Cancer-secreted long non-coding RNAs (lncRNAs) are emerging mediators of cancer-host cross talk. The aim of our study was to illustrate the clinical significance of the lncRNA CRNDE-h in exosomes purified from the serum of patients with colorectal cancer (CRC). The study was divided into four parts: (1) The exosome isolated methods and lncRNA detected methods which accurately and reproducibly measure CRC-related exosomal CRNDE-h in serum were optimized in preliminary pilot stage; (2) The stability of exosomal CRNDE-h was evaluated systematically; (3) The origin of exosomal CRNDE-h was explorated in vitro and in vivo; (4) The diagnostic and prognostic value of exosomal CRNDE-h for CRC were validated in 468 patients. In pilot study, our results indicated that exosomal CRNDE-h was detectable and stable in serum of CRC patients, and derived from tumor cells. Then, the increased expression of exosomal CRNDE-h was successfully validated in 148 CRC patients when compared with colorectal benign disease patients and healthy donors. Exosomal CRNDE-h level significantly correlated with CRC regional lymph node metastasis (P = 0.019) and distant metastasis (P = 0.003). Moreover, at the cut-off value of 0.020 exosomal CRNDE-h level of serum, the area under ROC curve distinguishing CRC from colorectal benign disease patients and healthy donors was 0.892, with 70.3% sensitivity and 94.4% specificity, which was superior to carcinoembryogenic antigen. In addition, high exosomal CRNDE-h level has a lower overall survival rates than that for low groups (34.6% vs. 68.2%, P < 0.001). In conclusion, detection of lncRNA CRNDE-h in exosome shed a light on utilizing exosomal CRNDE-h as a noninvasive serum-based tumor marker for diagnosis and prognosis of CRC.
Patients with sickle cell disease (SCD) suffer from intravascular hemolysis associated with vascular injury and dysfunction in mouse models, and painful vaso-occlusive crisis (VOC) involving increased attachment of sickle erythrocytes and activated leukocytes to damaged vascular endothelium. Patrolling monocytes, which normally scavenge damaged cells and debris from the vasculature, express higher levels of anti-inflammatory heme oxygenase 1 (HO-1), a heme degrading enzyme. Here, we show that HO-1-expressing patrolling monocytes protect SCD vasculature from ongoing hemolytic insult and vaso-occlusion. We found that a mean 37% of patrolling monocytes from SCD patients express very high levels of HO-1 (HO-1) vs 6% in healthy controls and demonstrated that HO-1 expression was dependent on uptake of heme-exposed endothelium. SCD patients with a recent VOC episode had lower numbers of HO-1 patrolling monocytes. Heme-mediated vaso-occlusion by mouse SCD red blood cells was exacerbated in mice lacking patrolling monocytes, and reversed following transfer of patrolling monocytes. Altogether, these data indicate that SCD patrolling monocytes remove hemolysis-damaged endothelial cells, resulting in HO-1 upregulation and dampening of VOC, and that perturbation in patrolling monocyte numbers resulting in lower numbers of HO-1 patrolling monocyte may predispose SCD patients to VOC. These data suggest that HO-1 patrolling monocytes are key players in VOC pathophysiology and have potential as therapeutic targets for VOC.
Increased macrophage phagocytosis of antibody-coated platelets, as well as decreased numbers and/or impaired function of CD4+CD25+Foxp3+ regulatory T (Treg) cells, has been shown to participate in the pathogenesis of immune thrombocytopenia (ITP). Low-dose histone deacetylase inhibitors (HDACi’s) are anti-inflammatory and immunomodulatory agents that can enhance immunosuppression in graft-versus-host disease by increasing the number and function of Foxp3+ Treg cells, but it is unclear whether they have the potential to promote immune tolerance and platelet release in ITP. In this study, we performed in vitro and in vivo experiments and found that a low-dose HDACi (chidamide) alleviated thrombocytopenia in passive and active murine models of ITP. Further, low-dose HDACi’s attenuated macrophage phagocytosis of antibody-coated platelets, stimulated the production of natural Foxp3+ Treg cells, promoted the peripheral conversion of T cells into Treg cells, and restored Treg cell suppression in vivo and in vitro. Finally, we confirmed that low-dose HDACi’s could regulate CTLA4 expression in peripheral blood mononuclear cells through modulation of histone H3K27 acetylation. Low-dose HDACi treatment in ITP could be offset by blocking the effect of CTLA4. Therefore, we propose that low-dose chidamide administration has potential as a novel treatment for ITP in the clinic.
Gypenosides (GPs) have been reported to have neuroprotective effects in addition to other bioactivities. The protective activity of GPs during stroke and their effects on neural stem cells (NSCs) in the ischemic brain have not been fully elucidated. Here, we test the effects of GPs during stroke and on the NSCs within the subventricular zone (SVZ) of middle cerebral artery occlusion (MCAO) rats. Our results show that pre-treatment with GPs can reduce infarct volume and improve motor function following MCAO. Pre-treatment with GPs significantly increased the number of BrdU-positive cells in the ipsilateral and contralateral SVZ of MCAO rats. The proliferating cells in both sides of the SVZ were glial fibrillary acidic protein (GFAP)/nestin-positive type B cells and doublecortin (DCX)/nestin-positive type A cells. Our data indicate that GPs have neuroprotective effects during stroke which might be mediated through the enhancement of neurogenesis within the SVZ. These findings provide new evidence for a potential therapy involving GPs for the treatment of stroke.
To evaluate whether the serum thrombopoietin levels in pregnancy-associated immune thrombocytopenia (ITP) differ from those in gestational thrombocytopenia, and reveal the possibility of thrombopoietin serving as a marker for differential diagnosis. Serum thrombopoietin concentration was determined in ITP in pregnancy (n = 35), gestational thrombocytopenia (n = 31), healthy pregnancy (n = 32), age-matched nonpregnant ITP (n = 32) and nonpregnant healthy controls (n = 35) by ELISA. The serum thrombopoietin level of ITP in pregnancy (1283 ± 646 pg/mL) was significantly higher than gestational thrombocytopenia (187 ± 64 pg/mL) (P < 0.01), although the platelet counts of these two disorders may overlap. Twenty-nine of 35 patients with ITP in pregnancy had thrombopoietin values >500 pg/mL, whereas none of the gestational thrombocytopenia patients' thrombopoietin levels exceeded 500 pg/mL. In addition, ITP in pregnancy presented a markedly higher thrombopoietin level than nonpregnant ITP (88 ± 41 pg/mL) (P < 0.01), indicating that the pathogenesis of pregnant and nonpregnant ITP was different. Our findings suggest that measurement of serum thrombopoietin concentration provides valuable diagnostic information for differentiating ITP in pregnancy from gestational thrombocytopenia. Thrombopoietin represents a reliable marker for ITP in pregnancy.
The results indicate that bitter receptor agonists induce relaxation of longitudinal smooth muscle strips of rat ileum, which is mediated by nitric oxide and BKCa channels.
Summary This retrospective study aimed to evaluate the relationship between plasma autoantibody species and rhTPO response in adult ITP patients who failed the first‐line treatments. Plasma anti‐glycoprotein (GP) IIb/IIIa and anti‐GPIb/IX autoantibodies were detected in 47·2% and 40·6% of the 123 patients, respectively. Overall response rate to rhTPO treatment in patients without anti‐GPIb/IX autoantibodies was significantly higher than patients with anti‐GPIb/IX autoantibodies (82·2% vs. 60·0%, P = 0·006). By contrast, no statistical difference in response rate was observed between patients with or without anti‐GPIIb/IIIa autoantibodies (74·1% vs. 72·3%, P = 0·819). Therefore, the presence of anti‐GPIb/IX autoantibodies might serve as a predictive factor for poor response to rhTPO treatment in ITP.
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