Rho kinase inhibitor Y-27632 downregulates IL-1ß expression in mice with experimental autoimmune myocarditis.

Autoimmune myocarditis is the limited or diffuse inflammation of the myocardium due to dysfunctional cellular and humoral immunity mechanisms. We constructed mouse models of experimental autoimmune myocarditis (EAM) using peptide MyHC-α614-629. On the day after secondary immunization, the mice were intraperitoneally injected with Rho kinase (ROCK) inhibitor Y-27632. On day 21, the cardiac tissues were harvested and weighed. The hearts of EAM mice were significantly enlarged and whitened. Furthermore, body weight (BW) slowly increased during the treatment period, the heart weight (HW) and the ratio of HW/eventual BW were increased, and inflammatory infiltration and fibrosis were aggravated in the myocardial tissue. Y-27632 treatment improved the aforementioned phenotypic and pathological features of EAM mice. Mechanistic analysis revealed a significant increase in Notch1, Hes1, Jag2, Dil1, Toll-like receptor (Tlr) 2, and interleukin (IL)-1ß expression in the myocardial tissue of EAM mice. Notably, IL-1ß expression was correlated with that of Notch1 and Tlr2. Following Y-27632 treatment, the expression of key target genes of the Notch signaling pathway (Notch1, Hes1, Dil1, and Jag2) and Tlr2 were obviously decreased. Y-27632 treatment also decreased the number of monocytes in the spleen of EAM mice. Thus, ROCK inhibitor Y-27632 exerted a protective effect in EAM mice by downregulating IL-1ß expression. This study aimed to provide a reference point for the future treatment of myocarditis in clinical settings.

Isoflavones isolated from the fruits of Ficus altissima and their anti-proliferative activities.

Ficus altissima, also known as lofty fig, is a monoecious plant from the Moraceae family commonly found in southern China. In this study, we isolated and identified one new isoflavone (1), three new hydroxycoumaronochromones (2a, 2b and 3a) and 12 known compounds from the fruits of F. altissima. Their chemical structures were determined using spectroscopic analysis methods. We also tested all the isolated compounds for their anti-proliferative activities against eight human tumour cell lines (A-549, AGS, K562, K562/ADR, HepG2, HeLa, SPC-A-1 and CNE2) using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. Our experiments showed that compound 6 exhibited obvious anti-proliferative activity against the K562 cell line with an IC50 value of 1.55 µM. Additionally, compounds 8 and 9 showed significant anti-proliferative activities against the AGS and K562 cell lines, respectively. Moreover, compound 6 induced apoptosis in K562 cells through the caspase family signalling pathway.

Antiproliferative piperidine alkaloids from the leaves of Alocasia macrorrhiza.

Seventeen piperidine alkaloids, including 15 previously undescribed 2-substituted-6-(9-phenylnonyl)-piperidine-3,4-diol alkaloids and a previously undescribed 2-substituted-6-(9-phenylnonyl)-piperidine-3-ol alkaloid, were isolated from the leaves of Alocasia macrorrhiza (L.) Schott. Their planar structures and configurations were elucidated based on HR-ESI-MS, 1D and 2D NMR, Snatzke's method, modified Mosher method, single-crystal X-ray crystallography, as well as quantum chemical calculation. It was found that ΔδH5b-H5a can be used to elucidate the relative configuration of 2,3,4,6-tetrasubstituted piperidine, by analyzing the NMR data of 2-substituted-6-(9-phenylnonyl)-piperidine-3,4-diol. Antiproliferative activity was evaluated for all of the alkaloids, and compounds 6-8 showed considerable inhibitory activity against K562 cell line, with the IC50 values of 17.24 ± 1.62, 19.31 ± 0.9 and 18.77 ± 1.09µM, respectively. Furthermore, compounds 6 and 7 exerted an antiproliferative effect by inducing apoptosis.

Patterns of de novo metastasis and survival outcomes by age in breast cancer patients: a SEER population-based study.

Background: The role of age in metastatic disease, including breast cancer, remains obscure. This study was conducted to determine the role of age in patients with de novo metastatic breast cancer. Methods: Breast cancer patients diagnosed with distant metastases between 2010 and 2019 were retrieved from the Surveillance, Epidemiology, and End Results database. Comparisons were performed between young (aged ≤ 40 years), middle-aged (41-60 years), older (61-80 years), and the oldest old (> 80 years) patients. Adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) were estimated using multivariate Cox proportional hazard models. Survival analysis was performed by the Kaplan-Meier method. Results: This study included 24155 (4.4% of all patients) de novo metastatic breast cancer patients. The number of young, middle-aged, older, and the oldest old patients were 195 (8.3%), 9397 (38.9%), 10224 (42.3%), and 2539 (10.5%), respectively. The 5-year OS rate was highest in the young (42.1%), followed by middle-aged (34.8%), older (28.3%), and the oldest old patients (11.8%). Multivariable Cox regression analysis showed that middle-aged (aHR, 1.18; 95% CI, 1.10-1.27), older (aHR, 1.42; 95% CI, 1.32-1.52), and the oldest old patients (aHR, 2.15; 95% CI, 1.98-2.33) had worse OS than young patients. Consistently, middle-aged (aHR, 1.16; 95% CI, 1.08-1.25), older (aHR, 1.32; 95% CI, 1.23-1.43), and the oldest old patients (aHR, 1.86; 95% CI, 1.71-2.03) had worse BCSS than young patients. Conclusion: This study provided clear evidence that de novo metastatic breast cancer had an age-specific pattern. Age was an independent risk factor for mortality in patients with de novo metastatic breast cancer.

Waste Lithium Ion Battery Evolves into Heteroatom Doped Carbon as Oxygen Reduction Electrocatalyst for Aqueous Al-Air Batteries.

Carbon based electrocatalysts prepared by recycling waste power batteries can not only realize the new utilization of waste energy materials, but also obtain cheap and efficient oxygen reduction electrocatalyst for metal-air battery. Based on the cathode carbon of waste LiFePO4 batteries, nitrogen doped carbon based catalyst NC-1000 is prepared by simple pyrolysis, acid dissolution of LiFePO4 and high temperature heteroatom doping. The catalyst is characterized by scanning electron microscope, transmission electron microscope and Raman spectrum, and the electrochemical performances of the catalyst and Al-air battery were tested. The results show that carbon based electrocatalyst NC-1000 is rich in structural defects and embedded with trace metal oxides. Compared with commercial 20 wt% Pt/C, it has higher electrocatalytic activity and faster kinetic with a half-wave potential of 0.828 V vs. RHE and the Tafel slope of 70.7 mV dec-1 . In addition, assembled into Al-air battery, the open circuit potential can reach 1.57 V along with the high power density of 141 mW cm-2 at 200 mA cm-2 . The discharge specific capacity at higher current of up to 100 mA cm-2 is even better than the commercial Pt/C. This study can not only improve the economic value of waste power batteries, but also obtain high-performance ORR electrocatalyst, which will greatly promote the commercial development of Al-air batteries.

Multivariate Analysis of Recurrence after Hysteroscopic Diagnosis and Treatment of Endometrial Polyps following IVF-ET Failure.

Objective: To explore the risk factors affecting the recurrence of endometrial polyps (EPs) after hysteroscopic diagnosis and treatment of EPs following in vitro fertilization-embryo transfer (IVF-ET) failure by multivariate analysis. Methods: The clinical data of 369 patients with EPs hysteroscopically treated in our department due to IVF-ET failure from January 2017 to January 2020 were retrospectively analyzed, including the number and size of polyps, postoperative treatment, endometriosis (EM), hydrosalpinx (HSP), and polycystic ovarian syndrome (PCOS), and the effects of these factors on EP recurrence were observed. Results: Of the patients enrolled, 184 cases (49.9%) were treated by curettage, and 185 cases (50.1%) by electrotomy. A total of 72 cases (19.5%) of postoperative recurrence were determined, including 34 cases (9.2%) without postoperative medication, 31 cases (8.4%) with one month of postoperative Didroxyprogesterone (DG) administration, and 7 cases (1.9%) with three months of postoperative DG administration. Surgical methods, 3 months of postoperative medication, PCOS, and polyp number and size significantly influence the recurrence of EPs, which were all the influencing factors of polyp recurrence. After controlling for other factors, the risk of EP recurrence after electrotomy was found to be lower than that after curettage, with an odds ratio (OR) (95% confidence interval (CI)) of 0.354 (0.163-0.767); the risk of EP recurrence after 3 months of postoperative medication was lower than that without postoperative medication, with an OR (95% CI) of 0.024 (0.005-0.104); the risk of EP recurrence in patients with PCOS was higher than that without PCOS, and the OR (95% CI) was 2.505 (1.113-5.639); patients with multiple polyps (≥2) were at an increased risk of recurrence than those with a single polyp, with an OR (95% CI) of 66.552 (14.711-301.084); patients with polyp diameter ≥ 2 cm had a higher risk of recurrence than those with polyp diameter < 2 cm, and the OR (95% CI) was 1084.76 (148.743-7910.999). Conclusions: PCOS patients are at an elevated risk of EP recurrence than non-PCOS patients. In patients with multiple polyps, those with a diameter ≥ 2 cm have an increased risk of polyp recurrence compared with those with polyp diameter < 2 cm; electrotomy is associated with a lower recurrence risk of EPs than curettage. The risk of EP recurrence in patients treated with postoperative progesterone for 3 months is lower than that of patients without postoperative medication.

The protective effect of MiR-27a on the neonatal hypoxic-ischemic encephalopathy by targeting FOXO1 in rats.

Background: Neonatal hypoxic-ischemic encephalopathy (HIE), a kind of hypoxic-ischemic brain damage caused by perinatal asphyxia, is the most crucial cause of neonatal death and long-term neurological dysfunction in children. We aimed to investigate the protective effects of micro (mi)R-27a on HIE in neonatal rats. Methods: A rat model of neonatal HIE was constructed by modification of the Rice-Vannucci model. Real-time quantitative polymerase chain reaction (RT-qPCR) was used to test the expressions of miR-27a, FOXO1 messenger RNA (mRNA), interleukin-1ß (IL-1ß) mRNA, and tumor necrosis factor-α (TNF-α) mRNA, and western blot was applied to test the expression of FOXO1. In order to overexpress miR-27a, an intracerebroventricular injection (i.c.v) of miR-27a mimic was administered. We adopted 2,3,5-triphenytetrazolium chloride (TTC) staining and brain water content measurement to test the effects of miR-27a on the infarcted volume and edema in brain after HIE. Flow cytometry (FCM) analysis was applied to test the effects of miR-27a on the infiltrated peripheral immune cells in the rat brains after HIE. Results: We successfully established a rat model of neonatal HIE. It was revealed that the expressions of miR-27a decreased gradually after HIE, however, the expressions of FOXO1 mRNA increased. After injection of the miR-27a mimic, the expression of miR-27a in the rat HIE model brains was significantly upregulated, however, the expression of FOXO1 was robustly downregulated. Both TTC staining and brain water content showed that the infarcted volume and brain edema was markedly increased after HIE. Interestingly, the overexpression of miR-27a reduced the infarcted volume and edema induced by HIE. Additionally, RT-qPCR and FCM analysis showed that HIE lead to increases of IL-1ß, TNF-α, and infiltrated immune cells. Overexpression of miR-27a could reduce the expressions of IL-1ß mRNA and TNF-α mRNA, and the cell numbers of infiltrated peripheral macrophages and neutrophils in the brain. Conclusions: MiR-27a plays protective roles by reducing infarct volume and brain edema, and inhibiting inflammatory factors and infiltrated peripheral immune cells by targeting FOXO1 in neonatal HIE rats.

Clinical application value of serum neutrophil gelatinase-associated lipocalin in neonatal sepsis.

BACKGROUND: To explore the value of serum neutrophil gelatinase-associated lipocalin (sNGAL) in the diagnosis and follow up of neonatal late-onset sepsis. METHODS: A total of 69 infants were enrolled in this prospective study, including 49 infants of late-onset neonatal sepsis in the observation group, and 20 infants without infection serving as the control group. The sNGAL, C-reactive protein (CRP), and procalcitonin (PCT) concentrations were determined in both groups and compared at different time points. A receiver operating characteristic (ROC) curve was drawn to evaluate the values of the 3 parameters in the forecast of neonatal late-onset sepsis. RESULTS: The levels of sNGAL, CRP, and PCT were all increased obviously (P<0.05) in the observation group on the first and second day following onset, compared to the control group. The sNGAL level was associated with the time of treatment. Surprisingly, the sNGAL level started to drop in the observation group with effective treatment on the 7th day following onset. A correlation was found between the concentration of sNGAL and inflammatory markers, such as CRP and PCT, on the first day. The area under the ROC curve (AUC) for sNGAL, CRP, and PCT was: 0.964, 0.925, and 0.94, respectively. CONCLUSIONS: Increased sNGAL levels could reflect the inflammatory status in the acute stage of neonatal sepsis. When combined with other sepsis markers, such as CRP and PCT, the sNGAL is a useful marker in the rapid diagnosis and follow up of neonatal sepsis.

The circular RNA circ_0030018/miR-136/migration and invasion enhancer 1 (MIEN1) axis promotes the progression of polycystic ovary syndrome.

The abnormal expression of circular RNAs (circRNAs) is associated with the progression of polycystic ovary syndrome (PCOS), which commonly causes infertility in women. In this study, we identified the role of circ_0030018 in PCOS. Quantitative polymerase chain reaction (qPCR) was used to detect the expression levels of circ_0030018, microRNA (miR)-136, and migration and invasion enhancer 1 (MIEN1). Cell counting kit-8 and 5-ethynyl-2'-deoxyuridine assays were performed to analyze the proliferation of KGN cells. Apoptosis was analyzed using fluorescence-activated cell sorting. Transwell assays were performed to measure the migration and invasion abilities of cells. qPCR and Western blotting were used to measure the levels of E-cadherin, N-cadherin, Snail, and vimentin. The correlation of circ_0030018 or MIEN1 expression with miR-136 expression was confirmed via luciferase reporter and RNA pull-down assays. Results showed that circ_0030018 expression was upregulated in patients with PCOS and KGN cells. Knockdown of circ_0030018 suppressed the proliferation, migration, and invasion of cells, while promoting their apoptosis. circ_0030018 sponged miR-136, which targeted MIEN1. Moreover, downregulation of miR-136 abrogated the effects of circ_0030018 silencing, while the overexpression of MIEN1 reversed the miR-136-induced effect on KGN cells. In summary, loss of circ_0030018 delayed the progression of PCOS via the miR-136/MIEN1 axis.

Association between serum iron levels and the risk of cervical cancer in Chinese: a meta-analysis.

OBJECTIVES: To evaluate the association between serum iron levels and cervical cancer risk in Chinese populations. METHODS: A literature search was conducted using the PubMed, WanFang, and SinoMed databases up to April 30, 2019. Pooled standard mean differences (SMD) and 95% confidence intervals (CI) were analyzed using R software with a random-effects model. RESULTS: Data from nine studies comprising 454 cervical cancer patients and 880 controls were used in the analysis. Our results demonstrated that serum iron levels in cervical cancer patients were significantly lower than those in controls in Chinese populations (summary SMD = -1.24, 95%CI = -1.37 to -1.10; I2 = 93.4%). No publications bias was detected. Sensitivity analysis indicated that no single study had a significant effect on the overall SMD. CONCLUSIONS: Our findings show that serum iron levels are lower in patients with cervical cancer than in control individuals. However, further high-quality studies are necessary to clarify the role of serum iron levels in cervical cancer risk.

Changes in body composition in children with acute graft-versus-host disease within the first 100 days after hematopoietic stem cell transplantation.

BACKGROUND: Acute graft-versus-host-disease (aGVHD) is one of the main complications of hematopoietic stem cell transplantation (HSCT). This study investigated the changes in body composition of pediatric patients with aGVHD during the first 100 days after HSCT. METHODS: Fifty-five children receiving HSCT were divided into two groups (aGVHD and non-aGVHD). Body mass index Z-scores (BMI-z), arm muscle area index (AMAI), fat mass index (FMI), and fat-free mass index (FFMI) were measured on the day of transplantation (H0), and on the 30th (H30), 60th (H60), and 100th day (H100) after the transplantation. The correlative factors on body composition were evaluated. RESULTS: In the aGVHD group, the rates of absolute change of BMI-z at H30, H60, and H100 showed a significant increase as compared to that at H0, especially at H30 which was remarkably higher than that of the non-aGVHD group (P = 0.008). AMAI showed a continuous decrease from H0 to H100 in the aGVHD group; also FFMI was found to be lower than that of the non-aGVHD group during the first 100 days after transplantation, however, no significant differences were found between the two groups. At H60 and H100, FFMI in the aGVHD group was lower than that in the non-aGVHD group (P = 0.014, P = 0.032, respectively). Glucocorticoid treatment and the occurrence of mucositis were the key factors for changes in body composition in the aGVHD group. CONCLUSIONS: Changes in body composition are characterized by a lean reduction in body mass and increase in adipose tissues in the early stage of post-transplantation in the aGVHD children. Glucocorticoid treatment and occurrence of mucositis are the two important factors that were found to affect body composition after HSCT.

Upregulation of Abelson interactor protein 1 predicts tumor progression and poor outcome in epithelial ovarian cancer.

Abelson interactor protein 1 (Abi1) is a key regulator of actin reorganization and lamellipodia formation. Because of its role in cell migration, Abi1 has been implicated in tumor progression. In the present study, we investigated the role of Abi1 in epithelial ovarian cancer (EOC) by analyzing its expression and correlation with clinicopathological and survival data. We evaluated the expression of Abi1 in 223 paraffin-embedded EOC specimens by immunohistochemistry and 46 frozen EOC samples by Western blot and real-time reverse transcription polymerase chain reaction analysis. Results showed that Abi1 protein and mRNA expression was significantly higher in EOC tissue compared with noncancerous tumors and normal ovaries (P < .05). Moreover, high level of Abi1 expression was significantly correlated with advanced stage, high grade, elevated Ca-125 level, and suboptimal surgical debulking (P < .05). By Western blot analysis, Abi1 was expressed in highly invasive cells compared with weakly invasive cells (P < .05). Immunofluorescence was performed to demonstrate Abi1 expression in SKOV3 cells. Additionally, upregulation of Abi1 significantly correlated with shorter survival (P < .05). Most importantly, multivariate analysis showed that Abi1 overexpression is an independent prognostic factor, complementary to clinical stage and residual tumor size. In conclusion, our findings suggest that Abi1 acts as a tumor-promoting gene in EOC progression, which may lead to unfavorable prognosis. Abi1 may serve as a potential effective prognostic marker for EOC.

Overexpression of c-Abl predicts unfavorable outcome in epithelial ovarian cancer.

OBJECTIVES: Abelson tyrosine kinase (c-Abl) has been shown to promote solid tumor invasion and metastasis. However, little is known regarding whether c-Abl contributes to the development or progression of epithelial ovarian cancer (EOC). The aims of this study are to determine the expression of c-Abl and investigate a possible relationship between c-Abl and prognosis in EOC. METHODS: c-Abl protein level was evaluated in 137 EOC specimens by immunohistochemical staining and 32 EOC specimens by Western blot analysis. Expression of c-Abl in ovarian cancer cell lines was measured by Western blot analysis and immunofluorescence. Survival analysis was performed to assess the correlation between c-Abl expression and survival. RESULTS: Immunohistochemical staining and Western blot analysis revealed that c-Abl was overexpressed in EOC compared with samples from a non-invasive ovarian tumor and normal ovaries (P<0.05). Furthermore, expression of c-Abl was significantly associated with advanced FIGO stage, poor grade, serum Ca-125 and residual tumor size (P<0.05). By Western blot analysis, c-Abl expression was examined in four ovarian cancer cell lines. Meanwhile, immunofluorescence was performed to show c-Abl expression in SKOV3 and 3AO cell lines. Survival analysis demonstrated that patients with low c-Abl staining had a significantly better survival compared to patients with high c-Abl staining (P<0.05). In multivariate analysis, c-Abl overexpression, poor grade, advanced stage and suboptimal surgical debulking were independent prognostic factors of poor survival. CONCLUSIONS: Our present study finds that c-Abl overexpression is associated with an unfavorable outcome. c-Abl may be a crucial predictor for EOC metastasis.

WAVE1 gene silencing via RNA interference reduces ovarian cancer cell invasion, migration and proliferation.

OBJECTIVE: Wiskott-Aldrich syndrome protein family verprolin-homologous protein 1 (WAVE1) has been implicated in cancer cell migration and invasion. We have previously shown that the overexpression of WAVE1 in epithelial ovarian cancer (EOC) tissues is associated with a poor prognosis. However, the mechanism of WAVE1 regulating the malignant behaviors in EOC remains unclear. METHODS: In the present study, we knocked down WAVE1 expression in SKOV3 and OVCAR-3 cells through RNA interference to detect the cell biology and molecular biology changes. Moreover, western-blot was used to investigate the underlying mechanism of WAVE1 regulating the proliferative and invasive malignant behaviors in ovarian cancer cells. RESULTS: The down-regulation of WAVE1 had a significant effect on cell morphological changes. WAVE1 silencing decreased cell migration, cell invasion, cell adhesion, colony formation and cell proliferation in vitro. In addition, we found that down-regulation of WAVE1 inhibited malignant behaviors in vivo. Furthermore, our study also indicated that the PI3K/AKT and p38MAPK signaling pathways might contribute to WAVE1 promotion of ovarian cancer cell proliferation, migration, and invasion. CONCLUSIONS: WAVE1 might promote the proliferative and invasive malignant behaviors through the activation of the PI3K/AKT and p38MAPK signaling pathways in EOC.

High level of WAVE1 expression is associated with tumor aggressiveness and unfavorable prognosis of epithelial ovarian cancer.

OBJECTIVES: Wiskott-Aldrich syndrome protein family verprolin-homologous protein 1 (WAVE1) has been shown to promote cancer invasion and metastasis. However, no evidence has been found to identify the role of WAVE1 in epithelial ovarian cancer (EOC). This study aims to determine the effect of WAVE1 expression and investigate a possible relationship between WAVE1 and prognosis in EOC. METHODS: WAVE1 protein level was measured in 223 EOC specimens by immunohistochemical staining and 46 EOC specimens by Western blot analysis. Expression of WAVE1 in ovarian cancer cell lines was evaluated by Western blot analysis and immunofluorescence. Survival analysis was performed to assess the correlation between WAVE1 expression and survival. RESULTS: Immunohistochemical staining and Western blot analysis showed that WAVE1 was overexpressed in EOC compared with samples from a non-invasive ovarian tumor and normal ovaries (P<0.05). Furthermore, expression of WAVE1 was significantly associated with advanced FIGO stage, poor grade, serum Ca-125 and residual tumor size (P<0.05). By Western blot analysis, WAVE1 expression was detected in four ovarian cancer cell lines. Immunofluorescence was performed to demonstrate WAVE1 expression in SKOV3 and 3AO cell lines. Survival analysis showed that patients with low WAVE1 staining had a significantly better survival compared to patients with high WAVE1 staining (P<0.05). In multivariate analysis, WAVE1 overexpression, advanced stage and suboptimal surgical debulking were independent prognostic factors of poor survival. CONCLUSIONS: Our present study finds that WAVE1 overexpression is associated with an unfavorable prognosis. WAVE1 is an independent prognostic factor for EOC, which suggests that it is a novel and crucial predictor for EOC metastasis.