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

登录后查看更多信息

100 项与 Botulism Antitoxin Heptavalent (A, B, C, D, E, F, G) - (Equine) 相关的转化医学

登录后查看更多信息

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

登录后查看更多信息

165

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

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.

2024-09-01·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: Vannucchi, Alessandro Maria ; Brown, Patrick ; Hernandez, Christopher ; Rose, Shelonitda ; Passamonti, Francesco ; Talpaz, Moshe ; Wang, Jia ; Al-Ali, Haifa Kathrin ; Benevolo, Giulia ; Kim, InHo ; Xicoy, Blanca ; Palandri, Francesca ; Mesa, Ruben ; Iurlo, Alessandra ; Harrison, Claire N ; Kiladjian, Jean-Jacques ; Mediavilla, Clemence

BACKGROUND:

Most 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.

METHODS:

FREEDOM2 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.

FINDINGS:

Between 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.

INTERPRETATION:

Findings 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.

FUNDING:

Bristol Myers Squibb.

2024-09-01·ADVANCES IN THERAPY

Momelotinib versus Continued Ruxolitinib or Best Available Therapy in JAK Inhibitor-Experienced Patients with Myelofibrosis and Anemia: Subgroup Analysis of SIMPLIFY-2

Article

作者: Yacoub, Abdulraheem ; Platzbecker, Uwe ; Sirhan, Shireen ; Gerds, Aaron T ; Ellis, Catherine ; Hernandez-Boluda, Juan Carlos ; Vannucchi, Alessandro M ; Passamonti, Francesco ; Harrison, Claire N ; Recher, Christian ; Strouse, Bryan ; Patel, Bharat

Abstract:

Introduction:

Some Janus kinase (JAK) inhibitors such as ruxolitinib and fedratinib do not address and may worsen anemia in patients with myelofibrosis. In these cases, the JAK inhibitor may be continued at a reduced dose in an effort to maintain splenic and symptom control, with supportive therapy and/or red blood cell (RBC) transfusions added to manage anemia. This post hoc descriptive analysis of the phase 3 SIMPLIFY-2 trial evaluated the relative benefits of this approach versus switching to the JAK1/JAK2/activin A receptor type 1 inhibitor momelotinib in patients for whom anemia management is a key consideration.

Methods:

SIMPLIFY-2 was a randomized (2:1), open-label, phase 3 trial of momelotinib versus best available therapy (BAT; 88.5% continued ruxolitinib) in JAK inhibitor-experienced patients with myelofibrosis (n = 156). Patient subgroups (n = 105 each) were defined by either baseline (1) hemoglobin (Hb) of < 100 g/L or (2) non-transfusion independence (not meeting the criteria of no transfusions and no Hb of < 80 g/L for the previous 12 weeks); outcomes have been summarized descriptively.

Results:

In both subgroups of interest, week 24 transfusion independence rates were higher with momelotinib versus BAT/ruxolitinib: baseline Hb of < 100 g/L, 22 (33.3%) versus 5 (12.8%); baseline non-transfusion independent, 25 (34.7%) versus 1 (3.0%). Mean Hb levels over time were also generally higher in both subgroups with momelotinib, despite median transfusion rates through week 24 with momelotinib being comparable to or lower than with BAT/ruxolitinib. Spleen and symptom response rates with momelotinib in these subgroups were comparable to the intent-to-treat population, while rates with BAT/ruxolitinib were lower.

Conclusion:

In patients with moderate-to-severe anemia and/or in need of RBC transfusions, outcomes were improved by switching to momelotinib rather than continuing ruxolitinib and using anemia supportive therapies.

Trial Registration:

ClinicalTrials.gov: NCT02101268.

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

2024-09-10

·生物探索

Cell Metab丨肖玲等揭示棕色脂肪中的m⁶A mRNA甲基化通过独立于UCP1的前列腺素信号调控全身胰岛素敏感性

引言棕色脂肪组织（BAT）因其通过解偶联蛋白1（UCP1）产生热量，成为治疗和预防肥胖及相关代谢疾病的潜在靶点。研究表明，冷刺激激活的BAT可以通过能量消耗减少体脂，改善心脏代谢健康，特别在超重和肥胖个体中效果显著。尽管BAT的产热功能备受关注，近年来越来越多的证据表明，BAT还通过分泌各种有益因子（"BATokine"，如肽类、蛋白质、脂质、miRNA等）对全身代谢产生积极调节。其中，一类被称为“BAT lipokine”的脂质因子尤为重要【1,2】，它与胰岛素敏感性、葡萄糖耐量以及炎症调节密切相关。 m6A（N6-甲基腺嘌呤）是RNA中最常见的内部甲基化修饰之一，广泛存在于真核生物的mRNA和非编码RNA中，在RNA剪接、翻译、稳定性和降解等过程中发挥重要作用。m6A修饰与干细胞分化、肿瘤发生、免疫调控和代谢紊乱等生理与病理过程密切相关。尽管已知m6A在棕色脂肪产热中具有重要作用，但m6A是否通过调控棕色脂肪分泌的"BATokine"影响全身代谢尚不清楚。 2024年9月9日，哈佛医学院及Joslin糖尿病研究中心（Joslin Diabetes Center）的Rohit N. Kulkarni教授团队在Cell Metabolism在线发表了题为m6A mRNA Methylation in Brown Fat Regulates Systemic Insulin Sensitivity via an Inter-Organ Prostaglandin Signaling Axis Independent of UCP1的研究成果。该研究通过基因组学、甲基化组学和脂质组学等多组学手段，首次揭示了：1. 由甲基转移酶14（METTL14）介导的m6A修饰，通过负向调控BAT中前列腺素合成酶的表达，抑制了前列腺素PGE2和PGF2α的合成；2. 敲除BAT中的METTL14显著提高了PGE2和PGF2α的水平，从而改善了胰岛素敏感性，促进了白色脂肪棕色化，并降低了肥胖小鼠体重；3. 揭示了PGE2和PGF2α作为新型胰岛素增敏剂的新分子机制。研究者首先检测了不同胰岛素抵抗小鼠模型中BAT的m6A甲基转移酶水平，发现胰岛素抵抗小鼠BAT中METTL14高表达，提示其与胰岛素敏感性负相关。进一步通过特异性敲除小鼠BAT中的METTL14，结果显示，敲除后小鼠全身多种代谢组织的胰岛素敏感性显著提升。这表明METTL14的缺失能够通过BAT与其他代谢组织的相互作用改善胰岛素敏感性，且不依赖于UCP1的产热功能。通过脂质组学分析，研究者发现，在METTL14缺失的小鼠棕色脂肪组织及人源性棕色脂肪细胞中，PGE2和PGF2α的水平显著升高。进一步研究表明，PGE2和PGF2α能够显著增强代谢细胞的胰岛素敏感性。在肥胖小鼠模型中注射这两种前列腺素，表现出胰岛素增敏及抗肥胖的表型特征，并伴随白色脂肪组织的米色化现象。值得注意的是，PGE2和PGF2α的血液水平在肥胖及胰岛素抵抗人体中与胰岛素敏感性呈显著正相关。机制研究进一步揭示，PGE2和PGF2α通过特异性GPCR介导的信号通路，抑制AKT磷酸酶的活性，从而提高胰岛素敏感性。模式图（Credit: Cell Metabolism）为了进一步研究m6A如何调控BAT中前列腺素的合成，研究者结合基因组学和m6A甲基化组学，发现METTL14的缺失通过降低m6A甲基化水平，增强了前列腺素合成酶基因的稳定性，增加了其表达。综上所述，该研究揭示了m6A通过调控前列腺素在棕色脂肪中的合成，进而影响全身代谢的新机制，拓展了m6A及其他表观遗传修饰在代谢调控中的研究思路。模式图（Credit: Cell Metabolism）参考文献 1 SHAMSI, F.; WANG, C. H.; TSENG, Y. H. The evolving view of thermogenic adipocytes - ontogeny, niche and function. Nat Rev Endocrinol, v. 17, n. 12, p. 726-744, Dec 2021. ISSN 1759-5029 (Print) 1759-5029. 2 CYPESS, A. M. Reassessing Human Adipose Tissue. N Engl J Med, v. 386, n. 8, p. 768-779, Feb 24 2022. ISSN 0028-4793. 3 DE JESUS, D. F. et al. m(6)A mRNA Methylation Regulates Human β-Cell Biology in Physiological States and in Type 2 Diabetes. In: (Ed.). Nat Metab. Germany, v.1, 2019. p.765-774. ISBN 2522-5812 (Electronic) 2522-5812 (Linking). 4 D, F. D. J. et al. Redox regulation of m(6)A methyltransferase METTL3 in β-cells controls the innate immune response in type 1 diabetes. Nat Cell Biol, v. 26, n. 3, p. 421-437, Mar 2024. ISSN 1465-7392. 5 KAHRAMAN, S. et al. m6A mRNA Methylation Regulates Early Pancreatic β-Cell Differentiation. bioRxiv, p. 2023.08.03.551675, 2023. Disponível em: < https://www.biorxiv.org/content/biorxiv/early/2023/08/03/2023.08.03.551675.full.pdf >. https://doi-org.libproxy1.nus.edu.sg/10.1016/j.cmet.2024.08.006 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

信使RNA

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.libproxy1.nus.edu.sg/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.libproxy1.nus.edu.sg/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

登录后查看更多信息

研发状态

10 条最早获批的记录,

后查看更多信息

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

登录后查看更多信息

临床结果

适应症

分期

评价

查看全部结果

研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


AAAAI2024	N/A	-	16	Methylprednisolone	繭淵廠夢淵鬱遞夢製網(獵鹽繭夢構構淵繭簾構) = 膚獵憲糧遞鑰築壓積糧觸構壓鏇選蓋窪範襯憲 (窪獵網築憲築壓壓網艱 )	积极	2024-02-23
AAAAI2024	N/A	-	16	Dexamethasone	繭淵廠夢淵鬱遞夢製網(獵鹽繭夢構構淵繭簾構) = 窪衊鹽憲淵鏇艱範淵廠觸構壓鏇選蓋窪範襯憲 (窪獵網築憲築壓壓網艱 )	积极	2024-02-23
NCT02055183 (Pubmed \| Clin Infect Dis)	N/A	肉毒中毒	162	BAT product	淵遞範鏇簾衊範鹹獵範(襯膚鏇襯鬱糧繭淵觸製) = 窪遞糧廠憲選觸醖簾廠餘憲壓鬱艱觸醖積淵鑰 (築廠淵鏇構鹹夢築淵鏇 ) 更多	-	2020-04-15