These data provide the first evidence, to our knowledge, of an important role of the vagus nerve in regulating the innate immune response to a severe bacterial infection.

genesis of HE. [2][3][4][5][6][7] Moreover, elevated brain glutamine concenThe aim of this study was to investigate the possible trations can induce cell swelling, resulting in brain edema, 8,9 role of N-methyl-D-aspartate (NMDA)-receptor overaca terminal event in patients with fulminant hepatic failure. creased CSF glutamate and aspartate concentrations This study was designed to investigate the role of NMDAand increased ICP and brain water content. Memantine receptor activity in hyperammonemia-induced encephalopaadministration in AI-PCS and LIS rats resulted in a sigthy and liver ischemia-induced HE, two experimental rat nificant improvement in clinical grading and less slowmodels that both are associated with intracranial hypertening of EEG activity (P õ .05), and smaller increases in sion. Therefore, the noncompetitive NMDA-receptor antago-CSF glutamate (P õ .05) concentrations. Moreover, ICP nist memantine 21-24 was administered to portacaval-shunted and brain water content were significantly lower in (PCS) rats with an ammonium-acetate infusion and to rats memantine-treated AI-PCS rats than in untreated AIwith complete liver ischemia. The severity of encephalopathy PCS rats (P õ .05). Memantine had no significant effect was quantified by clinical grading and electroencephalogram on ICP and brain water content in LIS rats, and on am-(EEG) spectral analysis. Plasma concentrations of ammonia monia concentrations in both models. These results indiand memantine, and CSF concentrations of amino acids, were cate that NMDA-receptor activation might be involved assessed. Intracranial pressure was measured with a presin the pathogenesis of hyperammonemia-induced ensure transducer connected to a cisterna magna cannula, and, cephalopathy and of acute hepatic encephalopathy in addition, brain water content was assessed at the end of caused by LIS. (HEPATOLOGY 1997;25:820-827.) the experiment.

Idiopathic pulmonary fibrosis constitutes the most devastating form of fibrotic lung disorders and remains refractory to current therapies. The coagulation cascade is frequently activated during pulmonary fibrosis, but this observation has so far resisted a mechanistic explanation. Recent data suggest that protease-activated receptor (PAR)-2, a receptor activated by (among others) coagulation factor (F)Xa, plays a key role in fibrotic disease; consequently, we assessed the role of PAR-2 in the development of pulmonary fibrosis in this study. We show that PAR-2 is up-regulated in the lungs of patients with idiopathic pulmonary fibrosis and that bronchoalveolar lavage fluid from these patients displays increased procoagulant activity that triggers fibroblast survival. Using a bleomycin model of pulmonary fibrosis, we show that bleomycin induces PAR-2 expression, as well as both myofibroblast differentiation and collagen synthesis. In PAR-2؊/؊ mice, both the extent and severity of fibrotic lesions are reduced, whereas myofibroblast differentiation is diminished and collagen expression is decreased. Moreover, fibrin deposition in the lungs of fibrotic PAR-2؊/؊ mice is reduced compared with wild-type mice due to differential tissue factor expression in response to bleomycin. Taken together , these results suggest an important role for PAR-2 in the development of pulmonary fibrosis , and the inhibition of the PAR-2-coagulation axis may provide a novel therapeutic approach to treat this devastating disease.

Betulinic acid (BetA) is a plant-derived pentacyclic triterpenoid with potent anticancer capacity that targets the mitochondrial pathway of apoptosis. BetA has a broad efficacy in vitro against prevalent cancer types, including lung, colorectal, prostate, cervix and breast cancer, melanomas, neuroblastomas, and leukemias. The cytotoxic effects of the compound against healthy cells are minimal, rendering BetA a promising potential anticancer drug. However, because of the weak hydrosolubility of BetA, it has been difficult to study its efficacy in vivo and a pharmaceutical formulation is not yet available. We report the development of a liposome formulation of BetA and show its successful application in mice. Large liposomes, assembled without cholesterol to reduce their rigidity, efficiently incorporated BetA. Nude mice xenografted with human colon and lung cancer tumors were treated intravenously with the BetA-containing liposomes. Tumor growth was reduced to more than 50% compared with the control treatment, leading to an enhanced survival of the mice. Oral administration of the liposomal formulation of BetA also slowed tumor growth. Any signs of systemic toxicity caused by BetA treatment were absent. Thus, liposomes are an efficient formulation vehicle for BetA, enabling its preclinical development as a nontoxic compound for the treatment of cancers.

Glioblastoma multiforme (GBM) is a devastating disease with high mortality and poor prognosis. Cancer stem cells (CSCs) have recently been defined as a fraction of tumor cells highly resistant to therapy and subsequently considered to be responsible for tumor recurrence. These cells have been characterized in GBM and suggested to reside in and be supported by the tumor microvascular niche. Here we evaluated the response of tumor microvascular endothelial cells (tMVECs) to radio- and chemotherapy, and analyzed how this affects their interaction with CSCs. Our data demonstrate that tMVECs exhibit extreme resistance to both therapies, with the main response to irradiation being senescence. Importantly, senescent tMVECs can be detected in human GBM samples as well as in mice upon irradiation. Even though permanently arrested, they are still viable and able to support CSC growth with the same efficacy as non-senescent tMVECs. Intriguingly, GBM CSCs themselves are capable of differentiating into cells with similar features as tMVECs that subsequently undergo senescence when exposed to radiation. This indicates that endothelial-like cells are therapy resistant and, more importantly, support expansion of GBM cells.