BACKGROUND AND PURPOSE:Although intracranial atherosclerotic disease is often encountered during endovascular treatment for acute vertebrobasilar occlusions, its clinical implication is not well-known. We aimed to evaluate whether intracranial atherosclerotic disease influences the clinical outcomes following endovascular treatment of acute vertebrobasilar occlusive stroke.

Palliative care improves cancer, CHF, COPD, and dementia outcomes. Effective models include nurses, social workers, and home-based components, and a focus on communication, psychosocial support, and the patient or caregiver experience. High-quality research on intervention costs and cost outcomes in palliative care is limited.

Reactive oxygen species (ROS) have been closely associated with both apoptotic and non-apoptotic/necrotic cell death. Our previous study has illustrated that c-Jun-N-terminal kinase 1 (JNK1) is the main executor in hydrogen peroxide (H 2 O 2 )-induced nonapoptotic cell death. The main objective of this study is to further elucidate the molecular mechanisms downstream of JNK1 in H 2 O 2 -induced cell death. In this study, poly(ADP-ribose) polymerase-1 (PARP-1), a key DNA repair protein, was readily activated by H 2 O 2 and inhibition of PARP-1 activation by either a pharmacological or genetic approach offered significant protection against H 2 O 2 -induced cell death. More importantly, H 2 O 2 -mediated PARP-1 activation is subject to regulation by JNK1. Suppression of JNK1 activation by a chemical inhibitor or genetic deletion markedly suppressed the late-phase PARP-1 activation induced by H 2 O 2 , suggesting that JNK1 contributes to the sustained activation of PARP-1. Such findings were supported by the temporal pattern of nuclear translocation of activated JNK and a direct protein-protein interaction between JNK1 and PARP-1 in H 2 O 2 -treated cells. Finally, in vitro kinase assay suggests that PARP-1 may serve as the direct phosphorylation target for JNK1. Taken together, data from our study reveal a novel underlying mechanism in H 2 O 2 -induced nonapoptotic cell death: JNK1 promotes a sustained PARP-1 activation via nuclear translocation, protein-protein interaction and PARP-1 phosphorylation.

β-Lapachone activates multiple cell death mechanisms including apoptosis, autophagy and necrotic cell death in cancer cells. In this study, we investigated β-lapachone-induced cell death and the underlying mechanisms in human hepatocellular carcinoma SK-Hep1 cells. β-Lapachone markedly induced cell death without caspase activation. β-Lapachone increased PI uptake and HMGB-1 release to extracellular space, which are markers of necrotic cell death. Necrostatin-1 (a RIP1 kinase inhibitor) markedly inhibited β-lapachone-induced cell death and HMGB-1 release. In addition, β-lapachone activated poly (ADP-ribosyl) polymerase-1(PARP-1) and promoted AIF release, and DPQ (a PARP-1 specific inhibitor) or AIF siRNA blocked β-lapachone-induced cell death. Furthermore, necrostatin-1 blocked PARP-1 activation and cytosolic AIF translocation. We also found that β-lapachone-induced reactive oxygen species (ROS) production has an important role in the activation of the RIP1-PARP1-AIF pathway. Finally, β-lapachone-induced cell death was inhibited by dicoumarol (a NQO-1 inhibitor), and NQO1 expression was correlated with sensitivity to β-lapachone. Taken together, our results demonstrate that β-lapachone induces programmed necrosis through the NQO1-dependent ROS-mediated RIP1-PARP1-AIF pathway.

OBJECTIVE:To investigate how and to what extent platycodin saponin (PS) from Platycodi Radix exerts a favorable influence on obesity and hyperlipidemia. DESIGN: Sprague-Dawley rats were fed with a high fat (HF) diet for 4 weeks and then the animals were treated with 35 or 70 mg/kg of PS for another 4 weeks. Changes in body weight and daily calorie intake were measured regularly during the experimental period and the degree of linear correlation for the above two variables was further analyzed. The in vitro lipase inhibition of each PS compound and the in vivo fecal lipid excretion were examined in hope of revealing their relationship. The concentrations of hepatic triglyceride and cholesterol in serum. RESULTS: The body weight reduction (1374% vs HF control, Po0.05) by PS administration was highly correlated to the food intake restriction (Pearson's linear coefficient r ¼ 0.752, Po0.005). The in vitro inhibition of lipase by each isolated compound and mixture of PS were virtually identical. Consequently, the fecal TG excretion was increased by 2.1-3.2 folds depending on the dose of PS. The serum TG and LDL-cholesterol concentrations were decreased without noticeable changes in HDLcholesterol levels. Concomitantly, the contents of the hepatic TG, cholesterol, and the liver surface fat pads were decreased in ubiquity, but no noticeable biochemical abnormalities or histological tissue damages were observed. CONCLUSIONS: The administration of PS produced profound effects on the control of obesity and lipid metabolism, which resulted in LDL-cholesterol reduction. PS also caused a remarkable reduction in calorie intake, which was highly correlated to the body weight loss. These results suggest that PS has a greater role in antiobesity, hypolipidemia, and liver protection than previously thought. Hence, PS could be a potential therapeutic alternative in the treatment of obesity and hyperlipidemia.

No abstract

Pancreatic ductal adenocarcinoma (PDAC) cells usually overexpress the epidermal growth factor receptor (EGFR); however, most are resistant to the anti-EGFR monoclonal antibody, cetuximab. In this study, we report that the molecular mechanism of resistance to cetuximab in PDAC cells is mediated by the overexpression of active integrin β1 with downstream Src-Akt activation; this triggers an EGFR ligand-independent proliferation signaling, bypassing EGFR-blocking effect. Knockdown of integrin β1 or inhibition of Src or Akt sensitized cetuximab-resistant (Ctx) PDAC cells to cetuximab. We found that neuropilin-1 (NRP1) physically interacts with active integrin β1, but not inactive one, on the cell surface. To inhibit active integrin β1-driven signaling by targeting NRP1, while suppressing EGFR signaling, we generated an EGFR and NRP1 dual targeting antibody, Ctx-TPP11, by genetic fusion of the NRP1-targeting peptide, TPP11, to the C terminus of the cetuximab heavy chain (Ctx-TPP11). We demonstrate that Ctx-TPP11 efficiently inhibited the growth of Ctx PDAC cells, in vitro and in vivo. The sensitization mechanism involved downregulating active integrin β1 levels through NRP1-coupled internalization mediated by the TPP11 moiety, leading to the inhibition of active integrin β1-driven bypass signaling. Our findings identify aberrant active integrin β1-driven Src-Akt hyperactivation as a primary resistance mechanism to cetuximab in PDAC cells and offer an effective therapeutic strategy to overcome this resistance using an EGFR and NRP1 dual targeting antibody.

The mammalian target of rapamycin (mTOR) is a highly conserved serine-threonine kinase activated in response to growth factors and nutrients. Because of frequent dysregulation of the mTOR signaling pathway in diverse human cancers, this kinase is a key therapeutic target. Redd1 is a negative regulator of mTOR, mediating dissociation of 14-3-3 from tuberous sclerosis complex (TSC)2, which allows formation of a TSC-TSC2 complex. In the present study, we identify TXNIP that inhibits mTOR activity by binding to and stabilizing Redd1 protein. Redd1 and TXNIP expression was induced by a synthetic glucose analog, 2-deoxyglucose (2-DG). Moreover, Redd1 expression in response to 2-DG was regulated by activating transcription factor 4 (ATF4). Overexpression of TXNIP was associated with reduced mTOR activity mediated by an increase in Redd1 level, whereas knockdown of TXNIP using small interfering RNA resulted in recovery of mTOR activity via downregulation of Redd1 during treatment with 2-DG. Interestingly, Redd1 was additionally stabilized via interactions with N-terminaltruncated TXNIP, leading to suppression of mTOR activity. Our results collectively demonstrate that TXNIP stabilizes Redd1 protein induced by ATF4 in response to 2-DG, resulting in potentiation of mTOR suppression. To the best of our knowledge, this is the first study to identify TXNIP as a novel member of the mTOR upstream that acts as a negative regulator in response to stress signals.