This is a study to determine if a certain drug, called telotristat ethyl (Xermelo®), can help reduce the chance of blood pressure and heart rate variations (known as carcinoid crisis) in individuals who have neuroendocrine tumors (also called carcinoid tumors). These complications can be life-threatening for patients who already have to experience challenging surgeries to remove their tumors. To determine if telotristat ethyl (Xermelo®) will help reduce these complications during surgery, researchers will give the drug to study participants before surgery.

开始日期2022-01-01

申办/合作机构

The University of Chicago

NCT04543955 / Terminated临床2期IIT

Study of Telotristat (Xermelo) in Combination With Luetetium Lu177 Dotatate (Lutathera) in Well-Differentiated Neuroendocrine Tumors

This trial will test the hypothesis that Telotristat treatment increases the antitumor efficacy of Lutetium Lu 177 Dotatate therapy in neuroendocrine tumors (NETs).

开始日期2021-09-13

申办/合作机构

University of Kentucky

[+1]

NCT04810091 / Active, not recruiting临床3期IIT

TELEHEART: Telotristat Ethyl in a Heart Biomarker Study

This phase III trial compares the effect of telotristat ethyl and the current standard of care somatostatin analog therapy or somatostatin analog therapy alone in treating patients with neuroendocrine tumor that has spread to other places in the body (metastatic). Telotristat ethyl and somatostatin analog therapy may help to control carcinoid syndrome and carcinoid heart disease.

开始日期2021-05-18

申办/合作机构

The University of Texas MD Anderson Cancer Center

100 项与 TPH1 x TPH2 相关的临床结果

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100 项与 TPH1 x TPH2 相关的转化医学

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0 项与 TPH1 x TPH2 相关的专利（医药）

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项与 TPH1 x TPH2 相关的文献（医药）

2024-11-01·Journal of Psychosomatic Research

The impact of genetic variations in the serotonergic system on symptom severity and clinical outcome in functional neurological disorders

Article

作者: Weber, Samantha ; Ansede-Bermejo, Juan ; Del Real, Álvaro ; Carracedo, Ángel ; Rey Álvarez, Lucía Trinidad ; Álvarez, Lucía Trinidad Rey ; Bühler, Janine ; Aybek, Selma ; del Real, Álvaro ; Cruz, Raquel

OBJECTIVEWe studied gene-environment, as well as gene-gene interaction to elucidate their effects on symptom severity and predict clinical outcomes in functional neurological disorders (FND).METHODSEighty-five patients with mixed FND were genotyped for ten single-nucleotide polymorphisms (SNP) from seven different stress-related genes. We tested cross-sectionally the association between genotype and the symptomatology of FND (symptom severity assessed with the examiner-based clinical global impression score [CGI] and age of onset). Clinical outcome was assessed in 52 patients who participated in a follow-up clinical visit after eight months (following their individual therapies as usual). We tested longitudinally the association between genotype and clinical outcome in FND. We examined the contribution of each SNP and their interaction between them to FND symptomatology and outcome.RESULTSWe identified a nominal association between tryptophan hydroxylase 1 (TPH1) rs1800532 and symptom severity (CGI₁) in FND under a codominant model (T/T: ß_T/T = 2.31, se_T/T = 0.57; G/T: ß_G/T = -0.18, se_G/T = 0.29, P = 0.035), with minor allele (T) carriers presenting more severe symptoms. An association was identified between TPH1 and clinical outcome, suggesting that major allele (G) carriers were more likely to have an improved outcome under a codominant model (G/T: OR_G/T = 0.18, CI_G/T = [0.02-1.34]; T/T: OR_T/T = 2.08, CI_T/T = [0.30-14.53], P = 0.041). Our analyses suggested a significant gene-gene interaction for TPH2 (rs4570625) and OXTR (rs2254298) on symptom severity, and a significant gene-gene interaction for TPH1, TPH2 and BDNF (rs1491850) on clinical outcome.CONCLUSIONFND might arise from a complex interplay between individual predisposing risk genes involved in the serotonergic pathway and their gene-gene interactions.

2024-10-01·Immunology Letters

Longitudinal analysis at pre- and post-flare of T peripheral helper and T follicular helper subsets in patients with systemic lupus erythematosus

Article

作者: Tsujimoto, Hideto ; Tanemura, Shuhei ; Takeuchi, Tsutomu ; Yoshimoto, Keiko ; Kikuchi, Jun ; Seki, Noriyasu ; Saito, Shuntaro ; Chiba, Kenji ; Kaneko, Yuko ; Akiyama, Mitsuhiro ; Sugahara, Kunio

OBJECTIVEWe focused to analyze the time-course changes at pre- and post-flare of T peripheral helper (Tph) cells and circulating T follicular helper (Tfh) cells in the blood of patients with systemic lupus erythematosus (SLE) with lupus low disease activity state (LLDAS) before flare.METHODSThis study included inactive (n=29) and active (n=55) patients with SLE. Tph subsets, Tfh subsets, CD11c^hi B cells, and plasma cells in the blood were determined by flow cytometry. The blood levels of cytokines including interferons (IFNs) were measured by electrochemiluminescence assay or cytokine beads array.RESULTSActive SLE patients exhibited the increased frequency of Tph1, Tph2, Tfh1, and Tfh2 subsets when compared to inactive patients, but no clear changes in the other subsets. During the treatment with medications, Tph1, Tph2, and Tfh2 subsets were significantly reduced along with disease activity and Tph1 and Tph2 subsets were positively correlated with SLE disease activity index (SLEDAI). The time course analysis of patients at pre- and post-flare revealed that in the patients at LLDAS before flare, Tph subsets and Tfh subsets were relatively low levels. At the flare, Tph cells, particularly Tph1 and Tph2 subsets, were increased and correlated with SLEDAI. Furthermore, the blood levels of IFN-α2a, IFN-γ, and IFN-λ1 were low in the patients with LLDAS before flare but these IFNs, particularly IFN-λ1, were increased along with flare.CONCLUSIONIncreased frequency of Tph1 and Tph2 subsets and elevated levels of serum IFN-λ1 are presumably critical for triggering of flare in SLE.

2024-07-01·Ecotoxicology and Environmental Safety

ERβ activation improves nonylphenol-induced depression and neurotransmitter secretion disruption via the TPH2/5-HT pathway

Article

作者: Yao, Hao ; Zhang, Yujie ; Zhu, Wei ; Yang, Xiao ; Xu, Jie ; Yu, Jie ; Zhang, Ziping

The aim of this study is to investigate the role of estrogen receptor β (ERβ) in nonylphenol (NP) - induced depression - like behavior in rats and its impact on the regulation of the TPH2/5-HT pathway. In the in vitro experiment, rat basophilic leukaemia cells (RBL-2H3) cells were divided into the four groups: blank group, NP group (20 μM), ERβ agonist group (0.01 μM), and NP＋ERβ agonist group (20 μM＋0.01 μM). For the in vivo experiment, 72 adult male Sprague-Dawley rats were randomly divided into following six groups: the Control, NP (40 mg/kg) group, ERβ agonist (2 mg/kg, Diarylpropionitrile (DPN)) group, ERβ inhibitor (0.1 mg/kg, 4-(2-phenyl-5,7-bis(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl) phenol (PHTPP)) group, NP+ERβ agonist (40 mg/kg NP ＋ 2 mg/kg DPN) group, and NP+ERβ inhibitor (40 mg/kg NP + 0.1 mg/kg PHTPP) group, with 12 rats in each group. Each rat in drug group were given NP by gavage and/or received a single intraperitoneal injection of DPN 2 mg/kg or PHTPP 0.1 mg/kg. Both in vivo and in vitro, NP group showed a decrease in the expression levels of ERβ, tryptophan hydroxylase (TPH1), and tryptophan hydroxylase-2 (TPH2) genes and proteins, and reduced levels of DA, NE, and 5-hydroxytryptophan (5-HT) neurotransmitters. RBL-2H3 cells showed signs of cell shrinkage, with rounded cells, increased suspension and more loosely arranged cells. The effectiveness of the ERβ agonist stimulation exhibited an increase exceeding 60% in RBL-2H3 cells. The application of ERβ agonist resulted in an alleviation the aforementioned alterations. ERβ agonist activated the TPH2/5-HT signaling pathways. Compared to the control group, the NP content in the brain tissue of the NP group was significantly increased. The latency to eat for the rats was longer and the amount of food consumed was lower, and the rats had prolonged immobility time in the behavioral experiment of rats. The expression levels of ERβ, TPH1, TPH2, 5-HT and 5-HITT proteins were decreased in the NP group, suggesting NP-induced depression-like behaviours as well as disturbances in the secretion of serum hormones and monoamine neurotransmitters. In the NP group, the midline raphe nucleus showed an elongated nucleus with a dark purplish-blue colour, nuclear atrophy, displacement and pale cytoplasm. ERβ might ameliorate NP-induced depression-like behaviors, and secretion disorders of serum hormones and monoamine neurotransmitters via activating TPH2/5-HT signaling pathways.

项与 TPH1 x TPH2 相关的新闻（医药）

2022-08-25

·生物谷

Br J Pharmacol: 5-羟色胺在肠道神经系统和肠内分泌细胞中的作用

在脊椎动物中，绝大多数5-羟色胺是在胃肠道(GI)的粘膜、肠嗜铬细胞(EC)中由色氨酸羟基酶-1(TPH1)合成的。在脊椎动物中，绝大多数5-羟色胺是在胃肠道(GI)的粘膜、肠嗜铬细胞(EC)中由色氨酸羟基酶-1(TPH1)合成的。肠道神经元(约占神经元的1%)也通过色氨酸羟化酶-2(TPH2)合成了相对微量的5-羟色胺。 20世纪50年代初，内源性5-羟色胺在肠道运动中发挥重要作用的概念首次被公布，当时牛津大学比尔布赖恩教授的实验室的开创性工作表明，内源性5-羟色胺可以在蠕动发生的同时周期性释放。这一观察，以及外源性5-羟色胺有效刺激蠕动的发现，被一些科学家解释为内源性5-羟色胺，从肠道内部合成，在不同的肠道运动模式的产生中发挥主要作用。自20世纪50年代以来，大量的间接证据表明，胃肠道(GI)壁内合成的内源性5-羟色胺(5-HT)在胃肠道的运动和转运中起着重要作用。然而，由于多种原因，很难确定肠源性5-羟色胺的确切功能。图片来源: https://pubmed.ncbi.nlm.nih.gov/35861711/ 近日，来自弗林德斯大学的研究者们在Br J Pharmacol杂志上发表了题为“Role of 5-HT in the enteric nervous system and enteroendocrine cells”的文章，该研究讨论了内源性5-羟色胺在肠嗜铬细胞和肠神经元中的功能作用，以及更广泛地说在一些主要的体内平衡途径中的作用。在过去的十年里，随着记录技术的显著进步和获得新的转基因动物的机会的增加，研究者对内源性5-羟色胺在胃肠道中的功能作用的理解有了重大的新的见解和重大的变化。来自许多不同实验室的数据表明，当所有内源性5-羟色胺被药物或基因从肠道中去除时，胃肠道动力和转运的主要模式仍然发生轻微或没有变化。此外，5-HT3受体拮抗剂同样或更有效地抑制内源性5-羟色胺完全耗尽的肠段的胃肠动力。 EC细胞激活内源性和外源性神经纤维，对大脑功能和肠道运动产生影响图片来源: https://pubmed.ncbi.nlm.nih.gov/35861711/ 5-羟色胺是一种具有多种生理功能的多效性信号分子。这些包括胃肠道内的重要功能。由于肠道中存在不同来源的5-羟色胺，以及在大多数器官上表达的广泛的5-羟色胺受体，这些作用的理解变得复杂起来。然而，EC细胞来源的5-羟色胺不是肠道运动和收缩频率所必需的，但可能调节肠道运动和收缩的频率。显然，5-羟色胺在生命早期的ENS发育和细胞迁移中起着重要作用。此外，肠道5-羟色胺提供所有循环中的5-羟色胺，而5-羟色胺本身参与多种生理功能，并可能受到局部肠道环境的改变，包括肠道微生物群、肠道收缩、营养摄入和长期的饮食变化。该领域面临的一个主要挑战是如何区分这些不同的成分如何联系在一起，以驱动不同的生理机制，并促进体内平衡途径。此外，在理解这一系统的变化如何导致不同的病理生理环境，以及我们如何随后改变这些机制，如治疗方式方面，存在着相当大的困难。迎接这些挑战是下一个十年5-羟色胺研究的重要前沿。（生物谷 Bioon.com）参考文献 Nick J. Spencer et al. Role of 5-HT in the enteric nervous system and enteroendocrine cells. Br J Pharmacol. 2022 Jul 21. doi: 10.1111/bph.15930.

2022-07-05

·生物谷

《细胞》子刊：中科院联合郑大破解肠道神经促进肠癌形成的机制

结直肠癌是全球癌症相关死亡的第二大原因，每年新发190万人，死亡93万人，其中绝大多数死于复发和转移[1]。结直肠癌是全球癌症相关死亡的第二大原因，每年新发190万人，死亡93万人，其中绝大多数死于复发和转移[1]。肿瘤干细胞是肿瘤组织中一小部分具有自我更新和分化能力的细胞，能形成肿瘤并使肿瘤产生异质性，是结直肠癌耐药、复发和转移的罪魁祸首。人体肠道富含神经元，多达6亿个神经元构成肠道的神经系统[2]，通过分泌神经递质调节肠道行为。在肠道肿瘤中，肠道神经元作为肿瘤微环境的一部分，参与肠道肿瘤的发生发展。然而，关于肠道神经调控肠道肿瘤的详细机制，尚缺乏清晰研究。近日，中国科学院大学范祖森教授和田勇教授，联合郑州大学朱平平教授，发现经肠道菌群代谢产物异戊酸刺激后，肠道神经元产生神经递质5-羟色胺，促进结直肠癌干细胞的自我更新，导致肿瘤形成。相关论文发表在神经科学顶级杂志Neuron上[3]。论文首页截图首先，研究人员使用神经递质处理结直肠癌干细胞，在体外探索肠道神经递质对结直肠癌干细胞的作用，发现在众多递质中，5-羟色胺能显著促进结直肠癌干细胞形成克隆，并且递质浓度越高，结直肠癌干细胞形成的克隆越大。随后，研究人员在动物体内进行了实验验证。结直肠癌小鼠经5-羟色胺合成抑制剂处理后，瘤体体积缩小，结直肠癌干细胞比例降低。这提示，5-羟色胺能促进结直肠癌干细胞的自我更新和肿瘤生成。图A：11种神经递质对结直肠癌干细胞克隆形成实验的影响（Veh为空白对照）；图B：5-羟色胺（5-HT）处理对结直肠癌干细胞干性标志物（Lgr5）表达的影响；5-羟色胺合成抑制剂（pCPA）处理对结直肠癌瘤体（图D）和结直肠癌干细胞比例（图E）的影响结直肠癌干细胞表达的5-羟色胺受体多达14种，5-羟色胺是通过结合哪种受体来发挥作用的呢？研究人员在体外依次沉默每种受体，发现只有敲除受体HTR1B、HTR1D和HTR1F能显著降低结直肠癌干细胞的增殖。另外，相比于其他受体，这三种受体也在结直肠癌瘤体和肿瘤干细胞中高度表达。随后，研究人员进行小鼠体内成瘤实验，发现荷瘤小鼠在敲除HTR1B/1D/1F后，结直肠肿瘤数目减少，瘤体内的肿瘤干细胞比例也降低。敲除这三种受体，或者使用抑制剂抑制它们，即使再给予5-羟色胺刺激，也不能促进结直肠癌干细胞形成克隆。这些结果表明，5-羟色胺是通过受体HTR1B、HTR1D和HTR1F来促进结直肠癌干细胞增殖。图A：依次敲除5-羟色胺的每种受体检测其对结直肠癌干细胞增殖能力的影响；图B：5-羟色胺受体HTR1B、HTR1D和HTR1F在结直肠癌肿瘤干细胞（LGR5 GFP+）中高表达；使用HTR1抑制剂Meth（图E），或敲除HTR1B/1D/1F（图H），抑制结直肠癌肿瘤干细胞增殖（图G），减轻肿瘤负荷（图F）接着，研究人员检测了5-羟色胺处理后，结直肠癌干细胞胞内信号通路的变化，发现Wnt/β-连环蛋白信号被显著激活。5-羟色胺刺激后，结直肠癌干细胞β-连环蛋白浓度升高，HTR1B/1D/1F敲除后，β-连环蛋白浓度降低。这表明，5-羟色胺通过HTR1B/1D/1F激活结直肠癌干细胞的Wnt/β-连环蛋白信号通路。 Wnt/β-连环蛋白是促进肿瘤干细胞增殖和维持干性的关键通路，其中，β-连环蛋白是通路的核心成分，由细胞质进入细胞核，激活cylinD1和c-myc等原癌基因促进细胞增殖[4]。当通路未激活时，β-连环蛋白结合axin后被降解，使β-连环蛋白保持在较低水平；而当通路激活时，β-连环蛋白与axin的结合被阻断，β-连环蛋白的降解被抑制，提升β-连环蛋白的浓度。通过质谱分析，研究人员发现，HTR1B/1D/1F能直接结合axin。HTR1B/1D/1F经5-羟色胺激动后，结合axin1使其发生转位，进而抑制axin结合β-连环蛋白，避免β-连环蛋白降解，从而促进结直肠癌干细胞的增殖。在肠道内，5-羟色胺由肠嗜铬细胞和血清素能神经元产生。那么，在结直肠癌中，促进结直肠癌干细胞自我更新的5-羟色胺，是由哪种细胞分泌的呢？肠嗜铬细胞表达5-羟色胺合成的限速酶Tph1，而血清素能神经元以限速酶Tph2为标志物。研究人员检测了结直肠癌中Tph1和Tph2的表达水平，发现只有Tph2在结直肠肿瘤中表达上调，与瘤内5-羟色胺水平呈正相关。分别敲除结直肠癌小鼠的Tph1和Tph2，研究人员发现，只有Tph2敲除鼠肿瘤减小，肿瘤内5-羟色胺水平降低，结直肠癌干细胞数目减少，增殖能力减弱。这表明在结直肠癌发病中，作用于癌干细胞的5-羟色胺是由血清素能神经元产生。因此，血清素能神经元是结直肠癌干细胞自我更新和结直肠肿瘤发生的必要条件。图A：小鼠成瘤实验显示Tph2敲除鼠，而不是Tph1敲除鼠，肿瘤减小；图B、C和D：Tph2敲除鼠结直肠癌干细胞数目减少，增殖能力减弱然而，在肠道内，又是什么促进血清素能神经元分泌5-羟色胺，从而刺激结直肠癌干细胞增殖的呢？由于肠道细胞暴露在数量惊人、种类繁多的肠道菌群中，肠道菌群通过神经、代谢和免疫等途径影响肠道健康，与肠道肿瘤的发生发展密切有关[5]。因此，研究人员把目光聚焦在肠道菌群上。把结直肠癌小鼠的肠道菌群移植给正常小鼠后，研究人员发现正常小鼠的Tph2的表达也随之上调。这提示，结直肠癌相关的菌群可能通过某种方式促进了Tph2的表达。短链脂肪酸是肠道菌群最重要的代谢物之一，具有神经活性，能调节肠道神经元[6]。研究人员检测到一种短链脂肪酸，异戊酸（IVA），能显著促进Tph2在血清素能神经元中的表达。荧光素酶实验验证了异戊酸对Tph2启动子的激活作用。本研究机制示意图总的来说，肠道菌群代谢产生异戊酸，异戊酸激活肠道血清素能神经元Tph2基因的启动子，上调Tph2的表达，Tph2促进神经元生成5-羟色胺，5-羟色胺与结直肠癌干细胞表面的受体HTR1B/1D/1F结合，HTR1B/1D/1F激动后在胞内结合axin1使其发生转位，进而抑制β-连环蛋白与axin的结合，避免β-连环蛋白降解，从而促进结直肠癌干细胞的自我更新和肿瘤的发生。参考文献 [1] Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71(3):209-249. doi:10.3322/caac.21660 [2] Drokhlyansky E, Smillie CS, Van Wittenberghe N, et al. The Human and Mouse Enteric Nervous System at Single-Cell Resolution. Cell. 2020;182(6):1606-1622.e23. doi:10.1016/j.cell.2020.08.003 [3] Zhu P, Lu T, Chen Z, et al. 5-hydroxytryptamine produced by enteric serotonergic neurons initiates colorectal cancer stem cell self-renewal and tumorigenesis [published online ahead of print, 2022 May 7]. Neuron. 2022;S0896-6273(22)00369-5. doi:10.1016/j.neuron.2022.04.024 [4] Bian J, Dannappel M, Wan C, Firestein R. Transcriptional Regulation of Wnt/β-连环蛋白 Pathway in Colorectal Cancer. Cells. 2020;9(9):2125. Published 2020 Sep 19. doi:10.3390/cells9092125 [5] Fan Y, Pedersen O. Gut microbiota in human metabolic health and disease. Nat Rev Microbiol. 2021;19(1):55-71. doi:10.1038/s41579-020-0433-9 [6] Silva YP, Bernardi A, Frozza RL. The Role of Short-Chain Fatty Acids From Gut Microbiota in Gut-Brain Communication. Front Endocrinol (Lausanne). 2020;11:25. Published 2020 Jan 31. doi:10.3389/fendo.2020.00025