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221.
Eun-Hye Lee Soon-Seok Hong So Hee Kim Mi-Kyung Lee Joon Seok Lim Soo-Jeong Lim 《Pharmaceutical research》2014,31(8):2022-2034
Purpose
In an effort to apply the imaging techniques currently used in disease diagnosis for monitoring the pharmacokinetics and biodisposition of particulate drug carriers, we sought to use computed tomography (CT) scanning methodology to investigate the impact of surfactant on the blood residence time of emulsions.Methods
We prepared the iodinated oil Lipiodol emulsions with different compositions of surfactants and investigated the impact of surfactant on the blood residence time of emulsions by CT scanning.Results
The blood circulation time of emulsions was prolonged by including Tween 80 or DSPE-PEG (polyethylene glycol 2000) in emulsions. Tween 80 was less effective than DSPE-PEG in terms of prolongation effect, but the blood circulating time of emulsions was prolonged in a Tween 80 content-dependent manner. As a proof-of-concept demonstration of the usefulness of CT-guided screening in the process of formulating drugs that need to be loaded in emulsions, paclitaxel was loaded in emulsions prepared with 87 or 65% Tween 80–containing surfactant mixtures. A pharmacokinetics study showed that paclitaxel loaded in 87% Tween 80 emulsions circulated longer in the bloodstream compared to those in 65% Tween 80 emulsions, as predicted by CT imaging.Conclusions
CT-visible, Lipiodol emulsions enabled the simple evaluation of surfactant composition effects on the biodisposition of emulsions. 相似文献222.
Various studies have been conducted to better understand the long-term corrosion mechanism for steels in a soil environment. Here, electrochemical acceleration methods present the most efficient way to simulate long-term corrosion. Among the various methods, galvanostatic testing allows for accelerating the surface corrosion reactions through controlling the impressed anodic current density. However, a large deviation from the equilibrium state can induce different corrosion mechanisms to those in actual service. Therefore, applying a suitable anodic current density is important for shortening the test times and maintaining the stable dissolution of steel. In this paper, to calibrate the anodic current density, galvanostatic tests were performed at four different levels of anodic current density and time to accelerate a one-year corrosion reaction of pipeline steel. To validate the appropriate anodic current density, analysis of the potential vs. time curves, thermodynamic analysis, and analysis of the specimen’s cross-sections and products were conducted using a validation algorithm. The results indicated that 0.96 mA/cm2 was the optimal impressed anodic current density in terms of a suitable polarized potential, uniform corrosion, and a valid corrosion product among the evaluated conditions. 相似文献
223.
Xiaolong Yang Lidong Liu Yawei Hao Eva So Sahar Sarmasti Emami Derek Zhang Yanping Gong Prameet M. Sheth Yutian Wang 《Viruses》2021,13(6)
The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is currently spreading and mutating with increasing speed worldwide. Therefore, there is an urgent need for a simple, sensitive, and high-throughput (HTP) assay to quantify virus–host interactions in order to quickly evaluate the infectious ability of mutant viruses and to develop or validate virus-inhibiting drugs. Here, we developed an ultrasensitive bioluminescent biosensor to evaluate virus–cell interactions by quantifying the interaction between the SARS-CoV-2 receptor binding domain (RBD) and its cellular receptor angiotensin-converting enzyme 2 (ACE2) both in living cells and in vitro. We have successfully used this novel biosensor to analyze SARS-CoV-2 RBD mutants and evaluated candidate small molecules (SMs), antibodies, and peptides that may block RBD:ACE2 interaction. This simple, rapid, and HTP biosensor tool will significantly expedite the detection of viral mutants and the anti-COVID-19 drug discovery process. 相似文献
224.
Han Sol Kang So Hyeon Bak Ha Yeun Oh Myoung-Nam Lim Yoon Ki Cha Hyun Jung Yoon Woo Jin Kim 《Journal of thoracic disease》2021,13(3):1495
BackgroundChronic obstructive pulmonary disease (COPD) has variable subtypes involving mixture of large airway inflammation, small airway disease, and emphysema. This study evaluated the relationship between visually assessed computed tomography (CT) subtypes and clinical/imaging characteristics.MethodsIn total, 452 participants were enrolled in this study between 2012 and 2017. Seven subtypes were defined by visual evaluation of CT images using Fleischner Society classification: normal, paraseptal emphysema (PSE), bronchial disease, and centrilobular emphysema (trace, mild, moderate and confluent/advanced destructive). The differences in several variables, including clinical, laboratory, spirometric, and quantitative CT features among CT-based visual subtypes, were compared using the chi-square tests and one-way analysis of variance.ResultsSubjects who had PSE had better forced expiratory volume in 1 second (FEV1) (P=0.03) percentage and higher lung density (P<0.05) than those with moderate to confluent/advanced destructive centrilobular emphysema. As the visual grade of centrilobular emphysema worsened, pulmonary function declined and modified Medical Research Council, COPD assessment test (CAT) score, and quantitative assessment (emphysema index and air trapping) increased. The bronchial subtype was associated with higher body mass index (BMI), better lung function and higher lung density. Participants with trace emphysema showed a rapid increase in functional small airway diseaseConclusionsClassifying subtypes using visual CT imaging features can reflect heterogeneity and pathological processes of COPD. 相似文献
225.
Rotenone, an inhibitor of mitochondrial complex I of the mitochondrial respiratory chain, is known to elevate mitochondrial reactive oxygen species and induce apoptosis via activation of the caspase-3 pathway. Bee venom (BV) extracted from honey bees has been widely used in oriental medicine and contains melittin, apamin, adolapin, mast cell-degranulating peptide, and phospholipase A2. In this study, we tested the effects of BV on neuronal cell death by examining rotenone-induced mitochondrial dysfunction. NSC34 motor neuron cells were pretreated with 2.5 μg/mL BV and stimulated with 10 μM rotenone to induce cell toxicity. We assessed cell death by Western blotting using specific antibodies, such as phospho-ERK1/2, phospho-JNK, and cleaved capase-3 and performed an MTT assay for evaluation of cell death and mitochondria staining. Pretreatment with 2.5 μg/mL BV had a neuroprotective effect against 10 μM rotenone-induced cell death in NSC34 motor neuron cells. Pre-treatment with BV significantly enhanced cell viability and ameliorated mitochondrial impairment in rotenone-treated cellular model. Moreover, BV treatment inhibited the activation of JNK signaling and cleaved caspase-3 related to cell death and increased ERK phosphorylation involved in cell survival in rotenone-treated NSC34 motor neuron cells. Taken together, we suggest that BV treatment can be useful for protection of neurons against oxidative stress or neurotoxin-induced cell death. 相似文献
226.
227.
Single pilus motor forces exceed 100 pN 总被引:27,自引:0,他引:27
Maier B Potter L So M Long CD Seifert HS Sheetz MP 《Proceedings of the National Academy of Sciences of the United States of America》2002,99(25):16012-16017
Force production by type IV pilus retraction is critical for infectivity of Neisseria gonorrhoeae and DNA transfer. We investigated the roles of pilus number and the retraction motor, PilT, in force generation in vivo at the single-molecule level and found that individual retraction events are generated by a single pilus fiber, and only one PilT complex powers retraction. Retraction velocity is constant at low forces but decreases at forces greater than 40 pN, giving a remarkably high average stall force of 110 +/- 30 pN. Further insights into the molecular mechanism of force generation are gained from the effect of ATP-depletion, which reduces the rate of retraction but not the stall force. Energetic considerations suggest that more than one ATP is involved in the removal of a single pilin subunit from a pilus. The results are most consistent with a model in which the ATPase PilT forms an oligomer that disassembles the pilus by a cooperative conformational change. 相似文献
228.
Qinglan Wang So Yeon Kim Hiroshi Matsushita Zhijun Wang Vijay Pandyarajan Michitaka Matsuda Koichiro Ohashi Takashi Tsuchiya Yoon Seok Roh Calvin Kiani Yutong Zhao Michael Chan Suzanne Devkota Shelly C. Lu Tomoko Hayashi Dennis A. Carson Ekihiro Seki 《Proceedings of the National Academy of Sciences of the United States of America》2021,118(1)
Effective therapies for alcohol-associated liver disease (ALD) are limited; therefore, the discovery of new therapeutic agents is greatly warranted. Toll-like receptor 7 (TLR7) is a pattern recognition receptor for single-stranded RNA, and its activation prevents liver fibrosis. We examined liver and intestinal damage in Tlr7−/− mice to determine the role of TLR7 in ALD pathogenesis. In an alcoholic hepatitis (AH) mouse model, hepatic steatosis, injury, and inflammation were induced by chronic binge ethanol feeding in mice, and Tlr7 deficiency exacerbated these effects. Because these results demonstrated that endogenous TLR7 signaling activation is protective in the AH mouse model, we hypothesized that TLR7 activation may be an effective therapeutic strategy for ALD. Therefore, we investigated the therapeutic effect of TLR7 agonistic agent, 1Z1, in the AH mouse model. Oral administration of 1Z1 was well tolerated and prevented intestinal barrier disruption and bacterial translocation, which thus suppressed ethanol-induced hepatic injury, steatosis, and inflammation. Furthermore, 1Z1 treatment up-regulated the expression of antimicrobial peptides, Reg3b and Reg3g, in the intestinal epithelium, which modulated the microbiome by decreasing and increasing the amount of Bacteroides and Lactobacillus, respectively. Additionally, 1Z1 up-regulated intestinal interleukin (IL)-22 expression. IL-22 deficiency abolished the protective effects of 1Z1 in ethanol-induced liver and intestinal damage, suggesting intestinal IL-22 as a crucial mediator for 1Z1-mediated protection in the AH mouse model. Collectively, our results indicate that TLR7 signaling exerts protective effects in the AH mouse model and that a TLR7 ligand, 1Z1, holds therapeutic potential for the treatment of AH.Alcohol-associated liver disease (ALD) is caused by chronic and excessive consumption of alcohol. The disease ranges from alcohol-associated fatty liver to alcoholic hepatitis (AH), fibrosis, cirrhosis, and hepatocellular carcinoma (HCC) (1). Alcohol-associated fatty liver is considered reversible and nonprogressive. Nearly 35% of heavy alcohol drinkers develop AH, and up to 40% of severe AH patients die within 6 mo (2). AH patients who survive may progress to alcohol-associated cirrhosis. Treatment options for AH involve the use of corticosteroids and have remained largely unchanged since the early 1970s. Unfortunately, not all patients respond to corticosteroids, and the benefits are temporary in responders (1, 2). Early liver transplant has been shown to be superior to medical management for severe AH, but it still has limitations and can only be considered in a highly selective group of patients (1, 2). Thus, the identification of a better molecular therapeutic target for ALD is a significantly unmet medical need for the development of effective therapies for AH.Previous studies have demonstrated the involvement of Toll-like receptors (TLRs), including TLR2, TLR4, and TLR9, in the development of ALD (3–8). In addition to the direct effect of alcohol and its metabolite, acetaldehyde, in hepatocytes, ethanol intake affects the function of the intestinal epithelial barrier. Chronic alcohol consumption disrupts intestinal tight junction integrity and increases gut permeability, resulting in elevated bacterial lipopolysaccharide (LPS) concentrations in the portal and systemic circulation (4). Translocated LPS activates resident hepatic macrophages, known as Kupffer cells, via TLR4, thereby promoting ALD (1, 2, 7, 8). Other TLRs, such as TLR2 and TLR9, recognize gram-positive bacterial components and bacterial CpG-DNA, respectively (3, 4). Furthermore, TLR2, TLR9, and MyD88 are required for the development of the preclinical AH murine model (5), whereas TLR4 and TLR9 exert protective effects against intestinal inflammation (9, 10).TLR7 signaling has been shown to be protective against liver fibrosis in mice (11). Tlr7−/− mice exhibit augmented cholestasis and carbon tetrachloride (CCl4)-induced liver fibrosis (11). TLR7 signaling also induces IFN-α production in dendritic cells (DCs), followed by interleukin (IL)-1 receptor antagonist (IL-1Ra) induction in Kupffer cells. IL-1Ra suppresses IL-1-induced hepatic stellate cell (HSC) activation, resulting in inhibition of liver fibrosis (11). Among the TLRs, TLR3 and TLR7 activation has been reported to ameliorate some liver diseases (11, 12). However, a major disadvantage of the currently available synthetic ligands for TLR3 and TLR7, such as poly I:C, imiquimod, and R848, is the excessive induction of proinflammatory cytokines (3, 4). Thus, developing agents without undesirable adverse effects is of great clinical interest.IL-22 is a hepatoprotective cytokine produced by T helper (Th) 17 cells, Th22 cells, γδ T cells, natural killer (NK) T cells, and innate lymphoid cells (ILCs) (13). Exogenous administration of IL-22 has a profound effect on tissue repair following liver injury via the promotion of proliferation and inhibition of apoptosis in hepatocytes of mouse models of AH (14), liver fibrosis, and drug- and LPS-induced liver injury. Also, IL-22 promotes tissue repair in the intestines and is protective against intestinal epithelial damage and inflammation (13). These findings suggest that IL-22 may suppress ALD via the maintenance of intestinal barrier function, thereby preventing increased intestinal permeability and bacterial translocation due to intestine-derived microbial products that promote ethanol-induced liver injury (15, 16).Here, we have developed a synthetic TLR7 ligand, 1Z1, that possesses antiinflammatory effects via IL-22 induction and that is devoid of systemic toxicity after oral administration (17–19). Treatment with 1Z1 has already been reported to be effective for allergic encephalomyelitis, arthritis, dextran sodium sulfate (DSS)-induced colitis, and type I diabetes in mice (17–20). We hypothesize that targeting TLR7 activation may be an effective treatment strategy for ALD. Our experimental results demonstrate that 1Z1 oral administration inhibits ethanol-induced liver and intestinal damage and that these beneficial effects are due to intestinal IL-22 induction in an AH murine model. 相似文献
229.
Roles of pilin and PilC in adhesion of Neisseria meningitidis to human epithelial and endothelial cells. 总被引:18,自引:0,他引:18
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X Nassif J L Beretti J Lowy P Stenberg P O''Gaora J Pfeifer S Normark M So 《Proceedings of the National Academy of Sciences of the United States of America》1994,91(9):3769-3773
Pili and pilin antigenic variation play important roles in adhesion of Neisseria meningitidis (MC) to human epithelial and endothelial cells. We recently identified one pilin variant that confers high adhesiveness of MC to human epithelial cells in culture. However, other factor(s) also play a role in MC adhesiveness, since some nonadhesive variants of MC strain 8013 are piliated and produce the same pilin variant as adhesive derivatives. PilC1 and PilC2, high molecular weight outer membrane proteins in Neisseria gonorrhoeae, are proposed to play roles in pilus assembly. Strain 8013 also contains pilC1 and pilC2; their products function in a similar if not identical manner in pilus biogenesis. PilC1 has an additional function in that it also modulates adhesiveness of strain 8013. 相似文献
230.
S Y So P Y Chau B M Jones P C Wu K K Pun W K Lam J W Lawton 《The American review of respiratory disease》1985,131(4):662-665
A 53-yr-old Chinese sailor developed prolonged pyrexia with unresolved lobar pneumonia, cervical lymphadenopathy, generalized subcutaneous abscesses, and pericardial effusion. Penicillium marneffei was isolated from pericardial fluid and subcutaneous pus and was demonstrated on histologic sections of lymph nodes and lung tissue. The penicilliosis was treated successfully with amphotericin B, ketoconazole, and 5-fluorocytosine. Subsequently, he also developed other T-lymphocyte-related opportunistic infections such as disseminated cutaneous herpes zoster and chronic osteomyelitis of sternum caused by Salmonella typhimurium. He was also a chronic carrier of cytomegalovirus. Further investigations showed that he had persistent depression of T-lymphocyte function and enhancement of B-lymphocyte activity, the cause of which was undetermined. 相似文献