A Multicenter, Randomized, Controlled Trial of Prednisone Combined with Ursodeoxycholic Acid in the Treatment of Primary Biliary Cholangitis with Moderate to Severe Interface Hepatitis Characteristics

About 1/3 of patients with primary biliary cholangitis (PBC) exhibit moderate to severe interface hepatitis, and this group of patients have poor response to UDCA treatment. However, as it is not yet sufficient to diagnose autoimmune hepatitis or overlap syndrome, it is difficult to initiate immunosuppressive therapy such as steroids according to current guidelines. The aim of this study is to explore whether PBC patients with moderate to severe interfacial inflammation can benefit from UDCA combined with prednisone therapy, and its treatment safety.

开始日期2024-09-15

申办/合作机构

西京医院第四军医大学

CTIS2023-505862-27-00 / Recruiting

- NUT-018/BIO

开始日期2023-10-10

申办/合作机构

Dr. Falk Pharma GmbH

100 项与 Cholesterol x Lipid 相关的临床结果

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100 项与 Cholesterol x Lipid 相关的转化医学

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0 项与 Cholesterol x Lipid 相关的专利（医药）

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项与 Cholesterol x Lipid 相关的文献（医药）

2025-01-01·Colloids and Surfaces B: Biointerfaces

Oxidation of lipid membrane cholesterol by cholesterol oxidase and its effects on raft model membrane structure

Article

作者: Zaborowska-Mazurkiewicz, Michalina ; Matyszewska, Dorota ; Fontaine, Philippe ; Bizoń, Teresa ; Bilewicz, Renata

The effects of a peripheral protein - cholesterol oxidase (3β-hydroxysteroid oxidase, ChOx) on the characteristics of model lipid membranes composed of cholesterol, cholesterol:sphingomyelin (1:1), and the raft model composed of DOPC:Chol:SM (1:1:1) were investigated using two membrane model systems: the flat monolayer prepared by the Langmuir technique and the curved model consisting of liposome of the same lipids. The planar monolayers and liposomes were employed to follow membrane cholesterol oxidation to cholestenone catalyzed by ChOx and changes in the lipid membrane structure accompanying this reaction. Changes in the structure of liposomes in the presence of the enzyme were reflected in the changes of hydrodynamic diameter and fluorescence microscopy images, while changes of surface properties of planar membranes were evaluated by grazing incidence X-ray diffraction (GIXD) and Brewster angle microscopy. UV-Vis absorbance measurements confirmed the activity of the enzyme in the tested systems. A better understanding of the interactions between the enzyme and the cell membrane may help in finding alternative ways to decrease excessive cholesterol levels than the common approach of treating hypercholesterolemia with statins, which are not free from undesirable side effects, repeatedly reported in the literature and observed by the patients.

2024-12-01·Cellular and Molecular Life Sciences

Alpha-hemolysin promotes internalization of Staphylococcus aureus into human lung epithelial cells via caveolin-1- and cholesterol-rich lipid rafts

Article

作者: Rohde, Manfred ; Lang, Julia C ; May, Tobias ; Lang, Julia C. ; Molinari, Gabriella ; Goldmann, Oliver ; Medina, Eva

AbstractStaphylococcus aureus is a pathogen associated with severe respiratory infections. The ability of S. aureus to internalize into lung epithelial cells complicates the treatment of respiratory infections caused by this bacterium. In the intracellular environment, S. aureus can avoid elimination by the immune system and the action of circulating antibiotics. Consequently, interfering with S. aureus internalization may represent a promising adjunctive therapeutic strategy to enhance the efficacy of conventional treatments. Here, we investigated the host-pathogen molecular interactions involved in S. aureus internalization into human lung epithelial cells. Lipid raft-mediated endocytosis was identified as the main entry mechanism. Thus, bacterial internalization was significantly reduced after the disruption of lipid rafts with methyl-β-cyclodextrin. Confocal microscopy confirmed the colocalization of S. aureus with lipid raft markers such as ganglioside GM1 and caveolin-1. Adhesion of S. aureus to α5β1 integrin on lung epithelial cells via fibronectin-binding proteins (FnBPs) was a prerequisite for bacterial internalization. A mutant S. aureus strain deficient in the expression of alpha-hemolysin (Hla) was significantly impaired in its capacity to enter lung epithelial cells despite retaining its capacity to adhere. This suggests a direct involvement of Hla in the bacterial internalization process. Among the receptors for Hla located in lipid rafts, caveolin-1 was essential for S. aureus internalization, whereas ADAM10 was dispensable for this process. In conclusion, this study supports a significant role of lipid rafts in S. aureus internalization into human lung epithelial cells and highlights the interaction between bacterial Hla and host caveolin-1 as crucial for the internalization process.

2024-11-21·Journal of Biomolecular Structure and Dynamics

Changes in free energy barrier for water permeation by stretch-induced phase transitions in phospholipid/cholesterol bilayers

Article

作者: Shigematsu, Taiki ; Koshiyama, Kenichiro

Water permeation through phospholipid/cholesterol bilayers is the key to understanding tension-induced rupture of biological cell membranes. We performed molecular dynamics simulations of stretched phospholipid/cholesterol bilayers to investigate changes in the free energy profile of water molecules across the bilayer and the lipid structure responsible for water permeation. We modeled stretching of the bilayer by applying areal strain. In stretched phospholipid/cholesterol bilayers, the hydrophobic tail of the phospholipids became disordered and the free energy barrier to water permeation decreased. Upon exceeding the critical areal strain, a phase transition to an interdigitated gel phase occurred before rupture, and the hydrophobic tail ordering as well as the free energy barrier were restored. In pure phospholipid bilayers, we did not observe such recoveries. These transient recoveries in the phospholipid/cholesterol bilayer suppressed water permeation and membrane rupture, followed by an increase in the critical areal strain at which the bilayer ruptured. This result agrees with experimental results and provides a reasonable molecular mechanism for the toughness of phospholipid/cholesterol bilayers under tension.Communicated by Ramaswamy H. Sarma.

项与 Cholesterol x Lipid 相关的新闻（医药）

2024-08-29

·BioSpace

Novartis Plots Leqvio Expansion After Lowering Cholesterol in Phase III Study

Novartis’ office building in Marburg, Germany iStock, TBE Armed with new late-stage data on reducing low-density lipoprotein cholesterol, Novartis is positioning its siRNA therapy Leqvio as a preventive treatment for atherosclerotic cardiovascular disease. Novartis on Wednesday released topline findings from the Phase III V-MONO study, demonstrating that its siRNA therapy Leqvio (inclisiran) strongly reduced levels of “bad” cholesterol in patients with atherosclerotic cardiovascular disease. The pharma did not provide specific data in its announcement, only revealing that monotherapy with Leqvio led to a “clinically meaningful and statistically significant” reduction in levels of low-density lipoprotein cholesterol (LDL-C), compared with both placebo and the lipid-lowering drug ezetimibe. Novartis will reveal more details from V-MONO at an upcoming scientific congress. The company will also share its findings with the FDA with an eye toward expanding Leqvio’s label, potentially opening up preventive use of the therapy. V-MONO is a randomized and double-blinded study that compared Leqvio versus placebo and the active control ezetimibe. The trial enrolled 350 patients at low or moderate risk of developing atherosclerotic cardiovascular disease (ASCVD) who were not on any lipid-loweing therapies. Its primary efficacy endpoint is the percent change in LDL-C after 150 days. “This trial adds to the growing body of evidence for Leqvio across the full spectrum of ASCVD as we strive to help more patients in need,” Chief Medical Officer Shreeram Aradhye said in a statement, noting that the pharma will “continue to advance the scientific understanding of using siRNA therapy” for cardiovascular diseases and to help people who “still struggle to reach their cholesterol goals.” Designed to be administered subcutaneously, Leqvio is a siRNA therapy that specifically targets liver cells. Once inside these hepatocytes, Leqvio targets and marks for destruction the mRNA molecule that encodes for the PCSK9, a central player in determining the volume of cholesterol receptors liver cells express. Through this mechanism of action, Leqvio leads to an overall increase in LDL-C receptors, which lowers circulating levels of the cholesterol. The FDA first approved Leqvio in December 2021 , greenlighting its use for lowering LDL-C on top of diet and maximally tolerated statin therapy in patients with ASCVD or heterozygous familial hypercholesterolemia. After an initiation regimen, the therapy is designed to be given only two times a year. In July 2023, the regulator agreed to an expanded indication of Leqvio, broadening its use to cover patients with elevated LDL-C levels in patients with primary hyperlipidemia who are at risk of heart disease. Leqvio was originally developed by Alnylam and was licensed by Novartis in January 2020 .

临床结果临床3期上市批准AHA会议

2024-08-22

·生物制品圈

一文读懂|mRNA-LNP器官靶向性（SORT）LNP包封方法与步骤详解

导读：脂质纳米颗粒（LNP）是目前领先的非病毒递送载体，作为COVID-19疫苗的一部分，在临床转化方面取得诸多令人兴奋的进展。mRNA-LNP在癌症疫苗、传染病预防、蛋白质替代疗法、基因编辑和罕见病治疗等方面具有广阔的应用前景。为改善mRNA-LNP治疗药物的靶向性，一种被称为选择性器官靶向（SORT）的策略被开发出来，能够将核酸可控地递送到靶组织。SORT LNP包含SORT分子，经静脉给药后精确地调整给药到小鼠的肝脏、肺和脾脏。SORT LNP是模块化的，可以通过工程化配方的开发搭建成熟的SORT LNP平台。 2023年，得克萨斯大学西南医学中心在Nature Protocols发表文章：《Preparation of selective organ-targeting (SORT) lipid nanoparticles (LNPs) using multiple technical methods for tissue-speciﬁc mRNA delivery》，报道了详细的SORT LNP制备步骤，包括移液管手动混合、涡旋混合和微流体混合方法。三种方法同样适用于常规LNP的包封，仅需微调LNP配方。 01 选择性器官靶向LNP（SORT LNP）组成尽管传统LNP是安全有效的，但它们仅限于肌肉注射（如COVID-19 mRNA-LNP疫苗）和针对肝细胞的静脉内给药，传统LNP的局限性很大程度上源于与极低密度脂蛋白的物理化学相似性以及吸附血浆中载脂蛋白E的倾向，促使载脂蛋白E在肝脏中积累并通过低密度脂蛋白受体摄取到肝细胞中，严重限制其在肝脏外的应用。为应对上述挑战，研究人员开发了可通过被动、主动和内源性靶向机制靶向体内特定细胞和器官的SORT-LNP，其在静脉给药后可准确地递送治疗分子以靶向肝脏和肝外组织（肺、脾脏）。基础四组分mDLNP制剂由4A3-SC8、DOPE、胆固醇和DMG-PEG和mRNA组成（脂质摩尔比为23.8：23.8：47.6：4.8，总脂质/mRNA=40/1，wt/wt）。为制备SORT-LNP，将SORT分子以特定量添加到上述LNP制剂中，保持基础四组分的相对摩尔比恒定，以保持有效的RNA包封和内体逃逸能力。组织趋向性的调节可能取决于特定的化学官能团和SORT分子的理化性质(如永久阳离子、阴离子、可电离阳离子、两性离子等)及添加量。肝脏靶向的SORT-LNP添加摩尔比为总脂质20%的DODAP（叔氨基脂质1,2-二油酰基-3-二甲基铵-丙烷），可增强肝脏中的递送特异性和效力；肺靶向的SORT-LNP添加摩尔比为总脂质50%的DOTAP（季氨基脂质1，2-二油酰基-3-三甲基铵丙烷）；脾脏靶向的SORT-LNP添加摩尔比为总脂质10%的18PA（1,2-二油酰基-sn-甘油-3-磷酸）。将MC3、DSC、胆固醇、DMG-PEG(摩尔比为50：10：38.5：1.5)和mRNA(总脂/mRNA=40/1, wt/wt)组合，通过添加50mol%的DOTAP靶向肺部；30mol%的18PA靶向脾脏，生成基于MC3的SORT-LNP，证明该法适用于其他类型的纳米颗粒系统。根据制备规模，SORT-LNP可选择通过移液器、涡旋和微流控技术等方法制备。菌菌将在下文详细介绍其实验流程。图1 五组分SORT-LNP的设计 02 SORT LNP微流控包封法使用微流控制备LNP的最大优势为质量可控、且重现性高，适用于动物体内研究和临床研究。实验室通常使用自制的定制微流控混合装置或商业混合系统（如NanoAssemblr）。该法在可重复性、LNP均匀性和混合参数的可控性等方面具有显著优势。将有机相和水相泵入两个入口，由人字形结构引起的混沌湍流导致两相快速混合，产生具有高度可重复性的有限尺寸的纳米颗粒。微流控包封适用于1-20mL（如NanoAssemblr Ignite）至0.01-1L（如NanoAssemblr Blaze）的实验室规模以及中试生产规模。微流控包封LNP-mRNA的流程为：① 制备含脂质组分的乙醇，和含mRNA的水相，将两相溶液分别转移至注射器中，去除气泡；② 将两个注射器接通至微流控设备；③ 设置微流控参数：总进样量、乙醇相和水相的流速、排废体积；④ 收集的样品经透析去除乙醇，最终保存在PBS缓冲液中。图2 微流控混合方法对应的LNP配方 03 SORT LNP移液器混合法移液器混合法是制备小批量LNP，用于体外实验的最常用方法，只需通过手动快速上下移液混合两种溶液，使其在特定时间内形成纳米颗粒。操作简单、成本低，通常适用于~6/18至~30/90（µL/µL，乙醇/水溶液）规模。移液器混合法的操作步骤为：脂质和mRNA样品的制备：将脂质组分溶解于乙醇中，8 μg mRNA溶解于酸性水溶液中。随后将mRNA缓冲液，快速加入步骤的脂质混合乙醇溶液中，然后立即上下快速移液20~30s，完成手动混合操作。最后通过透析去除乙醇、并换液至PBS缓冲液中。图3 移液器混合方法对应的LNP配方 04 SORT LNP涡旋混合相比手动混合法，涡旋混合法适用于稍大批量LNP的包封，常用于体外研究样品的制备。该法涉及在特定时间内将两种溶液在强烈的涡旋下快速混合以形成纳米颗粒。该法需涡流混合器，容易在实验室规模实施。适用于~20/60至~40/120(µL/µL，乙醇/水溶液)规模。且前述两种方法可在普通实验室条件下进行。与移液器手动混合不同的点在于，涡旋法是将含mRNA的水相在旋涡混合器上以中速旋转。然后将含脂质-乙醇混合液添加到涡旋中的水相中，将混合液继续旋转20~30s。图4 涡旋混合法对应的LNP配方 05 总结研究公开了三种方法制备SORT-LNP制剂的方法，包括移液管手动混合、涡旋混合和微流体混合方法。质量评估结果来看，三种方法的包封效率差别不大，对LNP-mRNA的靶向递送效率无显著差异。然而，从粒径数据来看，仅微流控包封法能够将LNP粒径控制在100 nm 以下。整体来看，微流控法在LNP粒径控制方面更具优势，推荐用于动物体内研究、临床研究、以及大规模生产等较高质量需求的场景。图5 不同包封方法的比较：4A3-SC8 SORT LNP(上图); MC3 SORT LNP(下图) 参考文献 [1] Wang X, Liu S, Sun Y, Yu X, Lee SM, Cheng Q, Wei T, Gong J, Robinson J, Zhang D, Lian X, Basak P, Siegwart DJ. Preparation of selective organ-targeting (SORT) lipid nanoparticles (LNPs) using multiple technical methods for tissue-specific mRNA delivery. Nat Protoc. 2023 Jan;18(1):265-291. doi: 10.1038/s41596-022-00755-x. 识别微信二维码，添加生物制品圈小编，符合条件者即可加入生物制品微信群！请注明：姓名+研究方向！版权声明本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。

信使RNA疫苗核酸药物

2024-07-31

·drugs

Cholesterol Absorption Inhibitors May Cut Risk for Liver Cancer

WEDNESDAY, July 31, 2024 -- The use of cholesterol absorption inhibitors is associated with a reduced risk for liver cancer, according to a study published online July 29 in Cancer . Shahriar A. Zamani, Ph.D., from the National Cancer Institute at the National Institutes of Health in Rockville, Maryland, and colleagues examined the risk for liver cancer for five nonstatin cholesterol-lowering medications (cholesterol absorption inhibitors, bile acid sequestrants, fibrates, niacin, and omega-3 fatty acids). The analysis included 3,719 cases and 14,876 matched controls. The researchers found that cholesterol absorption inhibitor use was associated with reduced liver cancer risk in the overall analysis (odds ratio, 0.69) and when considering type 2 diabetes and chronic liver disease status. Overall, bile acid sequestrant use was associated with increased liver cancer risk (odds ratio, 5.31), but findings were inconsistent when considering type 2 diabetes and chronic liver disease status. There were no associations seen for the other medications and liver cancer risk. "In conclusion, the current results suggest that use of cholesterol absorption inhibitors may be associated with reduced risk of liver cancer," the authors write. "Future studies are needed to confirm the results of this study and to clarify the association of all nonstatin cholesterol-lowering medications and liver cancer." Abstract/Full Text Whatever your topic of interest, subscribe to our newsletters to get the best of Drugs.com in your inbox.

临床结果