Abstract: Plumbagin (PLB), an active naphthoquinone compound, has shown potent anticancer effects in preclinical studies; however, the effect and underlying mechanism of PLB for the treatment of pancreatic cancer is unclear. This study aimed to examine the pancreatic cancer cell killing effect of PLB and investigate the underlying mechanism in human pancreatic cancer PANC-1 and BxPC-3 cells. The results showed that PLB exhibited potent inducing effects on cell cycle arrest in PANC-1 and BxPC-3 cells via the modulation of cell cycle regulators including CDK1/CDC2, cyclin B1, cyclin D1, p21 Waf1/Cip1, p27 Kip1, and p53. PLB treatment concentration- and time-dependently increased the percentage of autophagic cells and significantly increased the expression level of phosphatase and tensin homolog, beclin 1, and the ratio of LC3-II over LC3-I in both PANC-1 and BxPC-3 cells. PLB induced inhibition of phosphatidylinositol 3-kinase (PI3K)/protein kinase B/mammalian target of rapamycin and p38 mitogen-activated protein kinase (p38 MAPK) pathways and activation of 5'-AMP-dependent kinase as indicated by their altered phosphorylation, contributing to the proautophagic activities of PLB in both cell lines. Furthermore, SB202190, a selective inhibitor of p38 MAPK, and wortmannin, a potent, irreversible, and selective PI3K inhibitor, remarkably enhanced PLB-induced autophagy in PANC-1 and BxPC-3 cells, indicating the roles of PI3K and p38 MAPK mediated signaling pathways in PLB-induced autophagic cell death in both cell lines. In addition, PLB significantly inhibited epithelial to mesenchymal transition phenotype in both cell lines with an increase in the expression level of E-cadherin and a decrease in N-cadherin. Moreover, PLB treatment significantly suppressed the expression of Sirt1 in both cell lines. These findings show that PLB promotes cell cycle arrest and autophagy but inhibits epithelial to mesenchymal transition phenotype in pancreatic cancer cells with the involvement of PI3K/protein kinase B/ mammalian target of rapamycin and p38 MAPK mediated pathways. Keywords: Plumbagin, pancreatic cancer, cell cycle, autophagy, EMT, Sirt1
Imitating the microenvironment of bone formation is crucial for the design of bone defect repair materials. In this study, cell mono-culture and co-culture experiments were carried out using rat aorta endothelial cells (rAECs) and rat bone marrow mesenchymal stem cells (rBMMSCs) under the addition of increasing concentrations of magnesium chloride. The optimal magnesium ion (Mg2+) concentration for promoting in vitro vascularized osteogenesis was found to be 5 mM, which was possibly caused by the promotion of the PI3K-AKT signaling pathway. Accordingly, we designed a Mg2+-enriched Alginate photocrosslinked hydrogel (MAH) which could steadily release Mg2+. And, this modified Mg2+-enriched MAH possessed excellent It shows excellent ability to promote osteogenesis in the rat calvarial defect models.
Abstract Background: This study aimed to explore the effectiveness of thiamine and folic acid supplementation on the improvement of the cognitive function in patients with maintenance hemodialysis. Methods: In the present study, we randomly assigned patients undergoing hemodialysis who had the Montreal Cognitive Assessment (MoCA) score lower than 26 to treatment group (n=25, thiamine 90mg/day combined with folic acid 30mg/day) or control group (n=25, nonintervention). All subjects were followed up for 96 weeks. The primary outcome was the improvement of the MoCA score. The secondary outcomes included homocysteine level, survival and safety. Results: Patients in treatment group had an increase of the MoCA score from 21.95±3.81 at baseline to 25.68±1.96 at week 96 (P<0.001, primary outcome), as compared with the MoCA score from 20.69±3.40 to 19.62±3.58 in control group. Thiamine combined with folic acid treatment also resulted in lower level of serum homocysteine in treatment group compare with control group at week 96 (P<0.05, secondary outcome). 3 patients and 9 patients died during follow-up period in treatment and control group respectively (P=0.048). The proportion of adverse events in treatment group was significantly lower than that in control group. Conclusion: Hemodialysis patients with cognitive impairment treated with thiamine and folic acid had a significant improvement in MoCA score. Trial registration: Clinical trial registration number: ChiCTR-IPR-17012210.
Abstract Background and Aims Anemia is a common complication of chronic kidney disease (CKD), and associated with increased morbidity and mortality, as well as a reduced quality of life (QoL). Various studies have shown anemia treatment in CKD patients improved the QoL. However, in ROXSTAR Registry (ChiCTR2100046322), although roxadustat corrected anemia and maintained hemoglobin (Hb) effectively, no improvement in QoL was observed. Hence, we conduct this secondary analysis of ROXSTAR to evaluate the Hb response to roxadustat treatment and the change of QoL in dialysis-dependent (DD) and non-dialysis-dependent (NDD) patients stratified by baseline Hb. Method This was a secondary analysis using existing data collected in the ROXSTAR Registry. DD & NDD Patients who received at least one dose of roxadustat and had at least one post baseline Hb were included. We described the Hb response to roxadustat in patients with lower baseline (Hb <80) g/L & higher baseline Hb (≥80 g/L). The changes from baseline to week 12 & week 24 in Quality of Life (QoL) assessed by SF-36 Vitality (V) & Physical Function (PF) subscales, and Rapid Assessment of Physical Activity (RAPA) Strength & Flexibility scores were also analyzed respectively. Results Overall, 1998 patients (1508 DD patients and 490 NDD patients) were included, there were 238 patients (131 male [55.0%]) with a mean (standard deviation [SD]) age of 49.1 (13.6) years in the lower baseline Hb group, and 1760 patients (947 male [53.8%]) with a mean age of 50.3 (13.5) in the higher baseline Hb group. The overall mean baseline Hb was 97.3 (13.9) g/L, with 71.4 (7.2) g/L and 100.8 (10.5) g/L in the two groups respectively. The median (min, max) ferritin and mean transferrin saturation were 149.6 (3.3, 2304.0) ng/mL & 22.8% (15.5) % in the lower baseline Hb group and 169.8 (3.8, 3966.0) ng/mL & 30.6% (15.7%) in the higher baseline Hb group. More patients with CRP above normal limit were in the lower baseline Hb group (30.7%) compared to patients in the other group (19.7%) (Table 1). Mean weekly roxadustat dose started at 320 mg and was maintained during the first 12 weeks (correction phase) then slightly decreased to 300 mg from week 12 until week 52 (maintenance phase) in patients with baseline Hb <80 g/L, while it was from 286 mg to 260 mg during the correction phase then decreased and maintained at around 230 mg from week 12 to week 52 in patients with baseline Hb ≥80 g/L. The mean Hb change from baseline averaged over weeks 24-36 and 36-52 was 31.9 [95% CI: 29.9, 33.9] g/L & 33.7 [95% CI: 31.8, 35.6] g/L in the lower baseline Hb group, and 11.3 [95% CI: 10.6, 12.0] g/L & 11.1 [95% CI: 10.5, 11.8] g/L in the higher baseline Hb group. The proportion (%) of patients with mean Hb ≥100 g/L averaged over the same period were 58.8% [95% CI: 51.8%, 65.7%] & 68.6% [95% CI: 61.8%, 75.3%] in the lower baseline Hb group, and 86.5% [95% CI: 84.7%, 88.3%] & 88.2% [95% CI: 86.5%, 90.0%] in the higher baseline Hb group. Patients with baseline Hb <80 g/L had numerically higher mean increases from baseline to week 12 and 24 in SF-36 V and PF sub-scores (Table 2), though no clinical meaningful change was observed in either group. Conclusion Roxadustat effectively corrected anemia in DD and NDD patients regardless of baseline Hb level. There was no clinical meaningful improvement in QoL for either group. The weekly dose of roxadustat to correct and maintain Hb was higher in patient with baseline Hb <80 g/L than in patients with baseline Hb ≥80 g/L.
The potential protective role of eosinophils in the COVID-19 pandemic has aroused great interest, given their potential virus clearance function and the infection resistance of asthma patients to this coronavirus. However, it is unknown whether eosinophil counts could serve as a predictor of the severity of COVID-19.A total of 1004 patients with confirmed COVID-19 who were admitted to Leishenshan Hospital in Wuhan, China, were enrolled in this study, including 905 patients in the general ward and 99 patients in the intensive care unit (ICU). We reviewed their medical data to analyze the association between eosinophils and ICU admission and death.Of our 1004 patients with COVID-19, low eosinophil counts/ratios were observed in severe cases. After adjusting for confounders that could have affected the outcome, we found that eosinophil counts might not be a predictor of ICU admission. In 99 ICU patients, 58 of whom survived and 41 of whom died, low eosinophil level was an indicator of death in severe COVID-19 patients with a cutoff value of 0.04 × 109/L, which had an area under the curve of 0.665 (95% CI = 1.089-17.839; P = .045) with sensitivity and specificity of 0.569 and 0.7317, respectively.Our research revealed that a low eosinophil level is a predictor of death in ICU patients rather than a cause of ICU admission.
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