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91.
Andrea Cippitelli Jinhua Wu Kelly A Gaiolini Daniela Mercatelli Jennifer Schoch Michelle Gorman Alejandra Ramirez Roberto Ciccocioppo Taline V Khroyan Dennis Yasuda Nurulain T Zaveri Conrado Pascual Xinmin Xie Lawrence Toll 《British journal of pharmacology》2015,172(7):1834-1845
Background and Purpose
The α3β4 subtype of nicotinic acetylcholine receptors (nAChRs) has been implicated in mediating nicotine reinforcement processes. AT-1001 has been recently described as a high-affinity and selective α3β4 nAChR antagonist that blocks nicotine self-administration in rats. The aim of this study was to investigate the mechanism of action underlying the nicotine-suppressive effects of AT-1001.Experimental Approach
Effects of AT-1001 were determined using in vitro assays and rat models of nicotine addiction, and compared with varenicline.Key Results
AT-1001 and its analogue AT-1012 were functionally selective as antagonists for α3β4 over α4β2 nAChRs, but not to the same extent as the binding selectivity, and had partial agonist activity at α3β4 nAChRs. In contrast, varenicline was a partial agonist at α4β2, a weak agonist at α3β4 and inhibited α4β2 at a much lower concentration than it inhibited α3β4 nAChRs. AT-1001 and varenicline also had very different in vivo properties. Firstly, AT-1001 did not exhibit reinforcing properties per se while varenicline was self-administered. Secondly, systemic treatment with AT-1001 did not induce reinstatement of nicotine seeking but rather attenuated reinstatement induced by varenicline, as well as nicotine. Finally, unlike varenicline, AT-1001 selectively blocked nicotine self-administration without altering alcohol lever pressing as assessed in an operant co-administration paradigm.Conclusions and Implications
These findings describe a more complex AT-1001 in vitro profile than previously appreciated and provide further support for the potential of AT-1001 and congeners as clinically useful compounds for smoking cessation, with a mechanism of action distinct from currently available medications. 相似文献92.
Ultralow temperature cryoablation: Safety and efficacy of preclinical atrial and ventricular lesions
Felix Bourier MD Masateru Takigawa MD PhD Anna Lam MD Konstantinos Vlachos MD F. Daniel Ramirez MD MSc Claire A. Martin MD Antonio Frontera MD PhD Takeshi Kitamura MD Josselin Duchateau MD Thomas Pambrun MD Nicolas Derval MD Arnaud Denis MD Jerry Cox MD David Cabrita MD Alexander Babkin PhD Marion Constantin MA Pierre Jais MD Frédéric Sacher MD PhD Rémi Dubois MD PhD Oliver Bernus PhD Michel Haissaguerre MD Mélèze Hocini MD 《Journal of cardiovascular electrophysiology》2021,32(3):570-577
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Robin A. Aglietti Alberto Estevez Aaron Gupta Monica Gonzalez Ramirez Peter S. Liu Nobuhiko Kayagaki Claudio Ciferri Vishva M. Dixit Erin C. Dueber 《Proceedings of the National Academy of Sciences of the United States of America》2016,113(28):7858-7863
Gasdermin-D (GsdmD) is a critical mediator of innate immune defense because its cleavage by the inflammatory caspases 1, 4, 5, and 11 yields an N-terminal p30 fragment that induces pyroptosis, a death program important for the elimination of intracellular bacteria. Precisely how GsdmD p30 triggers pyroptosis has not been established. Here we show that human GsdmD p30 forms functional pores within membranes. When liberated from the corresponding C-terminal GsdmD p20 fragment in the presence of liposomes, GsdmD p30 localized to the lipid bilayer, whereas p20 remained in the aqueous environment. Within liposomes, p30 existed as higher-order oligomers and formed ring-like structures that were visualized by negative stain electron microscopy. These structures appeared within minutes of GsdmD cleavage and released Ca2+ from preloaded liposomes. Consistent with GsdmD p30 favoring association with membranes, p30 was only detected in the membrane-containing fraction of immortalized macrophages after caspase-11 activation by lipopolysaccharide. We found that the mouse I105N/human I104N mutation, which has been shown to prevent macrophage pyroptosis, attenuated both cell killing by p30 in a 293T transient overexpression system and membrane permeabilization in vitro, suggesting that the mutants are actually hypomorphs, but must be above certain concentration to exhibit activity. Collectively, our data suggest that GsdmD p30 kills cells by forming pores that compromise the integrity of the cell membrane.Pyroptosis is an inflammatory form of programmed cell death that occurs in response to microbial products in the cytoplasm or to cellular perturbations caused by diverse stimuli, including crystalline substances, toxins, and extracellular ATP (1, 2). Pyroptosis plays a critical role in the clearance of intracellular bacteria (3), but may also contribute to autoinflammatory and autoimmune disease pathology. Mechanistically, pyroptosis occurs when cytosolic nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs), including NLRP1, NLRP3, and NLRC4, or the pyrin domain-containing protein AIM2, nucleate a canonical inflammasome complex that activates the protease caspase-1 (2). Alternatively, intracellular lipopolysaccharide (LPS) from Gram-negative bacteria can trigger noncanonical activation of mouse caspase-11 and human caspases 4 and 5 (4–7). Caspases 1, 4, 5, and 11 can each cleave Gasdermin-D (GsdmD) to mediate pyroptotic cell death (8, 9). It is the N-terminal p30 fragment of GsdmD that is cytotoxic to cells, but precisely how it kills cells is unknown.Here we show that the human GsdmD p30 fragment liberated by active caspase-11 forms ring-like structures within membranes that function as pores. Therefore, we propose p30 kills cells by directly compromising the integrity of cellular membranes. We also show that the GsdmD I105N mutant that was unable to mediate macrophage pyroptosis (9) is hypomorphic at cell killing in a transient overexpression system and at liposome permeabilization in vitro—conditions where p30 concentration favors oligomerization. 相似文献
95.
Infection of human gastrointestinal cells by HIV-1 总被引:11,自引:0,他引:11
M P Moyer R I Huot A Ramirez S Joe M S Meltzer H E Gendelman 《AIDS research and human retroviruses》1990,6(12):1409-1415
Human immunodeficiency virus (HIV-1) infected and replicated in primary cultures of normal human ileal and colonic epithelial cells. Monocyte-tropic strains (ADA, 24, and 36) were better able to replicate in the gastrointestinal (GI) cells than the T-cell-tropic HIV strain HTLV-IIIB. In some cultures, virus replication persisted through several months. Intestinal epithelium may be an initial target and reservoir for HIV and a vector for virus dissemination and transmission. 相似文献
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97.
Ben Soussan E Antonietti M Hervé S Savoye G Ramirez S Lecleire S Ducrotté P Lerebours E 《Gastroentérologie clinique et biologique》2004,28(11):1068-1073
AIM: The main aim of this study was to evaluate efficacy and therapeutic impact of capsule endoscopy (CE) in obscure gastrointestinal bleeding (OGIB). In addition, we evaluated the software of automatic detection of red zones (SBI, Given Imaging). PATIENTS AND METHODS: From June 2002 to June 2003, thirty-five patients with OGIB underwent capsule endoscopy after negative upper and lower digestive endoscopy. Capsule endoscopy was performed following a 12-hour fasting period and some received 2 L of PEG the night before for bowel preparation. RESULTS: CE was performed for occult (N=18) or overt (N=17) OGIB. Potentially bleeding lesions were found in 16/35 patients (45.7%). Lesions were angiodysplasias (N=8), ulcerations (N=4), tumors (N=2) and active bleeding without visible lesion (N=2). Lesions were located in gastric antrum (N=1), duodenum (N=2) and jejuno-ileum (N=13). Endoscopic (N=10), surgical (N=2) or medical (N=1) treatments were performed in 13/35 (37%). SBI was retrospectively evaluated in 24 patients with sensitivity, specificity, positive and negative predictive value of respectively 45%, 73%, 50% and 69%. CE retention during 10 days occurred in a patient with a small bowel NSAID-induced stricture. CONCLUSION: CE is a safe and effective procedure in the management of OGIB and had a therapeutic impact in more than one third of patients. 相似文献
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99.
Outcomes of endoscopic treatment of gastroduodenal Dieulafoy's lesion with rubber band ligation and thermal/injection therapy 总被引:5,自引:0,他引:5
BACKGROUND: Dieulafoy's lesion is a rare but important cause of upper gastrointestinal bleeding. Current endoscopic methods used to treat Dieulafoy's lesion include injection, with or without thermal methods, and mechanical methods. The latter include variceal ligation and hemoclips. There are no studies comparing the outcomes of rubber band ligation and injection with or without thermal therapy. AIM: To report the outcomes of Dieulafoy's lesion treated endoscopically with rubber band ligation and injection with or without thermal therapy at a single institution. METHODS: Patients with the diagnosis of Dieulafoy's lesion treated endoscopically at the Carl T. Hayden VA Medical Center in Phoenix, between August 1994 and August 2002 were analyzed. Demographic data, mode of presentation, risk factors for gastrointestinal bleeding, hemodynamic parameters, blood transfusion requirements, endoscopic findings, details of endoscopic therapy, length of stay in ICU/hospital, complications, recurrence of bleeding, and mortality rates were collected and compared between those receiving endoscopic band ligation (EBL group) and those receiving injection with or without thermal therapy (non-EBL group). RESULTS: Twenty-three patients with Dieulafoy's lesion (14 in the EBL group and nine in the non-EBL group) were studied. All patients were men. The mean age, hemoglobin levels on admission, and the transfusion requirements before therapy were similar in both groups. Fourteen patients (eight in the EBL- and six in the non-EBL groups) presented with hematemesis and the remaining with melena. The majority of Dieulafoy's lesions (91.3%) were located in the stomach and two in the duodenum. Active bleeding at the time of endoscopy was seen in 61% of cases, and immediate hemostasis was achieved with either method in 100% of patients. Early rebleeding (within 72 hours of endoscopic therapy) occurred in only one patient treated with epinephrine plus heater probe therapy. The length of stay in ICU was longer in the non-EBL group (6.7 days) compared with the EBL group (1.8 days) (P = 0.2). There were six deaths (three in the non-EBL group and three in the EBL group) within 30 days of the index hospitalization. The causes of death included infection/sepsis (n = 3), complications of acute myocardial infarction (n = 2), and end-stage liver disease (n = 1). CONCLUSIONS: Endoscopic rubber band ligation is as effective as injection with or without thermal therapy in the treatment of Dieulafoy's lesion. 相似文献
100.