-di-AM(PS)2 combination adjuvanted VZV vaccine, administered intramuscularly, effectively induced higher gE-specific IgG responses than that induced by the Shingrix and imiquimod/2'3'-c-di-AM(PS)2 adjuvant vaccine. Notably, intranasal administration of the CpG-2722/2'3'-c-di-AM(PS)2 adjuvanted VZV vaccine to mice elicited a robust antigen-specific IgA response, which was barely detectable in intramuscularly administered vaccines. Two doses of the intranasal immunization, administered at a two-week interval, provided long-lasting protection, as antigen-specific IgG levels remained elevated for months without booster immunization. Further investigation into the functional mechanism revealed that CpG-2722 combined with 2'3'-c-di-AM(PS)2 induced a strong antigen-dependent T helper 1 (Th1) cytokine response, consistent with the antigen-independent cytokine-inducing properties of this adjuvant combination. This study demonstrates that the TLR9 and STING agonists formulated adjuvant induces a potent and long-lasting immune response, highlighting its potential as a promising adjuvant candidate for nasal VZV vaccines.

Rare disease rhabdomyosarcoma-derived RD cells and RH30 cells are defective in myogenesis. In this study, we demonstrate that mitochondria in these cells are enlarged and display a perinuclear distribution. Given that impaired mitochondrial morphology, trafficking, and activity are implicated in many human diseases, characterizing the link between these phenotypes and their physiological outcomes is essential. We found that RD cells had reduced levels of the myosin motor MYO19 and elevated levels of the dynein motor and MIRO1/2 adaptors. Our findings indicate that impaired local actin-based anterograde transport, together with enhanced microtubule-based retrograde transport, drives this perinuclear mitochondrial clustering. Overexpression of MYO19 in RD cells partially rescued this phenotype, while dynein inhibition altered mitochondrial distribution and restored myogenic differentiation in both RD and RH30 cells. Collectively, these findings reveal an intricate interplay among mitochondrial morphology, distribution, and myoblast fusion that underlies both normal physiology and disease.
[Display omitted]
•Mitochondria in human rhabdomyosarcoma (RMS) cells cluster at perinuclear region•RMS cells exhibit reduced myosin motor MYO19 and impaired actin-based anterograde•High level dynein in RMS cells increase retrograde transport of mitochondria•Inhibiting dynein rescues myogenic differentiation defect of RMS cells
Molecular biology; Cell biology; Specialized functions of cells

Background: Traumatic brain injury (TBI) disrupts anatomical structure and cellular signaling, yet the molecular mechanisms governing endogenous repair remain incompletely defined. Accumulating evidence implicate an increased risk of developing to neurodegenerative diseases for TBI patients, in part through chronic neuroinflammation, protein aggregation, and progressive synaptic dysfunction. However, a critical unmet need is that no approved medicine directly promotes neurite regrowth and functional recovery after TBI. Purpose: To identify candidate compounds that can promote neurite regrowth of injured brain neurons and improve functional outcome of TBI mice. The mechanism of action of the lead compound will be determined. Study design: Through an extensive screening of plant extracts, we have identified a nature compound, isorhoifolin, that promotes neurite regrowth of injured cortical and hippocampal neurons. Functional assays were conducted to assess behavioral efficacy and the direct protein targets of isorhoifolin were identified. Results: Using complementary in vitro, ex vivo, and in vivo models of TBI, we demonstrated that isorhoifolin attenuated both cytosolic and mitochondrial reactive oxygen species, highlighting its role in redox homeostasis. Comparative structure-activity analyses revealed that the closely related flavonoids exhibited divergent biological efficacy, indicating that specific chemical features determine functional outcomes. In vivo, isorhoifolin crossed the blood-brain barrier and significantly improved motor coordination following experimental TBI. Transcriptomic profiling and cellular thermal shift assay (CETSA) further revealed that isorhoifolin bound directly to sphingosine-1-phosphate receptor-3 (S1PR3) and exerted temporally structured effects on injury-responsive networks. In human transcriptomic data, we found activation of S1P receptor-related pathways in TBI patients and the expression of S1PR3 was increased approximately 40%. Importantly, the current work delineates a neuron-centric role for S1PR3 in regulating structural repair that is mechanistically distinct from the known functions of S1PRs in immune cells. Biochemical assays supported a model in which isorhoifolin facilitates neurite repair through inhibiting neuronal S1PR3-CK2-GSK3 beta signaling axis. In parallel, isorhoifolin interacted directly with N-ribosyldihydronicotinamide:quinone reductase 2 (NQO2) based on proteomic CESTA, and genetic knockdown as well as inhibition of NQO2 in astrocytes promote neurite regrowth of injured cortical neurons. Conclusion: Together, these findings define mechanistically distinct yet coordinated neuronal and astrocytic pathways that are responsible for isorhoifolin-enhanced structural and functional recovery after TBI, and identify S1PR3 and NQO2 as direct and druggable targets.

Eye diseases, including cataracts, glaucoma, diabetes retinopathy, and age-related macular degeneration, are major global health challenges and leading causes of blindness. This study leveraged genome-wide association studies (GWASs) involving over 100,000 individuals, integrating data from the Taiwan Biobank and National Health Insurance Research Database, to identify genetic loci associated with disease onset. Our findings suggest that these conditions are influenced by multifactorial etiologies, as pleiotropic loci including rs10811660, rs4710941, rs2283228, and rs7646518 were identified, linking ocular diseases to metabolic conditions. Notably, a strong genetic correlation was observed between cataract and depression. Mendelian randomization analysis further demonstrated a causal effect of depression on cataract risk, implicating shared biological pathways, particularly oxytocin signaling, in disease pathophysiology. This finding revealed a functional genetic variant near the OXTR gene, highlighting its potential as a causal candidate for genetic diagnosis in precision health. By bridging the gap between genetic discovery and clinical application, this research offers critical insights into shared genetic mechanisms across diverse health domains, paving the way for innovative diagnostic and therapeutic strategies.
This genome-wide study reveals novel and shared genetic factors underlying four major eye diseases and their comorbidities. Integrating Mendelian randomization and functional analyses, this study uncovers a causal role for depression in cataract development, offering insights into systemic influences on ocular health and potential precision medicine targets.

Rhabdomyosarcoma (RMS) is a rare disease that arises from skeletal muscle mainly affects children and adolescents. Patients with RMS have diverse symptoms and prognosis based on tumor sizes, tumor anatomical locations, histological subtypes of the tumors and genetic testing of paired-box-forkhead box O1 (PAX-FOXO1) fusion gene. The 4 subtypes of RMS include embryonal RMS (eRMS), alveolar RMS (aRMS), spindle cell/sclerosing RMS (scRMS) and pleomorphic RMS (pRMS). Treatment for RMS patients remains challenging due to its heterogeneous nature. Thus, a combinatory approach is likely to warrant better management of RMS. Given that PAX-FOXO1 fusion gene is the most common biomarker for RMS, though this fusion gene only accounts for 16-20% of RMS patients. Targeted therapy that tailors treatment plans to the individual patient may provide additional benefits for RMS patients. This review describes the frequent genetic mutations observed in RMS patients and drug development based on these mutations shall provide direction to develop targeted therapy leading to effective personalized treatment for RMS patients.

The use of implantable biomaterials has emerged as a promising therapeutic strategy for managing traumatic brain injury (TBI). We have previously demonstrated that mesenchymal stem cell (MSC) spheroid-derived three-dimensional decellularized extracellular matrix (3D dECM), enriched with stem cell secretome, serves as an effective biomaterial for promoting post-TBI brain repair. However, its limited antioxidant capacity and inadequate tissue adhesion remain significant challenges. To overcome these limitations, in the present study, we functionalized 3D dECM with polydopamine nanoparticles (PDANPs), renowned for their inherent antioxidant and adhesive properties, to enhance free radical scavenging and tissue adhesion. PDANP decoration imparted significant reactive oxygen/reactive nitrogen species-scavenging capacity to 3D dECM, thereby enhancing its neuroprotective potential and reducing oxidative stress-induced neuronal cell death in vitro. In a mouse TBI model, PDANP-decorated 3D dECM demonstrated robust adhesion to cortical tissues, effectively addressing post-TBI secondary injury by mitigating oxidative damage and suppressing neuroinflammation, ultimately promoting neuronal cell survival. The adhesive, antioxidant, and immunomodulatory properties together led to improved recovery of neurological function and reduced lesion volume in vivo. Overall, our findings highlight the potential of PDANP-decorated 3D dECM as a multifunctional and clinically translatable therapeutic platform for TBI management, while underscoring the adaptability of MSC spheroid-derived 3D dECM to be precisely tailored for diverse therapeutic applications.
[Display omitted]

Taurine, an amino acid with documented anti-cancer properties, has shown potential in breast cancer treatment. This review focuses on taurine's role in inhibiting tumor growth and metastasis by influencing cellular metabolism and enhancing immune responses. Taurine affects energy production pathways and intracellular amino acid levels, leading to reduced tumor growth. It also detoxifies reactive oxygen species in mitochondria and enhances the activity of antioxidant enzymes. Additionally, taurine modulates the immune system by increasing antitumor cytokines like IFN-γ and decreasing tumor-promoting cytokines such as IL-10. Furthermore, taurine enhances the effectiveness of CD8+ cytotoxic T cells and other effector T-cell subsets, while altering the immunological profile of CD4+CD25+ regulatory T cells (T regs) that suppress immune defenses. This combined immune modulation and metabolic influence of taurine promote tumor cell apoptosis by upregulating pro-apoptotic proteins (PUMA, Bax) and downregulating anti-apoptotic proteins (Bcl-2), potentially preventing metastasis and improving outcomes for breast cancer patients. Factors such as extracellular osmolarity, electrolyte imbalances, and nutrient levels (such as folate) can influence taurine uptake. Our review shows taurine's potential as an adjuvant therapy in breast cancer treatment and advocates for more clinical trials to validate its therapeutic benefits. Further research is necessary to determine its clinical efficacy, optimal dosage, and long-term safety.
•Taurine supplementation enhances immune responses and boosts CD8+ T cell function in breast cancer.•Taurine reduces oxidative stress in breast cancer, protecting cells from mitochondrial damage.•Taurine induces apoptosis in breast cancer cells, promoting cell death and preventing metastasis.•Taurine regulates metabolic pathways in breast cancer, inhibiting glucose dysregulation and lactate buildup.•Clinical evidence links higher taurine levels with improved long-term survival in breast cancer patients.

Background and AimsSepsis is a critical condition requiring optimized clinical management, especially in terms of hematocrit. The relationship between early stage of hematocrit and mortality in patients with sepsis remains underexplored.MethodThis observational cohort study used data from the eICU Collaborative Research Database. Hematocrit within the first 72 h of intensive care unit (ICU) admission in patients with sepsis was analyzed. The association of hematocrit with hospital and ICU mortality was assessed using generalized additive models, and inverse probability of treatment weighting was applied to ensure the balanced distributions of variables between the groups.ResultsOur analysis revealed a pivotal hematocrit threshold of 33%. Below this value, the risks of all-cause hospital and ICU mortality significantly decreased. This nonlinear association underscores the importance of maintaining hematocrit above this value. Thus, hematocrit can serve as a critical marker for predicting clinical outcomes and improving patient management in the early phase of sepsis treatment.ConclusionEarly management of hematocrit is critical in patients with sepsis; maintaining hematocrit above 33% can improve survival outcomes among these patients. These findings suggest that anemia treatment strategies in sepsis care should be re-evaluated, and they demonstrate the importance of personalized management of hematocrit for enhancing patient prognosis.