The metabolite GLP-1 (9-36) is neuroprotective and anti-inflammatory in cellular models of neurodegeneration.
The metabolite GLP-1 (9-36) is neuroprotective and anti-inflammatory in cellular models of neurodegeneration.
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DOI：
10.1111/jnc.15521
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发表时间：
2021-12
影响因子：
4.7
通讯作者：
Greig NH
中科院分区：
文献类型：
--
作者：
Li Y;Glotfelty EJ;Karlsson T;Fortuno LV;Harvey BK;Greig NH
胰高血糖素样肽-1(GLP-1)最为人所知的是其在食物摄入后的胰岛素调节作用。其代谢产物GLP-1(9-36)被认为是由于GLP-1受体(GLP-1R)低亲和力和非胰岛素样特性而不具有生物学活性；然而，最近的研究与这一假设相矛盾。FDA批准的GLP-1类似物用于治疗代谢紊乱和神经退行性疾病的增加引起了人们对GLP-1(9-36)S生物学作用的兴趣。我们使用人SH-SY5Y神经母细胞瘤细胞和GLP-1R高表达变种(#9)，在未分化和分化状态下，评估GLP-1(9-36)对谷氨酸中毒和其他氧化应激模型的神经营养/神经保护作用(通过MTS、LDH或ROS分析)。此外，我们还通过使用酶联免疫吸附试验、药物抑制剂或GLP-1R拮抗剂研究了GLP-1(9-36)的S信号通路，包括环磷酸腺苷(CAMP)、蛋白激酶A(PKA)和5‘-腺苷一磷酸激活的蛋白激酶(AMPK)。采用人HMC3和小鼠IMG小胶质细胞株，通过酶联免疫吸附试验(EL ISA)研究GLP-1(9-36)对内毒素(LPS)的抗炎作用。最后，我们将GLP-1(9-36)应用于用α-突触核蛋白或淀粉样蛋白-β攻击的原代分离培养物中，并通过免疫化学方法评估存活率和形态学。我们证明了GLP-1R、cAMP、PKA和AMPK介导的GLP-1(9-36)的神经营养和神经保护作用。该代谢产物显著降低HMC_3和IMG小胶质细胞的IL-6和肿瘤坏死因子-α水平。最后，我们展示了GLP-1(9-36)对用α-突触核蛋白或淀粉样蛋白-β挑战的原代神经元培养的轻微但显著的影响。这些研究加深了对GLP-1(9-36)S对神经系统的影响的了解，以及它作为病理背景下的主要或补充治疗的潜力。本研究评价了胰升糖素样肽-1(GLP-1)(7-36)代谢物GLP-1(9-36)的神经营养、神经保护和抗炎特性。内源性GLP-1(9-36)是由GLP-1(7-36)裂解而成，具有与其亲本多肽不同的性质。在这里，我们表征了GLP-1受体(GLP-1R)介导的GLP-1(9-36)对抗谷氨酸、H_2O_2、脂多糖以及与阿尔茨海默病(淀粉样蛋白-β)和帕金森病(α-突触核蛋白)相关的挑战的信号特性。这些研究加深了对GLP-1(9-36)S对神经系统的影响的了解，以及它作为病理背景下的主要或补充治疗的潜力。我们确认了抗微生物蛋白再生家族成员3阿尔法(REG3A)参与大血管缺血性卒中的病理生理反应的多种机制。REG3A与炎症细胞因子白介素6(IL6)和免疫调节蛋白白介素17C(IL17C)相互作用，诱导其他负责驱动和减轻炎症的细胞外和细胞内效应物。这些新发现有助于正在进行的对缺血性中风的炎症和治疗策略后遗症的研究。
Glucagon-like peptide-1 (GLP-1) is best known for its insulinotropic action following food intake. Its metabolite, GLP-1 (9–36), was assumed biologically inactive due to low GLP-1 receptor (GLP-1R) affinity and non-insulinotropic properties; however, recent studies contradict this assumption. Increased use of FDA approved GLP-1 analogues for treating metabolic disorders and neurodegenerative diseases raises interest in GLP-1 (9–36)’s biological role. We use human SH-SY5Y neuroblastoma cells and a GLP-1R overexpressing variety (#9), in both undifferentiated and differentiated states, to evaluate the neurotrophic/neuroprotective effects of GLP-1 (9–36) against toxic glutamate exposure and other oxidative stress models (via the MTS, LDH or ROS assays). In addition, we examine GLP-1 (9–36)’s signaling pathways, including cyclic-adenosine monophosphate (cAMP), protein kinase-A (PKA), and 5’ adenosine monophosphate activated protein kinase (AMPK) via use of ELISA, pharmacological inhibitors, or GLP-1R antagonist. Human HMC3 and mouse IMG microglial cell lines were used to study the anti-inflammatory effects of GLP-1 (9–36) against lipopolysaccharide (LPS) (via ELISA). Finally, we applied GLP-1 (9–36) to primary dissociation cultures challenged with α-synuclein or amyloid-β and assessed survival and morphology via immunochemistry. We demonstrate evidence of GLP-1R, cAMP, PKA, and AMPK mediated neurotrophic and neuroprotective effects of GLP-1 (9–36). The metabolite significantly reduced IL-6 and TNF-α levels in HMC3 and IMG microglial cells, respectively. Lastly, we show mild but significant effects of GLP-1 (9–36) in primary neuron cultures challenged with α-synuclein or amyloid-β. These studies enhance understanding of GLP-1 (9–36)’s effects on the nervous system and its potential as a primary or complementary treatment in pathological contexts. The current study evaluates the neurotrophic, neuroprotective, and anti-inflammatory properties of the glucagon-like peptide-1 (GLP-1) (7–36) metabolite, GLP-1 (9–36). Endogenous GLP-1 (9–36) is produced by the cleavage of GLP-1 (7–36) and has distinct properties from its parent peptide. Here, we characterize GLP-1 receptor (GLP-1R) mediated signaling properties of GLP-1 (9–36) against glutamate, H2O2, lipopolysaccharide and challenges associated with Alzheimer’s disease (amyloid-β) and Parkinson’s disease (α-synuclein). These studies enhance understanding of GLP-1 (9–36)’s effects on the nervous system and its potential as a primary or complementary treatment in pathological contexts. We identified multiple mechanisms by which anti-microbial protein Regenerating Family Member 3 Alpha (REG3A) participates in the pathophysiologic response to large-vessel ischemic stroke. REG3A interacts with inflammatory cytokine Interleukin-6 (IL6) and immunomodulatory protein Interleukin-17C (IL17C) to induce other extracellular and intracellular effectors responsible for both driving and attenuating inflammation. These novel findings contribute to the ongoing investigation of inflammation and therapeutic strategies sequela of ischemic stroke.
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DOI：
10.1016/s0140-6736(17)31585-4
发表时间：
2017-10-07
期刊：
Lancet (London, England)
影响因子：
--
作者：
Athauda D;Maclagan K;Skene SS;Bajwa-Joseph M;Letchford D;Chowdhury K;Hibbert S;Budnik N;Zampedri L;Dickson J;Li Y;Aviles-Olmos I;Warner TT;Limousin P;Lees AJ;Greig NH;Tebbs S;Foltynie T
通讯作者：
Foltynie T
影响因子：
48
作者：
Cukierman-Yaffe, Tali;Gerstein, Hertzel C.;Temelkova-Kurktschiev, Theodora
通讯作者：
Temelkova-Kurktschiev, Theodora
影响因子：
4.2
作者：
Callizot, Noelle;Combes, Maud;Poindron, Philippe
通讯作者：
Poindron, Philippe
影响因子：
4.8
作者：
Ban, Kiwon;Kim, Kyoung-Han;Husain, Mansoor
通讯作者：
Husain, Mansoor
DOI：
10.1152/ajpendo.00452.2001
发表时间：
2002-04-01
影响因子：
5.1
作者：
Deacon, CF;Plamboeck, A;Holst, JJ
通讯作者：
Holst, JJ