This study will investigate whether the drug called senicapoc can prevent worsening of the scarring in interstitial lung disease.
Researchers will compare senicapoc to a placebo (a look-alike substance that contains no drug) to see if senicapoc works to prevent lung function worsening
Participants will be asked to take 3 tablets a day for a period of 26 weeks. Within this period doctors will follow the participants, ask for experience of adverse events, check lung function and organ status, and participants will need to fill out quality-of-life questionnaires. A total of 3 visits is required, at initiation, after 13 and 26 weeks, in addition there is a phone call 4 weeks in. A final visit will occur 52 weeks after initiation and consist of a normal visit in the outpatient clinic where the doctor ask for any relevant information regarding the period after the study.

开始日期2025-05-01

申办/合作机构

Vejle Hospital

NCT04804241

/ Recruiting临床2期IIT

Proof of Mechanism Study of Senicapoc in Mild or Prodromal Alzheimer's Disease

Development of novel disease-modifying therapies for Alzheimer's disease (AD) remains of paramount importance. This study will be a Phase II randomized clinical trial testing Senicapoc in patients with mild or prodromal AD. This will be a small Proof of Mechanism study to prove biological activity and target engagement in humans with early AD. The investigators will study up to 55 patients over 52 weeks, with primary outcomes being Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAS-Cog) scores and blood and cerebrospinal fluid (CSF) markers of neuroinflammation. This pilot study will provide an estimate of treatment effect size on cognitive trajectory, daily function, and brain atrophy.

开始日期2022-03-18

申办/合作机构

University of California, Davis

NL-OMON20057

/ SuspendedN/A

Extension of the randomized, double-blind, placebo-controlled single ascending dose study to assess the safety and tolerability of AP30663 in healthy subjects.

开始日期2020-10-29

申办/合作机构

Acesion Pharma ApS

100 项与 KCa 相关的临床结果

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0 项与 KCa 相关的专利（医药）

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3,586

项与 KCa 相关的文献（医药）

2025-07-01·Cellular Signalling

KCa3.1 upregulation mediated by Ang II-induced JNK/AP-1 activation contributes to atrial fibrosis

Article

作者: Liu, Xiang ; Deng, Xiu-Ling ; Zhao, Limei ; Zheng, Dong ; Li, Min ; Ren, Yujie ; Li, Guangyao ; She, Gang ; Wu, Jie ; Zhao, Yinxia ; Zhang, Dongmei ; Wang, Yan

Atrial fibrillation is strongly associated with an increased risk of embolism, stroke, and heart failure. Current therapeutic approaches often have limited efficacy, and controlling atrial fibrosis remains a critical objective for upstream therapies. The specific mechanisms driving atrial fibrosis remain incompletely understood. The intermediate-conductance calcium-activated potassium channel K_Ca3.1 has been implicated in promoting fibroblast activation in various fibrotic diseases. This study investigates the role of angiotensin II (Ang II) in regulating K_Ca3.1, as well as its involvement in the pathogenesis of atrial fibrosis and the underlying signaling mechanisms. In a rat model, chronic Ang II infusion for 4 weeks induced atrial fibrosis, which was significantly attenuated by TRAM-34, a specific K_Ca3.1 channel blocker. In cultured rat atrial fibroblasts, Ang II treatment promoted fibroblast differentiation, proliferation, migration and collagen production, effects that were suppressed by TRAM-34 and K_Ca3.1 knockdown. Overexpression of K_Ca3.1 in fibroblasts further confirmed its pro-fibrotic role. Mechanistically, Ang II upregulated K_Ca3.1 expression and current density by activating the JNK/AP-1 signaling pathway. This involved phosphorylation of JNK, c-Jun, and c-Fos, leading to the formation of c-Jun/c-Fos heterodimers that directly bound to the K_Ca3.1 promoter to enhance its transcription. Together, these findings demonstrate that K_Ca3.1 mediates fibroblast activation and atrial fibrosis through the JNK/AP-1 pathway.

2025-07-01·Brain Research

Plasma and urinary metabolomic signatures differentiate genetic and idiopathic Parkinson’s disease

Article

作者: Valente, Ana Paula ; Cotrin, Juliana Cordovil ; Spitz, Mariana ; Santos-Rebouças, Cíntia Barros ; de Rosso, Ana Lúcia Zuma ; Cadaxo, André Simões ; Pimentel, Márcia Mattos Gonçalves ; Veras, Renato Peixoto ; Pereira, Joao Santos ; Dos Santos Junior, Gilson Costa

Parkinson's disease (PD) is marked by alpha-synuclein accumulation and progressive dopaminergic neuron loss. Using Nuclear Magnetic Resonance (NMR)-based metabolomics, we uncovered metabolic disturbances in idiopathic PD (iPD) and PD linked to LRRK2, GBA1, and PRKN variants in a Brazilian ethnically diverse cohort, free of comorbidities, in comparison to healthy, age-matched controls. In plasma, significant PD-associated metabolites included histidine, acetate, acetoacetate, glutamine, glucose, lipids and lipoproteins, N-acetyl-glycoproteins, and sarcosine. Urine samples revealed alterations in creatine, creatinine, L-asparagine, trimethylamine, 3-beta-hydroxybutyrate, isovaleric acid, glutamine, urea, glycine, choline, arginine, and cysteine in association with PD. Notably, creatine, creatinine, acetate, glucose, and histidine showed pathway influences from LRRK2, GBA1, and PRKN variants. Enrichment analyses highlighted disruptions in glyoxylate and dicarboxylate metabolism (plasma) as well as serine, threonine, and glycine metabolism (urine). Additionally, a metabolite-gene-disease interaction network identified 15 genes associated with PD that interact with key metabolites, highlighting MAPT, SNCA, RERE, and KCNN3 as key players in both plasmaandurine. NMR in saliva samples did not show significant differences between PD groups and controls. Our findings underscore PD-associated metabolites, particularly related to arginine metabolism, the urea cycle, glutamate metabolism, glucose metabolism, and gut microbiota. These pathways and gene interactions may serve as potential biomarkers for PD diagnosis and precision medicine strategies.

2025-06-01·Neurobiology of Disease

Disrupted synaptic gene expression in Fabry disease: Findings from RNA sequencing

Article

作者: Villacorta-Argüelles, Eduardo ; Leao-Teles, Elisa ; López, Lluis Lis ; Álvarez, J Víctor ; López-Valverde, Laura ; Hermida-Ameijeiras, Álvaro ; Couce, María L ; Vázquez-Mosquera, María E ; Colón-Mejeras, Cristóbal ; López-Mendoza, Manuel ; López-Pardo, Beatriz Martín ; López-Rodríguez, Mónica ; Goicoechea-Diezhandino, María A ; Ortolano, Saida ; Sánchez-Martínez, Rosario ; Guerrero-Márquez, Francisco J

Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by a deficiency in the enzyme α-galactosidase A. This defect leads to the progressive accumulation of glycosphingolipids, resulting in kidney, heart, and nervous system damage, which contributes to significant morbidity and mortality. Early diagnosis is essential to prevent irreversible damage and optimize treatment strategies. Recent research aims to provide a better understanding of FD pathophysiology to improve management approaches. This study is an international, multicenter, cross-sectional analysis that used RNA sequencing (RNA-seq) to compare blood samples from 50 FD patients and 50 age- and sex-matched healthy controls. The objective was to identify gene expression patterns and investigate secondary cellular pathways affected by lysosomal dysfunction. Among the more than 400 differentially expressed genes detected, 207 were protein-coding genes, most of which were overexpressed in the FD cohort. Functional enrichment analysis highlighted processes related to synaptic function, specifically concerning chemical synaptic transmission and membrane potential regulation. Identified genes included those related to voltage-gated ion channels, neurotransmitter receptors, cell adhesion molecules, scaffold proteins, and proteins associated with synaptic vesicles and neurotrophic signaling, all linked to lipid rafts. Notable identified genes included those encoding voltage-gated potassium channel genes (KCNQ2, KCNQ3, KCNMA1) and ionotropic receptor genes involved in glutamatergic (GRIN2A, GRIN2B) and GABAergic systems (GABRA4, GABRB1, GABRG2, GABRQ). These findings suggest that lysosomal dysfunction contributes to synaptic defects in FD, paving the way for further research into the role of synaptic pathology and lipid rafts in the underlying pathogenesis and clinical outcomes in FD.

项与 KCa 相关的新闻（医药）

2024-07-17

·生物探索

Sci Adv丨徐平稳/何彦林/王春梅/叶慧合作发现27-羟基胆固醇通过作用于POMC神经元表达的雌激素受体α调控摄食行为

引言 1978年Andrew Kandutsch及其同事在“胆固醇稳态的氧固醇假说”中首次提出氧固醇 (Oxysterol) 是胆固醇生物合成反馈调节的主要介质【1】。氧固醇是胆固醇的代谢产物，在外周组织中产生，能够反馈调节胆固醇的合成和吸收【2-3】。27-羟基胆固醇 (27HC) 是人体循环中最丰富的氧固醇之一。有趣的是，研究表明，27HC是体内合成的内源选择性雌激素受体调节剂 (selective estrogen receptor modulators，SERM)【4】，能够作用于雌激素受体α和β (estrogen receptorα/β, ERα/β)。而且，相对于胆固醇来说，27HC特殊的化学结构使其能够更好地通过磷脂膜扩散，从而穿过血脑屏障 (blood-brain barrier，BBB)【5】。值得关注的是，在大脑中表达的雌激素受体在能量和脂质稳态调节中起到致关重要的作用【6-7】。目前，已有相关文献提出，27HC可以作为信号载体将血液中胆固醇水平反馈到中枢神经，以调节各种代谢功能，包括胆固醇代谢【8】、神经衰老【9】、神经退化【10】、炎症反应【11】和神经元葡萄糖摄取【12】。然而，27HC是否是通过雌激素受体对大脑神经元活性产生影响从而调节全身能量稳态，目前尚不可知。 7月12日，来自伊利诺伊大学芝加哥分校 (University of Illinois Chicago，UIC) 的徐平稳博士，路易斯安那州立大学潘宁顿生物医学研究中心（Pennington Biomedical Research Center ，PBRC）的何彦林博士，美国贝勒医学院（Baylor College of Medicine，BCM）的王春梅博士，以及新加坡南洋理工大学（Nanyang Technological University，NTU）的叶慧博士研究团队，合作在Science Advances杂志上发表了研究成果：27-Hydroxycholesterol acts on estrogen receptor αexpressed by POMC neurons in the arcuate nucleus to modulate feeding behavior。该研究发现，27HC通过作用于下丘脑弓状核（The arcuate nucleus， ARH）阿黑皮素原（proopiomelanocortin ，POMCARH）神经元中表达的ERα抑制小电导钙离子激活钾通道（the small conductance of the calcium-activated potassium，SK）来激活该神经元，从而迅速地抑制食物摄入。这一27HC/ERα/SK/POMC信号通路可能是一种关键的负反馈机制。在高胆固醇食物摄入导致血液中胆固醇迅速上升的情况下，它能够通过减少食物摄入来有效降低血液中的胆固醇含量。这一成果揭示了当人们摄入高脂/油腻食物后，感到食欲降低的潜在原因之一。为了研究27HC是否能够通过中枢神经调节能量代谢，该合作团队首先比较了单次腹腔 (IP) 以及脑室（ICV）注射27HC照成的小鼠的摄食行为以及相关代谢参数的变化。他们通过记录并分析食物摄入量，摄入间隔时长，累积食物消耗量，呼吸商，氧气消耗量，二氧化碳产生量以及脂肪利用率等指标，发现27HC的外周和中枢给药均可引起小鼠的食欲减退，并且脑室注射导致的厌食作用还会引起小鼠全身底物利用方式从碳水化合物到脂肪的急剧转变。为了进一步研究27HC的中枢作用机理，研究人员首先利用转基因小鼠模型（ERα-ZsGreen）荧光标记ERα表达的神经元，并通过小鼠脑切片以及免疫组织化学染色发现27HC能够激活在下丘脑弓状核（ARH）中表达的ERα神经元。有趣的是，在这一区域，大部分的ERα表达在抑制采食的POMC神经元而非促进采食的刺鼠相关肽AGRP神经元。随后，研究人员利用POMCtdTOMATO小鼠模型结合电生理技术验证了27HC能够通过结合ERα的方式激活下丘脑弓状核中分布的POMC神经元（POMCARH）。这一实验结果表明POMC神经元以及ERα可能是27HC中枢调控食欲的两个重要介质。为了验证这一设想，研究人员脑室注射了27HC + BHPI (ERα拮抗剂) 或27HC + SHU9119 (POMC下游信号MC3/4-R的拮抗剂)，结果标明，BHPI和SHU9119均有效阻断了27HC 对小鼠采食行为的抑制作用。该药理学阻断实验进一步证明了POMC神经元以及ERα的关键作用。随后，研究人员为了更具体地检验POMC神经元中表达的ERα（ERαPOMC）在27HC采食调控中的作用，他们利用了Cre-LoxP重组技术，特异性地从POMC神经元中敲除ERα基因。实验结果表明，在ERαPOMC被敲除的情况下，由27HC引发的厌食效应显著降低。这一结果证实了ERαPOMC在27HC采食调节中起到不可或缺的作用。同时，研究人员利用化学遗传学技术（Designer Receptors Exclusively Activated by Designer Drugs，DREADD）特异性地抑制POMCARH神经元活性，随后对小鼠的采食行为进行监测。结果表明，POMCARH 静默能显著降低27HC的厌食作用。因此，研究人员得出结论，POMCARH神经元激活是27HC降低采食的关键一环。值得注意的是，SK3（一种 SK 离子通道的亚型）在POMCARH神经元中大量表达，是其细胞内信号传导的关键组成部分[13]。并且有报道指出，SK3离子通道能够参与整合神经元介导的食物摄入和外周代谢信号 (包括白脂素和雌激素) 的调节【14】。为进一步揭示27HC激活POMCARH神经元并调控食欲的神经元内分子作用机制。研究人员同样利用Cre-LoxP技术，特异性地敲除了SK3基因在POMCARH神经元中的表达。随后的电生理记录以及小鼠采食行为的监测实验均证实了SK3离子通路在27HC激活POMCARH神经元并抑制食欲中的关键角色。模式图 (Credit: Science Advances) 综上所述，本研究通过电生理学，化学遗传学，基因敲除等多种技术，揭示了27HC通过作用于ERα，抑制SK3离子通道，激活POMCARH神经元并且抑制食欲，从而维持体内胆固醇动态平衡的效果。参考文献 A. A. Kandutsch, H. W. Chen, H. J. Heiniger, Biological activity of some oxygenated sterols. Science 201, 498-501 (1978) S. Gill, R. Chow, A. J. Brown, Sterol regulators of cholesterol homeostasis and beyond: the oxysterol hypothesis revisited and revised. Prog Lipid Res 47, 391-404 (2008). N. B. Javitt, 25R,26-Hydroxycholesterol revisited: synthesis, metabolism, and biologic roles. J Lipid Res 43, 665-670 (2002) M. Umetani, P. W. Shaul, 27-Hydroxycholesterol: the first identified endogenous SERM. Trends in Endocrinology & Metabolism 22, 130-135 (2011). M. Hilsch, I. Haralampiev, P. Muller, D. Huster, H. A. Scheidt, Membrane properties of hydroxycholesterols related to the brain cholesterol metabolism. Beilstein J Org Chem 13, 720-727 (2017). P. Xu, X. Cao, Y. Xu, Targeting brain estrogen receptor for binge eating. Oncotarget 6, 23044-23045 (2015). 32. Y. Xu, M. Lopez, Central regulation of energy metabolism by estrogens. Mol Metab 15, 104-115 (2018) D. D. Zhang et al., 27-Hydroxycholesterol contributes to disruptive effects on learning and memory by modulating cholesterol metabolism in the rat brain. Neuroscience 300, 163-173 (2015). J. Liu et al., Resveratrol Alleviates 27-Hydroxycholesterol-Induced Senescence in Nerve Cells and Affects Zebrafish Locomotor Behavior via Activation of SIRT1-Mediated STAT3 Signaling. Oxid Med Cell Longev 2021, 6673343 (2021). M. A. Ismail et al., 27-Hydroxycholesterol impairs neuronal glucose uptake through an IRAP/GLUT4 system dysregulation. J Exp Med 214, 699-717 (2017). W. W. Ma, C. Q. Li, L. Zhao, Y. S. Wang, R. Xiao, NF-kappaB-mediated inflammatory damage is differentially affected in SH-SY5Y and C6 cells treated with 27-hydroxycholesterol. Food Sci Nutr 7, 1685-1694 (2019). R. Loera-Valencia et al., Hypercholesterolemia and 27-Hydroxycholesterol Increase S100A8 and RAGE Expression in the Brain: a Link Between Cholesterol, Alarmins, and Neurodegeneration. Mol Neurobiol 58, 6063-6076 (2021). M. Yu et al., SK3 in POMC neurons plays a sexually dimorphic role in energy and glucose homeostasis. Cell Biosci 12, 170 (2022). Feng B, Liu H, Mishra I, et al. Asprosin promotes feeding through SK channel–dependent activation of AgRP neurons[J]. Science Advances, 2023, 9(8): eabq6718. http://doi.org/10.1126/sciadv.adi4746 责编|探索君排版|探索君文章来源|“BioArt” End 往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文 Cell | 是什么决定了细胞的大小？热文 Nature | 2024年值得关注的七项技术热文 Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文 CRISPR技术进化史 | 24年Cell综述

临床研究

2024-06-08

·生物制品圈

陈化兰/步志高团队发现流感病毒关键受体——mGluR2

流感病毒感染细胞涉及多个环节，每个环节都借助和利用宿主细胞蛋白来完成。前期研究发现流感病毒利用细胞表面的唾液酸受体附着在细胞表面后，70%的病毒粒子通过网格蛋白介导的内吞（clathrin-mediated endocytosis，CME）进入细胞。CME是一个严格的受体介导的、信号调控的过程，细胞膜表面的受体与细胞外的配体结合后才能将信号传递至细胞内启动CME。然而，传递流感病毒吸附信号、介导流感病毒CME的受体一直是未解之谜，这也大大限制了从宿主角度开发抗流感病毒药物的进程。 2024年6月7日，中国农业科学院哈尔滨兽医研究所步志高研究员、陈化兰院士等在 Nature Microbiology 期刊发表了题为：Influenza virus uses mGluR2 as an endocytic receptor to enter cells 的研究论文。该研究发现，跨膜蛋白代谢型谷氨酸受体2（mGluR2）是介导流感病毒进入宿主细胞的关键受体。这项最新研究发现，信号转导分子、跨膜糖蛋白代谢型谷氨酸受体2（mGluR2）与流感病毒的血凝素蛋白互作，启动流感病毒的网格蛋白介导的内吞（clathrin-mediated endocytosis，CME）。mGluR2可溶性抗体封闭后，流感病毒感染细胞的效率大大下降。mGluR2的表达干扰后，流感病毒仍可吸附在细胞表面，但进入细胞的效率显著下降。该研究进一步发现，mGluR2与流感病毒结合后，激活钙离子激活的大电导钾离子通道（KCa1.1），活化后的KCa1.1促进F-actin多聚化，后者辅助完成流感病毒的CME。mGluR2的敲除显著提高了小鼠对不同亚型流感病毒的抵抗力。流感病毒在mGluR2敲除小鼠鼻甲、肺和脑等器官的复制滴度显著低于野生小鼠。H5和H7亚型病毒感染后，野生对照小鼠100%死亡，mGluR2敲除小鼠70%存活。该研究还发现，mGluR2不影响病毒吸附，mGluR2糖基化与否不影响其发挥内吞受体作用，明确了流感病毒的吸附和内吞过程是由不同受体分别介导的，为流感病毒感染的认知提供了重要数据。该研究为从宿主角度的抗病毒策略研究提供了新的视角： 1）阻断流感病毒HA和mGluR2之间的相互作用可以有效抑制病毒的感染； 2）可通过mGluR2基因敲除构建流感病毒抗性动物育种。中国农业科学院哈尔滨兽医研究所博士研究生倪子欣、王金良研究员为论文共同第一作者，步志高研究员和陈化兰院士为论文共同通讯作者。该研究得到国家重点研发项目（2021YFD1800200、2021YFC2301700、2023YFC2605001）、国家自然科学基金项目（32202773、32192451）等资助。论文链接：https://www.nature.com/articles/s41564-024-01713-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。

2023-02-08

·Science Daily

Unlocking the secrets to Strep A virulence

Researchers have unlocked one of the secrets as to why some forms of Strep A are associated with severe invasive infection. Griffith University researchers have unlocked one of the secrets as to why some forms of Strep A are associated with severe invasive infection. Invasive Strep A diseases are responsible for more than 163,000 deaths each year globally and a recent increase in cases of invasive Strep A disease has been observed in Victoria, New South Wales and internationally. For the past 10 years, Institute for Glycomics Associate Professor Manisha Pandey and Professor Michael Good have been researching the pathways in which Strep A can spread through the body. "The findings from this study will have far-reaching implications as Strep A is responsible for a significant number of invasive and non-invasive infections which cause significant morbidity and mortality globally," Associate Professor Pandey said. "The reason for this is that invasive organisms express significantly more of the toxin, streptolysin O (SLO), which was the main focus of this study. "SLO exerts potent cell and tissue destructive activity and promotes Strep A resistance to clearance by white cells in the body which is the critical first element of host defence against invasive Strep A infection." Professor Good said: "We found SLO alters interactions with host cell populations and increases Strep A viability at sites in the body such as the blood and spleen, and that its absence results in significantly less virulence." "Essentially, the less SLO present, the less severe the case of Strep A." SLO is secreted by nearly all Strep A isolates, but those that secrete the most SLO are the most virulent. This work underscores the importance of SLO in Strep A virulence while highlighting the complex nature of Strep A pathogenesis. This improved insight into host-pathogen interactions will enable a better understanding of host immune evasion mechanisms and inform streptococcal vaccine development programs. Dr Pandey said a key finding was the presence of SLO in invasive organisms did not impair the ability of the Strep A vaccine candidate developed by Griffith University's Institute for Glycomics and which is now in a clinical trial. The Strep A virulence study was part of a PhD project undertaken by Dr Emma Langshaw.

疫苗临床研究