DDX24 Is Essential for Cell Cycle Regulation in Vascular Smooth Muscle Cells During Vascular Development via Binding to FANCA mRNA.

BACKGROUND: The DEAD-box family is essential for tumorigenesis and embryogenesis. Previously, we linked the malfunction of DDX (DEAD-box RNA helicase)-24 to a special type of vascular malformation. Here, we aim to investigate the function of DDX24 in vascular smooth muscle cells (VSMCs) and embryonic vascular development. METHODS: Cardiomyocyte (CMC) and VSMC-specific Ddx24 knockout mice were generated by crossing Tagln-Cre mice with Ddx24flox/flox transgenic mice. The development of blood vessels was explored by stereomicroscope photography and immunofluorescence staining. Flow cytometry and cell proliferation assays were used to verify the regulation of DDX24 on the function of VSMCs. RNA sequencing and RNA immunoprecipitation coupled with quantitative real-time polymerase chain reaction were combined to investigate DDX24 downstream regulatory molecules. RNA pull-down and RNA stability experiments were performed to explore the regulation mechanism of DDX24. RESULTS: CMC/VSMC-specific Ddx24 knockout mice died before embryonic day 13.5 with defects in vessel formation and abnormal vascular remodeling in extraembryonic tissues. Ddx24 knockdown suppressed VSMC proliferation via cell cycle arrest, likely due to increased DNA damage. DDX24 protein bound to and stabilized the mRNA of FANCA (FA complementation group A) that responded to DNA damage. Consistent with the function of DDX24, depletion of FANCA also impacted cell cycle and DNA repair of VSMCs. Overexpression of FANCA was able to rescue the alterations caused by DDX24 deficiency. CONCLUSIONS: Our study unveiled a critical role of DDX24 in VSMC-mediated vascular development, highlighting a potential therapeutic target for VSMC-related pathological conditions.

H3K27 acetylation-induced FSTL1 upregulation by P300/RUNX1 co-activation exacerbated autophagy-mediated neuronal damage and NF-κB-stimulated inflammation in Alzheimer's disease.

Follistatin-like protein 1 (FSTL1) has been demonstrated to participate in the pathogenesis of several neurological diseases. The current study informed the role of H3K27 acetylation-induced FSTL1 upregulation in Alzheimer's disease (AD). Our investigation discovered the upregulated FSTL1 expression and enhanced autophagy activity in AD. FSTL1 knockdown successfully attenuated the injuries of Aß1-42-challenged SH-SY5Y cells through the inhibition of autophagy activity. Besides, FSTL1 deficiency suppresses the inflammatory response and NF-κB signaling in AD. Moreover, it was found that p300 was recruited by transcriptional factor RUNX1 to stimulate the H3K27 acetylation in FSTL1 promoter region, which caused the upregulation of FSTL1 in AD. To summarize, p300 acted as a co-activator of RUNX1 to trigger the activation of FSTL1 in AD, resulting in the exacerbated injuries and inflammatory responses of Aß1-42-induced SH-SY5Y cells.

RNA Helicase DDX24 Stabilizes LAMB1 to Promote Hepatocellular Carcinoma Progression.

Hepatocellular carcinoma (HCC) is one of the most aggressive malignancies. Elucidating the underlying mechanisms of this disease could provide new therapeutic strategies for treating HCC. Here, we identified a novel role of DEAD-box helicase 24 (DDX24), a member of the DEAD-box protein family, in promoting HCC progression. DDX24 levels were significantly elevated in HCC tissues and were associated with poor prognosis of HCC. Overexpression of DDX24 promoted HCC migration and proliferation in vitro and in vivo, whereas suppression of DDX24 inhibited both functions. Mechanistically, DDX24 bound the mRNA618-624nt of laminin subunit beta 1 (LAMB1) and increased its stability in a manner dependent upon the interaction between nucleolin and the C-terminal region of DDX24. Moreover, regulatory factor X8 (RFX8) was identified as a DDX24 promoter-binding protein that transcriptionally upregulated DDX24 expression. Collectively, these findings demonstrate that the RFX8/DDX24/LAMB1 axis promotes HCC progression, providing potential therapeutic targets for HCC. SIGNIFICANCE: The identification of a tumor-promoting role of DDX24 and the elucidation of the underlying regulatory mechanism provide potential prognostic indicators and therapeutic approaches to help improve the outcome of patients with hepatocellular carcinoma.

Activation of EphA4 induced by EphrinA1 exacerbates disruption of the blood-brain barrier following cerebral ischemia-reperfusion via the Rho/ROCK signaling pathway.

Vascular dementia (VD) is a syndrome characterized by progressive cognitive decline. According to previous studies, stroke is considered to be a risk factor for VD. The disruption of the blood-brain barrier (BBB) is pivotal to the pathology of stroke, as it contributes to post-stroke inflammation and edema. It has been reported that the Eph/Ephrin signaling pathway serves an important role in central nervous system injury. However, the role of EphrinA1/EphA4 signaling in BBB damage following ischemic stroke has not yet been reported. Oxygen-glucose deprivation/reperfusion was performed to detect changes in EphrinA1 and EphA4 expression in human brain microvascular endothelial cells (HBMECs). Male mice were randomly divided into four groups [Sham, ischemia-reperfusion (I/R), I/R+EphrinA1 and I/R+EphA4] to observe the role of EphrinA1 and EphA4 under I/R conditions in vivo. The results of the present study revealed that the expression of EphrinA1 and EphA4 was significantly increased following I/R in vitro and in vivo. The administration of soluble ligand EphrinA1 enhanced CD68+ cell accumulation, brain edema and dysfunction of the BBB, with lower expression levels of zonula occludens-1 (ZO-1) and Claudin-5. In addition, EphrinA1-treated mice had a higher level of caspase-3 and a lower level of phosphorylated-protein kinase B. However, the effects of EphrinA1 were abolished by EphA4-Fc, an inhibitor of EphA4. These results suggested that EphrinA1 exerted its effects on I/R injury via the activated EphA4 receptor. In addition, EphrinA1 decreased ZO-1 and Claudin-5 expression through the Rho/Rho associated kinase (ROCK) signaling pathway, which was attenuated by the pharmacological inhibition of Rho (C3 transferase) or ROCK (Y-27632). In conclusion, the present study provides evidence that the activation of EphA4 induced by EphrinA1 contributes to BBB damage following ischemic stroke through the Rho/ROCK signaling pathway, which highlights a potential therapeutic strategy for ischemic stroke and may help the development of preventative interventions for VD.

Diurnal neurobiological alterations after exposure to clozapine in first-episode schizophrenia patients.

BACKGROUND: Irregular circadian rhythm and some of its most characteristic symptoms are frequently observed in patients with schizophrenia. However, changes in the expression of clock genes or neuropeptides that are related to the regulation of circadian rhythm may influence the susceptibility to recurrence after antipsychotic treatment in schizophrenia, but this possibility has not been investigated. METHODS: Blood samples were collected from 15 healthy male controls and 13 male schizophrenia patients at 4h intervals for 24h before and after treatment with clozapine for 8 weeks. The outcome measures included the relative expression of clock gene mRNA PERIOD1 (PER1), PERIOD2 (PER2), PERIOD3 (PER3) and the levels of plasma cortisol, orexin, and insulin. RESULTS: Compared with healthy controls, schizophrenia patients presented disruptions in diurnal rhythms of the expression of PER1, PER3, and NPAS2 and the release of orexin, accompanied by a delayed phase in the expression of PER2, decreases in PER3 and NPAS2 expression, and an increase in cortisol levels at baseline. Several of these disruptions (i.e., in PER1 and PER3 expression) persisted after 8 weeks of clozapine treatment, similar to the decreases in the 24-h expression of PER3 and NPAS2. Clozapine treatment for 8 weeks significantly decreased the 24-h levels of PER2 and increased the 24-h levels of insulin. CONCLUSION: These persistent neurobiological changes that occur after 8 weeks of clozapine treatment may contribute to the vulnerability to recurrence and efficacy of long-term maintenance treatment in schizophrenia.

Identification of post traumatic stress disorder and risk factors in military first responders 6 months after Wen Chuan earthquake in China.

BACKGROUND: Military personnel commonly serve as first responders to natural disasters. Our aim is to identify Post-Traumatic Stress Disorder (PTSD) and determine risk in military responders to the Wen Chuan earthquake. METHODS: Analyses were carried out on 1056 of the 1125 soldiers enrolled. In addition to social demographic characteristics, the Davidson Trauma Scale (DTS) and an Earthquake exposure screening scale were administered. RESULTS: PTSD prevalence was 6.53% (69 cases). Logistic regression indicated that intensity of traumatic exposure (odds ratio 6.46, 95% CI 4.47-9.32, p<0.001), not having received psychological counseling (odds ratio 3.28, 95% CI 1.31-8.20, p<0.02) and regular drinking (odds ratio 2.42, 95% CI 1.04-5.62, p<0.05) were significant predictors of PTSD. Being a single-child, not being raised by both parents and regular smoking also independently predicted PTSD if intensity of earthquake traumatic exposure was not included in the model. LIMITATIONS: The self-rated DTS was used to classify PTSD in this study and psychiatric co-morbidity outside of PTSD was not assessed in this sample. CONCLUSION: PTSD is a concern for Military disaster responders; to identify those with high risk of developing PTSD would be important and beneficial.