Clinical significance of stroke nurse in patients with acute ischemic stroke receiving intravenous thrombolysis.

BACKGROUND: Reports have proven that shorter door-to-needle time (DTN time) indicates better outcomes in AIS patients received intravenous thrombolysis. Efforts have been made by hospitals and centers to minimize DTN time in many ways including introducing a stroke nurse. However, there are few studies to discuss the specific effect of stroke nurse on patients' prognosis. This study aimed to compare consecutive AIS patients before and after the intervention to analyze the effect of stroke nurse on clinical outcome of AIS patients. METHODS: In this retrospective study, we observed 1003 patients from November 2016 to December 2020 dividing in two groups, collected and analyzed AIS patients' medical history, clinical assessment information, important timelines, 90 mRS score, etc. Comparative analysis and mediation analysis were also used in this study. RESULTS: A total of 418 patients was included in this study, and 199 patients were enrolled in the stroke nurse group and 219 was in the preintervention group. Baseline characteristics of patients showed no significant difference except there seems more patients with previous ischemic stroke history in the group of stroke nurse. (p = 0.008). The median DTN time significantly decreased in the stroke nurse group (25 min versus 36 min, p < 0.001) and multivariate logistic regression analysis showed the 90-day mRS clinical outcome significantly improved in the stroke nurse group (p = 0.001). Mediation analysis indicated the reduction of DTN time plays a partial role on the 90 days mRS score and the stroke nurse has some direct effect on the improvement of clinical outcome (p = 0.006). CONCLUSIONS: The introduction of stroke nurse is beneficial to clinical outcome of AIS patients and can be use of reference in other hospitals or centers.

Vanillin derivative VND3207 activates DNA-PKcs conferring protection against radiation-induced intestinal epithelial cells injury in vitro and in vivo.

Vanillin is a natural compound endowed with antioxidant and anti-mutagenic properties. We previously identified the vanillin derivative VND3207 with strong radio-protective and antioxidant effects and found that VND3207 confers survival benefit and protection against radiation-induced intestinal injury (RIII) in mice. We also observed that VND3207 treatment enhanced the expression level of the catalytic subunit of the DNA-dependent protein kinase (DNA-PKcs) in human lymphoblastoid cells with or without γ-irradiation. DNA-PKcs is a critical component of DNA double strand break repair pathway and also regulates mitotic progression by stabilizing spindle formation and preventing mitotic catastrophe in response to DNA damage. In the present study, we found that VND3207 protected intestinal epithelial cells in vitro against ionizing radiation by promoting cell proliferation and inhibiting cell apoptosis. In addition, VND3207 promoted DNA-PKcs activity by increasing autophosphorylation at S2056 site. Consistent with this, VND3207 significantly decreased the number of γH2AX foci and mitotic catastrophe after radiation. DNA-PKcs deficiency abolished these VND3207 radio-protective effects, indicating that DNA-PKcs activation is essential for VND3207 activity. In conclusion, VND3207 promoted intestinal repair following radiation injury by regulating the DNA-PKcs pathway.

p53-inducible gene 3 promotes cell migration and invasion by activating the FAK/Src pathway in lung adenocarcinoma.

The p53-inducible gene 3 (PIG3) is one of the p53-induced genes at the onset of apoptosis, which plays an important role in cell apoptosis and DNA damage response. Our previous study reported an oncogenic role of PIG3 associated with tumor progression and metastasis in non-small cell lung cancer (NSCLC). In this study, we further analyzed PIG3 mRNA expression in 504 lung adenocarcinoma (LUAD) and 501 lung squamous cell carcinoma (LUSC) tissues from The Cancer Genome Atlas database and we found that PIG3 expression was significantly higher in LUAD with lymph node metastasis than those without, while no difference was observed between samples with and without lymph node metastasis in LUSC. Gain and loss of function experiments were performed to confirm the metastatic role of PIG3 in vitro and to explore the mechanism involved in its oncogenic role in NSCLC metastasis. The results showed that PIG3 knockdown significantly inhibited the migration and invasion ability of NSCLC cells, and decreased paxillin, phospho-focal adhesion kinase (FAK) and phospho-Src kinase expression, while its overexpression resulted in the opposite effects. Blocking FAK with its inhibitor reverses PIG3 overexpression-induced cell motility in NSCLC cells, indicating that PIG3 increased cell metastasis through the FAK/Src/paxillin pathway. Furthermore, PIG3 silencing sensitized NSCLC cells to FAK inhibitor. In conclusion, our data revealed a role for PIG3 in inducing LUAD metastasis, and its role as a new FAK regulator, suggesting that it could be considered as a novel prognostic biomarker or therapeutic target in the treatment of LUAD metastasis.

The vanillin derivative 6-bromine-5-hydroxy-4-methoxybenzaldehyde induces aberrant mitotic progression and enhances radio-sensitivity accompanying suppression the expression of PLK1 in esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is the most common form of esophageal cancer in China. Since chemotherapy is the standard clinical intervention for advanced ESCC, the development of highly effective and minimal/non-toxic drugs is essential to improve the clinical outcome and prognosis of the patients. A novel derivative of vanillin, 6-bromine-5-hydroxy-4-methoxybenzaldehyde (BVAN08), has been recently reported to activate different cell death pathways in cancer cells. In this study, we demonstrate that BVAN08 exhibits a potent anti-proliferation effect on ESCC cells (TE-1 and ECA-109) by inhibiting the expression of PLK1, an important mitotic kinase. Consistent with this, BVAN08 induces mitotic arrest and chromosomal misalignment in ESCC cells. The disruption of microtubule nucleation around centrosomes is also observed in BVAN08 treated ESCC cells. Furthermore, BVAN08 enhances radio-sensitivity of ESCC cells by prolonging DNA damage repair. These findings underscore the potential value of BVAN08 in cancer therapeutics and demonstrate the underlying mechanism by which BVAN08 induces mitotic catastrophe and enhances radio-sensitivity in ESCC cells.

Black Phosphorus Quantum Dots Enhance the Radiosensitivity of Human Renal Cell Carcinoma Cells through Inhibition of DNA-PKcs Kinase.

Renal cell carcinoma (RCC) is one of the most aggressive urological malignancies and has a poor prognosis, especially in patients with metastasis. Although RCC is traditionally considered to be radioresistant, radiotherapy (RT) is still a common treatment for palliative management of metastatic RCC. Novel approaches are urgently needed to overcome radioresistance of RCC. Black phosphorus quantum dots (BPQDs) have recently received great attention due to their unique physicochemical properties and good biocompatibility. In the present study, we found that BPQDs enhance ionizing radiation (IR)-induced apoptotic cell death of RCC cells. BPQDs treatment significantly increases IR-induced DNA double-strand breaks (DSBs), as indicated by the neutral comet assay and the DSBs biomarkers γH2AX and 53BP1. Mechanistically, BPQDs can interact with purified DNA-protein kinase catalytic subunit (DNA-PKcs) and promote its kinase activity in vitro. BPQDs impair the autophosphorylation of DNA-PKcs at S2056, and this site phosphorylation is essential for efficient DNA DSBs repair and the release of DNA-PKcs from the damage sites. Consistent with this, BPQDs suppress nonhomologous end-joining (NHEJ) repair and lead to sustained high levels of autophosphorylated DNA-PKcs on the damaged sites. Moreover, animal experiments indicate that the combined approach with both BPQDs and IR displays better efficacy than monotreatment. These findings demonstrate that BPQDs have potential applications in radiosensitizing RCC cells.

The vanillin derivative VND3207 protects intestine against radiation injury by modulating p53/NOXA signaling pathway and restoring the balance of gut microbiota.

The intestine is a highly radiosensitive tissue that is susceptible to structural and functional damage due to systemic as well as localized radiation exposure. Unfortunately, no effective prophylactic or therapeutic agents are available at present to manage radiation-induced intestinal injuries. We observed that the vanillin derivative VND3207 improved the survival of lethally irradiated mice by promoting intestinal regeneration and increasing the number of surviving crypts. Pre-treatment with VND3207 significantly increased the number of Lgr5+ intestinal stem cells (ISCs) and their daughter cells, the transient Ki67+ proliferating cells. Mechanistically, VND3207 decreased oxidative DNA damage and lipid peroxidation and maintained endogenous antioxidant status by increasing the level of superoxide dismutase and total antioxidant capacity. In addition, VND3207 maintained appropriate levels of activated p53 that triggered cell cycle arrest but were not sufficient to induce NOXA-mediated apoptosis, thus ensuring DNA damage repair in the irradiated small intestinal crypt cells. Furthermore, VND3207 treatment restores the intestinal bacterial flora structures altered by TBI exposure. In conclusion, VND3207 promoted intestinal repair following radiation injury by reducing reactive oxygen species-induced DNA damage and modulating appropriate levels of activated p53 in intestinal epithelial cells.

Oral administration of hydroxylated-graphene quantum dots induces intestinal injury accompanying the loss of intestinal stem cells and proliferative progenitor cells.

Graphene quantum dots (GQDs) have gained significant attention in various biomedical applications. The physicochemical properties of these nanoparticles, including toxic effects, are largely determined by their surface modifications. Previous studies have demonstrated high in vitro cytotoxicity of the hydroxylated GQDs (OH-GQDs). The focus of this study was on the intestinal toxicity of OH-GQDs. Briefly, C57BL/6J mice were given daily oral gavage of 0.05, 0.5 or 5 mg/kg OH-GQD for 7 days, and the indices of intestinal damage were evaluated. Higher doses of the OH-GQDs caused significant intestinal injuries, such as enhanced intestinal permeability, shortened villi and crypt loss. The number of Lgr5+ intestinal stem cells also decreased dramatically upon OH-GQDs exposure, which also inhibited the Ki67+ proliferative progenitor cells. In addition, an increased number of crypt cells harboring the oxidized DNA base 8-OHdG and γH2AX foci were also detected in the intestines of OH-GQD-treated mice. Mechanistically, the OH-GQDs up-regulated both total and phosphorylated p53. Consistent with this, the average number of TUNEL+ and cleaved caspase-3+ apoptotic intestinal epithelial cells were significantly increased after OH-GQDs treatment. Finally, a 3-dimensional organoid culture was established using isolated crypts, and OH-GQDs treatment significantly reduced the size of the surviving intestinal organoids. Taken together, the intestinal toxicity of the OH-GQDs should be taken into account during biomedical applications.

Hydroxylated-Graphene Quantum Dots Induce DNA Damage and Disrupt Microtubule Structure in Human Esophageal Epithelial Cells.

Graphene quantum dots (GQDs) have attracted significant interests due to their unique chemical and physical properties. In this study, we investigated the potential effects of hydroxyl-modified GQDs (OH-GQDs) on the human esophageal epithelial cell line HET-1A. Our data revealed significant cytotoxicity of OH-GQDs which decreased the viability of HET-1A in a dose and time-dependent manner. The moderate concentration (25 or 50 µg/ml) of OH-GQDs significantly blocked HET-1A cells in G0/G1 cell cycle phase. An increased percentage of γH2AX-positive and genomically unstable cells were also detected in cells treated with different doses of OH-GQDs (25, 50, and 100 µg/ml). Microarray data revealed that OH-GQDs treatment down-regulated genes related to DNA damage repair, cell cycle regulation and cytoskeleton signal pathways indicating a novel role of OH-GQDs. Consistent with the microarray data, OH-GQDs disrupted microtubule structure and inhibited microtubule regrowth around centrosomes in HET-1A cells. In conclusion, our findings provide important evidence for considering the application of OH-GQDs in biomedical fields.

PIG3 promotes NSCLC cell mitotic progression and is associated with poor prognosis of NSCLC patients.

BACKGROUND: Non-small cell lung cancer (NSCLC) is the most commonly diagnosed type of lung cancer that is associated with poor prognosis. In this study we explored the potential role of p53-induced gene 3 (PIG3) in the progression of NSCLC. METHODS: Immunohistochemistry was used to determine the expression levels of PIG3 in 201 NSCLC patients. We performed in vitro studies and silenced endogenous PIG3 by using specific siRNAs that specific target PIG3. Immunofluorescent staining was performed to determine the effect of PIG3 on mitotic progression in NSCLC cells. The growth rates of microtubules were determined by microtubule nucleation analysis. Cell proliferation and chemosensitivity were analyzed by CCK8 assays. Annexin V staining and ß-galactosidase activity analysis were used to evaluate PIG3 deficiency-related apoptosis and senescence, respectively. RESULTS: PIG3 expression levels negatively correlated with overall survival and disease-free survival of NSCLC patients. Knock down of PIG3 resulted in repressed proliferation of NSCLC cells and increased aberrant mitosis, which included misaligning and lagging chromosomes, and bi- or multi-nucleated giant cells. In addition, PIG3 contributed to mitotic spindle assembly by promoting microtubule growth. Furthermore, loss of PIG3 sensitized NSCLC cells to docetaxel by enhancing docetaxel-induced apoptosis and senescence. CONCLUSIONS: Our results indicate that PIG3 promotes NSCLC progression and therefore suggest that PIG3 may be a potential prognostic biomarker and novel therapeutic target for the treatment of NSCLC.