Methylation-mediated silencing of PTPRD induces pulmonary hypertension by promoting pulmonary arterial smooth muscle cell migration via the PDGFRB/PLCγ1 axis

OBJECTIVE: Pulmonary hypertension is a lethal disease characterized by pulmonary vascular remodeling and is mediated by abnormal proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs). Platelet-derived growth factor BB (PDGF-BB) is the most potent mitogen for PASMCs and is involved in vascular remodeling in pulmonary hypertension development. Therefore, the objective of our study is to identify novel mechanisms underlying vascular remodeling in pulmonary hypertension. METHODS: We explored the effects and mechanisms of PTPRD downregulation in PASMCs and PTPRD knockdown rats in pulmonary hypertension induced by hypoxia. RESULTS: We demonstrated that PTPRD is dramatically downregulated in PDGF-BB-treated PASMCs, pulmonary arteries from pulmonary hypertension rats, and blood and pulmonary arteries from lung specimens of patients with hypoxic pulmonary arterial hypertension (HPAH) and idiopathic PAH (iPAH). Subsequently, we found that PTPRD was downregulated by promoter methylation via DNMT1. Moreover, we found that PTPRD knockdown altered cell morphology and migration in PASMCs via modulating focal adhesion and cell cytoskeleton. We have demonstrated that the increase in cell migration is mediated by the PDGFRB/PLCγ1 pathway. Furthermore, under hypoxic condition, we observed significant pulmonary arterial remodeling and exacerbation of pulmonary hypertension in heterozygous PTPRD knock-out rats compared with the wild-type group. We also demonstrated that HET group treated with chronic hypoxia have higher expression and activity of PLCγ1 in the pulmonary arteries compared with wild-type group. CONCLUSION: We propose that PTPRD likely plays an important role in the process of pulmonary vascular remodeling and development of pulmonary hypertension in vivo

Involvement of Cathepsins in Innate and Adaptive Immune Responses in Periodontitis

Periodontitis is an infectious disease whereby the chronic inflammatory process of the periodontium stimulated by bacterial products induces specific host cell responses. The activation of the host cell immune system upregulates the production of inflammatory mediators, comprising cytokines and proteolytic enzymes, which contribute to inflammation and bone destruction. It has been well known that periodontitis is related to systemic inflammation which links to numerous systemic diseases, including diabetes and arteriosclerosis. Furthermore, periodontitis has been reported in association with neurodegenerative diseases such as Alzheimer’s disease (AD) in the brain. Regarding immune responses and inflammation, cathepsin B (CatB) plays pivotal role for the induction of IL-1β, cathepsin K- (CatK-) dependent active toll-like receptor 9 (TLR9) signaling, and cathepsin S (CatS) which involves in regulating both TLR signaling and maturation of the MHC class II complex. Notably, both the production and proteolytic activities of cathepsins are upregulated in chronic inflammatory diseases, including periodontitis. In the present review, we focus on the roles of cathepsins in the innate and adaptive immune responses within periodontitis. We believe that understanding the roles of cathepsins in the immune responses in periodontitis would help to elucidate the therapeutic strategies of periodontitis, thus benefit for reduction of systemic diseases as well as neurodegenerative diseases in the global aging society

Hypoglycemic Activity and the Potential Mechanism of the Flavonoid Rich Extract from Sophora tonkinensis Gagnep. in KK-Ay Mice

This study investigated the active principles, hypoglycemic activity and potential mechanisms of the flavonoid rich extract from Sophora tonkinensis Gagnep. (SS-EtOAc) in KK-Ay diabetic mice. An off-line semipreparative LC-NMR and LC-UV-ESIMS protocol was performed to determine 13 flavonoids from SS-EtOAc. SS-EtOAc administrated orally to the KK-Ay mice significantly increased their sensibility to insulin, reduced fasting blood-glucose levels and blood lipid indexes such as triglyceride and cholesterol. Moreover, SS-EtOAc exhibited a strong effect of stimulation on GLUT4 translocation by 2.7 fold in L6 cells. However, the selective AMP-activated protein kinase (AMPK) inhibitor Compound C can completely inhibit the activation of the AMPK pathway and prevent the GLUT4 translocation caused by SS-EtOAc. In vivo, phosphorylation of the AMPK expression in the liver and skeletal muscle was measured. The results showed phosphorylation of the AMPK had been improved and GLUT4 expression had been also enhanced. In this paper we conclude that, SS-EtOAc seems to have potential beneficial effects on the treatment of type 2 diabetes mellitus (T2DM) with the probable mechanism of stimulating GLUT4 translocation modulated by the AMPK pathway

Impact of measurable residual disease in combination with CD19 on postremission therapy choices for adult t(8;21) acute myeloid leukemia in first complete remission

Abstract Background The post‐remission therapy (PRT) choices for adult t(8;21) acute myeloid leukemia (AML) in first complete remission (CR1) need to be further explored. Aims We aimed to investigate the impact of measurable residual disease (MRD) combined with CD19 on PRT choices for adult t(8;21) AML in CR1. Methods A total of 150 t(8;21) AML patients were enrolled, including 67 underwent chemotherapy (CMT) and 83 allogeneic hematopoietic stem cell transplantation (allo‐SCT) as PRT in CR1. Subgroup analyses were performed according to MRD level after three cycles of chemotherapy combined with CD19 expression. Results Multivariate analysis indicated MRDhigh after three courses of treatment (HR, 0.14 [95% CI, 0.03–0.66]; p = 0.013) and CD19 negativity (HR, 0.14 [95% CI, 0.02–0.96]; p = 0.045) were risk factors for relapse, while allo‐SCT was protective factor for relapse (HR, 0.34 [95% CI, 0.15–0.75]; p = 0.008). Grouped by MRD after three courses of chemotherapy, allo‐SCT had lower CIR (p < 0.001) and better OS (p = 0.003) than CMT for MRDhigh patients, CMT showed a higher CIR (35.99% vs. 15.34%, p = 0.100) but comparable OS (p = 0.588) than allo‐SCT for MRDlow patients. Grouped by CD19 expression, allo‐SCT demonstrated lower CIR (p < 0.001) and better OS (p = 0.002) than CMT for CD19− patients. CMT had a higher CIR (41.37% vs. 10.48%, p = 0.007) but comparable OS (p = 0.147) than allo‐SCT for CD19+ patients. Grouped by MRD combined with CD19, MRDhigh/CD19+ subsets were identified out of CD19+ patients benefiting from allo‐SCT with lower CIR (p = 0.002) and superior OS (p = 0.020) than CMT. CMT preserved comparable CIR (p = 0.939) and OS (p = 0.658) with allo‐SCT for MRDlow/CD19+ patients. MRDlow/CD19− subsets were also identified from MRDlow patients requiring allo‐SCT with lower CIR (p < 0.001) and superior OS (p = 0.008) than CMT. Allo‐SCT maintained lower CIR (p < 0.001) and superior OS (p = 0.008) than CMT for MRDhigh/CD19− patients. Conclusions MRD combined with CD19 might optimize PRT choices for adult t(8;21) AML patients in CR1

Two new megastigmanes from Chinese traditional medicinal plant <i>Sedum sarmentosum</i>

<p>To discover new bioactive compounds from nature plants, a primary screening of traditional Chinese medicines had been taken. The screening results showed that a EtOAc extract of <i>Sedum sarmentosum</i> displayed a certain degree of cytotoxic activity and bioassay-directed isolation of EtOAc extract gave two new megastigmanes, <i>(6S,9R)</i>-2-hydroxy-4-(2,6,6-trimethyl-4-oxo-cyclohex-2-enyl)-butyric acid (<b>1</b>) and <i>(6S,9R)</i>-2-hydroxy-4-(2,6,6-trimethyl-4-oxo-cyclohex-2-enyl)-butyric acid methyl ester (<b>2</b>) together with seven known flavonoids. The chemical structures of <b>1</b> and <b>2</b> were elucidated on the basis of detailed 1D, 2D NMR and MS data. When tested against HepG2 and Hep3B hepatocellular carcinoma cell lines, compounds <b>1</b>–<b>9</b> showed weak anti-HCC activity. In addition, <i>in vitro</i> antioxidant activities of <b>1</b>–<b>9</b> were evaluated by ABTS radical cation-scavenging assay. <b>1</b> and <b>2</b> exhibited weak activity with per micromoles equivalent to 0.039 and 0.042 μM of Trolox, respectively. The flavonoid component, quercetin (<b>9</b>) showed the highest antioxidant activities with per micromoles equivalent 0.67 μM of Trolox.</p

Janus particle-engineered structural lipiodol droplets for arterial embolization

Abstract Embolization (utilizing embolic materials to block blood vessels) has been considered one of the most promising strategies for clinical disease treatments. However, the existing embolic materials have poor embolization effectiveness, posing a great challenge to highly efficient embolization. In this study, we construct Janus particle-engineered structural lipiodol droplets by programming the self-assembly of Janus particles at the lipiodol-water interface. As a result, we achieve highly efficient renal embolization in rabbits. The obtained structural lipiodol droplets exhibit excellent mechanical stability and viscoelasticity, enabling them to closely pack together to efficiently embolize the feeding artery. They also feature good viscoelastic deformation capacities and can travel distally to embolize finer vasculatures down to 40 μm. After 14 days post-embolization, the Janus particle-engineered structural lipiodol droplets achieve efficient embolization without evidence of recanalization or non-target embolization, exhibiting embolization effectiveness superior to the clinical lipiodol-based emulsion. Our strategy provides an alternative approach to large-scale fabricate embolic materials for highly efficient embolization and exhibits good potential for clinical applications

Impact of genetic patterns on sorafenib efficacy in patients with FLT3-ITD acute myeloid leukemia undergoing allogeneic hematopoietic stem cell transplantation: a multi-center, cohort study

Abstract Sorafenib therapy improves overall survival (OS) in patients with FLT3 internal tandem duplication (ITD) acute myeloid leukemia (AML) undergoing allogeneic hematopoietic stem cell transplantation. We explored the efficacy of sorafenib therapy in this population with different concomitant genetic patterns. In this multi-center, cohort study, we enrolled patients with FLT3-ITD AML undergoing allogenic hematopoietic cell transplantation. Patients with sorafenib maintenance post-transplantation for at least four weeks were allocated to the sorafenib group, and otherwise to the control group. Endpoints were OS, disease-free survival, and relapse for the whole cohort and OS for genetic pattern subgroups. Among 613 patients enrolled, 275 were in the sorafenib and 338 the control group. Median follow-up was 36.5 (interquartile range (IQR), 25.2–44.7) months post-transplantation. The 3-year OS post-transplantation was 79.6% (95% confidential interval (CI) 74.8%–84.6%) and 65.2% (95% CI 60.3%–70.6%) (Hazard ratio (HR) 0.50, 95% CI 0.37–0.69; P < 0.0001) in both groups. Sorafenib maintenance post-transplantation improved OS in the favorable (HR 0.33, 95% CI 0.14–0.77; P = 0.011) and adverse (HR 0.56, 95% CI 0.33–0.93; P = 0.026) ELN 2017 risk subgroups. Patients with mutated NPM1, DNMT3A, co-occurring NPM1/DNMT3A, “activated signaling” and “DNA methylation” genes benefited in OS from sorafenib maintenance, while those carrying CEBPA, “tumor suppressors” and “myeloid transcription factors” genes did not. Patients with FLT3-ITDhigh and FLT3-ITDlow AML both benefited in OS from sorafenib maintenance. Our results identify the response of genetic patterns to sorafenib maintenance, providing new viewpoints for the optimal use of sorafenib in FLT3-ITD AML in the transplantation setting