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Injection of lentiviral vectors expressing GH and IGF1 increases body and muscle mass in male rats 注射表达生长激素和IGF1的慢病毒载体可增加雄性大鼠的体重和肌肉质量
IF 1.6 4区 医学 Q4 CELL BIOLOGY Pub Date : 2025-08-28 DOI: 10.1016/j.ghir.2025.101663
Zahra Roudbari , Akram Alizadeh , Mohammadreza Nassiri , Ali Fallah , Ali Javadmanesh
The aim of this study was to increase growth hormone (GH1) and insulin-like growth factor-1 (IGF1) levels in rat muscle indirectly through the transduction of C2C12 cells via lentivectors and to compare their effects on muscle mass. The coding sequences of GH1, IGF1, and GH1-IGF1, linked by the 2 A self-cleaving peptide to enable polycistronic expression, were synthesized, cloned and inserted into the pCDH vector. Recombinant pseudolentiviruses containing our target genes were produced in HEK293T cells. C2C12 cells were transduced with pseudo lentiviruses and selected through resistance to puromycin antibiotics. The expression of the GH1 and IGF1 genes at the mRNA and protein levels was verified by RT–PCR and Western blotting, respectively. The recombinant pseudo lentiviruses and transduced C2C12 cells were injected into the tibialis anterior (TA), gastrocnemius and quadriceps muscle groups of eight-week-old rats. The body weights of the rats were measured weekly for eight weeks after the injection. The leg weight and histology of the muscle after eight weeks were also measured. The results revealed the expression of the GH1 and IGF1 genes at the mRNA and protein levels in C2C12 cells. An increase in both hormones, either directly or indirectly through C2C12 cells, increased the animal body weight, leg weight, and muscle fibre size after eight weeks. The direct and indirect transfer of IGF1 increased body weight, leg weight and muscle fibre size more than did the direct or indirect transfer of GH1. In the direct transfer groups, the body weight was greater than that in the indirect transfer groups after eight weeks. We demonstrated that nonpituitary secretion of GH1 mimicked some physiological effects of pituitary GH1 in a rat model. Further investigations are needed to study other possible effects of extra copy of GH1 and IGF1 genes over a longer period on other tissues.
本研究的目的是通过慢载体介导C2C12细胞间接增加大鼠肌肉中生长激素(GH1)和胰岛素样生长因子-1 (IGF1)的水平,并比较它们对肌肉质量的影响。合成GH1、IGF1和GH1-IGF1编码序列,通过2a自裂肽连接,实现多顺反子表达,克隆并插入pCDH载体。在HEK293T细胞中产生了含有我们的靶基因的重组假病毒。用伪慢病毒转导C2C12细胞,通过对嘌呤霉素耐药筛选。RT-PCR和Western blotting分别检测GH1和IGF1基因在mRNA和蛋白水平上的表达。将重组伪慢病毒和转导的C2C12细胞注射于8周龄大鼠胫骨前肌、腓肠肌和股四头肌群。注射后8周,每周测量大鼠体重。8周后还测量了腿部重量和肌肉组织学。结果显示,GH1和IGF1基因在C2C12细胞中mRNA和蛋白水平表达。8周后,直接或间接通过C2C12细胞增加的两种激素增加了动物的体重、腿重和肌肉纤维大小。IGF1的直接和间接传递比GH1的直接和间接传递更能增加体重、腿重和肌纤维大小。8周后,直接转移组的体重明显大于间接转移组。我们在大鼠模型中证明了GH1的非垂体分泌模拟了垂体GH1的一些生理作用。需要进一步研究GH1和IGF1基因的额外拷贝在较长时间内对其他组织的其他可能影响。
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引用次数: 0
Administration study of somapacitan, a long-acting growth hormone derivative, in horse for doping control purpose 一种长效生长激素衍生物somapacitan在马体内用于兴奋剂控制的研究
IF 1.6 4区 医学 Q4 CELL BIOLOGY Pub Date : 2025-08-25 DOI: 10.1016/j.ghir.2025.101662
Yoshibumi Shimizu , Michiko Sugai-Bannai , Haruka Tanabe , Kazunobu Saito , Hiroki Ito , Hirotaka Tokushige , Kazuhiro Kamiya , Misato Hirano-Kodaira , Masayuki Yamada , Gary Ngai-Wa Leung
Somapacitan is the second generation of recombinant human growth hormone (rhGH) medication that retains the pharmacological effects of rhGH but exhibits a longer duration of action due to its reversible albumin-binding in the body. In general, the use of all recombinant growth hormone (rGH) analogues is banned by the human and animal sports regulatory authorities due to their anabolic and lipolytic effects. However, little is known about the elimination kinetics and biological effects of the newly introduced long-acting rhGH, somapacitan, in horses. This paper describes the administration study of somapacitan and its elimination in horses, its correlation with plasma insulin-like growth factor-1 (IGF-1) levels, an established indicator for rGH abuse, and the evaluation of the detection capability of our recently developed liquid chromatography high-resolution mass spectrometry (LC-HRMS) method in equine plasma after extraction and trypsin digestion specifically designed for controlling the misuse or abuse of somapacitan. Three thoroughbred mares were each administered 90 mg somapacitan subcutaneously. Plasma IGF-1 concentration significantly increased in all horses after administration of somapacitan. The somapacitan-specific T10 peptide fragment that allows discriminative identification of somapacitan and rhGH was detected up to 14 days and confirmed in post-administration samples collected up to 10 days. Several shared peptide fragments between somapacitan and rhGH were also detected and confirmed in plasma samples collected 14 days post-administration, supporting the applicability of the test strategy for the analysis of authentic doping control samples in horses.
Somapacitan是第二代重组人生长激素(rhGH)药物,它保留了rhGH的药理作用,但由于其在体内的可逆白蛋白结合而表现出更长的作用时间。一般来说,所有重组生长激素(rGH)类似物的使用都是被人类和动物运动监管机构禁止的,因为它们具有合成代谢和脂溶作用。然而,对新引入的长效rhGH somapacitan在马体内的消除动力学和生物效应知之甚少。本文介绍了somapacitan的给药研究及其在马体内的消除,其与血浆胰岛素样生长因子-1 (IGF-1)水平的相关性,这是一种已建立的rGH滥用指标,以及我们最近开发的用于控制somapacitan滥用的提取和胰蛋白酶消化后的马血浆中液相色谱高分辨率质谱(LC-HRMS)检测能力的评估。3匹良种母马,每匹皮下注射90 mg somapacitan。给药后,所有马的血浆IGF-1浓度显著升高。在14天内检测到可区分somapacitan和rhGH的somapacitan特异性T10肽片段,并在给药后10天收集的样本中得到证实。在给药后14天收集的血浆样本中,还检测到并确认了somapacitan和rhGH之间的几个共享肽片段,支持了该检测策略对马的真实兴奋剂控制样本分析的适用性。
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引用次数: 0
Efficacy, safety, and outcomes of growth hormone treatment in children with idiopathic short stature 生长激素治疗特发性矮小儿童的疗效、安全性和结局
IF 1.6 4区 医学 Q4 CELL BIOLOGY Pub Date : 2025-08-09 DOI: 10.1016/j.ghir.2025.101661
Agnès Linglart , Andrew Dauber , Alexander de Lima Jorge , Xiaoping Luo , Tsutomu Ogata , Lars Sävendahl

Background

Growth hormone (GH) is a treatment option in some countries for children with idiopathic short stature (ISS) given to enable them to attain height within the expected range. Currently, it is not often utilised in clinical practice. A literature review was conducted to summarise the efficacy, safety, and outcomes associated with GH treatment in children with ISS.

Summary

Guidelines for the diagnosis and treatment of ISS may benefit from revision to accommodate recent findings on genetic factors that influence height. Clinical trials and observational studies designed to investigate the effect of GH treatment on children with ISS have shown that it is effective in enabling them to attain height within the normal range. In some instances, height improvements are reported up to adult height. The safety of GH treatment in this patient population has also been investigated and no new safety concerns have been observed. In analyses that were designed to investigate the effect of GH on quality of life, improvements in psychosocial scores were observed, either by the patient, parent, or the treating physician.

Key message

GH treatment is effective in improving height outcomes and quality of life in children with ISS, with an acceptable safety profile.
在一些国家,生长激素(GH)是特发性身材矮小(ISS)儿童的一种治疗选择,用于使他们达到预期范围内的身高。目前,它在临床实践中并不常用。一篇文献综述总结了生长激素治疗ISS患儿的有效性、安全性和相关结果。摘要:ISS的诊断和治疗指南可能会受益于修订,以适应影响身高的遗传因素的最新发现。旨在调查生长激素治疗对ISS儿童影响的临床试验和观察性研究表明,它能有效地使他们达到正常范围内的身高。在某些情况下,身高的提高可以达到成人的身高。生长激素治疗在这一患者群体中的安全性也进行了调查,没有观察到新的安全问题。在旨在调查生长激素对生活质量影响的分析中,无论是患者、父母还是治疗医生都观察到心理社会评分的改善。关键信息:egh治疗可有效改善ISS患儿的身高结局和生活质量,并具有可接受的安全性。
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引用次数: 0
Growth hormone regulates deiodinase type 2 and 3 expression via GATA 生长激素通过GATA调控2型和3型脱碘酶的表达
IF 1.6 4区 医学 Q4 CELL BIOLOGY Pub Date : 2025-05-21 DOI: 10.1016/j.ghir.2025.101659
Mana Mitsutani , Hiromi Hano , Mei Yokoyama , Midori Matsushita , Misa Hayashi , Ichiro Yamauchi , Tetsuya Tagami , Kenji Moriyama

Objective

Growth hormone (GH) is involved in bone and skeletal muscle growth directly or indirectly via STAT5 and/or insulin-like growth factor (IGF)-1. Thyroid hormone (TH) is essential for general cellular growth and metabolic regulation. While both GH and TH are essential for growth, their actions may partially complement each other in conditions of hormonal deficiency. For example, TH can enhance GH secretion and sensitivity, while GH is ineffective in Refetoff syndrome due to TH receptor dysfunction. However, the underlying molecular mechanism remains unclear. In this study, we investigated the molecular mechanisms underlying the complementarity between GH and TH, paying special attention to the effects of GH on the expression of both iodothyronine deiodinase (DIO) type 2 (DIO2) and type 3 (DIO3).

Design

The effects of growth hormone (GH) on DIOs were examined using reporter assays, chromatin immunoprecipitation, quantitative PCR, and western blotting using HEK293-derived TSA201 cells and mouse ATDC5 chondrocytes.

Results

GH induced the mRNA and protein expression of DIOs in ATDC5 cells via STAT5/GATA. GATAs activate the promoter activity of both DIOs. The binding sites for GATA on the DIO promoter were located −87 bp and − 75 bp upstream from the TSS for the DIO2 promoter and − 6 bp upstream from the TSS for the DIO3 promoter, respectively. GH-induced expression of DIOs in ATDC5 cells was abolished by K-7174, a GATA-specific inhibitor.

Conclusion

The present study demonstrates that GH regulates DIO2 and DIO3 expression via JAK/STAT5/GATAs after binding to GHR. This is the first report on the molecular mechanisms underlying GH-dependent compensation of TH action. (256 words).
目的:生长激素(GH)通过STAT5和/或胰岛素样生长因子(IGF)-1直接或间接参与骨和骨骼肌生长。甲状腺激素(TH)是一般细胞生长和代谢调节所必需的。虽然生长激素和促甲状腺激素都是生长所必需的,但在激素缺乏的情况下,它们的作用可能部分互补。例如,TH可以增强GH的分泌和敏感性,而GH由于TH受体功能障碍,对Refetoff综合征无效。然而,潜在的分子机制尚不清楚。在这项研究中,我们研究了GH和TH互补的分子机制,特别关注GH对碘甲状腺原氨酸脱碘酶(DIO) 2型(DIO2)和3型(DIO3)表达的影响。使用hek293衍生的TSA201细胞和小鼠ATDC5软骨细胞,采用报告基因法、染色质免疫沉淀法、定量PCR和western blotting检测生长激素(GH)对DIOs的影响。结果gh通过STAT5/GATA诱导ATDC5细胞中DIOs mRNA和蛋白的表达。GATAs激活两个DIOs的启动子活性。GATA在DIO启动子上的结合位点分别位于DIO2启动子的TSS上游- 87 bp和- 75 bp, DIO2启动子的TSS上游- 6 bp。gata特异性抑制剂K-7174可抑制gh诱导的ATDC5细胞中DIOs的表达。结论GH与GHR结合后,通过JAK/STAT5/GATAs调控DIO2和DIO3的表达。这是关于gh依赖的TH作用补偿的分子机制的第一份报告。(256字)。
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引用次数: 0
Impact of disease activity on cognitive and psychological outcomes in acromegaly: A prospective study 肢端肥大症患者疾病活动对认知和心理结果的影响:一项前瞻性研究
IF 1.6 4区 医学 Q4 CELL BIOLOGY Pub Date : 2025-05-08 DOI: 10.1016/j.ghir.2025.101650
Serhat Uysal , Zehra Kara , Cem Sulu , Serdar Sahin , Ahmet Numan Demir , Esra Gungormus , Selin Yagci Kurtish , Elif Ersoy Yilmaz , Senol Turan , Hande Mefkure Ozkaya , Pinar Kadioglu

Purpose

To investigate the cognitive and psychological aspects of acromegaly and to assess how disease activity may affect these outcomes.

Methods

This prospective study included patients with acromegaly who consecutively admitted to Pituitary Center between June 2021 and July 2023. Cognitive functions were assessed using a series of standardized tests targeting memory, attention, executive function, verbal fluency, and visuospatial skills. Additionally, Beck Depression Inventory (BDI), Beck Anxiety Inventory, and Acromegaly Quality of Life Questionnaire (AcroQoL) assessments were conducted. These evaluations were performed preoperatively and at the 9th month postoperatively following transsphenoidal surgery (TSS) to assess the anticipated changes in neuropsychological functions based on disease activity.

Results

A total of 19 patients with acromegaly were included. Remission was achieved through TSS alone in 9 patients, while 10 patients required postoperative somatostatin receptor ligands. Cognitive functions (Montreal Cognitive Assessment Test) were better in the remission phase compared to the initial active disease phase (23.36 ± 3.46 vs 24.93 ± 3.73; p = 0.035). Cognitive flexibility and selective attention (Stroop Test) were impaired during the active period of the disease (17.79 ± 12.31 vs 12.29 ± 8.23; p = 0.016). Memory functions (Wechsler Memory Scale-Logical Memory Test: immediate recall, delayed recall, recognition) showed improvement from the active phase to remission (p = 0.016, p = 0.003, p = 0.008; respectively). BDI scores were significantly higher in the active phase compared to remission (7.36 ± 3.48 vs 5.43 ± 3.03; p = 0.009). Additionally, AcroQoL scores were lower during the active disease phase than in the remission phase (65.30 ± 17.75 vs 80.43 ± 13.61; p = 0.007).

Conclusion

Acromegaly may impair cognitive and psychological functions, which appear to improve with effective treatment.
目的探讨肢端肥大症的认知和心理方面的问题,并评估疾病活动如何影响这些结果。方法本前瞻性研究纳入2021年6月至2023年7月期间连续入住垂体中心的肢端肥大症患者。认知功能通过一系列针对记忆、注意力、执行功能、语言流畅性和视觉空间技能的标准化测试来评估。此外,进行贝克抑郁量表(BDI)、贝克焦虑量表(Beck Anxiety Inventory)和肢端肥大症生活质量问卷(AcroQoL)评估。这些评估在术前和经蝶窦手术(TSS)后9个月进行,以评估基于疾病活动的神经心理功能的预期变化。结果共纳入肢端肥大症患者19例。9例患者仅通过TSS获得缓解,10例患者术后需要使用生长抑素受体配体。认知功能(蒙特利尔认知评估测验)在缓解期优于初始活动性疾病期(23.36±3.46 vs 24.93±3.73;p = 0.035)。认知灵活性和选择性注意(Stroop Test)在疾病活动期受到损害(17.79±12.31 vs 12.29±8.23;p = 0.016)。记忆功能(韦氏记忆量表-逻辑记忆测试:即时回忆、延迟回忆、识别)从活跃阶段到缓解阶段均有改善(p = 0.016, p = 0.003, p = 0.008;分别)。活动期BDI评分明显高于缓解期(7.36±3.48 vs 5.43±3.03;p = 0.009)。此外,活动性疾病期的AcroQoL评分低于缓解期(65.30±17.75 vs 80.43±13.61;p = 0.007)。结论肢端肥大症可损害患者的认知和心理功能,经有效治疗可改善其认知和心理功能。
{"title":"Impact of disease activity on cognitive and psychological outcomes in acromegaly: A prospective study","authors":"Serhat Uysal ,&nbsp;Zehra Kara ,&nbsp;Cem Sulu ,&nbsp;Serdar Sahin ,&nbsp;Ahmet Numan Demir ,&nbsp;Esra Gungormus ,&nbsp;Selin Yagci Kurtish ,&nbsp;Elif Ersoy Yilmaz ,&nbsp;Senol Turan ,&nbsp;Hande Mefkure Ozkaya ,&nbsp;Pinar Kadioglu","doi":"10.1016/j.ghir.2025.101650","DOIUrl":"10.1016/j.ghir.2025.101650","url":null,"abstract":"<div><h3>Purpose</h3><div>To investigate the cognitive and psychological aspects of acromegaly and to assess how disease activity may affect these outcomes.</div></div><div><h3>Methods</h3><div>This prospective study included patients with acromegaly who consecutively admitted to Pituitary Center between June 2021 and July 2023. Cognitive functions were assessed using a series of standardized tests targeting memory, attention, executive function, verbal fluency, and visuospatial skills. Additionally, Beck Depression Inventory (BDI), Beck Anxiety Inventory, and Acromegaly Quality of Life Questionnaire (AcroQoL) assessments were conducted. These evaluations were performed preoperatively and at the 9th month postoperatively following transsphenoidal surgery (TSS) to assess the anticipated changes in neuropsychological functions based on disease activity.</div></div><div><h3>Results</h3><div>A total of 19 patients with acromegaly were included. Remission was achieved through TSS alone in 9 patients, while 10 patients required postoperative somatostatin receptor ligands. Cognitive functions (Montreal Cognitive Assessment Test) were better in the remission phase compared to the initial active disease phase (23.36 ± 3.46 vs 24.93 ± 3.73; <em>p</em> <em>=</em> 0.035). Cognitive flexibility and selective attention (Stroop Test) were impaired during the active period of the disease (17.79 ± 12.31 vs 12.29 ± 8.23; <em>p</em> <em>=</em> 0.016). Memory functions (Wechsler Memory Scale-Logical Memory Test: immediate recall, delayed recall, recognition) showed improvement from the active phase to remission (<em>p</em> <em>=</em> 0.016, <em>p</em> <em>=</em> 0.003, <em>p</em> <em>=</em> 0.008; respectively). BDI scores were significantly higher in the active phase compared to remission (7.36 ± 3.48 vs 5.43 ± 3.03; <em>p</em> <em>=</em> 0.009). Additionally, AcroQoL scores were lower during the active disease phase than in the remission phase (65.30 ± 17.75 vs 80.43 ± 13.61; <em>p</em> <em>=</em> 0.007).</div></div><div><h3>Conclusion</h3><div>Acromegaly may impair cognitive and psychological functions, which appear to improve with effective treatment.</div></div>","PeriodicalId":12803,"journal":{"name":"Growth Hormone & Igf Research","volume":"81 ","pages":"Article 101650"},"PeriodicalIF":1.6,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143937157","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Corrigendum to “Pharmacodynamics, pharmacokinetics, and toxicology of Fc-growth hormone fusion protein in macaques” 《猕猴体内fc -生长激素融合蛋白的药效学、药代动力学和毒理学》的勘误表
IF 1.6 4区 医学 Q4 CELL BIOLOGY Pub Date : 2025-04-22 DOI: 10.1016/j.ghir.2025.101649
Han Liu , Binghuai Peng , Baisong Zhou , Yu Zhang , Yunnan Liu , Yulin Liu , Ruixin Sun , Zhuonan Li , Qiumei Zhu , Lu Yu , Ruili Fu , Qiong Wang , Jinghui Liu , Chunying Pang
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引用次数: 0
Pharmacodynamics, pharmacokinetics, and toxicology of Fc-growth hormone fusion protein in macaques fc -生长激素融合蛋白在猕猴体内的药效学、药代动力学和毒理学研究
IF 1.6 4区 医学 Q4 CELL BIOLOGY Pub Date : 2025-03-19 DOI: 10.1016/j.ghir.2025.101648
Han Liu, Binghuai Peng, Baisong Zhou, Yu Zhang, Yunnan Liu, Yulin Liu, Ruixin Sun, Zhuonan Li, Qiumei Zhu, Lu Yu, Ruili Fu, Qiong Wang, Jinghui Liu, Chunying Pang

Purpose

Growth hormone (GH) therapy for GH deficiency is used to treat multiple conditions. However, the short half-life of GH necessitates frequent dosing, which limits patient adherence. Fc fusion proteins, created by binding an active peptide to the Fc portion of IgG, are known to prolong the plasma half-life of the peptide. Pharmacodynamics and pharmacokinetics of Fc-GH in rats have been reported; however, studies in primate models are lacking. Therefore, in this study, we aimed to investigate the pharmacodynamics, pharmacokinetics, and toxicology of Fc-GH in rhesus and crab-eating macaques.

Methods

In rhesus macaques, Fc-GH was injected subcutaneously at 0.8, 1.6, and 3.2 mg/kg and intravenously at 1.6 mg/kg. The 1.6 mg/kg subcutaneous dose was administered five times, once every 7 days; other doses were administered as single injections for pharmacodynamic and pharmacokinetic assessments. In crab-eating macaques, potential toxicity was evaluated after single subcutaneous injections at 30, 45, and 62.5 mg/kg and repeated injections at 3, 10, and 30 mg/kg once every 7 days, followed by an 8-week recovery.

Results

No adverse events were observed following Fc-GH administrations. Fc-GH achieved Cmax slowly after subcutaneous administration and rapidly after intravenous administration, with plasma levels being maintained over time. In rhesus macaques, the half-life increased dose-dependently: 23.72 ± 2.17 h (0.8 mg/kg), 49.44 ± 14.77 h (1.6 mg/kg), and 76.07 ± 13.19 h (3.2 mg/kg). After five injections of 1.6 mg/kg, the half-life of Fc-GH was 60.42 ± 18.29 h. Insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein 3 (IGFBP-3) levels significantly increased and remained elevated for 28–42 days after Fc-GH injections. In crab-eating macaques, no Fc-GH accumulation was observed. The maximum tolerated single subcutaneous dose was 62.5 mg/kg; no adverse effects were observed at 30 mg/kg during repeated administration over 29 injections with an 8-week recovery.

Conclusions

Fc-GH demonstrated favorable pharmacokinetics and pharmacodynamics in macaques, significantly extending the half-life and enhancing IGF-1 and IGFBP-3 levels without adverse effects. These findings suggest Fc-GH as a promising long-acting GH therapy that could improve patient adherence.
目的:生长激素(GH)治疗生长激素缺乏症可用于治疗多种疾病。然而,生长激素的半衰期短,需要频繁给药,这限制了患者的依从性。Fc融合蛋白是通过将活性肽与IgG的Fc部分结合而产生的,已知可以延长肽的血浆半衰期。Fc-GH在大鼠体内的药效学和药代动力学已有报道;然而,缺乏对灵长类动物模型的研究。因此,在本研究中,我们旨在研究Fc-GH在恒河猴和食蟹猕猴体内的药效学、药代动力学和毒理学。方法恒河猴分别以0.8、1.6、3.2 mg/kg皮下注射和1.6 mg/kg静脉注射Fc-GH。1.6 mg/kg皮下给药5次,每7天1次;其他剂量以单次注射方式进行药效学和药代动力学评估。对食蟹猕猴进行30、45和62.5 mg/kg单次皮下注射,并每7天重复注射一次3、10和30 mg/kg,随后8周恢复,评估潜在毒性。结果给药后无不良反应发生。Fc-GH在皮下给药后缓慢达到Cmax,在静脉给药后迅速达到Cmax,血浆水平随时间保持不变。恒河猴的半衰期分别为23.72±2.17 h (0.8 mg/kg)、49.44±14.77 h (1.6 mg/kg)和76.07±13.19 h (3.2 mg/kg)。注射5次1.6 mg/kg后,Fc-GH的半衰期为60.42±18.29 h,胰岛素样生长因子1 (IGF-1)和胰岛素样生长因子结合蛋白3 (IGFBP-3)水平显著升高,并在注射后28-42 d内保持升高。在食蟹猕猴中,未观察到Fc-GH积累。单次皮下最大耐受剂量为62.5 mg/kg;在30 mg/kg的剂量下重复给药29次,恢复时间为8周,未观察到不良反应。结论sfc - gh在猕猴体内具有良好的药代动力学和药效学特性,可显著延长半衰期,提高IGF-1和IGFBP-3水平,且无不良反应。这些发现表明Fc-GH是一种很有希望的长效生长激素疗法,可以提高患者的依从性。
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引用次数: 0
Picropodophyllotoxin alters EMT in neuroblastoma via inhibition of surface receptors IFG1R and ALK 微鬼臼毒素通过抑制表面受体IFG1R和ALK改变神经母细胞瘤的EMT
IF 1.6 4区 医学 Q4 CELL BIOLOGY Pub Date : 2025-02-20 DOI: 10.1016/j.ghir.2025.101638
Poonam Bhagriya , Afridi Shaikh , Hetal Roy
Neuroblastoma (NB) is a type of paediatric cancer that originates from embryonic sympathoadrenal cells. Despite its paediatric origin, NB is mostly treated with strategy of non-small cell lung cancer like adults due to lack of specific therapeutic approach. To improve treatment outcome for NB patients, developing drugs that specifically target the genetic mutations or molecular pathways involved in neuroblastoma is necessary. Overexpression of the insulin-like growth factor 1 receptor (IGF1R) has been linked to various malignancies, including paediatric cancers. We hypothesized that inhibiting IGF1R with ALK (NB specific mutation) by phytochemical compound could effectively treat NB while avoiding undesirable cytotoxic effects. We evaluated the efficacy of Picropodophyllotoxin (PPP) as IGF1R inhibitor, for treatment of NB. The IC50 value of PPP on SH-SY5Y, NB cells after 24 h of treatment was found to be 0.501 μM. Molecular docking studies revealed that PPP had a binding score of −7.5 kcal/mol with IGF1R and − 8.8 kcal/mol with ALK. This suggests that PPP not only binds to and inhibits IGF1R but also has a strong affinity for ALK. Gene expression studies, densitometric analysis, scratch assays, and AO/EtBr differential staining were used to evaluate the efficacy of PPP in NB cells. Transcript expression and densitometric analysis revealed that PPP could downregulate IGF1R and ALK in NB cells. Downregulation of SNAIL, a mesenchymal marker, and upregulation of E-cadherin, an epithelial marker, indicated a mesenchymal to epithelial transition in NB cells, suggesting that PPP treatment inhibited NB cell migration and proliferation. This was further supported by scratch assay results in our study. Furthermore, gene expression analysis of p53, BAX and BCL2 indicated that PPP induces apoptosis in NB cells. AO/EtBr differential staining revealed apoptotic phenomena in NB cells after 24 h of PPP treatment. Although further research is needed to explore the receptor targeting approach using PPP for IGF1R and ALK inhibition.
神经母细胞瘤(NB)是一种起源于胚胎交感肾上腺细胞的儿科癌症。尽管它起源于儿科,但由于缺乏特异性的治疗方法,NB主要像成人一样采用非小细胞肺癌的治疗策略。为了改善神经母细胞瘤患者的治疗效果,开发专门针对神经母细胞瘤基因突变或分子通路的药物是必要的。胰岛素样生长因子1受体(IGF1R)的过度表达与多种恶性肿瘤有关,包括儿科癌症。我们假设通过植物化学化合物抑制IGF1R与ALK (NB特异性突变)可以有效地治疗NB,同时避免不良的细胞毒性作用。我们评估了Picropodophyllotoxin (PPP)作为IGF1R抑制剂治疗NB的疗效。24 h后,PPP对SH-SY5Y、NB细胞的IC50值为0.501 μM。分子对接研究表明,PPP与IGF1R的结合评分为−7.5 kcal/mol,与ALK的结合评分为−8.8 kcal/mol。这表明PPP不仅结合并抑制IGF1R,而且对ALK也有很强的亲和力。通过基因表达研究、密度分析、划痕试验和AO/EtBr差异染色来评估PPP对NB细胞的作用。转录物表达和密度分析显示,PPP可下调NB细胞中的IGF1R和ALK。间充质标志物SNAIL的下调和上皮标志物E-cadherin的上调表明NB细胞从间充质向上皮转变,表明PPP处理抑制了NB细胞的迁移和增殖。在我们的研究中,划痕试验结果进一步支持了这一点。此外,p53、BAX和BCL2基因表达分析表明,PPP诱导NB细胞凋亡。AO/EtBr鉴别染色显示PPP作用24 h后NB细胞出现凋亡现象。虽然还需要进一步的研究来探索使用PPP来抑制IGF1R和ALK的受体靶向方法。
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引用次数: 0
Cellular senescence and PAPP-A 细胞衰老与PAPP-A
IF 1.6 4区 医学 Q4 CELL BIOLOGY Pub Date : 2025-01-23 DOI: 10.1016/j.ghir.2025.101637
Cheryl A. Conover
Cellular senescence and its accompanying secretome have major impact on growth and aging of mammalian organisms. A novel protease, PAPP-A, regulates the bioavailability of an important growth factor, insulin-like growth factor (IGF)-I, and has major impact on growth and aging. This short review will explore a new perspective of cellular senescence and PAPP-A.
细胞衰老及其伴随的分泌组对哺乳动物的生长和衰老具有重要影响。一种新型蛋白酶PAPP-A调节重要生长因子胰岛素样生长因子(IGF)- 1的生物利用度,对生长和衰老有重要影响。本文将从新的角度探讨细胞衰老与PAPP-A的关系。
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引用次数: 0
Identification and differentiation of somapacitan, a long-acting growth hormone derivative, and recombinant human growth hormone in equine plasma by LC-HRMS for doping control purpose hplc - hrms鉴别马血浆中长效生长激素衍生物somapacitan和重组人生长激素
IF 1.6 4区 医学 Q4 CELL BIOLOGY Pub Date : 2024-11-10 DOI: 10.1016/j.ghir.2024.101628
Yoshibumi Shimizu, Michiko Sugai-Bannai, Kazunobu Saito, Misato Hirano-Kodaira, Gary Ngai-Wa Leung
Somapacitan, a long-acting growth hormone derivative, and recombinant human growth hormone (rhGH) are protein-based drugs generally used to treat growth disorders and GH deficiency in humans. Due to their potential to enhance the horse performance, the use of these drugs is prohibited at-all-times by the International Federation of Horseracing Authorities for horseracing and the Fédération Equestre Internationale for equestrian sports. In this study, we developed a test method for the identification and differentiation of somapacitan and rhGH in equine plasma by using liquid chromatography high-resolution mass spectrometry (LC–HRMS). The method involved C4 solid-phase extraction after ammonium sulfate precipitation, followed by chloroform/methanol precipitation, trypsin digestion, and analysis by LC-HRMS. The discriminative identification of somapacitan and rhGH was successfully achieved through the detection of their respective unique T10 peptide fragments. Noteworthy, the T10 peptide fragment of somapacitan was detected with its side chain structure remaining intact. The limit of identification (confirmation) (LOI) was determined to be 5 ng/mL for somapacitan and 2 ng/mL for rhGH in equine plasma, while the limit of detection (LOD) was 5 ng/mL for somapacitan and 1 ng/mL for rhGH. Furthermore, using the peptide fragments T1, T8, and T9 (which are shared between somapacitan and rhGH), the presence of somapacitan in equine plasma could be confirmed with higher sensitivity, achieving down to LOIs of 2 ng/mL and LODs of 1 ng/mL. The method was validated with respect to specificity, identification capability, robustness, precision, and reproducibility, paving the way for the analysis of post-administration samples from our already planned administration trials and future potential positive cases.
Somapacitan是一种长效生长激素衍生物,重组人生长激素(rhGH)是一种基于蛋白质的药物,通常用于治疗人类生长障碍和生长激素缺乏症。由于这些药物有可能提高马匹的表现,国际赛马当局联合会和国际马术协会在任何时候都禁止使用这些药物。本研究建立了马血浆中somapacitan和rhGH的液相色谱-高分辨率质谱(LC-HRMS)鉴别鉴别方法。方法采用硫酸铵沉淀后C4固相萃取,氯仿/甲醇沉淀,胰蛋白酶消化,LC-HRMS分析。通过检测其各自独特的T10肽片段,成功实现了somapacitan和rhGH的鉴别鉴定。值得注意的是,somapacitan的T10肽片段被检测到,其侧链结构保持完整。马血浆中somapacitan的检出(确认)限为5 ng/mL, rhGH的检出限为2 ng/mL, somapacitan的检出限为5 ng/mL, rhGH的检出限为1 ng/mL。此外,利用somapacitan和rhGH共有的肽片段T1、T8和T9,可以以更高的灵敏度确认马血浆中somapacitan的存在,LOIs可低至2 ng/mL, LODs可达1 ng/mL。该方法在特异性、鉴定能力、稳健性、精确性和重复性方面得到了验证,为分析我们已经计划的给药试验和未来潜在阳性病例的给药后样本铺平了道路。
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Growth Hormone & Igf Research
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