An Open Label, Six-period Cross-over, Single and Repeat Dose Study to Determine the Pharmacokinetics of Fluticasone Furoate and GSK961081 When Administered Alone, in Combination, or Concurrently Via the ELLIPTA

Batefenterol (BAT) is a novel bifunctional molecule that combines muscarinic antagonism and beta2-agonism in a single molecule and is in development for the treatment of chronic obstructive pulmonary disease (COPD). FF is a corticosteroid approved as the inhaled corticosteroid (ICS) component of a combination product, with vilanterol (VI), a long-acting beta2-agonist for COPD. In the current study FF will be investigated as an inhaled product in combination with BAT, for treatment of COPD.
This study is an open-label, six-way crossover, single and repeat dose study to evaluate the systemic pharmacokinetics, safety and tolerability of FF and BAT when administered via the ELLIPTA™ alone, in combination, or concurrently at 3 times the clinical dose, following a single dose, and at the proposed clinical dose, following repeat doses.
This study will consist of screening period, 6 treatment periods, and a follow-up visit. Each subject will have 3 periods in which they receive a single dose treatment regimen (3 inhalations on Day 1 of each single dose study period) and 3 periods in which they receive a single dose treatment regimen followed by a 7-day, once-daily, repeated dose. On Day 1 of those periods, subjects will receive their single dose as 3 inhalations. On Days 2-8, subjects will receive 1 inhalation per day for the repeated dose regimen. There will be a minimum of 7-day washout between each treatment periods. All subjects will receive 9 treatments and follow-up procedures will be done 7 14 days after the last dose.
Forty eight healthy subjects will be enrolled into the study, such that approximately 40 subjects complete dosing and PK assessments. The total duration of participation for each subject in this study will be up to 15 weeks. ELLIPTA is a registered trademark of the GlaxoSmithKline [GSK] group of companies.

开始日期2016-01-27

申办/合作机构

GSK Plc

[+1]

NCT02055183 / CompletedN/A

Botulinum Antitoxin Patient Registry for the Evaluation of Safety and Clinical Outcomes of Pediatric and Adult Patients Following BAT Treatment for Confirmed or Suspected Exposure to Botulinum Toxin.

The purpose of the Registry was to evaluate patient safety following Botulism Antitoxin Heptavalent (A, B, C, D, E, F, G) - (Equine) (BAT®) administration in adult and pediatric patients with a confirmed or suspected exposure to botulinum toxin.

开始日期2014-10-01

申办/合作机构

Emergent BioSolutions, Inc.

[+2]

NCT00360737 / Completed临床1期

Pharmacokinetics of a Heptavalent Equine-derived Botulinum Antitoxin (NP-018)

The primary purpose of the study is to evaluate the safety of the 7 Botulinum Antitoxin Serotypes derived from horses using various laboratory measurements, clinical examinations and adverse events. In addition, following intravenous (injected into the vein) administration assessing how much 7 Botulinum Antitoxin remains in the body.

开始日期2006-07-01

申办/合作机构

Emergent BioSolutions, Inc.

[+1]

100 项与 Botulism Antitoxin Heptavalent (A, B, C, D, E, F, G) - (Equine) 相关的临床结果

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100 项与 Botulism Antitoxin Heptavalent (A, B, C, D, E, F, G) - (Equine) 相关的专利（医药）

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项与 Botulism Antitoxin Heptavalent (A, B, C, D, E, F, G) - (Equine) 相关的文献（医药）

2024-10-01·Science of The Total Environment

Using organic amendments in disturbed soil to enhance soil organic matter, nutrient content and turfgrass establishment

Article

作者: Pamuru, Sai Thejaswini ; Lea-Cox, John D ; Ristvey, Andrew G ; Davis, Allen P ; Aydilek, Ahmet H ; Morash, Jennifer

Disturbed soils, including manufactured topsoils, often lack physical and chemical properties conducive to vegetation establishment. As a result, efforts to stabilize disturbed soils with vegetation are susceptible to failure. Urban organic waste products such as wood mulch, composted leaf and yard waste, and biosolids are widely distributed as organic amendments that enhance sustainability and plant establishment. Correct use can be determined by examining soil properties such as pH; the concentration of soluble salts (SS); and plant available nutrients - particularly N, C and P; as well as root and shoot growth. This research examined the effects of three typical organic amendments on fertility, establishment, and nutrient loss. A manufactured topsoil was used as the base soil for all treatments, including a control unamended soil (CUT), and soil amended with either mulch (MAT), composted leaf and yard waste (LAT), or biosolids (BAT). A 2 % organic matter concentration increase was sought but not achieved due to difficulty in reproducing lab results at a larger scale. Results showed that LAT improved soil fertility, particularly N-P-K concentrations while maintaining a good C:N ratio, pH, and SS concentration. BAT was the most effective at enhancing shoot growth but results suggest that improved growth rates could result in increased maintenance. Additionally, biosolids were an excellent source of nutrients, especially N-P-K and S, but diminished root growth and N leachate losses indicate that N was applied in excess of turfgrass requirements. Therefore, biosolids could be used as fertilizer, subject to recommended rates for turfgrass establishment to prevent poor root growth and waterborne N pollution. To ensure establishment efforts are successful, MAT is not recommended without a supplemental source of soluble N. Altogether, study results and conclusions could inform others seeking to improve specifications for disturbed soil where turfgrass establishment is needed to stabilize soil.

2024-10-01·Clinical Lymphoma Myeloma and Leukemia

Longitudinal Assessment of Transfusion Intensity in Patients With JAK Inhibitor–Naive or –Experienced Myelofibrosis Treated With Momelotinib

Article

作者: Gerds, Aaron T ; Gonzalez Carreras, Francisco J ; Foltz, Lynda ; Gupta, Vikas ; Gonzalez Carreras, Francisco J. ; Strouse, Bryan ; Passamonti, Francesco ; McLornan, Donal ; Talpaz, Moshe ; Lee, Sung-Eun ; Koschmieder, Steffen ; Perkins, Andrew ; Harrison, Claire N ; Palmer, Jeanne ; Mesa, Ruben ; Harrison, Claire N. ; Oh, Stephen T. ; Goh, Yeow Tee ; Gerds, Aaron T. ; Fox, Maria Laura ; Vannucchi, Alessandro ; Ellis, Catherine ; Oh, Stephen T

PURPOSEAnemia is a cardinal feature of myelofibrosis often managed with red blood cell (RBC) transfusions, which may contribute to negative prognostic, quality-of-life, and healthcare-related economic impacts. The Janus kinase (JAK) 1/JAK2/activin A receptor type 1 inhibitor momelotinib was approved for the treatment of patients with myelofibrosis and anemia based on clinical trial evidence of anemia, spleen, and symptom benefits illustrated using binomial response/nonresponse endpoints. In the present post hoc, descriptive analyses, the impact of momelotinib on RBC transfusion burden over time was further characterized across JAK inhibitor-naive and -experienced patients.METHODSAll RBC units transfused were collected during the baseline and 24-week treatment periods, initially in a single-arm phase 2 study as proof-of-concept analysis, and then versus comparators (ruxolitinib, best available therapy [BAT], and danazol) in the phase 3 SIMPLIFY-1, SIMPLIFY-2, and MOMENTUM studies, respectively.RESULTSIn the phase 2 study, mean transfusion requirement changed by -1.5 units/28 days, with 85% of patients (35/41) achieving numeric transfusion reduction. Across SIMPLIFY-1, SIMPLIFY-2, and MOMENTUM, mean transfusion requirements decreased with momelotinib (-0.1, -0.36, and -0.86 units/28 days), while mean requirements with ruxolitinib, BAT, and danazol changed by +0.39, 0, and ‒0.28 units/28 days, respectively. Overall, 87% (185/213), 77% (79/103), and 85% (110/130) of patients had improved or stable transfusion intensities with momelotinib versus 54% (117/216), 62% (32/52), and 63% (41/65) with ruxolitinib, BAT, and danazol.CONCLUSIONThese novel time-dependent transfusion burden analyses demonstrate that momelotinib is associated with anemia-related benefits in most patients and greater transfusion burden reduction versus comparators.TRIAL REGISTRATIONClinicalTrials.gov identifiers: NCT02515630, NCT01969838, NCT02101268, NCT04173494.

2024-10-01·The Lancet Haematology

Efficacy and safety of fedratinib in patients with myelofibrosis previously treated with ruxolitinib (FREEDOM2): results from a multicentre, open-label, randomised, controlled, phase 3 trial

Article

作者: Passamonti, Francesco ; Xicoy, Blanca ; Wang, Jia ; Talpaz, Moshe ; Al-Ali, Haifa Kathrin ; Kiladjian, Jean-Jacques ; Benevolo, Giulia ; Vannucchi, Alessandro Maria ; Brown, Patrick ; Hernandez, Christopher ; Kim, InHo ; Harrison, Claire N ; Palandri, Francesca ; Iurlo, Alessandra ; Rose, Shelonitda ; Mediavilla, Clemence ; Mesa, Ruben

BACKGROUNDMost patients with myelofibrosis develop ruxolitinib intolerance or disease that is relapsed or refractory, and survival rates after ruxolitinib discontinuation are poor. We aimed to evaluate the safety and efficacy of fedratinib versus best available therapy (BAT) in patients with myelofibrosis previously treated with ruxolitinib.METHODSFREEDOM2 was a multicentre, open-label, randomised, controlled, phase 3 trial in 86 clinics in 16 countries, in which patients aged at least 18 years with intermediate-2 or high-risk myelofibrosis that was relapsed or refractory or intolerant to ruxolitinib with Eastern Cooperative Oncology Group performance status 0-2 were stratified by spleen size by palpation, platelet count, and previous ruxolitinib treatment, and randomly assigned 2:1 by interactive response technology to receive fedratinib 400 mg per day (4 × 100 mg capsules orally once daily, open-label) or BAT. Patients received prophylactic antiemetics and thiamine supplementation, and symptomatic antidiarrhoeals as required. Primary endpoint was proportion of patients reaching spleen volume reduction (SVR) of at least 35% (SVR35) at end of cycle 6 in the intention-to-treat population. This manuscript reports the primary analysis of the trial; follow-up is ongoing. This trial is registered at clinicaltrials.gov, NCT03952039.FINDINGSBetween Sept 9, 2019 and June 24, 2022, of 316 patients screened, 201 were randomly assigned and treated (134 to fedratinib, 67 to BAT [including 52 receiving ruxolitinib]); 46 patients from the BAT group crossed over to fedratinib. Approximately half of enrolled patients were male (fedratinib 75 [56%] of 134; BAT 30 [45%] of 67) and most were White (fedratinib 106 [79%] of 134; BAT 58 [87%] of 67). At data cutoff (Dec 27, 2022), median survival follow-up was 64·5 weeks (IQR 37·9-104·9). SVR35 at end of cycle 6 was seen in 48 (36%) of 134 patients receiving fedratinib versus four (6%) of 67 patients receiving BAT (30% difference; 95% CI 20-39; one-sided p-value <0·0001). During the first six cycles 53 (40%) of 134 patients in the fedratinib group and 8 (12%) of 67 patients in the BAT group had grade 3 or greater treatment-related adverse events, most frequently anaemia (fedratinib 12 [9%] of 134; BAT 6 [9%] of 67) and thrombocytopenia (fedratinib 16 [12%] of 134; BAT 2 [3%] of 67); one patient in the fedratinib group died from acute kidney injury suspected to be related to study drug (no treatment-related deaths in the BAT group). Gastrointestinal adverse events occurred more frequently in the fedratinib group compared with the BAT group, but were mostly grade 1-2 in severity and more frequent in early cycles, and were less frequent than in prior clinical trials. A total of 28 (21%) of 134 patients in the fedratinib group and 3 (4%) of 67 patients in the BAT group had thiamine levels below lower limit of normal per central laboratory assessment, with only one case of low thiamine in the fedratinib arm after the introduction of prophylactic thiamine supplementation.INTERPRETATIONFindings from FREEDOM2 support fedratinib as a second-line Janus kinase inhibitor option to reduce spleen size after ruxolitinib failure or intolerance in patients with myelofibrosis, and shows effective strategies for management of gastrointestinal adverse events and low thiamine concentrations through prophylaxis, monitoring, and treatment.FUNDINGBristol Myers Squibb.

项与 Botulism Antitoxin Heptavalent (A, B, C, D, E, F, G) - (Equine) 相关的新闻（医药）

2024-11-01

·生物探索

Nat Metab | ACLY在棕色脂肪组织中调节产热与代谢应激的新机制

引言棕色脂肪组织（BAT）在哺乳动物能量代谢中扮演着重要角色，尤其在寒冷环境下，它通过非颤栗性产热帮助维持体温。BAT的产热过程由去甲肾上腺素激活，依赖线粒体内膜上的解偶联蛋白1（UCP1），通过消耗线粒体内的电化学质子梯度，将能量转化为热量，从而实现产热功能【1】。此外，BAT还能够通过产热消耗多余的营养物质，帮助预防心脏代谢疾病和某些类型的癌症。 BAT的产热功能与脂肪酸氧化（FAO）关系密切，通过将脂肪酸氧化生成的能量转化为TCA循环的燃料，支持了线粒体的解偶联呼吸【2】。令人费解的是，BAT活跃进行脂肪酸氧化的同时，也大幅增加了细胞质中的脂肪酸合成（FAS），形成了所谓的“无效代谢循环（futile metabolic cycles）”【3】。这一现象表面上与其能量消耗的生理功能相矛盾，特别是考虑到BAT是脂质合成最活跃的组织之一。乙酰辅酶A是从非脂质前体（如葡萄糖）合成脂肪酸和新生脂质的底物，而细胞质中的柠檬酸裂解酶（ACLY）是生成乙酰辅酶A的主要催化酶；在特定条件下，乙酰辅酶A合成酶短链家族成员2（ACSS2）也能通过醋酸生成乙酰辅酶A，为脂肪酸合成提供了另一来源【4】。在寒冷条件下，BAT中的ACLY和ACSS2表达上调，伴随葡萄糖摄取和脂肪合成的活化，但这些合成的脂肪酸不会长时间储存，而是迅速被氧化。虽然这种脂肪酸“合成-氧化”的FAS-FAO循环已被发现多年，其确切功能和生物学意义仍待深入研究，BAT的能量代谢机制比表面上单纯的能量消耗更为复杂。 2024年10月17日，麻省大学医学院David A. Guertin实验室领衔在Nature Metabolism杂志发表了题为Brown fat ATP-citrate lyase links carbohydrate availability to thermogenesis and guards against metabolic stress的研究文章，揭示了ACLY在BAT中通过缓解代谢压力来促进产热的关键作用。研究发现，BAT中ACLY的缺失会导致TCA循环超负荷，激活整合应激反应（ISR），并抑制产热功能。此外，BAT中同时敲除脂肪酸合成酶（Fasn）和Acly的编码基因能够激活替代的代谢途径，恢复正常的产热功能。本研究为理解BAT中脂肪酸“合成-氧化”间“矛盾”而复杂的代谢调控关系提供了新见解。为了研究ACLY和ACSS2在BAT中的作用，作者构建了BAT组织特异性敲除Acly或Acss2的转基因小鼠模型（AclyBATKO和Acss2BATKO）。利用该模型，作者发现ACLY的缺失导致小鼠BAT发生“白化”、组织质量增加，并在寒冷环境中体温迅速下降。相比之下，ACSS2的缺失并未引起类似的生理变化，表明ACLY在BAT产热和应对寒冷刺激中的关键性。此外，AclyBATKO小鼠BAT“白化”表明脂质发生累积，但脂质合成相关基因的表达反而降低，暗示了此时FAO功能被抑制，而非脂质合成增加，导致了BAT变白。这些变化还伴随着新生脂质合成、葡萄糖摄取、Glut4表达以及脂质摄取相关基因的表达下调，进一步表明BAT中ACLY缺失抑制了FAO活性。研究还发现，Acly的缺失严重损害了BAT中的线粒体功能，表现为UCP1、ETC亚基以及多种线粒体相关磷脂水平的下降，但未见线粒体超微结构的显著变化。此外，ACLY在BAT中的缺失还显著降低了线粒体生物发生和代谢相关的关键基因表达，进而导致产热能力减弱，并伴随耗氧率和细胞外酸化率的下降。因此，ACLY在维持BAT中线粒体功能和解偶联呼吸中发挥了关键作用，进而调控了BAT的产热活性。长期剧烈的寒冷应激会在皮下白色脂肪组织（WAT）中诱导棕色样脂肪细胞，称为米色或亮棕色脂肪细胞，这一过程称为WAT的“棕化”。为了检测ACLY是否也对WAT的棕化至关重要，作者将脂肪组织Acly特异性敲除小鼠（AclyFATKO）置于6°C的寒冷环境4周，发现缺乏ACLY的小鼠无法在寒冷环境中形成米色/亮棕色脂肪细胞，且伴随着UCP1、线粒体相关基因及产热基因的表达降低。因此，ACLY不仅在BAT中调节产热功能，还在寒冷应激下影响WAT的棕化过程。进一步探究ACLY缺失影响产热的机制后，作者发现诱导ACLY敲除的小鼠中编码线粒体、呼吸链和脂质代谢的基因下调，而炎症标志物基因上调。同时，ISR（整合应激反应）和线粒体质量控制通路也被激活，从而抑制产热并诱导代谢重塑。可见，ACLY的缺失通过触发代谢应激和ISR途径对棕色脂肪组织的功能产生了广泛的影响。接下来，作者对AclyBATKO小鼠进行了酰基辅酶A谱分析和[13C]葡萄糖同位素示踪实验，发现ACLY缺失导致了棕色脂肪组织中TCA循环过载，进而激发ISR，表明ACLY能够通过平衡TCA循环的负荷，缓解代谢应激并维持BAT的正常功能。值得注意的是，双敲除Fasn和Acly能够抵消ACLY缺失导致的BAT白化和代谢应激。Fasn和Acly的双敲除通过调节碳代谢途径，恢复了乙酰辅酶A的水平，缓解了ACLY缺失引发的代谢失调。这表明Fasn与ACLY之间的互作对于调节乙酰辅酶A的利用及碳通量的平衡至关重要。此外， Fasn和Acly的双敲除显著抑制了与代谢压力相关的ISR信号通路的激活和炎症反应。因此，BAT中Fasn和Acly的双敲除通过在产热过程中重新平衡进入线粒体的碳通量及TCA循环活性，挽救了Acly缺失引起的代谢失衡。模式图（Credit: Nature Metabolism）综上所述，本研究揭示了ATP-柠檬酸裂解酶（ACLY）通过缓解代谢应激，维持棕色脂肪组织产热功能的关键作用。ACLY的缺失会引发TCA循环超负荷并激活整合应激反应，最终抑制产热功能，而同时敲除Fasn和ACLY能够激活替代代谢途径，恢复正常产热功能。这项研究为理解BAT中脂肪酸合成与氧化之间的复杂关系提供了新的见解。参考文献 1. Cannon, B. & Nedergaard, J. Brown adipose tissue: function and physiological significance. Physiol. Rev. 84, 277–359 (2004). 2. Hankir, M. K. & Klingenspor, M. Brown adipocyte glucose metabolism: a heated subject. EMBO Rep.19, e46404 (2018). 3. Mottillo, E. P. et al. Coupling of lipolysis and de novo lipogenesis in brown, beige, and white adipose tissues during chronic beta3-adrenergic receptor activation. J. Lipid Res. 55, 2276–2286 (2014). 4. Guertin, D. A. & Wellen, K. E. Acetyl-CoA metabolism in cancer. Nat. Rev. Cancer 23, 156–172 (2023). https://www.nature.com/articles/s42255-024-01143-3 责编|探索君排版|探索君来源|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

2024-08-30

·今日头条

【Nature】牛津大学团队：神经肽Y在交感神经元中，抑制肥胖的奥秘

【导读】神经肽Y（NPY）的人类突变与高体重指数有关，但与饮食模式的改变无关。在这项研究中，团队揭示了NPY在交感神经元中，防止肥胖的机制。 2024年8月28日，牛津大学Ana Domingos团队在期刊《Nature》上发表了题为“Sympathetic neuropeptide Y protects from obesity by sustaining thermogenic fat”的研究论文。研究结果表明，相对于中枢NPY，交感神经产生的外周NPY，通过维持独立于食物摄入的能量消耗，对体重产生相反的影响。 https://www.nature.com/articles/s41586-024-07863-6#Abs1 研究介绍 01 BAT和WAT内的交感神经，局部释放去甲肾上腺素，以触发脂肪分解和产热。许多报告表明，大脑中的NPY会刺激食欲，敲除NPY对日常食物消费，没有影响。此外，尽管吃得少，但没有NPY受体的小鼠，会发展为迟发性肥胖。在人类中，NPY的突变与高体重指数（BMI）有关，但与饮食模式的改变无关。这些发现表明，来自大脑和交感神经系统的NPY，在体重调节中的作用截然不同。为了检验这一假设，团队使用了动物模型，其中NPY从交感神经元中去除，同时在大脑中保持完整。研究进展 02 交感神经NPY调节渗漏为了检验交感神经元衍生的NPY，在体内维持壁细胞所必需的假设，团队生成了一个模型：Th Cre ；Npy Flox/Flox 小鼠，其中NPY从交感神经元中被去除。团队首先证实，在Th Cre ；Npy Flox/Flox 小鼠中，NPY从交感神经节和支配iWAT和iBAT的交感神经轴突中被去除，而一般TH交感神经支配，不受影响。使用这种小鼠模型，团队证明，交感神经元中NPY的缺失，下调了ND处理小鼠iBAT和iWAT的耗尽壁细胞中的标志物。因为壁细胞是血管完整性所必需的，团队观察到Th Cre ；Npy Flox/Flox 小鼠的iBAT和iWAT血管渗漏增加。团队进一步评估了静脉注射右旋糖酐-70kDa的活体方法中，附膜WAT的血管渗漏。Th Cre ；Npy Flox/Flox 小鼠血管渗漏增加，表现为Dextran-70kDa泄漏到实质中，而血流保持不变。与血管渗漏增加一致，团队在iBAT中观察到，促炎基因上调和ND处理的Th Cre ；Npy Flox/Flox 小鼠的iBAT和 iWAT免疫浸润增加。这些观察结果证实， NPY是维持脂肪组织中壁细胞和防止免疫浸润所必需的。交感神经元NPY的丢失，会耗尽iBAT和iWAT中的壁细胞，并增加血管渗漏。交感神经NPY可防止肥胖团队发现，ND处理的Th Cre ；Npy Flox/Flox 小鼠的iBAT变白和增大，并且它们的iBAT在产热方面功能失调。与此一致，Th Cre ；Npy Flox/Flox 小鼠的每日能量消耗和高级呼吸交换较低，表明脂肪作为代谢底物的使用减少。当食物受到限制时，Th Cre ；Npy Flox/Flox 小鼠在14小时的禁食期间，表现出较低的iBAT温度和更少的体重减轻，这表明能量守恒。冷暴露8小时后，与它们的野生型（WT）同窝伴侣相比，Th Cre ；Npy Flox/Flox 小鼠的直肠温度较低，iBAT中产热基因和iWAT中Prdm16下调。这些改变不太可能与肌肉活动有关，因为Th Cre ；Npy Flox/Flox 小鼠具有与WT小鼠相同的体重和运动活性。作为产热能力不足和能量消耗减少的累积结果，ND处理的Th Cre ；Npy Flox/Flox 小鼠，在30周时出现成人发病的肥胖；与WT小鼠相比，脂肪库更重。当使用HFD时，Th Cre ；Npy Flox/Flox 小鼠比WT小鼠更早、更快地肥胖，却没有增加食物摄入量。此外，HFD处理的Th Cre ；Npy Flox/Flox 小鼠的脂肪库明显更重，它们的iBAT含有较大的脂滴。最后，代谢表型在性别之间是一致的。与对照小鼠相比，HFD治疗的雌性Th Cre ；Npy Flox/Flox 小鼠的体重、WAT和iBAT也更重。团队可以确定，在Th Cre ；Npy Flox/Flox 小鼠中观察到的代谢表型，不是由大脑中的NPY神经元或全身性NPY引起的，因为（1）在下丘脑中没有儿茶酚胺能神经元，共表达NPY或腹侧被盖区；并且NPY在Th Cre ；Npy Flox/Flox 小鼠下丘脑中的表达，没有改变。（2）代谢表型不是由全身性NPY引起的，因为Th Cre ；Npy Flox/Flox 小鼠血浆中的NPY浓度保持不变。（3）即使后脑中有NPY儿茶酚胺能神经元，从后脑敲除NPY，对产热或iBAT都没有影响。综上所述，脂肪组织中交感神经元衍生的NPY，是维持能量消耗和瘦弱所必需的。交感神经元的NPY丢失，会使BAT变白，减少能量消耗和产热，并使小鼠更容易感染DIO，而不会增加食物摄入量。研究结论 03 本研究提供了WAT和BAT中NPY神经支配的解剖图，表明只有1/3的交感神经支配是神经肽能的，并且它优先靶向存在壁细胞的小动脉。该研究表明，脂肪组织内的交感神经轴突，会随着肥胖的发作而回缩和退化。 NPY通过促进脂肪细胞在体外增殖来维持壁细胞，这些细胞是产热脂肪细胞的来源。在体内，来源于交感神经元的NPY，对于支持壁细胞和产热脂肪细胞的正常发育，是必需的。交感神经元中NPY（NPY-cKO）的条件敲除，会在肥胖开始之前，耗尽壁细胞并美白棕色脂肪，使该组织肥大并产热能力降低。这些NPY-cKO小鼠的产热能力降低，能量消耗降低，表现出对寒冷的不耐受，在常规食物饮食中发展为迟发性肥胖，并在喂食高脂肪饮食而没有吃得更多时，迅速发展为肥胖。这些代谢表型与全身NPY受体敲除小鼠的代谢表型相匹配，即使它们吃得稍微少一些，它们也会在常规食物饮食中，发展为迟发性肥胖。尽管如此，壁细胞增殖破坏和脂肪细胞分化，是NPY-cKO小鼠脂肪功能障碍的原因，并且是多种可能性之一，包括血管渗漏和脂肪组织炎症之间的相互因果关系。综上所述，团队阐明了NPY的中枢和外围来源在体重稳态中，具有对跖作用。这项研究中描述的生物学机制，可能解释了为什么产食欲NPY的突变与人类的高BMI相关。最后，根据这些研究确定的机制，在某些个体中，能量耗散可能比食欲更重要。参考资料： 1.Dornbos, P. et al. Evaluating human genetic support for hypothesized metabolic disease genes. Cell Metab. 34, 661–666 (2022). 2.Lundberg, J. M. et al. Neuropeptide Y (NPY)‐like immunoreactivity in peripheral noradrenergic neurons and effects of NPY on sympathetic function. Acta Physiol. Scand. 116, 477–480 (1982). 【关于投稿】转化医学网（360zhyx.com）是转化医学核心门户，旨在推动基础研究、临床诊疗和产业的发展，核心内容涵盖组学、检验、免疫、肿瘤、心血管、糖尿病等。如您有最新的研究内容发表，欢迎联系我们进行免费报道（公众号菜单栏-在线客服联系），我们的理念：内容创造价值，转化铸就未来！转化医学网（360zhyx.com）发布的文章旨在介绍前沿医学研究进展，不能作为治疗方案使用；如需获得健康指导，请至正规医院就诊。热门推荐活动点击免费报名 🕓 上海｜09月11日 ▶ 微驭万物-单细胞空间组学技术前沿与临床应用研讨会 🕓 北京｜09月20日-21日 ▶ 第五届单细胞技术应用研讨会暨空间组学前沿研讨会 🕓 上海｜11月15日-16日 ▶ 2024第一届中国类器官转化医学大会点击对应文字查看详情

2024-06-25

·生物探索

JCI丨孔星星团队阐明MSTN在棕色脂肪组织调节系统代谢的关键作用

引言棕色脂肪组织（BAT）在全身能量平衡中发挥至关重要的作用。产热脂肪细胞中丰富的线粒体以及UCP1的表达使棕色脂肪具有独特的产热能力。同时，BAT也是一个内分泌器官，可分泌脂肪因子、微囊泡，靶向白色脂肪组织、肝脏和骨骼肌等外周组织。 Myostatin（MSTN），又称生长分化因子8（GDF-8），是转化生长因子β（TGF-β）家族的重要成员。自从1997年首次被发现以来，Myostatin因其在肌肉生长中的负调控作用而受到广泛关注。Myostatin通过抑制肌肉细胞的生长和分化来控制肌肉质量，基因突变或敲除Myostatin会导致肌肉质量显著增加。在肌肉萎缩症和肌肉衰减综合征等疾病中，抑制Myostatin被认为是一种潜在的治疗策略。然而，近年来的研究表明，Myostatin不仅影响肌肉，还对脂肪组织和整体代谢有重要影响。 2024年6月19日，复旦大学生命科学学院孔星星教授团队在JCI杂志在线发表Myostatin regulates energy homeostasis through autocrine- and paracrine-mediated microenvironment communications的研究论文，阐述了棕色脂肪细胞MSTN调控系统代谢的作用。为肥胖和代谢紊乱的治疗提供了新的途径。孔星星团队一直来研究脂肪组织与骨骼肌等组织器官的代谢与网络调控。之前的研究工作（Brown Adipose Tissue Controls Skeletal Muscle Function via the Secretion of Myostatin. Cell Metabolism, 28:631–643, 2018）首次阐释了BAT可以调控骨骼肌的结构与功能，从而影响运动；同时发现BAT可以分泌MSTN。紧接着，团队很好奇肌肉质量的关键负调控因子MSTN为何会被BAT分泌？会不会发挥代谢功能？深入研究发现，棕色脂肪组织特异性缺失MSTN的小鼠表现出饮食诱导的肥胖、胰岛素抵抗、脂肪肝，以及骨骼肌功能受损，与MSTN全身敲除小鼠的表型矛盾。进一步的研究表明，Kruppel样因子4（KLF4）负责介导代谢表型的变化，而FGF21参与了由于棕色脂肪组织缺失MSTN诱导的棕色脂肪细胞和巨噬细胞之间的微环境改变。此外，MSTN-SMAD2/3-p38信号通路介导脂肪细胞中KLF4和FGF21的表达。模式图（Credit:J Clin Invest）总的来说，该研究证实了棕色脂肪细胞来源的MSTN通过自分泌和旁分泌作用调控BAT产热，进而调节全身能量稳态，还提示更好地了解脂肪组织中的MSTN有可能为控制体重和体脂带来新的临床应用前景。参考文献 https://pubmed.ncbi.nlm.nih.gov/38889010/ 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

100 项与 Botulism Antitoxin Heptavalent (A, B, C, D, E, F, G) - (Equine) 相关的药物交易

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适应症	国家/地区	公司	日期
肉毒中毒	美国	Cangene Corp.	2013-03-22
肉毒中毒	美国	Emergent BioSolutions Canada, Inc.	2013-03-22

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT02055183 (Pubmed \| Clin Infect Dis)	N/A	肉毒中毒	162	BAT product	(夢壓構襯淵簾淵廠衊繭) = 衊鹹餘壓蓋簾願膚鑰蓋築窪鏇構鹹糧鏇齋壓願 (憲網觸鑰鹽糧糧選淵壓 ) 更多	-	2020-04-15
NCT02666287 (Pubmed)	临床1期	慢性阻塞性肺疾病	48	BAT/FF	餘淵襯願醖鹹製壓艱廠(齋鹽窪製醖夢鏇鹽願窪): P-Value = 0.79 更多	-	2019-02-01
NCT02666287 (Pubmed)	临床1期	慢性阻塞性肺疾病	48	FF	餘淵襯願醖鹹製壓艱廠(齋鹽窪製醖夢鏇鹽願窪): P-Value = 0.79 更多	-	2019-02-01