Objective To investigate the role of Ddx56 and Galnt13 associated with the pathogenesis of early-onset Parkinson disease (PD) in maintaining survival of dopaminergic (DA) neurons during early development of zebrafish. Methods In situ hybridization and qPCR were used to detect the temporal expression and tissue-specific distribution of Ddx56 and Galnt13 in AB zebrafish, and the changes in expressions of PD- and DA neuron-associated genes following Ddx56 or Galnt13 knockdown were detected. In SH-SY5Y cells, effects of Ddx56 knockdown and overexpression on cell apoptosis were analyzed using flow cytometry. RNA-seq technique was used to investigate the changes in gene expression profiles following Ddx56 knockdown to explore the role of Ddx56 in early development of the nervous system. Results Both Ddx56 and Galnt13 were extensively expressed in early zebrafish embryos. Ddx56 was highly expressed predominantly in the brain and testis, and Galnt13 in the brain and eye of the zebrafish. Ddx56 knockdown resulted in significant changes in expressions of the PD-related genes Sncga, Sncgb, Polg, Pink1, Parkin, Lrrk2, Gba, and Sncb, while Galnt13 knockdown affected the expressions of Sncgb, Syn2b, and Lrrk2. Ddx56 knockdown caused a significant increase of apoptosis in SH-SY5Y cells and differential expressions of an array of genes, which were enriched mainly in the immune system, energy metabolism, protein translation, and signal transduction; no fewer than 20 genes in the ribosome pathway and the metabolic pathway each, in particular, showed differential expressions following Ddx56 knockdown. These differentially expressed genes were significantly associated with neurodegenerative diseases, and their alterations resulted in changes in the level of oxidative phosphorylation. Conclusion Ddx56 is highly expressed in the brain during early development of zebrafish. Ddx56 knockdown causes changes in PD- and DA-associated genes and induces apoptosis of DA neurons, suggesting its potential as a biomarker for early diagnosis of PD.
Objective To explore the effects of 40 Hz flicker light stimulation on cognitive dysfunction in mice with subacute Parkinson disease (PD) induced by 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) and the underlying mechanisms. Methods Forty 8-week-old male C57BL/6 mice were randomly allocated to a control group and 4 MPTP-induced PD model groups receiving blank treatment, 40 Hz flicker light stimulation, or stereotactic intraventricular injection of a control AAV (sh-NC) or an AVV carrying sh-STING. After the treatments, the mice were examined for changes in motor functions and cognitive behaviors. Immunofluorescence staining, Nissl staining, ELISA, Western blotting and RT-qPCR were used to detect hippocampal co-localization of S100A10 and C3 with GFAP, Nissl neuron count, serum interleukins, and nigral and hippocampal expressions of u03B1-syn, TH, synaptic, astrocytic, inflammatory, SOCS3, JAK2-STAT3, and the STING pathway at the mRNA and protein levels. Results The PD mouse models exhibited impaired motor and cognitive functions with lowered TH and elevated u03B1-syn expressions. 40 Hz light flicker stimulation improved cognitive function of the PD mice, significantly increased the number of hippocampal neurons and S100A10 expression, and reduced the expressions of p-STING/STING, C3, GFAP, IL-6, and TNF-u03B1. Compared with the PD mice with sh-NC injection, the mice receiving sh-STING AVV injection showed significantly improved cognitive function with lowered hippocampal expression level of C3 and increased expression of S100A10 without significant changes in the expression levels of SOCS3 and JAK2-STAT3. Conclusion 40 Hz flicker light stimulation mitigates impairment of cognitive function in mice with MPTP-induced PD by inhibiting STING overactivation to promote A2 astrocyte polarization and enhance hippocampal synaptic plasticity.
Transarterial chemoembolization (TACE) is a minimally invasive interventional technique developed specifically for hypervascular tumours, including intermediate-to-advanced hepatocellular carcinoma (HCC). This procedure achieves dual therapeutic mechanisms through catheter-based delivery of chemotherapeutic agents using embolic materials directly into tumor-feeding arteries, thereby inducing both localized chemotherapy and ischemic necrosis. TACE demonstrates distinct advantages, including precise tumor targeting, minimal invasiveness, and procedural repeatability, and has been established as a standard treatment modality for unresectable intermediate-to-advanced HCC. This review systematically summarizes recent advances in embolic microspheres and their applications in TACE procedures for HCC. The dual functional roles of embolic microspheres in inducing tumor ischemia while delivering chemotherapeutics were comprehensively analyzed. A systematic analysis of current research progress was provided regarding embolic microsphere development from 3 critical perspectives: material physical properties, radiographic visibility characteristics, and manufacturing methodologies. The challenges in standardizing embolization protocols, optimizing drug release kinetics, translating novel biomaterials into clinical practice, and establishing robust efficacy evaluation metrics were discussed with a brief analysis of future directions for studies of embolic microspheres.
Objective To investigate the mechanism of Jiawei Qingluo Yin (JWQLY) for alleviating rheumatoid arthritis (RA) in rats. Methods Network pharmacology, molecular docking and dynamics analyses were performed to identify the core components, key targets, and pathways of JWQLY against RA and the core component-key target binding. In a rat model of antigen-induced arthritis (AIA) established using complete Freund's adjuvant, the effects of MTX (0.5 mg/kg) and low-, medium-, and high-dose JWQLY (1.03, 3.1, and 9.3 g/kg, respectively) were tested on paw swelling, arthritis index (AI), synovial histopathology, apoptosis, and serum IL-1u03B2 and VEGF levels. In the mechanistic investigation, the rat models were treated with high-dose (9.3 g/kg) JWQLY, vismodegib (a Hedgehog inhibitor, 10 mg/kg), or both, and the changes in paw swelling, AI, histopathology, and expressions of Bcl-2, Bax, Ihh, Smo, Gli1, cleaved caspase-3, and cleaved caspase-9 were examined. Results A total of 306 intersecting targets were identified between JWQLY and RA. GO and KEGG enrichment analyses revealed enrichment of the targets in negative regulation of apoptosis and inflammation and in Hedgehog and apoptosis pathways. Molecular docking studies confirmed stable binding of the core components in JWQLY to Shh and other Hedgehog targets. The rat models of AIA showed obvious paw swelling and significantly elevated AI, pathology scores, and serum IL-1u03B2 and VEGF levels, and these changes were dose-dependently alleviated by JWQLY treatment. The rat models receiving treatment with vismodegib or JWQLY+ vismodegib exhibited significantly reduced Ihh, Smo, Gli1, and Bcl-2 expression with increased expressions of Bax, cleaved-caspase-3, and cleaved-caspase-9 and apoptosis rates of the synovial cells. JWQLY and vismodegib synergistically suppressed Hedgehog signaling and enhanced synovial cell apoptosis. Conclusion JWQLY alleviates RA in rats by inhibiting Hedgehog pathway activation, down-regulating the Bcl-2/Bax ratio, and promoting synovial cell apoptosis.
Objective To investigate the mechanism by which Suanzaoren Decoction (SZRD) ameliorates hippocampal neuronal injury in APP/PS1 mice. Methods Thirty 7-month-old APP/PS1 transgenic mice were randomized into 3 groups for daily gavage with saline or SZRD at 12.96 or 25.92 g/kg (n=10) for 28 consecutive days, with 10 saline-treated age-matched male C57BL/6J mice as the blank control group. Spatial learning and memory abilities of the mice were evaluated using Morris water maze test. Neuronal integrity and amyloid u03B2 (Au03B2) deposition were examined with Nissl staining and Thioflavin S staining, respectively, and hippocampal IBA1 expression was detected by immunohistochemistry. IBA1/Au03B2 immunofluorescence double staining was used to evaluate the spatial relationship between hippocampal microglia and Au03B2 plaques. RNA sequencing was employed to identify the key targets. Western blotting was performed to detect hippocampal expressions of nuclear factor kappa-B (NF-u03BAB p65), p-NF-u03BAB p65-ser536, interleukin (IL)-6, IL-1u03B2, tumor necrosis factor-u03B1 (TNF-u03B1), and the Hippo-YAP pathway proteins including mammalian sterile 20-like kinase 1 (MST1), large tumor suppressor 1 (LATS1), Yes-associated protein (YAP1), and p-YAP1-s127. Results In APP/PS1 mice, SZRD at both the low and high doses significantly improved learning and memory performance and neuronal organization, increased hippocampal neuronal number, and reduced amyloid-u03B2 (Au03B2) deposition and IBA1 expression. The treatments also significantly decreased IBA1-positive area, Au03B2 -positive area, and IBA1/Au03B2 co-localization in the transgenic mice. RNA sequencing revealed that SZRD downregulated the key genes in the Hippo signaling pathway and inflammation-related genes in APP/PS1 mice. Western blotting demonstrated that SZRS treatment significantly lowered hippocampal expressions of MST1, LATS1, p-YAP1-s127/YAP1, p-NF-u03BAB p65-Ser536/NF-u03BAB p65, IL-1u03B2, IL-6, and TNF-u03B1 in APP/PS1 mice. Conclusion SZRD ameliorates hippocampal neuronal injury in APP/PS1 mice by regulating the Hippo-YAP signaling pathway and inhibiting neuroinflammation.
