AMPK x sGC

更新于：2025-09-12

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100 项与 AMPK x sGC 相关的临床结果

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0 项与 AMPK x sGC 相关的专利（医药）

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项与 AMPK x sGC 相关的文献（医药）

2025-08-01·JOURNAL OF NEUROSCIENCE RESEARCH

Transcriptomic Profiling Reveals Injury Responses of Peripheral Glial Cells in Sensory Neuron Microenvironment

Article

作者: Shen, Nimei ; Jin, Jiaxin ; Wang, Dong ; Lv, Saizhen ; Xu, Jiacheng ; Pan, Yanyu ; Wang, Youhua

ABSTRACT:

Schwann cells and satellite glial cells (SGCs) are important peripheral glial cells in the dorsal root ganglion (DRG) and commendable participants in regulating neuronal functions. Herein, through re‐analysis of publicly available single‐nucleus RNA sequencing data from naïve and injured DRG at 1 and 3 days following sciatic nerve crush, we systematically characterized the transcriptomic alterations in Schwann cells and SGCs. Cell clustering and counting showed that peripheral glial cells occupied a large population after sciatic nerve crush injury. Using differentially expression analysis, we found that apoptosis and immune responses were involved in all these examined peripheral glial cells. Unique glial cells also responded differently to sciatic nerve crush injury, with myelinating Schwann cells characterized by enriched adenosine 5′‐monophosphate activated protein kinase (AMPK) metabolic signaling, non‐myelinating Schwann cells characterized by enriched tissue‐remodeling‐related signaling, and SGCs characterized by enriched ion channels. Using single‐cell regulatory network inference and clustering (SCENIC) to determine essential transcription factors in specific cell type at the naïve state and at multiple time points after sciatic nerve crush injury, we found that Schwann cells and SGCs possessed their own elevated transcription factor‐coding genes, with activating factor 3 (Atf3) commonly highly up‐regulated in all peripheral glial cells. This study provides a profiling map of peripheral glial cells at the naïve and injured states, expands the acknowledgment of the molecular background of nerve injury, and can lead to novel strategies to promote sensory nerve regeneration.

2024-08-01·Heliyon

GPRASP2 deficiency contributes to apoptosis in the spiral ganglion cells via the AMPK/DRP1 signaling pathway

Article

作者: Cao, Xin ; Yao, Jun ; Lu, Yajie ; Wang, Tianming ; Cai, Jing ; Chen, Zhibin ; Wei, Qinjun ; Huang, Kun ; Yue, Shen

G protein-coupled receptor-associated sorting protein 2 (GPRASP2) deficiency has been implicated in immunological inflammation, cancers, and neurological disorders. Our previous work revealed that the pathogenic mutation in GPRASP2 was responsible for X-linked recessive syndromic hearing loss (SHL). Given the specific high expression of GPRASP2 in the spiral ganglion, GPRASP2 likely contributes to the maintenance and functionality of neurons, potentially playing a role in synaptic transmission. The impact of GPRASP2 deficiency on spiral ganglion cells (SGCs) and their underlying pathogenic mechanisms will be investigated in this study. The primary culture of SGCs obtained from mouse cochleae was treated with Gprasp2-targeting short hairpin RNA (Gprasp2-shRNA) via lentivirus infection. The results showed that GPRASP2 deficiency enhanced SGCs apoptosis and decreased cell viability. Meanwhile, a significant abnormality of mitochondrial morphology and decreased membrane potential were observed in GPRASP2-deficient SGCs. These effects could be mitigated by treatment with the mitochondrial division inhibitor 1 (Mdivi-1). In addition to enhancing SGCs apoptosis and decreasing cell viability, GPRASP2 deficiency also inhibited the development of SGCs in mouse cochlear explant culture. Our study further revealed that this deficiency resulted in increased phosphorylation of AMPK and activation of the AMPK/DRP1 pathway, promoting SGCs apoptosis. These findings provide insight into the pathogenic mechanisms by which GPRASP2 deficiency is implicated in auditory dysfunction.

2023-09-01·Molecular metabolism

CaMKK2 is not involved in contraction-stimulated AMPK activation and glucose uptake in skeletal muscle

Article

作者: Larsen, Jeppe K ; Ling, Naomi X Y ; Hossain, Mohammad A ; Sakamoto, Kei ; Brault, Jeffrey J ; Oakhill, Jonathan S ; Witczak, Carol A ; Hafen, Paul S ; Bringas, Conchita Fraguas ; Drewry, David H ; Deshmukh, Atul S ; Lewis, Christopher T A ; Negoita, Florentina ; Addinsall, Alex B ; Sermersheim, Tyler J ; Scott, John W ; Ahwazi, Danial ; Hellberg, Kristina ; Sankar, Uma ; Ochala, Julien ; Agerholm, Marianne

OBJECTIVE:

The AMP-activated protein kinase (AMPK) gets activated in response to energetic stress such as contractions and plays a vital role in regulating various metabolic processes such as insulin-independent glucose uptake in skeletal muscle. The main upstream kinase that activates AMPK through phosphorylation of α-AMPK Thr172 in skeletal muscle is LKB1, however some studies have suggested that Ca²⁺/calmodulin-dependent protein kinase kinase 2 (CaMKK2) acts as an alternative kinase to activate AMPK. We aimed to establish whether CaMKK2 is involved in activation of AMPK and promotion of glucose uptake following contractions in skeletal muscle.

METHODS:

A recently developed CaMKK2 inhibitor (SGC-CAMKK2-1) alongside a structurally related but inactive compound (SGC-CAMKK2-1N), as well as CaMKK2 knock-out (KO) mice were used. In vitro kinase inhibition selectivity and efficacy assays, as well as cellular inhibition efficacy analyses of CaMKK inhibitors (STO-609 and SGC-CAMKK2-1) were performed. Phosphorylation and activity of AMPK following contractions (ex vivo) in mouse skeletal muscles treated with/without CaMKK inhibitors or isolated from wild-type (WT)/CaMKK2 KO mice were assessed. Camkk2 mRNA in mouse tissues was measured by qPCR. CaMKK2 protein expression was assessed by immunoblotting with or without prior enrichment of calmodulin-binding proteins from skeletal muscle extracts, as well as by mass spectrometry-based proteomics of mouse skeletal muscle and C2C12 myotubes.

RESULTS:

STO-609 and SGC-CAMKK2-1 were equally potent and effective in inhibiting CaMKK2 in cell-free and cell-based assays, but SGC-CAMKK2-1 was much more selective. Contraction-stimulated phosphorylation and activation of AMPK were not affected with CaMKK inhibitors or in CaMKK2 null muscles. Contraction-stimulated glucose uptake was comparable between WT and CaMKK2 KO muscle. Both CaMKK inhibitors (STO-609 and SGC-CAMKK2-1) and the inactive compound (SGC-CAMKK2-1N) significantly inhibited contraction-stimulated glucose uptake. SGC-CAMKK2-1 also inhibited glucose uptake induced by a pharmacological AMPK activator or insulin. Relatively low levels of Camkk2 mRNA were detected in mouse skeletal muscle, but neither CaMKK2 protein nor its derived peptides were detectable in mouse skeletal muscle tissue.

CONCLUSIONS:

We demonstrate that pharmacological inhibition or genetic loss of CaMKK2 does not affect contraction-stimulated AMPK phosphorylation and activation, as well as glucose uptake in skeletal muscle. Previously observed inhibitory effect of STO-609 on AMPK activity and glucose uptake is likely due to off-target effects. CaMKK2 protein is either absent from adult murine skeletal muscle or below the detection limit of currently available methods.

项与 AMPK x sGC 相关的新闻（医药）

2023-08-10

·CPHI制药在线

植提 | 倍半萜内酯类化合物抗肿瘤作用的研究进展

关注并星标CPHI制药在线倍半萜内酯是一大类次生代谢产物，绝大多数来源于菊科植物，具有抗肿瘤、抗炎、抗菌等多种生物活性。根据羧基骨架、取代基的类型和位置，倍半萜内酯类可分为吉马内酯（germacranolides）、愈创木内酯（guaianolides）、伪愈创木内酯（pseudoguaianolides）、桉烷内酯类（eudesmanolides）、榄香烷内酯（elemanolides）等。近年来发现具有抗肿瘤活性的倍半萜内酯主要来源于青蒿素类、土木香内酯类、地胆草内酯类、鹅不食草内酯类、小白菊内酯类等。青蒿素是在菊科植物黄花蒿中发现的倍半萜内酯类化合物，其衍生物双氢青蒿素和青蒿琥酯对多种肿瘤具有显著的抑制作用。在土木香 Inula helenium L.中发现的具有抗肿瘤活性的倍半萜内酯类化合物主要有土木香内酯、异土木香内酯、木香烃内酯和去氢木香内酯。在地胆草Elephantopus scaber L.中发现的具有抗肿瘤活性的倍半萜内酯类化合物主要有去氧地胆草素、异去氧苦地胆苦素和地胆草种内酯等。在鹅不食草 Centipeda minima L.中发现的具有抗肿瘤活性的倍半萜内酯类化合物主要有山金车内酯 D和短叶老鹳草素。在小白菊 Tanacetum parthenium L.中发现的具有抗肿瘤活性的倍半萜内酯类化合物主要有小白菊内酯、二甲氨基小白菊内酯、乌心石内酯、Epoxymicheliolide和Dimethylaminomicheliolide。此外，从其他植物中分离的倍半萜内酯也具有肿瘤抑制作用，如从旋覆花属植物 Inula aucheriana 中分离得到的化合物旋覆花内酯 Britannin对多数肿瘤细胞具有抑制作用；来自中药白术 Atractylodes macrocephala中的倍半萜内酯有白术内酯Ⅰ、白术内酯Ⅱ；来自泥胡菜 Hemistepta lyrata Bunge的有Hemistepsin A；来自中药苍耳Xanthium strumarium L. 的有叶黄制菌素；来自肿柄菊Tithonia diversifolia A. Gray. 的有圆叶肿柄菊素 C tagitinin C；来自于毒伞芹 Thapsia garganica L. 的有毒胡萝卜素；来自牛樟芝Antrodia cinnamomea 的有 Antrocin；来自于旋覆花属植物 Inula oculus-christi 的有天人菊内酯。倍半萜内酯类化合物的抗肿瘤作用机制倍半萜内酯类天然产物抗肿瘤活性的作用机制主要包括氧化应激、铁死亡、诱导凋亡、诱导自噬以及调节和提高免疫力。 1氧化应激倍半萜内酯可通过抑制硫氧还蛋白还原酶（TrxR1）或核因子红细胞2相关因子2（Nrf2）诱导 ROS 的产生。土木香内酯在胃癌细胞 BGC-823和SGC-7901 中，通过抑制 TrxR1 的活性诱导 ROS 生成，进而激活 MAPK 通路，最终诱导肿瘤细胞的凋亡。土木香内酯可通过 ROS 积累和内质网应激，抑制三阴乳腺癌细胞 MDAMB-231 细胞活性。此外，土木香内酯在食管腺癌细胞 KYAE-1中，可下调 Nrf2 表达，诱导细胞内ROS 积累，进而诱导细胞凋亡。 2铁死亡铁死亡是一种铁依赖性的调节性细胞死亡形式，是由细胞膜上的脂质过氧化物的毒性积累引发的。青蒿素和双氢青蒿素在非小细胞肺癌A549细胞中，可下调铁死亡的核心负调节器胱氨酸/谷氨酸转运体（xCT），上调铁死亡正向调节因子转铁蛋白受体（TFRC）的 mRNA 水平，诱导 A549 细胞铁死亡。去氧地胆草素及其衍生物DETD-35 在黑色素瘤细胞 A375 和A375-R中，可重塑谷胱甘肽和初级代谢、脂质/氧脂质代谢并造成线粒体损伤，诱导黑色素瘤细胞的脂质ROS 积累并触发铁死亡。 3诱导凋亡细胞凋亡是肿瘤细胞程序性死亡最重要的途径。大多数倍半萜内酯是通过诱导肿瘤细胞凋亡达到抗肿瘤的目的。乌心石内酯能上调肝癌细胞HepG2 和 Hepa 1-6 中细胞凋亡诱导因子（AIF）和细胞色素 C 的表达，诱导凋亡。木香烃内酯在结直肠癌细胞 HCT-15、HCT-116 和DLD1中，通过激活和诱导 p53 的稳定性，诱导凋亡。异木香内酯在食管鳞癌细胞 KYSE30中，上调 PDCD4 的表达，下调Bcl-xL和XIAP的表达，诱导细胞凋亡。青蒿琥酯可使荷 H22肝癌小鼠的实体瘤组织标本中的 Bax 基因表达增加、Bcl-2 基因表达减少、Bcl -2 /Bax 比例下降，表明青蒿琥酯可下调PCNA和Bcl-2的表达、上调 Bax 的表达，诱导细胞凋亡。小白菊内酯( PN) 能诱导多发性骨髓瘤细胞凋亡，而正常淋巴细胞在同等条件下不受影响。PN 的凋亡活性是通过引起MM细胞的氧化应激而介导的，并进一步推测 NADPH 的氧化活性与PN介导的MM 细胞ROS的产生相关。泽兰内酯可上调Hela 细胞 p53 的表达、上调 Bax 的表达、下调 Bcl-2 的表达，使Bcl-2 /Bax比值降低，诱导细胞凋亡。 4细胞自噬细胞自噬可介导细胞凋亡和细胞周期阻滞。例如青蒿琥酯在膀胱癌细胞T24和EJ中可诱导自噬，随后激活细胞凋亡，且 AMPK-mTORULK1 途径参与自噬和凋亡的过程。小白菊内酯在胰腺癌细胞 Panc-1中，可诱导肿瘤细胞自噬，并显著上调 p62/SQSTM1、 Beclin 1和LC3Ⅱ的表达，最终诱导凋亡。青蒿素和双氢青蒿素在上皮性卵巢癌细胞 SKOV3 中，可阻滞细胞周期在 G2/M 期，且诱导自噬。 5双向调节和提高免疫力灌胃给予S180 荷瘤小鼠青蒿琥酯，青蒿琥酯60、30、15 g·kg-1·d -1均能显著抑制S180 的生长和升高S180荷瘤小鼠血清 IgG 的抗体水平，对2，4-二硝基氟苯( DNFB) 诱导的迟发性超敏反应有增强作用，并可诱导淋巴细胞转化为淋巴母细胞，提高小鼠的免疫功能。双氢青蒿素对豆蛋白 A( ConA) 诱导的小鼠 T 细胞的增殖有明显的抑制作用，是一种潜在的免疫抑制剂。异土木香内酯对人肝肿瘤细胞( HLE) 的增殖具较强的抑制活性，还对小鼠移植性肿瘤 H22的生长有抑制作用，并且不降低荷瘤小鼠的胸腺指数和脾指数，推测异土木香内酯有可能是通过提高机体的免疫能力来实现其抗肿瘤活性的。倍半萜内酯类化合物与抗肿瘤药物的联用肿瘤耐药性是肿瘤治疗的一大障碍，越来越多的研究表明，将天然产物与抗肿瘤药物联用可以带来更好的治疗效果。在倍半萜内酯类化合物与抗肿瘤药物的联用中，主要是与化疗、放疗和免疫治疗联用。倍半萜内酯类化合物可与多种化疗药物联用，对多种肿瘤细胞的增殖有抑制作用，可达到增敏、增效的协同作用。在联合放疗中，乌心石内酯可增强X线对宫颈癌Hela 细胞的抑制作用和凋亡诱导作用，抑制 HeLa 细胞的硫氧还蛋白还原酶（TrxR）活性，诱导活性氧（ROS）生成。Dimethylaminomicheliolide 可提高小鼠结直肠癌细胞 CT26 和胶质母细胞瘤细胞 GL261 对放疗的敏感，诱导 ROS 生成、细胞凋亡和 DNA双链断裂，且可与抗 PD-L1 抗体（α-PD-L1）结合，产生协同抗肿瘤效果。双氢青蒿素可通过抑制冷诱导 RNA 结合蛋白（CIRBP）的表达减少肺癌 A549细胞的线粒体自噬和辐射抗性，敲除CIRBP 基因可抑制 A549R 细胞的线粒体自噬和辐射抗性，与双青蒿素联用可进一步抑制 A549R 细胞的线粒体自噬和辐射抗性。Antrocin 与放疗联用可抑制前列腺癌 DAB2IP 基因敲除抗辐射细胞系（LAPC4-KD 和 PC3-KD）及 shControl 细胞系（LAPC4-Con 和 PC3-Con）的增殖并诱导其凋亡，下调 PI3K/AKT 和 MAPK信号通路，调节细胞周期并诱导凋亡。在联合免疫治疗中，青蒿素可增敏人慢性髓原白血病 K562 细胞和淋巴瘤 Raji 细胞以及小鼠淋巴瘤 YAC-1 细胞对 NK 细胞介导的细胞溶解。白术内酯Ⅰ可显著促进人结直肠癌细胞 HCT116、 SW837 和小鼠结直肠癌细胞 MC38、CT26 的肿瘤抗原呈递，增强 CD8+T细胞的细胞毒性反应，提高肿瘤对免疫疗法的反应。目前，倍半萜内酯类中以小白菊内酯为基础合成的Dimethylaminomicheliolide 和以毒胡萝卜素为基础合成的 Mipsagargin 均已进入临床试验阶段，展示出巨大的潜力。倍半萜内酯类天然产物不仅可抑制耐药肿瘤细胞，在药物联用中也呈现增敏、增效的作用，倍半萜内酯类化合物可增加细胞对化疗药物、放疗射线以及免疫疗法的敏感性，产生协同作用，增强细胞毒性，诱导细胞凋亡。所以寻找抗肿瘤药物作用的新靶点，研究开发天然抗癌新药，可以降低化疗的成本，更能减轻肿瘤患者的痛苦，使更多的肿瘤患者都能得到及时、有效的治疗，提高肿瘤患者的生活质量。参考资料 [1]朱华野,朴惠顺.倍半萜内酯类化合物抗肿瘤作用机制的研究进展[J].华西药学杂志,2015,30(03):381-383. [2]林金榕,陈四保.倍半萜内酯类天然产物抗肿瘤活性及机制研究进展[J].中南药学,2023,21(06):1589-1598. 作者简介小米虫，药品质量研究工作者，长期致力于药品质量研究及药品分析方法验证工作，现就职于国内某大型药物研发公司，从事药品检验分析及分析方法验证。智药研习社近期直播报名来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com▼更多制药资讯，请关注CPHI制药在线▼点击阅读原文，进入智药研习社~

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