首页 > 最新文献

Function最新文献

英文 中文
Identification and properties of TRPV4 mutant channels present in polycystic kidney disease patients 多囊肾患者体内 TRPV4 突变通道的鉴定和特性
Pub Date : 2024-06-13 DOI: 10.1093/function/zqae031
Ana M. Hernández-Vega, Itzel Llorente, Raúl Sánchez-Hernández, Yayoi Segura, Teresa Tusié-Luna, Luis E Morales-Buenrostro, R. García-Villegas, León D Islas, Tamara Rosenbaum
Polycystic kidney disease (PKD), a disease characterized by enlargement of the kidney through cystic growth is the fourth leading cause of end-stage kidney disease world-wide. TRPV4, a calcium-permeable TRP, channel participates in kidney cell physiology and since TRPV4 forms complexes with another channel whose malfunction is associated to PKD, TRPP2 (or PKD2), we sought to determine whether patients with PKD, exhibit previously unknown mutations in TRPV4. Here, we report the presence of mutations in the TRPV4 gene in patients diagnosed with PKD and determine that they produce gain-of-function (GOF). Mutations in the sequence of the TRPV4 gene have been associated to a broad spectrum of neuropathies and skeletal dysplasias but not PKD, and their biophysical effects on channel function have not been elucidated. We identified and examined the functional behavior of a novel E6K mutant and of the previously known S94L and A217S mutant TRVP4 channels. The A217S mutation has been associated to mixed neuropathy and/or skeletal dysplasia phenotypes, however, the PKD carriers of these variants had not been diagnosed with these reported clinical manifestations. The presence of certain mutations in TRPV4 may influence the progression and severity of PKD through GOF mechanisms. PKD patients carrying TRVP4 mutations are putatively more likely to require dialysis or renal transplant as compared to those without these mutations.
多囊肾病(PKD)是一种以肾脏因囊性增生而增大为特征的疾病,是全球第四大终末期肾病病因。TRPV4是一种钙离子渗透性TRP通道,参与肾脏细胞的生理功能,由于TRPV4与另一种通道TRPP2(或PKD2)形成复合物,而TRPP2的功能失常与PKD有关,因此我们试图确定PKD患者是否表现出以前未知的TRPV4突变。在这里,我们报告了在确诊为 PKD 的患者中存在 TRPV4 基因突变,并确定这些突变会产生功能增益(GOF)。TRPV4 基因序列中的突变与多种神经病和骨骼发育不良有关,但与 PKD 无关,它们对通道功能的生物物理影响尚未阐明。我们发现并研究了一种新型 E6K 突变体以及之前已知的 S94L 和 A217S 突变体 TRVP4 通道的功能行为。A217S突变与混合神经病变和/或骨骼发育不良表型有关,但这些变体的PKD携带者并未被诊断出这些临床表现。TRPV4中某些突变的存在可能会通过GOF机制影响PKD的进展和严重程度。与没有 TRVP4 突变的患者相比,携带 TRVP4 突变的 PKD 患者需要透析或肾移植的可能性更大。
{"title":"Identification and properties of TRPV4 mutant channels present in polycystic kidney disease patients","authors":"Ana M. Hernández-Vega, Itzel Llorente, Raúl Sánchez-Hernández, Yayoi Segura, Teresa Tusié-Luna, Luis E Morales-Buenrostro, R. García-Villegas, León D Islas, Tamara Rosenbaum","doi":"10.1093/function/zqae031","DOIUrl":"https://doi.org/10.1093/function/zqae031","url":null,"abstract":"\u0000 Polycystic kidney disease (PKD), a disease characterized by enlargement of the kidney through cystic growth is the fourth leading cause of end-stage kidney disease world-wide. TRPV4, a calcium-permeable TRP, channel participates in kidney cell physiology and since TRPV4 forms complexes with another channel whose malfunction is associated to PKD, TRPP2 (or PKD2), we sought to determine whether patients with PKD, exhibit previously unknown mutations in TRPV4. Here, we report the presence of mutations in the TRPV4 gene in patients diagnosed with PKD and determine that they produce gain-of-function (GOF). Mutations in the sequence of the TRPV4 gene have been associated to a broad spectrum of neuropathies and skeletal dysplasias but not PKD, and their biophysical effects on channel function have not been elucidated. We identified and examined the functional behavior of a novel E6K mutant and of the previously known S94L and A217S mutant TRVP4 channels. The A217S mutation has been associated to mixed neuropathy and/or skeletal dysplasia phenotypes, however, the PKD carriers of these variants had not been diagnosed with these reported clinical manifestations. The presence of certain mutations in TRPV4 may influence the progression and severity of PKD through GOF mechanisms. PKD patients carrying TRVP4 mutations are putatively more likely to require dialysis or renal transplant as compared to those without these mutations.","PeriodicalId":503843,"journal":{"name":"Function","volume":"61 23","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141349491","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
PAR1-mediated Non-periodical Synchronized Calcium Oscillations in human Mesangial Cells 人间质细胞中 PAR1 介导的非周期性同步钙振荡
Pub Date : 2024-06-10 DOI: 10.1093/function/zqae030
Mariia Stefanenko, M. Fedoriuk, M. Mamenko, M. Semenikhina, Tamara K Nowling, Joshua H Lipschutz, Oleksandr Maximyuk, Alexander Staruschenko, Oleg Palygin
Mesangial cells offer structural support to the glomerular tuft and regulate glomerular capillary flow through their contractile capabilities. These cells undergo phenotypic changes, such as proliferation and mesangial expansion, resulting in abnormal glomerular tuft formation and reduced capillary loops. Such adaptation to the changing environment is commonly associated with various glomerular diseases, including diabetic nephropathy and glomerulonephritis. Thrombin-induced mesangial remodeling was found in diabetic patients, and expression of the corresponding protease-activated receptors (PARs) in the renal mesangium was reported. However, the functional PAR-mediated signaling in mesangial cells was not examined. This study investigated protease-activated mechanisms regulating mesangial cell calcium waves that may play an essential role in the mesangial proliferation or constriction of the arteriolar cells. Our results indicate that coagulation proteases like thrombin induce synchronized oscillations in cytoplasmic Ca2+ concentration of mesangial cells. The oscillations required PAR1 GPCRs-related activation, but not a PAR4, and were further mediated presumably through store-operated calcium entry and TRPC3 channel activity. Understanding thrombin signaling pathways and their relation to mesangial cells' contractile or synthetic (proliferative) phenotype may play a role in the development of chronic kidney disease and requires further investigation.
间质细胞为肾小球束提供结构支撑,并通过其收缩能力调节肾小球毛细血管的流量。这些细胞会发生表型变化,如增殖和系膜扩张,导致肾小球束形成异常和毛细血管襻减少。这种对环境变化的适应通常与各种肾小球疾病有关,包括糖尿病肾病和肾小球肾炎。在糖尿病患者中发现了凝血酶诱导的肾间质重塑,并报道了相应的蛋白酶激活受体(PAR)在肾间质中的表达。然而,PAR 介导的间质细胞信号传导功能尚未得到研究。本研究调查了蛋白酶激活调节间质细胞钙波的机制,该机制可能在间质增殖或动脉细胞收缩中发挥重要作用。我们的研究结果表明,凝血蛋白酶(如凝血酶)可诱导间质细胞胞质 Ca2+ 浓度的同步振荡。这种振荡需要与 PAR1 GPCRs 相关的激活,但不需要 PAR4,并可能通过储存操作的钙离子进入和 TRPC3 通道活性进一步介导。了解凝血酶信号通路及其与系膜细胞收缩或合成(增殖)表型的关系可能会在慢性肾病的发展中发挥作用,因此需要进一步研究。
{"title":"PAR1-mediated Non-periodical Synchronized Calcium Oscillations in human Mesangial Cells","authors":"Mariia Stefanenko, M. Fedoriuk, M. Mamenko, M. Semenikhina, Tamara K Nowling, Joshua H Lipschutz, Oleksandr Maximyuk, Alexander Staruschenko, Oleg Palygin","doi":"10.1093/function/zqae030","DOIUrl":"https://doi.org/10.1093/function/zqae030","url":null,"abstract":"\u0000 Mesangial cells offer structural support to the glomerular tuft and regulate glomerular capillary flow through their contractile capabilities. These cells undergo phenotypic changes, such as proliferation and mesangial expansion, resulting in abnormal glomerular tuft formation and reduced capillary loops. Such adaptation to the changing environment is commonly associated with various glomerular diseases, including diabetic nephropathy and glomerulonephritis. Thrombin-induced mesangial remodeling was found in diabetic patients, and expression of the corresponding protease-activated receptors (PARs) in the renal mesangium was reported. However, the functional PAR-mediated signaling in mesangial cells was not examined. This study investigated protease-activated mechanisms regulating mesangial cell calcium waves that may play an essential role in the mesangial proliferation or constriction of the arteriolar cells. Our results indicate that coagulation proteases like thrombin induce synchronized oscillations in cytoplasmic Ca2+ concentration of mesangial cells. The oscillations required PAR1 GPCRs-related activation, but not a PAR4, and were further mediated presumably through store-operated calcium entry and TRPC3 channel activity. Understanding thrombin signaling pathways and their relation to mesangial cells' contractile or synthetic (proliferative) phenotype may play a role in the development of chronic kidney disease and requires further investigation.","PeriodicalId":503843,"journal":{"name":"Function","volume":"101 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141362759","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Dmxl1 is an Essential Mammalian Gene that is Required for V-ATPase Assembly and Function In Vivo Dmxl1 是哺乳动物体内 V-ATP 酶组装和功能所必需的基因
Pub Date : 2024-05-16 DOI: 10.1093/function/zqae025
Amity F. Eaton, Elizabeth C Danielson, Diane Capen, M. Merkulova, Dennis Brown
The proton pumping V-ATPase drives essential biological processes, such as acidification of intracellular organelles. Critically, the V-ATPase domains, V1 and VO, must assemble to produce a functional holoenzyme. V-ATPase dysfunction results in cancer, neurodegeneration, and diabetes, as well as systemic acidosis caused by reduced activity of proton-secreting kidney intercalated cells (ICs). However, little is known about the molecular regulation of V-ATPase in mammals. We identified a novel interactor of the mammalian V-ATPase, Drosophila melanogaster X chromosomal gene-like 1 (Dmxl1), aka Rabconnectin-3A. The yeast homologue of Dmxl1, Rav1p, is part of a complex that catalyzes the reversible assembly of the domains. We, therefore, hypothesized that Dmxl1 is a mammalian V-ATPase assembly factor. Here, we generated kidney IC-specific Dmxl1 knockout (KO) mice, which had high urine pH, like B1 V-ATPase KO mice, suggesting impaired V-ATPase function. Western blotting showed decreased B1 expression and B1 (V1) and a4 (VO) subunits were more intracellular and less colocalized in Dmxl1 KO ICs. In parallel, subcellular fractionation revealed less V1 associated B1 in the membrane fraction of KO cells relative to the cytosol. Furthermore, a Proximity Ligation Assay (PLA) performed using probes against B1 and a4 V-ATPase subunits also revealed decreased association. We propose that loss of Dmxl1 reduces V-ATPase holoenzyme assembly, thereby inhibiting proton pumping function. Dmxl1 may recruit the V1 domain to the membrane and facilitate assembly with the VO domain and in its absence V1 may be targeted for degradation. We conclude that Dmxl1 is a bona-fide mammalian V-ATPase assembly factor.
质子泵 V-ATP 酶驱动着重要的生物过程,如细胞内细胞器的酸化。重要的是,V-ATPase 的 V1 和 VO 结构域必须组装成一个功能性全酶。V-ATPase 功能障碍会导致癌症、神经变性和糖尿病,以及因分泌质子的肾脏间质细胞(IC)活性降低而引起的全身性酸中毒。然而,人们对哺乳动物体内 V-ATP 酶的分子调控知之甚少。我们发现了哺乳动物 V-ATP 酶的一种新型互作因子--黑腹果蝇 X 染色体基因样 1(Dmxl1),又名 Rabconnectin-3A。Dmxl1 的酵母同源物 Rav1p 是催化结构域可逆组装的复合体的一部分。因此,我们推测 Dmxl1 是哺乳动物的 V-ATPase 组装因子。在这里,我们产生了肾脏IC特异性Dmxl1基因敲除(KO)小鼠,它们的尿液pH值很高,就像B1 V-ATP酶KO小鼠一样,表明V-ATP酶功能受损。Western 印迹显示,在 Dmxl1 KO IC 中,B1 表达减少,B1(V1)和 a4(VO)亚基在细胞内的分布更多,共定位更少。同时,亚细胞分馏显示,相对于细胞质,KO 细胞膜分馏中与 V1 相关的 B1 更少。此外,使用针对 B1 和 a4 V-ATPase 亚基的探针进行的邻近连接测定(PLA)也显示出关联性降低。我们认为,Dmxl1 的缺失减少了 V-ATPase 全酶的组装,从而抑制了质子泵功能。Dmxl1 可能会将 V1 结构域募集到膜上,并促进其与 VO 结构域的组装。我们的结论是,Dmxl1是哺乳动物V-ATP酶的真正组装因子。
{"title":"Dmxl1 is an Essential Mammalian Gene that is Required for V-ATPase Assembly and Function In Vivo","authors":"Amity F. Eaton, Elizabeth C Danielson, Diane Capen, M. Merkulova, Dennis Brown","doi":"10.1093/function/zqae025","DOIUrl":"https://doi.org/10.1093/function/zqae025","url":null,"abstract":"\u0000 The proton pumping V-ATPase drives essential biological processes, such as acidification of intracellular organelles. Critically, the V-ATPase domains, V1 and VO, must assemble to produce a functional holoenzyme. V-ATPase dysfunction results in cancer, neurodegeneration, and diabetes, as well as systemic acidosis caused by reduced activity of proton-secreting kidney intercalated cells (ICs). However, little is known about the molecular regulation of V-ATPase in mammals. We identified a novel interactor of the mammalian V-ATPase, Drosophila melanogaster X chromosomal gene-like 1 (Dmxl1), aka Rabconnectin-3A. The yeast homologue of Dmxl1, Rav1p, is part of a complex that catalyzes the reversible assembly of the domains. We, therefore, hypothesized that Dmxl1 is a mammalian V-ATPase assembly factor. Here, we generated kidney IC-specific Dmxl1 knockout (KO) mice, which had high urine pH, like B1 V-ATPase KO mice, suggesting impaired V-ATPase function. Western blotting showed decreased B1 expression and B1 (V1) and a4 (VO) subunits were more intracellular and less colocalized in Dmxl1 KO ICs. In parallel, subcellular fractionation revealed less V1 associated B1 in the membrane fraction of KO cells relative to the cytosol. Furthermore, a Proximity Ligation Assay (PLA) performed using probes against B1 and a4 V-ATPase subunits also revealed decreased association. We propose that loss of Dmxl1 reduces V-ATPase holoenzyme assembly, thereby inhibiting proton pumping function. Dmxl1 may recruit the V1 domain to the membrane and facilitate assembly with the VO domain and in its absence V1 may be targeted for degradation. We conclude that Dmxl1 is a bona-fide mammalian V-ATPase assembly factor.","PeriodicalId":503843,"journal":{"name":"Function","volume":"27 11","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140970978","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Physiology Brings Relevance to Biological Research: A Vision for Function 生理学为生物研究带来现实意义:功能展望
Pub Date : 2024-05-06 DOI: 10.1093/function/zqae023
David M Pollock
{"title":"Physiology Brings Relevance to Biological Research: A Vision for Function","authors":"David M Pollock","doi":"10.1093/function/zqae023","DOIUrl":"https://doi.org/10.1093/function/zqae023","url":null,"abstract":"","PeriodicalId":503843,"journal":{"name":"Function","volume":"53 18","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141009915","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Brain Ballet: The Choreography of Left-Right Neuroendocrine Signals in Injury. A Perspective on “The Left-Right Side-Specific Neuroendocrine Signaling from Injured Brain: An Organizational Principle” 大脑芭蕾:损伤中左右神经内分泌信号的编排。透视 "来自损伤大脑的左右侧特异性神经内分泌信号:组织原则 "的视角
Pub Date : 2024-05-03 DOI: 10.1093/function/zqae022
M.T. Holland, Bryan Becker
{"title":"Brain Ballet: The Choreography of Left-Right Neuroendocrine Signals in Injury. A Perspective on “The Left-Right Side-Specific Neuroendocrine Signaling from Injured Brain: An Organizational Principle”","authors":"M.T. Holland, Bryan Becker","doi":"10.1093/function/zqae022","DOIUrl":"https://doi.org/10.1093/function/zqae022","url":null,"abstract":"","PeriodicalId":503843,"journal":{"name":"Function","volume":"4 9","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141015439","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
It's all about the CREY! 这一切都与 CREY 有关!
Pub Date : 2024-04-22 DOI: 10.1093/function/zqae021
Stephanie Franzén
{"title":"It's all about the CREY!","authors":"Stephanie Franzén","doi":"10.1093/function/zqae021","DOIUrl":"https://doi.org/10.1093/function/zqae021","url":null,"abstract":"","PeriodicalId":503843,"journal":{"name":"Function","volume":"40 15","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140676126","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Exit, O Sodium! 出口,钠啊!
Pub Date : 2024-04-08 DOI: 10.1093/function/zqae018
S. Pirkmajer, A. Chibalin
{"title":"Exit, O Sodium!","authors":"S. Pirkmajer, A. Chibalin","doi":"10.1093/function/zqae018","DOIUrl":"https://doi.org/10.1093/function/zqae018","url":null,"abstract":"","PeriodicalId":503843,"journal":{"name":"Function","volume":"134 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140731363","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Combination of The CRAC Channel Inhibitor CM4620 And Galactose as A Potential Therapy for Acute Pancreatitis CRAC通道抑制剂CM4620与半乳糖的联合疗法有望治疗急性胰腺炎
Pub Date : 2024-04-05 DOI: 10.1093/function/zqae017
S. Lewis, D. Evans, T. Tsugorka, S. Peng, K. Stauderman, O. Gerasimenko, J. Gerasimenko
Acute pancreatitis (AP) is a life-threatening inflammatory disease with no specific therapy. Excessive cytoplasmic Ca2+ elevation and intracellular ATP depletion are responsible for the initiation of AP. Inhibition of CRAC channels has been proposed as a potential treatment and currently, a novel selective CRAC channel inhibitor CM4620 (AuxoraTM, CalciMedica), is in Phase 2b human trials. While CM4620 is on track to become the first effective treatment for AP, it does not produce complete protection in animal models. Recently, an alternative approach has suggested reducing ATP depletion with a natural carbohydrate galactose. Here we have investigated the possibility of using the smallest effective concentration of CM4620 in combination with galactose. Protective effects of CM4620, in the range of 1-100 nM, have been studied against necrosis induced by either bile acids, palmitoleic acid or L-asparaginase. CM4620 markedly protected against necrosis induced by bile acids or asparaginase starting from 50 nM, and palmitoleic acid starting from 1 nM. Combining CM4620 and galactose (1 mM) significantly reduced the extent of necrosis to near-control levels. In the palmitoleic acids-alcohol-induced experimental mouse model of AP, CM4620 at a concentration of 0.1 mg/kg alone significantly reduced oedema, necrosis, inflammation, and the total histopathological score. A combination of 0.1 mg/kg CM4620 with galactose (100 mM) significantly reduced further necrosis, inflammation, and histopathological score. Our data show that CM4620 can be used at much lower concentrations than reported previously, reducing potential side effects. The novel combination of CM4620 with galactose synergistically targets complementary pathological mechanisms of AP.
急性胰腺炎(AP)是一种危及生命的炎症性疾病,目前尚无特效疗法。细胞质 Ca2+ 过度升高和细胞内 ATP 耗竭是引发 AP 的原因。目前,一种新型选择性 CRAC 通道抑制剂 CM4620(AuxoraTM,CalciMedica 公司)正在进行 2b 期人体试验。虽然 CM4620 有望成为首个有效治疗 AP 的药物,但它在动物模型中并不能产生完全的保护作用。最近,有一种替代方法建议使用天然碳水化合物半乳糖来减少 ATP 的消耗。在这里,我们研究了将最小有效浓度的 CM4620 与半乳糖结合使用的可能性。我们研究了 CM4620 在 1-100 nM 范围内对胆汁酸、棕榈油酸或 L-天冬酰胺酶诱导的坏死的保护作用。从 50 nM 开始,CM4620 对胆汁酸或天冬酰胺酶诱导的坏死有明显的保护作用;从 1 nM 开始,CM4620 对棕榈油酸诱导的坏死有明显的保护作用。将 CM4620 与半乳糖(1 mM)结合使用,可显著降低坏死程度,使其接近对照组水平。在棕榈油酸-酒精诱导的小鼠 AP 实验模型中,单用 0.1 mg/kg 浓度的 CM4620 可明显减轻水肿、坏死、炎症和组织病理学总评分。0.1 毫克/千克 CM4620 与半乳糖(100 毫摩尔)联合使用可明显减少进一步的坏死、炎症和组织病理学评分。我们的数据表明,CM4620的使用浓度远低于之前的报道,从而减少了潜在的副作用。CM4620 与半乳糖的新型组合可协同作用于 AP 的互补病理机制。
{"title":"Combination of The CRAC Channel Inhibitor CM4620 And Galactose as A Potential Therapy for Acute Pancreatitis","authors":"S. Lewis, D. Evans, T. Tsugorka, S. Peng, K. Stauderman, O. Gerasimenko, J. Gerasimenko","doi":"10.1093/function/zqae017","DOIUrl":"https://doi.org/10.1093/function/zqae017","url":null,"abstract":"\u0000 Acute pancreatitis (AP) is a life-threatening inflammatory disease with no specific therapy. Excessive cytoplasmic Ca2+ elevation and intracellular ATP depletion are responsible for the initiation of AP. Inhibition of CRAC channels has been proposed as a potential treatment and currently, a novel selective CRAC channel inhibitor CM4620 (AuxoraTM, CalciMedica), is in Phase 2b human trials. While CM4620 is on track to become the first effective treatment for AP, it does not produce complete protection in animal models. Recently, an alternative approach has suggested reducing ATP depletion with a natural carbohydrate galactose. Here we have investigated the possibility of using the smallest effective concentration of CM4620 in combination with galactose.\u0000 Protective effects of CM4620, in the range of 1-100 nM, have been studied against necrosis induced by either bile acids, palmitoleic acid or L-asparaginase. CM4620 markedly protected against necrosis induced by bile acids or asparaginase starting from 50 nM, and palmitoleic acid starting from 1 nM. Combining CM4620 and galactose (1 mM) significantly reduced the extent of necrosis to near-control levels. In the palmitoleic acids-alcohol-induced experimental mouse model of AP, CM4620 at a concentration of 0.1 mg/kg alone significantly reduced oedema, necrosis, inflammation, and the total histopathological score. A combination of 0.1 mg/kg CM4620 with galactose (100 mM) significantly reduced further necrosis, inflammation, and histopathological score.\u0000 Our data show that CM4620 can be used at much lower concentrations than reported previously, reducing potential side effects. The novel combination of CM4620 with galactose synergistically targets complementary pathological mechanisms of AP.","PeriodicalId":503843,"journal":{"name":"Function","volume":"3 11‐12","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140739846","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Lipidomic Profiling of Kidney Cortical Tubule Segments Identifies Lipotypes with Physiological Implications 肾皮质小管部分的脂质组图谱鉴定出具有生理意义的脂型
Pub Date : 2024-03-30 DOI: 10.1093/function/zqae016
L. Cheval, Virginie Poindessous, Julio L Sampaio, Gilles Crambert, Nicolas Pallet
A detailed knowledge of the lipid composition of components of nephrons is crucial for understanding physiological processes and the development of kidney diseases. However, the lipidomic composition of kidney tubular segments is unknown. We manually isolated the proximal convoluted tubule (PCT), the cortical thick ascending limb of Henle's loop (cTAL) and the cortical collecting duct (CCD) from five lean and obese mice and subjected the samples to shotgun lipidomics analysis by high resolution mass spectrometry acquisition. Across all samples, more than five hundred lipid species were identified, quantified and compared. We observed significant compositional differences among the three tubular segments, which serve as true signatures. These intrinsic lipidomic features are associated with a distinct proteomic program that regulates highly specific physiological functions. The distinctive lipidomic features of each of the three segments are mostly based on the relative composition of neutral lipids, long-chain polyunsaturated fatty acids, sphingolipids, and ether phospholipids. These features support the hypothesis of a lipotype assigned to specific tubular segments. Obesity profoundly impacts the lipotype of proximal convoluted tubules. In conclusion, we present a comprehensive lipidomic analysis of three cortical segments of mouse kidney tubules. This valuable resource provides unparalleled detail that enhances our understanding of tubular physiology and the potential impact of pathological conditions.
详细了解肾小管成分的脂质组成对于了解生理过程和肾脏疾病的发展至关重要。然而,肾小管各节段的脂质组成尚不清楚。我们人工分离了五只瘦小鼠和肥胖小鼠的近曲小管(PCT)、Henle's襻皮质粗升支(cTAL)和皮质集合管(CCD),并通过高分辨质谱采集对样本进行了枪式脂质组学分析。对所有样本中的五百多种脂质进行了鉴定、量化和比较。我们观察到三个管段之间存在明显的成分差异,这就是真正的特征。这些固有的脂质体特征与调节高度特异性生理功能的独特蛋白质组程序有关。三个节段各自不同的脂质体特征主要基于中性脂质、长链多不饱和脂肪酸、鞘脂和醚磷脂的相对组成。这些特征支持为特定管段分配脂型的假设。肥胖对近曲小管的脂质型有深远影响。总之,我们对小鼠肾小管的三个皮质区段进行了全面的脂质体分析。这一宝贵的资源提供了无与伦比的细节,加深了我们对肾小管生理学和病理条件潜在影响的理解。
{"title":"Lipidomic Profiling of Kidney Cortical Tubule Segments Identifies Lipotypes with Physiological Implications","authors":"L. Cheval, Virginie Poindessous, Julio L Sampaio, Gilles Crambert, Nicolas Pallet","doi":"10.1093/function/zqae016","DOIUrl":"https://doi.org/10.1093/function/zqae016","url":null,"abstract":"\u0000 A detailed knowledge of the lipid composition of components of nephrons is crucial for understanding physiological processes and the development of kidney diseases. However, the lipidomic composition of kidney tubular segments is unknown. We manually isolated the proximal convoluted tubule (PCT), the cortical thick ascending limb of Henle's loop (cTAL) and the cortical collecting duct (CCD) from five lean and obese mice and subjected the samples to shotgun lipidomics analysis by high resolution mass spectrometry acquisition. Across all samples, more than five hundred lipid species were identified, quantified and compared. We observed significant compositional differences among the three tubular segments, which serve as true signatures. These intrinsic lipidomic features are associated with a distinct proteomic program that regulates highly specific physiological functions. The distinctive lipidomic features of each of the three segments are mostly based on the relative composition of neutral lipids, long-chain polyunsaturated fatty acids, sphingolipids, and ether phospholipids. These features support the hypothesis of a lipotype assigned to specific tubular segments. Obesity profoundly impacts the lipotype of proximal convoluted tubules. In conclusion, we present a comprehensive lipidomic analysis of three cortical segments of mouse kidney tubules. This valuable resource provides unparalleled detail that enhances our understanding of tubular physiology and the potential impact of pathological conditions.","PeriodicalId":503843,"journal":{"name":"Function","volume":"8 7","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140362549","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Systems Approaches to Cell Culture-Derived Extracellular Vesicles for Acute Kidney Injury Therapy: Prospects And Challenges 细胞培养产生的细胞外囊泡用于急性肾损伤治疗的系统方法:前景与挑战
Pub Date : 2024-03-28 DOI: 10.1093/function/zqae012
David J. Lundy, Barbara Szomolay, Chia-Te Liao
Acute kidney injury (AKI) is a heterogeneous syndrome, comprising diverse aetiologies of kidney insults which result in high mortality and morbidity if not well-managed. Although great efforts have been made to investigate underlying pathogenic mechanisms of AKI, there are limited therapeutic strategies available. Extracellular vesicles (EV) are membrane-bound vesicles secreted by various cell types which can serve as cell-free therapy through transfer of bioactive molecules. In this review, we first overview the AKI syndrome and EV biology, with a particular focus on the technical aspects and therapeutic application of cell culture-derived EVs. Secondly, we illustrate how multi-omic approaches to EV miRNA, protein and genomic cargo analysis can yield new insights into their mechanisms of action and address unresolved questions in the field. We then summarise major experimental evidence regarding the therapeutic potential of EVs in AKI, which we subdivide into stem cell and non-stem cell-derived EVs. Finally, we highlight the challenges and opportunities related to clinical translation of animal studies into human patients.
急性肾损伤(AKI)是一种异质性综合征,由多种病因引起的肾脏损伤组成,如果处理不当,死亡率和发病率都很高。尽管人们一直在努力研究 AKI 的潜在致病机制,但可用的治疗策略却很有限。细胞外囊泡(EV)是由各种细胞分泌的膜结合囊泡,可通过转移生物活性分子作为无细胞疗法。在这篇综述中,我们首先概述了 AKI 综合征和 EV 生物学,尤其侧重于细胞培养衍生 EV 的技术方面和治疗应用。其次,我们说明了用多组学方法对 EV 的 miRNA、蛋白质和基因组货物进行分析如何能对其作用机制产生新的认识,并解决该领域尚未解决的问题。然后,我们总结了EVs在AKI中治疗潜力的主要实验证据,并将其细分为干细胞和非干细胞衍生的EVs。最后,我们强调了将动物研究临床转化为人类患者所面临的挑战和机遇。
{"title":"Systems Approaches to Cell Culture-Derived Extracellular Vesicles for Acute Kidney Injury Therapy: Prospects And Challenges","authors":"David J. Lundy, Barbara Szomolay, Chia-Te Liao","doi":"10.1093/function/zqae012","DOIUrl":"https://doi.org/10.1093/function/zqae012","url":null,"abstract":"\u0000 Acute kidney injury (AKI) is a heterogeneous syndrome, comprising diverse aetiologies of kidney insults which result in high mortality and morbidity if not well-managed. Although great efforts have been made to investigate underlying pathogenic mechanisms of AKI, there are limited therapeutic strategies available. Extracellular vesicles (EV) are membrane-bound vesicles secreted by various cell types which can serve as cell-free therapy through transfer of bioactive molecules. In this review, we first overview the AKI syndrome and EV biology, with a particular focus on the technical aspects and therapeutic application of cell culture-derived EVs. Secondly, we illustrate how multi-omic approaches to EV miRNA, protein and genomic cargo analysis can yield new insights into their mechanisms of action and address unresolved questions in the field. We then summarise major experimental evidence regarding the therapeutic potential of EVs in AKI, which we subdivide into stem cell and non-stem cell-derived EVs. Finally, we highlight the challenges and opportunities related to clinical translation of animal studies into human patients.","PeriodicalId":503843,"journal":{"name":"Function","volume":"105 17","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140370705","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
期刊
Function
全部 Acc. Chem. Res. ACS Applied Bio Materials ACS Appl. Electron. Mater. ACS Appl. Energy Mater. ACS Appl. Mater. Interfaces ACS Appl. Nano Mater. ACS Appl. Polym. Mater. ACS BIOMATER-SCI ENG ACS Catal. ACS Cent. Sci. ACS Chem. Biol. ACS Chemical Health & Safety ACS Chem. Neurosci. ACS Comb. Sci. ACS Earth Space Chem. ACS Energy Lett. ACS Infect. Dis. ACS Macro Lett. ACS Mater. Lett. ACS Med. Chem. Lett. ACS Nano ACS Omega ACS Photonics ACS Sens. ACS Sustainable Chem. Eng. ACS Synth. Biol. Anal. Chem. BIOCHEMISTRY-US Bioconjugate Chem. BIOMACROMOLECULES Chem. Res. Toxicol. Chem. Rev. Chem. Mater. CRYST GROWTH DES ENERG FUEL Environ. Sci. Technol. Environ. Sci. Technol. Lett. Eur. J. Inorg. Chem. IND ENG CHEM RES Inorg. Chem. J. Agric. Food. Chem. J. Chem. Eng. Data J. Chem. Educ. J. Chem. Inf. Model. J. Chem. Theory Comput. J. Med. Chem. J. Nat. Prod. J PROTEOME RES J. Am. Chem. Soc. LANGMUIR MACROMOLECULES Mol. Pharmaceutics Nano Lett. Org. Lett. ORG PROCESS RES DEV ORGANOMETALLICS J. Org. Chem. J. Phys. Chem. J. Phys. Chem. A J. Phys. Chem. B J. Phys. Chem. C J. Phys. Chem. Lett. Analyst Anal. Methods Biomater. Sci. Catal. Sci. Technol. Chem. Commun. Chem. Soc. Rev. CHEM EDUC RES PRACT CRYSTENGCOMM Dalton Trans. Energy Environ. Sci. ENVIRON SCI-NANO ENVIRON SCI-PROC IMP ENVIRON SCI-WAT RES Faraday Discuss. Food Funct. Green Chem. Inorg. Chem. Front. Integr. Biol. J. Anal. At. Spectrom. J. Mater. Chem. A J. Mater. Chem. B J. Mater. Chem. C Lab Chip Mater. Chem. Front. Mater. Horiz. MEDCHEMCOMM Metallomics Mol. Biosyst. Mol. Syst. Des. Eng. Nanoscale Nanoscale Horiz. Nat. Prod. Rep. New J. Chem. Org. Biomol. Chem. Org. Chem. Front. PHOTOCH PHOTOBIO SCI PCCP Polym. Chem.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1