HNG

The S14G substitution in HNG appears to increase receptor binding affinity and/or signaling efficacy at the humanin receptors (FPR2, CNTFR complex). HNG activates STAT3, Akt/PI3K, and MAPK pathways that promote cell survival, inhibit apoptosis, and reduce inflammatory signaling. The enhanced potency makes HNG suitable for in vivo studies where humanin doses would be prohibitively high.

HNG retains humanin mitochondrial protective properties, preventing mitochondrial membrane potential collapse and cytochrome c release under ischemic or oxidative stress conditions. This mitochondrial cytoprotection is critical in neurons, cardiomyocytes, and other post-mitotic cells that are highly dependent on mitochondrial function.

HNG prevents amyloid-beta-induced neuronal apoptosis with ~1000x greater potency than humanin. In APP transgenic mouse models, intranasal or subcutaneous HNG reduces amyloid plaque burden, neuroinflammation, and cognitive deficits. HNG also protects against tau-induced neurodegeneration. These results support HNG as one of the most potent endogenous neuroprotective peptides identified.

HNG improves insulin sensitivity and glucose metabolism in diabetic mouse models, surpassing humanin in efficacy. In cardiac ischemia-reperfusion models, HNG reduces infarct size and improves recovery of cardiac function. HNG also reduces atherosclerotic plaque formation and improves endothelial function in apolipoprotein E knockout mice.