Prognostic significance of DAPK promoter methylation in lymphoma: A meta-analysis.

We aimed to characterize the clinical significance of epigenetic loss of death-associated protein kinase (DAPK) gene function through promoter methylation in the development and prognosis of lymphoma. PubMed, Web of Science and ProQuest databases were searched for relevant studies. Twelve studies involving 709 patients with lymphoma were identified. The prognostic value of DAPK methylation was expressed as risk ratio (RR) and its corresponding 95% confidence interval (CI), while the associations between DAPK methylation and the clinical characteristics of patients with lymphoma were expressed as odd ratios (ORs) and their corresponding 95% CIs. Meta-analysis showed that the 5-year survival rate was significantly lower in lymphoma patients with hypermethylated DAPK (RR = 0.85, 95% CI (0.73, 0.98), P = 0.025). Sensitivity analysis demonstrated consistent result. However, no associations were found between DAPK methylation and clinicopathological features of lymphoma, in relation to gender (OR = 1.07, 95% CI (0.72, 1.59), P = 0.751), age (OR = 1.01, 95% CI (0.66, 1.55), P = 0.974), international prognostic index (OR = 1.20, 95% CI (0.63, 2.27), P = 0.575), B symptoms (OR = 0.76, 95% CI (0.38, 1.51), P = 0.452), serum lactate dehydrogenase (OR = 1.13, 95% CI (0.62, 2.05), P = 0.683), and BCL-2 expression (OR = 1.55, 95% CI (0.91, 2.66), P = 0.106). Lymphoma patients with hypermethylated DAPK are at risk for poorer 5-year survival rate. DAPK methylation may serve as a negative prognostic biomarker among lymphoma patients, although it may not be associated with the progression of lymphoma.

Folic Acid Supplementation for Stroke Prevention in Patients With Cardiovascular Disease.

BACKGROUND: Controversy remains regarding the efficacy of folic acid supplementation in reducing the risk of stroke. This study aimed to evaluate the effect of folic acid supplementation on stroke prevention in patients with cardiovascular disease (CVD). MATERIALS AND METHODS: We searched the PubMed, EMBASE and Cochrane Library databases through October 2016 to identify randomized clinical trials of folic acid supplementation to prevent stroke in patients with CVD. Relative risks (RRs) with 95% CIs were used to examine the association between folic acid supplementation and the risk of stroke with a fixed-effect model. Stratified analyses were performed according to modifiers that may affect the efficacy of folic acid supplementation. RESULTS: Eleven studies with a total of 65,790 participants were included. Folic acid supplementation was associated with a significant benefit in reducing the risk of stroke in patients with CVD (RR = 0.90; 95% CI: 0.84-0.97; P = 0.005). In the stratified analysis, greater beneficial effects were observed in participants with a decrease in homocysteine concentrations of 25% or greater (RR = 0.85; 95% CI: 0.74-0.97; P = 0.03), those with a daily folate dose of less than 2mg (RR = 0.78; 95% CI: 0.68-0.89; P = 0.01), and populations in regions with no or partly fortified grain (RR = 0.87; 95% CI: 0.81-0.94; P = 0.04). CONCLUSIONS: Our meta-analysis demonstrated that folic acid supplementation is effective in stroke prevention in patients with CVD.

Left Ventricular Noncompaction in Older Patients.

BACKGROUND: Information on left ventricular noncompaction (LVNC) in older people is sparse. This study aimed to investigate the clinical profile of LVNC in an older cohort. MATERIALS AND METHODS: Between August 2007 and September 2015, older patients (age ≥ 60 years) who were diagnosed with LVNC using cardiovascular magnetic resonance were prospectively enrolled at our hospital. RESULTS: A total of 35 patients (male, 80%; mean age, 65 ± 5 years) were prospectively included in this study. LVNC was not detected in 18 patients (51%) at the initial echocardiographic evaluation. Of the 21 patients who received coronary imaging, 8 patients (38%) had coronary artery disease. Left ventricular (LV) dysfunction and dilation were detected in 31 patients (89%) and 30 patients (86%), respectively. Nine patients (26%) died during a follow-up period of 2.9 ± 2.3 years. Cox analysis showed that patients with syncope (hazard ratio [HR] = 20.51; 95% CI: 1.70-246.60; P = 0.02), increased LV end-diastolic diameter (HR = 1.12; 95% CI: 1.01-1.24; P = 0.03), decreased LV ejection fraction (HR = 0.87; 95% CI: 0.77-0.98; P = 0.02) and the presence of late gadolinium enhancement on cardiovascular magnetic resonance (HR = 8.9; 95% CI: 1.07-74.08; P = 0.04) had a higher risk for death. CONCLUSIONS: The diagnosis of LVNC is easily missed at echocardiographic assessment in older patients. Coronary artery disease is a common concomitant disorder in these patients. Older patients with LVNC have a high risk for mortality. Syncope, LV dilation, systolic dysfunction and late gadolinium enhancement are related to adverse outcomes in older patients.

A novel snake venom-derived GPIb antagonist, anfibatide, protects mice from acute experimental ischaemic stroke and reperfusion injury.

BACKGROUND AND PURPOSE: Ischaemic stroke is a serious disease with limited therapy options. Glycoprotein (GP)Ib binding to von Willebrand factor (vWF) exposed at vascular injury initiates platelet adhesion and contributes to platelet aggregation. GPIb has been suggested as an effective target for antithrombotic therapy in stroke. Anfibatide is a GPIb antagonist derived from snake venom and we investigated its protective effect on experimental brain ischaemia in mice. EXPERIMENTAL APPROACH: Focal cerebral ischaemia was induced by 90 min of transient middle cerebral artery occlusion (MCAO). These mice were then treated with anfibatide (4, 2, 1 µg·kg(-1) ), injected i.v., after 90 min of MCAO, followed by 1 h of reperfusion. Tirofiban, a GPIIb/IIIα antagonist, was used as a positive control. KEY RESULTS: Twenty-four hours after MCAO, anfibatide-treated mice showed significantly improved ischaemic lesions in a dose-dependent manner. The mice had smaller infarct volumes, less severe neurological deficits and histopathology of cerebrum tissues compared with the untreated MCAO mice. Moreover, anfibatide decreased the amount of GPIbα, vWF and accumulation of fibrin(ogen) in the vasculature of the ischaemic hemisphere. Tirofiban had similar effects on infarct size and fibrin(ogen) deposition compared with the MCAO group. Importantly, the anfibatide-treated mice showed a lower incidence of intracerebral haemorrhage and shorter tail bleeding time compared with the tirofiban-treated mice. CONCLUSIONS AND IMPLICATIONS: Our data indicate anfibatide is a safe GPIb antagonist that exerts a protective effect on cerebral ischaemia and reperfusion injury. Anfibatide is a promising candidate that could be beneficial for the treatment of ischaemic stroke.

Protective effect of iridoid glycosides from Paederia scandens (LOUR.) MERRILL (Rubiaceae) on uric acid nephropathy rats induced by yeast and potassium oxonate.

Iridoid glycosides of Paederia scandens (IGPS) are an active component isolated from Chinese herb P. scandens (LOUR.) MERRILL (Rubiaceae). Uric acid nephropathy (UAN) is caused by excessive uric acid, which results in damage of kidney tissue via urate crystals deposition in the kidneys. This study aimed to investigate the protective effects of IGPS on UAN in rats induced by yeast and potassium oxonate. Treatment groups received different doses of IGPS and allopurinol (AP) daily for 35 days respectively. The results showed that treatment with IGPS significantly prevented the increases of uric acid in serum and the elevation of systolic blood pressure (SBP), attenuated renal tissue injury, improved renal function and reserved the biological activity of NOS-1. IGPS also inhibited the biological activity of TNF-α and TGF-ß1, and suppressed the mRNA expressions of TNF-α and TGF-ß1 in renal tissue. Taken together, the present and our previous findings suggest that IGPS exerts protective effects against kidney damage in UAN rats through its uric acid-lowering, anti-inflammatory and immunomodulatory properties. Furthermore, decreasing SBP by up regulation of NOS-1 expression and down regulation of TNF-α and TGF-ß1 expression are involved in the effect of IGPS on high uric acid-induced nephropathy.

Anti-proliferative effect of recombinant human endostatin on synovial fibroblasts in rats with adjuvant arthritis.

Rheumatoid arthritis (RA) is characterized by pronounced synovial hyperplasia resulting in pannus formation, cartilage erosion and ultimately joint destruction. Activated RA synovial fibroblasts (SFs) mediate the invasion and destruction of cartilage and bone. We previously demonstrated that recombinant human endostatin (rhEndostatin) is sufficient to induce SF apoptosis in adjuvant arthritis (AA) rats. However, the effect of this protein on SF proliferation is unknown. This study was designed to assess the inhibitory effect and mechanisms of rhEndostatin on the proliferation of cultured AA SFs. MTT assay and flow cytometric detection were performed to investigate SF proliferation and cell cycle progression, respectively. Also, the expression levels of p53, p21, cyclin D1, CDK4 and PCNA in AA SFs were detected by real-time PCR and western blotting assays. Our data revealed that AA SF proliferation was significantly inhibited by rhEndostatin in a concentration-dependent manner. In addition, rhEndostatin (50µg/ml) caused the G0/G1 cell cycle arrest of AA SFs. There were significant decreases in the expression levels of p53, p21, cyclin D1 and PCNA in AA SFs treated with rhEndostatin, and a significant increase in CDK4 expression. Collectively, our data suggest that rhEndostatin inhibits AA SF proliferation, which is preceded by cell cycle arrest at the G0/G1 phase. This is partly due to the inhibitory effect of rhEndostatin on cyclin D1 and PCNA by a p53-p21-CDK4-independent mechanism. Taken together, these findings highlight the potential use of rhEndostatin for RA treatment.

Relationship between podophyllotoxin accumulation and soil nutrients and the influence of Fe2+ and Mn2+ on podophyllotoxin biosynthesis in Podophyllum hexandrum tissue culture.

Podophyllotoxin (PDT) and its derivatives, which are isolated from the Podophyllum species, are widely used in the clinical setting. The present study was designed to analyze the correlation between PDT levels in the rhizomes of Podophyllum hexandrum (P. hexandrum) and Dysosma versipellis (D. versipellis) and the nutrients in soil. We also aimed to investigate the influence of Fe(2+) and Mn(2+) on the enzyme activity of phenylalanine ammonia lyase (PAL), cinnamyl alcohol-dehydrogenase (CAD), and deoxypodophyllotoxin 6-hydroylase (DOP6H) and PDT accumulation via P. hexandrum tissue culture. The results showed that PDT accumulation was positively correlated with the NO3(-), PO4(3-), Na(+), Fe, and Mn levels and was negatively correlated with the SO4(2-) and K(+) levels, while the correlation with the Mg(2+), Ca(2+), Cu and Zn levels was not significant. The Fe(2+) and Mn(2+) levels were associated with the increased activity of PAL and CAD at 3-18 days; Fe(2+) enhanced the activity levels by 2.66- and 1.76-fold, respectively, and Mn(2+) was associated with a 1.68- and 1.10-fold increase in activity levels, respectively, compared with the control (CK) at 18 days. DOP6H activity was enhanced by Mn(2+), but it was not significantly affected by Fe(2+). Finally, PDT production was enhanced approximately 60% and 34% by Fe(2+) and Mn(2+), respectively, compared with CK at 16 days. These observations may be useful for the generation of PDT and related lignans via commercial cultivation as well as cell and tissue culture of P. hexandrum and other related plant resources.

Effects of extracts from Paederia scandens (LOUR.) MERRILL (Rubiaceae) on MSU crystal-induced rats gouty arthritis.

The effects of extract of Paederia scandens (LOUR.) MERRILL (Rubiaceae) (EPS), a Chinese traditional herbal medicine, on inflammatory and immune responses and their mechanisms in MSU crystals-induced (GA) rats were studied. GA rats were established. Ankle joint volume of rats was measured by volume meter; the level of TNF-alpha and IL-1beta was determined by radioimmunoassay. mRNA expressions of TNF-alpha and IL-1beta in synovial tissue of GA rats were analyzed by RT-PCR, and the expression of NF-kappaB was detected by immunohistochemistry. The administration of EPS (2.25, 4.5 g/kg, ig 9 days) inhibited the inflammatory response in GA rats. The mRNA expressions of TNF-alpha and IL-1beta were also significantly suppressed in synovial tissue. In addition, EPS (2.25, 4.5 g/kg, ig 9 days) inhibited the expression of TNF-alpha and IL-1beta and the biological activity of NF-kappaB. These results suggested that EPS possesses antiinflammatory effects by modulating pro-inflammatory mediators' production in synovial tissue and inactivating NF-kappaB pathway transmembrane signal transduction which plays a crucial role in the pathogenesis of this disease.

MicroRNA expression profiles and miR-10a target in anti-benzo[a] pyrene-7, 8-diol-9, 10-epoxide-transformed human 16HBE cells.

OBJECTIVE: To screen miRNA profiles of malignantly transformed human bronchial epithelial cells, 16HBE-T, induced by anti-benzo[a]pyrene-trans-7,8-diol-9,10-epoxide (anti-BPDE), and to analyze putative miR-10a targets in 16HBE-T. METHODS: A novel microarray platform was employed to screen miRNA profiles of 16HBE-T cells transformed by anti-BPDE. Microarray data for miR-10a and miR-320 were validated using quantitative real time polymerase chain reaction (QRT-PCR). The expression of a putative target for miR-10a, HOXA1, was analyzed by reverse transcription polymerase chain reaction (RT-PCR) and QRT-PCR. RESULTS: In comparison with the vehicle-treated cells (16HBE-N), 16HBE-T exhibited differential expression of 54 miRNAs, in which, 45 were over-expressed and 9 were down-regulated. The five most highly expressed miRNAs were miR-494, miR-320, miR-498, miR-129, and miR-106a. The lowest expressed miRNAs were miR-10a, miR-493-5p, and miR-363*. Three members of miR-17-92 cluster, miR-17-5p, miR-20a, and miR-92, showed significantly higher abundance in 16BHE-T as miR-21, miR-141, miR-27a, miR-27b, miR-16 and miRNAs of the let-7 family. The putative target for miR-10a, HOXA1 mRNA was up-regulated 3-9-fold in 16HBE-T, as compared with 16HBE-N. CONCLUSION: The findings of the study provide information on differentially expressed miRNA in malignant 16HBE-T, and also suggest a potential role of these miRNAs in cell transformation induced by anti-BPDE. HOXA1 is similarly up-regulated, suggesting that miR-10a is associated with the process of HOXA 1-mediated transformation.

Protective effect of total flavones of Abelmoschus manihot L. Medic against poststroke depression injury in mice and its action mechanism.

Total flavones of Abelmoschus manihot L. Medic (TFA) is the major active component isolated from the traditional Chinese herb Abelmoschus manihot L. Medic. We investigated the protective effect of TFA against poststroke depression (PSD) injury in mice and its action mechanism. A mouse model of PSD was induced by middle cerebral artery occlusion (MACO) 30 min/reperfusion, followed by isolation feeding and chronic unpredictable mild stress for 2 weeks. Treatment groups received TFA at three different doses (160, 80, and 40 mg/kg, p.o.) or fluoxetine (Flu, 2.5 mg/kg, p.o.) daily for 24 days. Change in behavior, brain tissue malondialdehyde (MDA) levels, and the activity of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) were measured. The expression of brain-derived neurotrophic factor (BDNF) was detected by immunohistochemistry, and mRNA expression of BDNF and cAMP response element-binding protein (CREB) analyzed by reverse transcription-polymerase chain reaction (RT-PCR). Treatment with TFA (160, 80, and 40 mg/kg) significantly ameliorated mice escape-directed behavioral impairment induced by PSD, markedly reduced MDA levels, and increased the activity of SOD, GSH-Px close to normal levels. TFA administration also attenuated PSD-induced neuronal death/losses, upregulated expression of BDNF both at mRNA and protein levels, as well as CREB mRNA levels. TFA had a protective effect against PSD injury in mice. Cardioprotection involves the inhibition of lipid peroxidation and upregulation of BDNF-CREB levels in the hippocampus, which may also be important mechanism of its antidepressants. This potential protection makes TFA a promising therapeutic agent for the PSD.

[MicroRNA profiles of malignantly transformed cells induced by anti-benzo-a-pyrene-trans-7, 8-dihydrodiol-9, 10-epoxide].

OBJECTIVE: To screen microRNA (miRNA) profiles of malignantly transformed cells induced by anti-benzo-a-pyrene-trans-7, 8-dihydrodiol-9, 10-epoxide (BPDE) and to look for miRNAs which is expressed differently between malignantly transformed cells and normal human bronchial epithelial cells 16HBE. METHODS: Experimental group was the malignantly transformed 16HBE which was induced by cultured with final concentration 2.0 micromol/L of BPDE which was dissolved in dimethyl sulphoxide. The control group was 16HBE that was cultured with minimal essential medium including dimethyl sulphoxide. 327 miR-NAs were tested be-tween those two groups with miRNA microarray analysis. MiR-10a that was down expressed and miR-320 that was overexpressed were selected to be validated by miRNA specific quantitative real-time reverse transcriptase chain reaction (miR qRT-PCR). RESULTS: 327 human miRNAs were tested with miRNA microarray analysis. 55 miRNAs were found expressing differently between those two groups and of which 46 were overexpressed and 9 were down expressed. Some data were validated by quantitative RT-PCR. CONCLUSION: miRNAs expressed significantly between malignantly transformed 16HBE and normal cells and this helps us look for unique miRNAs of malignantly transformed cells induced by BPDE, but there should have more sufficient evidences to prove their functions in malignant cells.

Antidepressant-like effects of BCEF0083 in the chronic unpredictable stress models in mice.

BACKGROUND: Up to now there have been no satisfactory drugs to treat psychiatric disorders, and now bioactive compound from entomagenous fungi (BCEF0083) is a new type of bioactive compound from entomopathogenic fungi. Our previous investigations have shown that BCEF has an inhibition effect on monoamine oxidase. So, BCEF may be a latent antidepressant. This study aimed at observing the antidepressant effects and its mechanism of BCEF in the chronic unpredictable stress models in mice. METHODS: The antidepressant effects of BCEF were examined on the chronic unpredictable stress models in mice. Sixty mice were randomly divided to six groups. Animals were housed and isolated except saline group. Mice were exposed to different stressors per day randomly from day 1 to day 21. Body weight were weighed on day 1, day 10 and on day 21 during the 21-day stress procedure. Awarding response was detected by using method of calculating the 24-hour consumption of saccharum water. Step through test was used to evaluate the behavioral response. AVP contents in plasma were also detected by using radioimmunoassays. RESULTS: Chronic unpredictable stress resulted in a significant decrease of the body weight and could apparently cause escape behavior disturbance and gradual reduction of sensitivity to reward in animal models. Drug treatment (BCEF 25, 50, 100 mg/kg) could significantly ameliorate the decreased body weight and effectively reverse the escape behavior disturbance. The gradual reduction of sensitivity to reward, the anhedonic state, was also effectively reversed by BCEF. BCEF (50, 100 mg/kg) could also effectively restore the AVP content in the plasma. CONCLUSIONS: This evidence suggests that BCEF can effectively inhibit the depression behavior and show strong antidepressant effect. BCEF can effectively restore the plasma AVP release and this may be an important mechanism of its antidepressant effect.