首页 > 最新文献

Function (Oxford, England)最新文献

英文 中文
Renal Dysfunction due to Tenofovir-Diphosphate Inhibition of Mitochondrial Complex V (ATP Synthase). 替诺福韦-二磷酸抑制线粒体复合体V (ATP合酶)所致肾功能障碍。
Q2 CELL BIOLOGY Pub Date : 2023-01-01 DOI: 10.1093/function/zqad010
Nicolas Sluis-Cremer
Prescription drugs are a common cause of kidney injury. Druginduced nephrotoxicity, however, is a complex process, and likely involves a combination of factors, including (i) drug characteristics (eg, solubility, structure, and charge); (ii) drug dose and duration of therapy; (iii) inherent drug toxicity; (iv) renal metabolism and excretion of the drug; and (v) patient characteristics that enhance their risk for kidney injury. The mechanisms of drug-induced nephrotoxicity and prevention strategies have been reviewed extensively elsewhere.1,2 Tenofovir disoproxil fumarate (TDF) is a nucleoside reverse transcriptase inhibitor used to treat HIV and HBV infections. TDF therapy, however, has been associated with renal impairment, characterized by a decline in glomerular filtration rate and proximal tubular dysfunction.3 TDF is a prodrug that is rapidly metabolized to the active component tenofovir in plasma. In cells, tenofvoir is metabolized to its active diphosphate form by adenylate monophosphate kinase (tenofovir monophosphate) and 5′-nucleoside diphosphate (tenofovir diphosphate).4 Renal injury is likely related to intracellular tenofovir accumulation in proximal tubule cells. A molecular mechanism of TDF-induced renal toxicity, however, is lacking, but it is thought to be via mitochondrial depletion and structural change, including size and shape changes, and leakage of mitochondrial proteins into the cytosol, with resultant DNA damage, which may even induce apoptosis of the cell. In a recent study, Pearson et al. developed an innovative approach to screen for disease-related functional defects in RPTEC/TERT1 cells, a well-differentiated human-derived cell line that replicates many of the major characteristics of proximal tubular kidney cells in vivo.5 The RPTEC/TERT1 cells were exposed to TDF, and high-throughput imaging was used to generate quantitative readouts of solute transport and mitochondrial morphology, which facilitated development of treatment protocols that reproduced well-described features in patients. By using multiparametric metabolic profiling, including metabolomic screening, oxygen consumption measurements, and RNA-sequencing, the authors determined a molecular fingerprint of TDF toxicity. They found that TDF results in a dose-dependent decrease in mitochondrial ATP synthase, or complex V (EC 3.6.3.14) activity and expression, whereas other mitochondrial functions and pathways were well preserved. Tenofovir disphosphate was found to directly inhibit complex V. Downregulation of complex V expression was also observed in human biopsies. Complex V synthesizes ATP from ADP in the mitochondrial matrix using the energy provided by the proton electrochemical gradient, and mutations in complex V give rise to severe mitochondrial disease phenotypes, ranging from neuropathy, ataxia, and retinitis pigmentosa to maternally inherited Leigh syndrome.6 Of note, in a rat model of TDF nephrotoxicity, the activities of the electron chain compl
{"title":"Renal Dysfunction due to Tenofovir-Diphosphate Inhibition of Mitochondrial Complex V (ATP Synthase).","authors":"Nicolas Sluis-Cremer","doi":"10.1093/function/zqad010","DOIUrl":"https://doi.org/10.1093/function/zqad010","url":null,"abstract":"Prescription drugs are a common cause of kidney injury. Druginduced nephrotoxicity, however, is a complex process, and likely involves a combination of factors, including (i) drug characteristics (eg, solubility, structure, and charge); (ii) drug dose and duration of therapy; (iii) inherent drug toxicity; (iv) renal metabolism and excretion of the drug; and (v) patient characteristics that enhance their risk for kidney injury. The mechanisms of drug-induced nephrotoxicity and prevention strategies have been reviewed extensively elsewhere.1,2 Tenofovir disoproxil fumarate (TDF) is a nucleoside reverse transcriptase inhibitor used to treat HIV and HBV infections. TDF therapy, however, has been associated with renal impairment, characterized by a decline in glomerular filtration rate and proximal tubular dysfunction.3 TDF is a prodrug that is rapidly metabolized to the active component tenofovir in plasma. In cells, tenofvoir is metabolized to its active diphosphate form by adenylate monophosphate kinase (tenofovir monophosphate) and 5′-nucleoside diphosphate (tenofovir diphosphate).4 Renal injury is likely related to intracellular tenofovir accumulation in proximal tubule cells. A molecular mechanism of TDF-induced renal toxicity, however, is lacking, but it is thought to be via mitochondrial depletion and structural change, including size and shape changes, and leakage of mitochondrial proteins into the cytosol, with resultant DNA damage, which may even induce apoptosis of the cell. In a recent study, Pearson et al. developed an innovative approach to screen for disease-related functional defects in RPTEC/TERT1 cells, a well-differentiated human-derived cell line that replicates many of the major characteristics of proximal tubular kidney cells in vivo.5 The RPTEC/TERT1 cells were exposed to TDF, and high-throughput imaging was used to generate quantitative readouts of solute transport and mitochondrial morphology, which facilitated development of treatment protocols that reproduced well-described features in patients. By using multiparametric metabolic profiling, including metabolomic screening, oxygen consumption measurements, and RNA-sequencing, the authors determined a molecular fingerprint of TDF toxicity. They found that TDF results in a dose-dependent decrease in mitochondrial ATP synthase, or complex V (EC 3.6.3.14) activity and expression, whereas other mitochondrial functions and pathways were well preserved. Tenofovir disphosphate was found to directly inhibit complex V. Downregulation of complex V expression was also observed in human biopsies. Complex V synthesizes ATP from ADP in the mitochondrial matrix using the energy provided by the proton electrochemical gradient, and mutations in complex V give rise to severe mitochondrial disease phenotypes, ranging from neuropathy, ataxia, and retinitis pigmentosa to maternally inherited Leigh syndrome.6 Of note, in a rat model of TDF nephrotoxicity, the activities of the electron chain compl","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":"4 3","pages":"zqad010"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10165542/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9479236","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Endogenous Amyloid-formed Ca2+-permeable Channels in Aged 3xTg AD Mice. 老年3xTg AD小鼠内源性淀粉样蛋白形成的Ca2+可渗透通道。
Q2 CELL BIOLOGY Pub Date : 2023-01-01 DOI: 10.1093/function/zqad025
Shuangtao Li, Xiaoyu Ji, Ming Gao, Bing Huang, Shuang Peng, Jie Wu

Alzheimer's disease (AD), the leading cause of dementia, is characterized by the accumulation of beta-amyloid peptides (Aβ). However, whether Aβ itself is a key toxic agent in AD pathogenesis and the precise mechanism of Aβ-elicited neurotoxicity are still debated. Emerging evidence demonstrates that the Aβ channel/pore hypothesis could explain Aβ toxicity, because Aβ oligomers are able to disrupt membranes and cause edge-conductivity pores that may disrupt cell Ca2+ homeostasis and drive neurotoxicity in AD. However, all available data to support this hypothesis have been collected from "in vitro" experiments using high concentrations of exogenous Aβ. It is still unknown whether Aβ channels can be formed by endogenous Aβ in AD animal models. Here, we report an unexpected finding of the spontaneous Ca2+ oscillations in aged 3xTg AD mice but not in age-matched wild-type mice. These spontaneous Ca2+ oscillations are sensitive to extracellular Ca2+, ZnCl2, and the Aβ channel blocker Anle138b, suggesting that these spontaneous Ca2+ oscillations in aged 3xTg AD mice are mediated by endogenous Aβ-formed channels.

阿尔茨海默病(AD)是痴呆症的主要原因,其特征是β -淀粉样肽(Aβ)的积累。然而,a β本身是否是AD发病机制中的关键毒性因子以及a β引发神经毒性的确切机制仍存在争议。新出现的证据表明,Aβ通道/孔假说可以解释Aβ毒性,因为Aβ寡聚物能够破坏膜并引起边缘导电性孔,从而可能破坏细胞Ca2+稳态并驱动AD的神经毒性。然而,支持这一假设的所有可用数据都是从使用高浓度外源性Aβ的“体外”实验中收集的。内源性Aβ能否在AD动物模型中形成Aβ通道尚不清楚。在这里,我们报告了一个意外的发现,在3xTg老年AD小鼠中自发的Ca2+振荡,而在年龄匹配的野生型小鼠中没有。这些自发的Ca2+振荡对细胞外Ca2+、ZnCl2和Aβ通道阻滞剂Anle138b敏感,这表明3xTg AD小鼠的这些自发Ca2+振荡是由内源性Aβ形成的通道介导的。
{"title":"Endogenous Amyloid-formed Ca<sup>2+</sup>-permeable Channels in Aged 3xTg AD Mice.","authors":"Shuangtao Li,&nbsp;Xiaoyu Ji,&nbsp;Ming Gao,&nbsp;Bing Huang,&nbsp;Shuang Peng,&nbsp;Jie Wu","doi":"10.1093/function/zqad025","DOIUrl":"https://doi.org/10.1093/function/zqad025","url":null,"abstract":"<p><p>Alzheimer's disease (AD), the leading cause of dementia, is characterized by the accumulation of beta-amyloid peptides (Aβ). However, whether Aβ itself is a key toxic agent in AD pathogenesis and the precise mechanism of Aβ-elicited neurotoxicity are still debated. Emerging evidence demonstrates that the Aβ channel/pore hypothesis could explain Aβ toxicity, because Aβ oligomers are able to disrupt membranes and cause edge-conductivity pores that may disrupt cell Ca<sup>2+</sup> homeostasis and drive neurotoxicity in AD. However, all available data to support this hypothesis have been collected from \"in vitro\" experiments using high concentrations of exogenous Aβ. It is still unknown whether Aβ channels can be formed by endogenous Aβ in AD animal models. Here, we report an unexpected finding of the spontaneous Ca<sup>2+</sup> oscillations in aged 3xTg AD mice but not in age-matched wild-type mice. These spontaneous Ca<sup>2+</sup> oscillations are sensitive to extracellular Ca<sup>2+</sup>, ZnCl<sub>2</sub>, and the Aβ channel blocker Anle138b, suggesting that these spontaneous Ca<sup>2+</sup> oscillations in aged 3xTg AD mice are mediated by endogenous Aβ-formed channels.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":"4 4","pages":"zqad025"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10278988/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10337522","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 1
Ion Channels and Transporters in Immunity-Where do We Stand? 免疫中的离子通道和转运体——我们的研究进展如何?
Q2 CELL BIOLOGY Pub Date : 2023-01-01 DOI: 10.1093/function/zqac070
Birgit Hoeger, Susanna Zierler
Ions are indispensable for cellular integrity. They constitute organellar identity and homeostasis within the physical barrier of biomembranes, support electrical potential across membranes, provide nutritional support, and serve as signaling entities that are able to adapt to varying challenges within milliseconds. Ion channels are the molecular mediators that shuttle ions between the different cellular compartments, often rather unspecific for certain cations or anions, often in a surprisingly selective manner. Their critical role in every cell type is undoubted. Immune cells are specialized cell types with unique molecular properties. They need to be able to rapidly adapt to various kinds of sudden environmental changes, and, to defend the body from dangerous intruders, consequently respond by massive cellular rearrangements in terms of activation, differentiation, or function. These require pronounced molecular rearrangements, among which ions and ion channels take a central part. Within the last two decades, a number of excellent studies have shed light on the role of distinct ion channels and transporters in immunity. Foremost, the identification of the molecular components ORAI and STIM that mediate store-operated calcium signals in activating lymphocytic and innate immune cells has significantly pushed the field toward studying ion movements and their regulation as the basis for understanding immunity.1–3 With the identification of detrimental mutations in ORAIand STIM-encoding genes causing human immunodeficiencies due to lack of appropriate calcium entry machineries,4 the stage was set for a comprehensive investigation of ion channels in health and disease. Since then, we have gained considerable insight into certain ion channel families and mechanisms. Much attention has been attributed to understanding ion homeostasis and ion signaling in T-cell immunity. Very recently, the attention has moved to VGCCs (voltage-gated Ca2+ channel subunits) being relevant in calcium signaling and triggering downstream effector functions in T cells, without functioning as ion channels themselves.5 To date, a growing number of ion-conducting channels and transporters have been identified to modulate T-, B-, NK, and dendritic cell function, monocytes, macrophages, and neutrophils, as well as mast cell homeostasis (Figure 1).3 This is impressive, but we are still far away from understanding the complex relationships of ion conductance and cellular responses, notwithstanding their contribution to (human) diseases. So where do we go from here? In our opinion, there are a few critical questions that will guide our immediate and longterm attention, and require joint efforts to be deciphered. First, it is still partly unclear which ion channels and family members are functionally expressed in diverse immune cell subsets, which proteins they colocalize or interact with, and under which preconditions they are active. We will surely untangle yet unrecognized ion c
{"title":"Ion Channels and Transporters in Immunity-Where do We Stand?","authors":"Birgit Hoeger,&nbsp;Susanna Zierler","doi":"10.1093/function/zqac070","DOIUrl":"https://doi.org/10.1093/function/zqac070","url":null,"abstract":"Ions are indispensable for cellular integrity. They constitute organellar identity and homeostasis within the physical barrier of biomembranes, support electrical potential across membranes, provide nutritional support, and serve as signaling entities that are able to adapt to varying challenges within milliseconds. Ion channels are the molecular mediators that shuttle ions between the different cellular compartments, often rather unspecific for certain cations or anions, often in a surprisingly selective manner. Their critical role in every cell type is undoubted. Immune cells are specialized cell types with unique molecular properties. They need to be able to rapidly adapt to various kinds of sudden environmental changes, and, to defend the body from dangerous intruders, consequently respond by massive cellular rearrangements in terms of activation, differentiation, or function. These require pronounced molecular rearrangements, among which ions and ion channels take a central part. Within the last two decades, a number of excellent studies have shed light on the role of distinct ion channels and transporters in immunity. Foremost, the identification of the molecular components ORAI and STIM that mediate store-operated calcium signals in activating lymphocytic and innate immune cells has significantly pushed the field toward studying ion movements and their regulation as the basis for understanding immunity.1–3 With the identification of detrimental mutations in ORAIand STIM-encoding genes causing human immunodeficiencies due to lack of appropriate calcium entry machineries,4 the stage was set for a comprehensive investigation of ion channels in health and disease. Since then, we have gained considerable insight into certain ion channel families and mechanisms. Much attention has been attributed to understanding ion homeostasis and ion signaling in T-cell immunity. Very recently, the attention has moved to VGCCs (voltage-gated Ca2+ channel subunits) being relevant in calcium signaling and triggering downstream effector functions in T cells, without functioning as ion channels themselves.5 To date, a growing number of ion-conducting channels and transporters have been identified to modulate T-, B-, NK, and dendritic cell function, monocytes, macrophages, and neutrophils, as well as mast cell homeostasis (Figure 1).3 This is impressive, but we are still far away from understanding the complex relationships of ion conductance and cellular responses, notwithstanding their contribution to (human) diseases. So where do we go from here? In our opinion, there are a few critical questions that will guide our immediate and longterm attention, and require joint efforts to be deciphered. First, it is still partly unclear which ion channels and family members are functionally expressed in diverse immune cell subsets, which proteins they colocalize or interact with, and under which preconditions they are active. We will surely untangle yet unrecognized ion c","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":"4 1","pages":"zqac070"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/93/e3/zqac070.PMC9846422.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9133762","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
"Study the Past if You Would Define the Future."-Confucius. “要决定未来,就要研究过去。”——孔子。
Q2 CELL BIOLOGY Pub Date : 2023-01-01 DOI: 10.1093/function/zqac073
Anant B Parekh, Lord Bhikhu C Parekh
{"title":"\"Study the Past if You Would Define the Future.\"-Confucius.","authors":"Anant B Parekh,&nbsp;Lord Bhikhu C Parekh","doi":"10.1093/function/zqac073","DOIUrl":"https://doi.org/10.1093/function/zqac073","url":null,"abstract":"","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":"4 1","pages":"zqac073"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9850269/pdf/zqac073.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9133763","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Integration of High-Throughput Imaging and Multiparametric Metabolic Profiling Reveals a Mitochondrial Mechanism of Tenofovir Toxicity. 高通量成像和多参数代谢谱的结合揭示了替诺福韦毒性的线粒体机制。
Q2 CELL BIOLOGY Pub Date : 2023-01-01 DOI: 10.1093/function/zqac065
Adam Pearson, Dominik Haenni, Jamal Bouitbir, Matthew Hunt, Brendan A I Payne, Ashwin Sachdeva, Rachel K Y Hung, Frank A Post, John Connolly, Stellor Nlandu-Khodo, Nevena Jankovic, Milica Bugarski, Andrew M Hall

Nephrotoxicity is a major cause of kidney disease and failure in drug development, but understanding of cellular mechanisms is limited, highlighting the need for better experimental models and methodological approaches. Most nephrotoxins damage the proximal tubule (PT), causing functional impairment of solute reabsorption and systemic metabolic complications. The antiviral drug tenofovir disoproxil fumarate (TDF) is an archetypal nephrotoxin, inducing mitochondrial abnormalities and urinary solute wasting, for reasons that were previously unclear. Here, we developed an automated, high-throughput imaging pipeline to screen the effects of TDF on solute transport and mitochondrial morphology in human-derived RPTEC/TERT1 cells, and leveraged this to generate realistic models of functional toxicity. By applying multiparametric metabolic profiling-including oxygen consumption measurements, metabolomics, and transcriptomics-we elucidated a highly robust molecular fingerprint of TDF exposure. Crucially, we identified that the active metabolite inhibits complex V (ATP synthase), and that TDF treatment causes rapid, dose-dependent loss of complex V activity and expression. Moreover, we found evidence of complex V suppression in kidney biopsies from humans with TDF toxicity. Thus, we demonstrate an effective and convenient experimental approach to screen for disease relevant functional defects in kidney cells in vitro, and reveal a new paradigm for understanding the pathogenesis of a substantial cause of nephrotoxicity.

肾毒性是肾脏疾病和药物开发失败的主要原因,但对细胞机制的了解有限,强调需要更好的实验模型和方法方法。大多数肾毒素损害近端小管(PT),引起溶质重吸收功能障碍和全身代谢并发症。抗病毒药物富马酸替诺福韦二氧吡酯(TDF)是一种典型的肾毒素,可引起线粒体异常和尿溶质浪费,原因此前尚不清楚。在这里,我们开发了一种自动化的高通量成像管道,以筛选TDF对人源性RPTEC/TERT1细胞中溶质转运和线粒体形态的影响,并利用它来生成功能毒性的真实模型。通过应用多参数代谢谱-包括耗氧量测量,代谢组学和转录组学-我们阐明了TDF暴露的高度稳健的分子指纹。至关重要的是,我们发现活性代谢物抑制复合体V (ATP合成酶),TDF治疗导致复合体V活性和表达的快速、剂量依赖性丧失。此外,我们在TDF中毒患者的肾脏活检中发现了复合V抑制的证据。因此,我们展示了一种有效和方便的实验方法来筛选体外肾细胞中与疾病相关的功能缺陷,并揭示了一个新的范式来理解肾毒性的一个重要原因的发病机制。
{"title":"Integration of High-Throughput Imaging and Multiparametric Metabolic Profiling Reveals a Mitochondrial Mechanism of Tenofovir Toxicity.","authors":"Adam Pearson,&nbsp;Dominik Haenni,&nbsp;Jamal Bouitbir,&nbsp;Matthew Hunt,&nbsp;Brendan A I Payne,&nbsp;Ashwin Sachdeva,&nbsp;Rachel K Y Hung,&nbsp;Frank A Post,&nbsp;John Connolly,&nbsp;Stellor Nlandu-Khodo,&nbsp;Nevena Jankovic,&nbsp;Milica Bugarski,&nbsp;Andrew M Hall","doi":"10.1093/function/zqac065","DOIUrl":"https://doi.org/10.1093/function/zqac065","url":null,"abstract":"<p><p>Nephrotoxicity is a major cause of kidney disease and failure in drug development, but understanding of cellular mechanisms is limited, highlighting the need for better experimental models and methodological approaches. Most nephrotoxins damage the proximal tubule (PT), causing functional impairment of solute reabsorption and systemic metabolic complications. The antiviral drug tenofovir disoproxil fumarate (TDF) is an archetypal nephrotoxin, inducing mitochondrial abnormalities and urinary solute wasting, for reasons that were previously unclear. Here, we developed an automated, high-throughput imaging pipeline to screen the effects of TDF on solute transport and mitochondrial morphology in human-derived RPTEC/TERT1 cells, and leveraged this to generate realistic models of functional toxicity. By applying multiparametric metabolic profiling-including oxygen consumption measurements, metabolomics, and transcriptomics-we elucidated a highly robust molecular fingerprint of TDF exposure. Crucially, we identified that the active metabolite inhibits complex V (ATP synthase), and that TDF treatment causes rapid, dose-dependent loss of complex V activity and expression. Moreover, we found evidence of complex V suppression in kidney biopsies from humans with TDF toxicity. Thus, we demonstrate an effective and convenient experimental approach to screen for disease relevant functional defects in kidney cells in vitro, and reveal a new paradigm for understanding the pathogenesis of a substantial cause of nephrotoxicity.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":"4 1","pages":"zqac065"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9840465/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9444607","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 2
Slowing Heart Rate Protects Against Pathological Cardiac Hypertrophy. 减慢心率可防止病理性心脏肥大。
Q2 CELL BIOLOGY Pub Date : 2023-01-01 DOI: 10.1093/function/zqac055
Sonia Sebastian, Lee S Weinstein, Andreas Ludwig, Patricia Munroe, Andrew Tinker

We aimed to determine the pathophysiological impact of heart rate (HR) slowing on cardiac function. We have recently developed a murine model in which it is possible to conditionally delete the stimulatory heterotrimeric G-protein (Gαs) in the sinoatrial (SA) node after the addition of tamoxifen using cre-loxP technology. The addition of tamoxifen leads to bradycardia. We used this approach to examine the physiological and pathophysiological effects of HR slowing. We first looked at the impact on exercise performance by running the mice on a treadmill. After the addition of tamoxifen, mice with conditional deletion of Gαs in the SA node ran a shorter distance at a slower speed. Littermate controls preserved their exercise capacity after tamoxifen. Results consistent with impaired cardiac capacity in the mutants were also obtained with a dobutamine echocardiographic stress test. We then examined if HR reduction influenced pathological cardiac hypertrophy using two models: ligation of the left anterior descending coronary artery for myocardial infarction and abdominal aortic banding for hypertensive heart disease. In littermate controls, both procedures resulted in cardiac hypertrophy. However, induction of HR reduction prior to surgical intervention significantly ameliorated the hypertrophy. In order to assess potential protein kinase pathways that may be activated in the left ventricle by relative bradycardia, we used a phospho-antibody array and this revealed selective activation of phosphoinositide-3 kinase. In conclusion, HR reduction protects against pathological cardiac hypertrophy but limits physiological exercise capacity.

我们的目的是确定心率(HR)减慢对心功能的病理生理影响。我们最近开发了一种小鼠模型,在添加他莫昔芬后,使用cre-loxP技术可以有条件地删除窦房结(SA)中的刺激性异三聚体g蛋白(Gαs)。他莫昔芬的加入会导致心动过缓。我们使用这种方法来检查心率减慢的生理和病理生理效应。我们首先通过让老鼠在跑步机上跑步来观察对运动表现的影响。添加他莫昔芬后,SA结条件缺失g - αs小鼠的跑步距离较短,速度较慢。对照组在服用他莫昔芬后保持了运动能力。通过多巴酚丁胺超声心动图压力测试也获得了与突变体心脏容量受损一致的结果。然后,我们使用两种模型检查HR降低是否影响病理性心脏肥厚:心肌梗死的左冠状动脉前降支结扎和高血压心脏病的腹主动脉束带。在同窝的对照组中,这两种方法都导致心脏肥厚。然而,在手术干预前诱导HR降低可显著改善肥厚。为了评估可能在左心室被相对心动过缓激活的潜在蛋白激酶途径,我们使用了磷酸抗体阵列,这显示了磷酸肌醇-3激酶的选择性激活。总之,HR降低可以防止病理性心肌肥厚,但限制了生理性运动能力。
{"title":"Slowing Heart Rate Protects Against Pathological Cardiac Hypertrophy.","authors":"Sonia Sebastian,&nbsp;Lee S Weinstein,&nbsp;Andreas Ludwig,&nbsp;Patricia Munroe,&nbsp;Andrew Tinker","doi":"10.1093/function/zqac055","DOIUrl":"https://doi.org/10.1093/function/zqac055","url":null,"abstract":"<p><p>We aimed to determine the pathophysiological impact of heart rate (HR) slowing on cardiac function. We have recently developed a murine model in which it is possible to conditionally delete the stimulatory heterotrimeric G-protein (Gα<sub>s</sub>) in the sinoatrial (SA) node after the addition of tamoxifen using cre-loxP technology. The addition of tamoxifen leads to bradycardia. We used this approach to examine the physiological and pathophysiological effects of HR slowing. We first looked at the impact on exercise performance by running the mice on a treadmill. After the addition of tamoxifen, mice with conditional deletion of Gα<sub>s</sub> in the SA node ran a shorter distance at a slower speed. Littermate controls preserved their exercise capacity after tamoxifen. Results consistent with impaired cardiac capacity in the mutants were also obtained with a dobutamine echocardiographic stress test. We then examined if HR reduction influenced pathological cardiac hypertrophy using two models: ligation of the left anterior descending coronary artery for myocardial infarction and abdominal aortic banding for hypertensive heart disease. In littermate controls, both procedures resulted in cardiac hypertrophy. However, induction of HR reduction prior to surgical intervention significantly ameliorated the hypertrophy. In order to assess potential protein kinase pathways that may be activated in the left ventricle by relative bradycardia, we used a phospho-antibody array and this revealed selective activation of phosphoinositide-3 kinase. In conclusion, HR reduction protects against pathological cardiac hypertrophy but limits physiological exercise capacity.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":"4 1","pages":"zqac055"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9761894/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10750916","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 2
Physiology and Pathophysiology 2023. 生理学与病理生理学2023。
Q2 CELL BIOLOGY Pub Date : 2023-01-01 DOI: 10.1093/function/zqad005
Ole H Petersen
{"title":"Physiology and Pathophysiology 2023.","authors":"Ole H Petersen","doi":"10.1093/function/zqad005","DOIUrl":"https://doi.org/10.1093/function/zqad005","url":null,"abstract":"","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":"4 2","pages":"zqad005"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9912100/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10737772","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Lipidomics Moves to Center Stage of Biomedicine. 脂质组学走向生物医学的中心舞台。
Q2 CELL BIOLOGY Pub Date : 2023-01-01 DOI: 10.1093/function/zqac071
Valerie B O'Donnell
Ple a s e no t e: Ch a n g e s m a d e a s a r e s ul t of p u blishing p roc e s s e s s uc h a s copy-e di ting, for m a t ting a n d p a g e n u m b e r s m ay no t b e r eflec t e d in t his ve r sion. For t h e d efini tive ve r sion of t his p u blica tion, ple a s e r ef e r to t h e p u blish e d sou rc e. You a r e a dvise d to cons ul t t h e p u blish e r’s ve r sion if you wish to ci t e t his p a p er.
{"title":"Lipidomics Moves to Center Stage of Biomedicine.","authors":"Valerie B O'Donnell","doi":"10.1093/function/zqac071","DOIUrl":"https://doi.org/10.1093/function/zqac071","url":null,"abstract":"Ple a s e no t e: Ch a n g e s m a d e a s a r e s ul t of p u blishing p roc e s s e s s uc h a s copy-e di ting, for m a t ting a n d p a g e n u m b e r s m ay no t b e r eflec t e d in t his ve r sion. For t h e d efini tive ve r sion of t his p u blica tion, ple a s e r ef e r to t h e p u blish e d sou rc e. You a r e a dvise d to cons ul t t h e p u blish e r’s ve r sion if you wish to ci t e t his p a p er.","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":"4 1","pages":"zqac071"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9830535/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10740531","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
What Mediates the Inflammation Resolution? 什么介导炎症消退?
Q2 CELL BIOLOGY Pub Date : 2023-01-01 DOI: 10.1093/function/zqac067
Nils Helge Schebb, Dieter Steinhilber
The concept of specialized proresolving lipid mediators (SPMs) is such a perfect model: Different enzymes of the arachidonic acid cascade lead to formation of specific multiply hydroxylated PUFAs. These SPM stop inflammation at high potency through the binding to G-protein-coupled receptors (GPCRs). 1 A year ago we showed, based on own data and current lit-erature, that neither the formation routes of trihydroxylated specialized proresolving lipid mediators such as lipoxins and resolvins via lipoxygenases are convincing nor the signaling through particular GPCRs has been conclusively demonstrated. 2 This challenges the biological role of these SPMs. However, most attention focused on the finding that analytical methods to demonstrate their formation and occurrence in biological samples are inappropriate, while methods validated accord-ing to internationally agreed standards largely fail to detect the molecules. 2 − 4 Although this started an intense discussion, our questions regarding the formation route, the signaling, and the validity of detection methods have not yet been addressed. Meanwhile, many SPM papers, which show “illustrations” of LC–MS chro-matograms instead of original data are marked in PubPeer but theauthorsareyettoprovideoriginaldatatoprovetheexistence of SPMs in their samples. Instead, arguments such as the testing of SPM in clinical trials, the own h -index or the number of SPM
{"title":"What Mediates the Inflammation Resolution?","authors":"Nils Helge Schebb,&nbsp;Dieter Steinhilber","doi":"10.1093/function/zqac067","DOIUrl":"https://doi.org/10.1093/function/zqac067","url":null,"abstract":"The concept of specialized proresolving lipid mediators (SPMs) is such a perfect model: Different enzymes of the arachidonic acid cascade lead to formation of specific multiply hydroxylated PUFAs. These SPM stop inflammation at high potency through the binding to G-protein-coupled receptors (GPCRs). 1 A year ago we showed, based on own data and current lit-erature, that neither the formation routes of trihydroxylated specialized proresolving lipid mediators such as lipoxins and resolvins via lipoxygenases are convincing nor the signaling through particular GPCRs has been conclusively demonstrated. 2 This challenges the biological role of these SPMs. However, most attention focused on the finding that analytical methods to demonstrate their formation and occurrence in biological samples are inappropriate, while methods validated accord-ing to internationally agreed standards largely fail to detect the molecules. 2 − 4 Although this started an intense discussion, our questions regarding the formation route, the signaling, and the validity of detection methods have not yet been addressed. Meanwhile, many SPM papers, which show “illustrations” of LC–MS chro-matograms instead of original data are marked in PubPeer but theauthorsareyettoprovideoriginaldatatoprovetheexistence of SPMs in their samples. Instead, arguments such as the testing of SPM in clinical trials, the own h -index or the number of SPM","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":"4 1","pages":"zqac067"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/9a/85/zqac067.PMC9825276.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10303937","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Soluble Aβ Oligomers Formed Channels Leading to Calcium Dysregulation. 可溶性Aβ低聚物形成通道导致钙失调。
Q2 CELL BIOLOGY Pub Date : 2023-01-01 DOI: 10.1093/function/zqad037
Shaomin Li
essi v el y impairs cogniti v e function,
{"title":"Soluble Aβ Oligomers Formed Channels Leading to Calcium Dysregulation.","authors":"Shaomin Li","doi":"10.1093/function/zqad037","DOIUrl":"https://doi.org/10.1093/function/zqad037","url":null,"abstract":"essi v el y impairs cogniti v e function,","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":"4 5","pages":"zqad037"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10423025/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10006229","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
期刊
Function (Oxford, England)
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