(Gly¹⁴)-Humanin (human)

Humanin is both an intracellular protein and a secreted protein. It is the first newly discovered peptide encoded in the mitochondrial genome, which exerts robust protective effects against a myriad of cytotoxic stimuli in many cell types^[2]. Replacement of serine at position 14 of the HN peptide chain (Ser14) with glycine (Gly) leads to the formation of (Gly14)-Humanin (human), which has cytoprotective activity enhanced by 1000-fold when compared with that of Humanin^[3].

(Gly14)-Humanin (human) reduced Dil-ox-LDL accumulation in the RAW 264.7 macrophages. (Gly14)-Humanin (human) could inhibit ox-LDL-induced macrophage-derived foam cell formation, which occurs because of a decrease in lipid uptake and an increase in cholesterol efflux from macrophage cells^[7]. (Gly14)-Humanin (human) pretreatment inhibits HG-induced apoptosis of vascular endothelial cells by down-regulating miR-155, which was transferred to adjacent vascular endothelial cells via cell-derived EMPs. EMPs could serve as a potential tool for the specific delivery of miRNAs, contributing to a stronger therapeutic effect of (Gly14)-Humanin (human) in anti-diabetic vascular complications therapy^[1]. (Gly14)-Humanin (human) could restore cathepsin D activity and protein level in HUVECs to repair lysosomal functional damage induced by Ox-LDL, further repairing Ox-LDL-induced autophagic damage in HUVECs^[4].

Pretreatment with (Gly14)-Humanin (human) not only protected spatial memory but also rescued STAT3 from Aβ-induced disruption; and the neuroprotective effects of (Gly14)-Humanin (human) were effectively counteracted by genistein, a specific tyrosine kinase inhibitor. Sequence 31-35 in Aβ is the shortest active center responsible for the neurotoxicity of Aβ from molecule to behavior; and (Gly14)-Humanin (human) protects spatial learning and memory in rats against Aβ-induced insults; and probably involves the activation of tyrosine kinases and subsequent beneficial modulation of STAT3 and caspase3^[5]. Mice administered (Gly14)-Humanin (human) intracerebroventricularly (i.c.v.) prior to TBI had decreased cells with plasmalemma permeability in the injured cortex and hippocampus, reduced brain lesion volume, improved motor performance and ameliorated performance in the Morris water maze test post TBI. Reduced lesion volume was also observed even when (Gly14)-Humanin (human) was administered intraperitoneally (i.p.) at 1h and 2h post TBI, and minor amelioration in motor and Morris water maze test deficits was also observed. (Gly14)-Humanin (human) treatment improved morphological and functional outcomes after TBI in mice and the protective effect of (Gly14)-Humanin (human) against TBI may be associated with down-regulating apoptosis and autophagy^[6].

References:
[1]: Shen MY, Wang M, et,al. [Gly14]-Humanin Ameliorates High Glucose-Induced Apoptosis by Inhibiting the Expression of MicroRNA-155 in Endothelial Microparticles. Diabetes Metab Syndr Obes. 2021 May 24;14:2335-2347. doi: 10.2147/DMSO.S306026. PMID: 34079312; PMCID: PMC8163639.
[2]: Kim SJ, Mehta HH, et,al. Mitochondrial peptides modulate mitochondrial function during cellular senescence. Aging (Albany NY). 2018 Jun 10;10(6):1239-1256. doi: 10.18632/aging.101463. PMID: 29886458; PMCID: PMC6046248.
[3]: Hashimoto Y, Niikura T, et,al. A rescue factor abolishing neuronal cell death by a wide spectrum of familial Alzheimer's disease genes and Abeta. Proc Natl Acad Sci U S A. 2001 May 22;98(11):6336-41. doi: 10.1073/pnas.101133498. Erratum in: Proc Natl Acad Sci U S A 2001 Oct 23;98(22):12854. PMID: 11371646; PMCID: PMC33469.
[4]: Ding Y, Feng Y, et,al. [Gly14]-humanin restores cathepsin D function via FPRL1 and promotes autophagic degradation of Ox-LDL in HUVECs. Nutr Metab Cardiovasc Dis. 2020 Nov 27;30(12):2406-2416. doi: 10.1016/j.numecd.2020.07.022. Epub 2020 Jul 25. PMID: 32917500.
[5]: Yuan L, Liu XJ, et,al. [Gly14]-Humanin Protects Against Amyloid β Peptide-Induced Impairment of Spatial Learning and Memory in Rats. Neurosci Bull. 2016 Aug;32(4):374-82. doi: 10.1007/s12264-016-0041-x. Epub 2016 Jun 15. PMID: 27306655; PMCID: PMC5563781.
[6]: Wang T, Zhang L, et,al. [Gly14]-Humanin reduces histopathology and improves functional outcome after traumatic brain injury in mice. Neuroscience. 2013 Feb 12;231:70-81. doi: 10.1016/j.neuroscience.2012.11.019. Epub 2012 Nov 20. PMID: 23178909.
[7]: Zhu WW, Wang SR, et,al. Gly[14]-humanin inhibits ox-LDL uptake and stimulates cholesterol efflux in macrophage-derived foam cells. Biochem Biophys Res Commun. 2017 Jan 1;482(1):93-99. doi: 10.1016/j.bbrc.2016.10.138. Epub 2016 Nov 1. PMID: 27815075.

Humanin 既是细胞内蛋白又是分泌蛋白。它是第一个新发现的在线粒体基因组中编码的肽，对许多细胞类型的无数细胞毒性刺激具有强大的保护作用^[2]。 HN 肽链 14 位丝氨酸 (Ser14) 被甘氨酸 (Gly) 取代导致 (Gly14)-Humanin (human) 的形成，与 Humanin 相比，其细胞保护活性增强了 1000 倍^[3].

(Gly14)-Humanin（人类）减少了 RAW 264.7 巨噬细胞中的 Dil-ox-LDL 积累。 (Gly14)-Humanin（人）可抑制 ox-LDL 诱导的巨噬细胞衍生泡沫细胞形成，这是由于巨噬细胞脂质摄取减少和胆固醇流出增加所致^[7] . (Gly14)-Humanin（人）预处理通过下调 miR-155 抑制 HG 诱导的血管内皮细胞凋亡，miR-155 通过细胞衍生的 EMP 转移到邻近的血管内皮细胞。 EMP 可作为特异性递送 miRNA 的潜在工具，有助于增强 (Gly14)-Humanin (human) 在抗糖尿病血管并发症治疗中的疗效^[1]。 (Gly14)-Humanin (human) 可恢复 HUVECs 组织蛋白酶 D 活性和蛋白水平，修复 Ox-LDL 诱导的溶酶体功能损伤，进一步修复 Ox-LDL 诱导的 HUVECs 自噬损伤^[4] .

用 (Gly14)-Humanin（人）预处理不仅可以保护空间记忆，还可以从 Aβ 诱导的破坏中拯救 STAT3； (Gly14)-Humanin（人）的神经保护作用被染料木黄酮（一种特定的酪氨酸激酶抑制剂）有效抵消。 Aβ中的31-35序列是负责Aβ从分子到行为的神经毒性的最短活性中心； (Gly14)-Humanin（人类）保护大鼠的空间学习和记忆免受 Aβ 诱导的损伤；并且可能涉及酪氨酸激酶的激活和随后对 STAT3 和 caspase3 的有益调节^[5]。在 TBI 前脑室内 (i.c.v.) 施用 (Gly14)-Humanin（人）的小鼠在受损皮层和海马体中具有质膜通透性的细胞减少、脑损伤体积减小、运动性能改善以及 TBI 后莫里斯水迷宫测试中的性能改善。即使在 TBI 后 1 小时和 2 小时腹膜内 (i.p.) 施用 (Gly14)-Humanin（人）时，也观察到损伤体积减小，并且还观察到运动和莫里斯水迷宫测试缺陷的轻微改善。 (Gly14)-Humanin（人）治疗改善了小鼠 TBI 后的形态学和功能结果，并且（Gly14）-Humanin（人）对 TBI 的保护作用可能与下调细胞凋亡和自噬有关^{[6]< /sup>.}