Akt1/protein Kinase Bα is Involved in Gastric Cancer Progression and Cell Proliferation

Akt (also known as protein kinase B, PKB) is involved in a variety of biological processes, for example cell development, proliferation, and angiogenesis. Clinical studies in support of the idea that increased activity of Akt could contribute directly to gastric carcinogenesis are rare, however. In this study we discovered that phospho-Akt1 was overexpressed in human gastric cancers and its levels correlated with tumor differentiation and pTNM. Akt1 activation promoted cell survival, because the phosphatidylinositol 3-kinase(PI3K) inhibitor LY294002 inhibited Akt1 phosphorylation and inhibited cell growth, especially in cells with active Akt1. Dominant negative Akt inhibited proliferation of gastric cancer cells and induced G1 cell-cycle arrest whereas constitutively active Akt increased cell proliferation. We have therefore identified Akt1 as an active kinase that contributes to gastric cancer progression and promotes proliferation of gastric cancer cells.     

Ischemic Evaluation in Patients Presenting with Hypertensive Emergency / Urgency and Acute Systolic Heart Failure: Is Coronary Angiography Required for all?

BackgroundPatients presenting with hypertensive urgency / emergency (HUE) often have systolic heart failure(SHF). Coronary angiography is routinely done for these patients to rule out obstructive coronary artery disease (Obs-CAD). We performed a retrospective study to investigate predictors of ObsCAD in this population.MethodsPatients who underwent angiography to investigate SHF and had hospital admission(s) for HUE in the preceding 6 months were included in the study. Chart review was performed to obtain demographic, clinical and imaging / angiographic data. A risk score was formulated based on multivariable logistic regression analysis.Results205 patients [age 58.9 ± 14.4 years; 62.4% male; 39.5% diabetic; median EF 25% (Inter Quartile Range: 11)] were included in the study. 33.1% patients (n = 68) had obs-CAD. Patients with obs-CAD were older, diabetic, more likely to have a history of stroke, echocardiographic regional wall motion abnormalities (RWMA) while African Americans were less likely to have obs-CAD. On multivariable analysis, only non-African American race (OR: 2.18; CI: 1.08–4.4) and RWMA (OR: 5.62; CI: 2.47–12.81) remained significant predictors of obs-CAD. A risk score (RANDS) from 0 to 9 was formulated which had a c-statistic of 0.75 with a sensitivity and specificity of 84% and 53% for predicting obsCAD respectively.ConclusionOur results suggest that only a minority of patients with HUE and SHF have obs-CAD. A simple risk score may be used to stratify this population and lower risk individuals may be screened with non-invasive testing instead of invasive catheterization. These results should be validated in large registry populations.     

Allyl isothiocyanate ameliorates lipid accumulation and inflammation in nonalcoholic fatty liver disease via the Sirt1/AMPK and NF-κB signaling pathways

BACKGROUND Allyl isothiocyanate(AITC),a classic anti-inflammatory and antitumorigenic agent,was recently identified as a potential treatment for obesity and insulin resistance.However,little is known about its direct impact on the liver.AIM To investigate the effect and underlying mechanism of AITC in nonalcoholic fatty liver disease(commonly referred to as NAFLD).METHODS To establish a mouse and cellular model of NAFLD,C57BL/6 mice were fed a high fat diet(HFD)for 8 wk,and AML-12 cells were treated with 200μM palmitate acid for 24 h.For AITC treatment,mice were administered AITC(100 mg/kg/d)orally and AML-12 cells were treated with AITC(20μmol/L).RESULTS AITC significantly ameliorated HFD-induced weight gain,hepatic lipid accumulation and inflammation in vivo.Furthermore,serum alanine aminotransferase and aspartate aminotransferase levels were markedly reduced in AITC-treated mice.Mechanistically,AITC significantly downregulated the protein levels of sterol regulatory elementbinding protein 1(SREBP1)and its lipogenesis target genes and upregulated the levels of proteins involved in fatty acidβ-oxidation,as well as the upstream mediators Sirtuin 1(Sirt1)and AMPactivated protein kinaseα(AMPKα),in the livers of HFD-fed mice.AITC also attenuated the nuclear factor kappa B(NF-κB)signaling pathway.Consistently,AITC relieved palmitate acid-induced lipid accumulation and inflammation in AML-12 cells in vitro through the Sirt1/AMPK and NF-κB signaling pathways.Importantly,further studies showed that the curative effect of AITC on lipid accumulation was abolished by siRNA-mediated knockdown of either Sirt1 or AMPKαin AML-12 cells.CONCLUSION AITC significantly ameliorates hepatic steatosis and inflammation by activating the Sirt1/AMPK pathway and inhibiting the NF-κB pathway.Therefore,AITC is a potential therapeutic agent for NAFLD.     

Neuroprotective effect of tanshinone IIA against neuropathic pain in diabetic rats through the Nrf2/ARE and NF-κB signaling pathways

The study aims to investigate whether tanshinone (TSN) IIA affects diabetic neuropathic pain (DNP) via the Nrf2/AR and NF-κB signaling pathways. Rats were randomly assigned into DNP group, TSN group (injected with TSN IIA), TSN + DRB group (injected with TSN IIA and 15 mg/kg Nrf2/ARE inhibitors), TSN + PDTC group (injected with TSN IIA and 60 mg/kg NF-κB inhibitors) or control group. The first four groups were successfully established as DNP models after injection of streptozotocin. The blood glucose level, mechanical withdrawal threshold (MWT), thermal withdrawal latency (TWL), nerve conduction velocity (NCV) and antioxidase level were detected. Transmission electron microscopy and toluidine blue staining were utilized to observe the sciatic nerve. RT-qPCR and western blot were used to measure expression levels of Nrf2/ARE and NF-κB signaling pathway-related genes. Blood glucose, malondialdehyde (MDA) and erythrocyte glutathione peroxidase (GSH-Px) levels as well as expression of Keap1 and NF-κB were increased in the TSN, TSN + DRB and TSN + PDTC groups compared to control group. Furthermore, the MWT, TWL, NVC, and superoxide dismutase (SOD) levels and expression of Nrf2, heme oxygenase 1 (HO-1) and inhibitory kappa B (IκB) decreased in the treatment groups. The TSN + DRB and TSN + PDTC groups showed similar trend when compared with the TSN group, while the opposite trend was observed in the TSN group when compared with the DNP group. Our study demonstrates that TSN IIA alleviates neuropathic pain by activating the Nrf2/ARE signaling pathway and inhibiting the NF-κB signaling pathway in diabetic rats.     

The association between the decreased expression levels of FOXJ1 and the activation of NF-κB pathway in interstitial lung disease of MRL/Lpr mice

Background: Pulmonary manifestations of systemic lupus erythematosus (SLE) are appearing in 4-5% of patients involving lung in almost half of the cases during the disease course. Objective: We compared the autoimmune pulmonary inflammation in the lung tissue of mice to determine the association between decreased expression levels of Forkhead Box J1 (FOXJ1) and the activation of the NF-κB pathway in autoimmune pulmonary inflammation of MRL/Lpr mice. Methods: The female BALB/c mice (n=6) and MRL/Lpr mice (n=30) were divided into 5 groups including a control group (BALB/c), and five MRL/Lpr mice groups (8W, 12W, 16W, 24W, and 32W). The infiltration of the inflammatory cells was determined in lung tissue by performing the histological analysis. The western blotting was used to examine the expression levels of the age-related FOXJ1, and p50 and p65 proteins in the lungs of MRL/Lpr mice. The expression levels of MMP2 and MMP9 were determined via immunohistochemistry and immunofluorescence. Results: There were severe infiltrates of lung cells with high levels of tracheal damage, perivascular injury and interstitial inflammatory cell infiltration when the MRL/Lpr mice from 16w to 32w comparing to the 8w old healthy MRL/Lpr mice in the control group (p <0.05). Moreover, the reduced expression levels of FOXJ1 were associated with the activation of the NF-κB pathway in interstitial lung disease of MRL/Lpr mice via the modulation of p50 and p65. In addition, the expression levels of MMP2 and MMP9 pro-inflammation factors increased in the lungs of the MRL/Lpr mice from 16w to 32w. Conclusions: The expression level of FOXJ1 might be an indicator of the degree of lung disease in lupus-prone mice.     

Clinical efficacy of Modified Shuyu Pill for mild and moderate Alzheimer's disease and its effects on expressions of IL-1β/NF-κB/miR-146a in peripheral blood

<正>Objective To explore the clinical efficay of Modified Shuyu Pill (MSP) for treatment of mild and moderate Alzheimer’s disease (AD) and its effect on the expressions of interleukin-1β(IL-1β)/nuclear factor-kappa B(NF-κB)/microRNA-146a (miR-146a) in peripheral     

Micro RNA-146a expression,NF-κB/P65 activity and serum pentosidine levels as potential biomarkers for disease severity in primary knee osteoarthritis patients

IntroductionIdentifying osteoarthritis (OA) patients at high risk for progression is important.Aim of the workTo study the expression pattern of micro RNA-146a (miR-146a), NF-κB/p65 binding activity and serum pentosidine levels in patients with primary knee OA (KOA) in order to assess their value as potential markers for disease prognosis and severity and to clarify their role in disease pathogenesis.Patient and methodsThis study was conducted on 36 female patients with primary KOA divided radiologically into those with moderate KOA and severe KOA as well as 20 controls. The expression patterns of miR-146a were analyzed using quantitative real time-PCR, NF-κB/p65 binding activity and serum pentosidine levels determined using ELISA kits.ResultsmiR-146a expression levels were significantly higher in KOA patients than controls being significantly higher in moderate KOA compared to severe cases. NF-κB/p65 binding activity and serum pentosidine levels were significantly higher in severe KOA patients (0.74 ± 0.06 and 425.2 ± 40.3 pg/ml) compared to moderate cases (0.3 ± 0.03 and 311.4 ± 30 pg/ml) (p < 0.05) and were higher compared to controls (0.15 ± 0.08 and 257 ± 32.3 pg/ml respectively) (p < 0.05).ConclusionThis study may emphasize the role of miR-146a expression, and NFKB/p65 binding activity in primary KOA. Assessment of NFKB/p65 binding activity, miR-146a expression, and serum pentosidine in primary KOA patients could extend the panel of laboratory tests available to monitor the severity and progress of the disease and might benefit as markers for detection of patients with high risk for disease progression; and hence to be a novel therapeutic target to inhibit cartilage destruction.     

Non-SMC condensin Ⅰ complex subunit D2 and non-SMC condensin Ⅱ complex subunit D3 induces inflammation via the IKK/NF-κB pathway in ulcerative colitis

BACKGROUND Ulcerative colitis(UC) is a chronic, nonspecific intestinal inflammatory disease with undefined pathogenesis. Non-SMC condensin I complex subunit D2(NCAPD2) and non-SMC condensin II complex subunit D3(NCAPD3) play pivotal roles in chromosome assembly and segregation during both mitosis and meiosis. To date, there has been no relevant report about the functional role of NCAPD2 and NCAPD3 in UC.AIM To determine the level of NCAPD2/3 in intestinal mucosa and explore the mechanisms of NCAPD2/3 in UC.METHODS Levels of NCAPD2/3 in intestinal tissue were detected in 30 UC patients and 30 healthy individuals with in situ hybridization(ISH). In vitro, NCM60 cells were divided into the NC group, model group, si-NCAPD2 group, si-NCAPD3 group and si-NCAPD2+si-NCAPD3 group. Inflammatory cytokines were measured by ELISA, IKK and NF-κB were evaluated by western blot, and IKK nucleation and NF-κB volume were analyzed by immunofluorescence assay.RESULTSCompared with expression in healthy individuals, NCAPD2 and NCAPD3 expression in intestinal tissue was significantly upregulated(P 0.001) in UC patients. Compared with levels in the model group, IL-1β, IL-6 and TNF-α in the si-NCAPD2, si-NCAPD3 and si-NCAPD2+si-NCAPD3 groups were significantly downregulated(P 0.01). IKK and NF-κB protein expression in the si-NCAPD2,si-NCAPD3 and si-NCAPD2+si-NCAPD3 groups was significantly decreased(P 0.01). Moreover, IKK nucleation and NF-κB volume were suppressed upon siNCAPD2, si-NCAPD3 and si-NCAPD2+ si-NCAPD3 transfection.CONCLUSION NCAPD2/3 is highly expressed in the intestinal mucosa of patients with active UC. Overexpression of NCAPD2/3 promotes the release of pro-inflammatory cytokines by modulating the IKK/NF-κB signaling pathway.     

Is There Any Time Left for Primary Percutaneous Coronary Intervention According to the 2007 Updated American College of Cardiology/American Heart Association ST-Segment Elevation Myocardial Infarction Guidelines and the D2B Alliance?

Early reperfusion therapy is essential in the treatment of patients with ST-segment elevation myocardial infarction. Fibrinolytic therapy is a feasible reperfusion strategy to be initiated at any hospital and preferably in the pre-hospital phase. Primary percutaneous coronary intervention (PPCI) is acknowledged as a superior reperfusion strategy when initiated in a timely fashion. It is also the preferred reperfusion therapy in patients who exhibit cardiogenic shock and in patients with contraindications to fibrinolysis. However, in many regions, it is difficult to establish a successful PPCI strategy because it mandates optimal pre-hospital and in-hospital triage to ensure acceptable treatment delays. The 2007 updated American College of Cardiology/American Heart Association ST-Segment Elevation Myocardial Infarction Guidelines stress that "the focus for PPCI is from first medical contact because in regionalization strategies, extra time may be taken to transport patients to a center that performs the procedure" and that "time from Emergency Medical Services arrival to balloon inflation should be <90 minutes." When considering fibrinolysis, however, the guidelines accept a door-to-needle time of 30 min from arrival at the local hospital. Is there evidence to justify that, in the PPCI setting, the clock starts ticking upon the arrival of the Emergency Medical Services but, in the setting of in-hospital fibrinolysis, it does not start until a patient's arrival at the local hospital?