Notoginseng Leaf Triterpenes Ameliorates OGD/R-Induced Neuronal Injury via SIRT1/2/3-Foxo3a-MnSOD/PGC-1α Signaling Pathways Mediated by the NAMPT-NAD Pathway

Abstract

Background. Cerebral ischemic stroke (CIS) is a common cerebrovascular disease whose main risks include necrosis, apoptosis, and cerebral infarction. But few therapeutic advances and prominent drugs seem to be of value for ischemic stroke in the clinic yet. In the previous study, notoginseng leaf triterpenes (PNGL) from Panax notoginseng stem and leaf have been confirmed to have neuroprotective effects against mitochondrial damages caused by cerebral ischemia in vivo. However, the potential mechanisms of mitochondrial protection have not been fully elaborated yet. Methods. The oxygen and glucose deprivation and reperfusion (OGD/R)-induced SH-SY5Y cells were adopted to explore the neuroprotective effects and the potential mechanisms of PNGL in vitro. Cellular cytotoxicity was measured by MTT, viable mitochondrial staining, and antioxidant marker detection in vitro.Mitochondrial functions were analyzed by ATP content measurement, MMP determination, ROS, NAD, and NADH kit in vitro. And the inhibitor FK866 was adopted to verify the regulation of PNGL on the target NAMPT and its key downstream. Results. In OGD/R models, treatment with PNGL strikingly alleviated ischemia injury, obviously preserved redox balance and excessive oxidative stress, inhibited mitochondrial damage, markedly alleviated energy metabolism dysfunction, improved neuronal mitochondrial functions, obviously reduced neuronal loss and apoptosis in vitro, and thus notedly raised neuronal survival under ischemia and hypoxia. Meanwhile, PNGL markedly increased the expression of nicotinamide phosphoribosyltransferase (NAMPT) in the ischemic regions and OGD/R-induced SH-SY5Y cells and regulated the downstream SIRT1/2-Foxo3a and SIRT1/3-MnSOD/PGC-1α pathways. And FK866 further verified that the protective effects of PNGL might be mediated by the NAMPT in vitro. Conclusions. The mitochondrial protective effects of PNGL are, at least partly, mediated via the NAMPT-NAD+ and its downstream SIRT1/2/3-Foxo3a-MnSOD/PGC-1α signaling pathways. PNGL, as a new drug candidate, has a pivotal role in mitochondrial homeostasis and energy metabolism therapy via NAMPT against OGD-induced SH-SY5Y cell injury.

Nicotinamide Mononucleotide Alleviates Hyperosmolarity-Induced IL-17a Secretion and Macrophage Activation in Corneal Epithelial Cells/Macrophage Co-Culture System

“… 33 , 34 It had confirmed that NMN after systemic or local application would always be transformed to NAD+ and then demonstrated important regulation effects for kinds of diseases. 35 , 36 SIRT1 was one of the most confirmed NAD+ consuming enzyme, thus higher SIRT1 would be induced by NMN application in various disorders and biological progresses, including hepatocellular carcinoma, 37 adaptive thermogenesis 38 and osteogenesis. 39 In this current experiment, it was found that NMN-induced expression of SIRT1 could lead to a decreased level of IL-17a and this result might explain the biological mechanism of NMN application on DED, at least in part.…”

Nicotinamide Phosphoribosyltransferase as a Key Molecule of the Aging/Senescence Process

“…Notoginseng leaf triterpenes (PNGL), which are the total saponins extracted from Panax notoginseng stems and leaves [ 100 , 101 ], are novel natural compounds that have recently been shown to activate Nampt gene expression [ 102 ]. PNGL has already been shown to possess antioxidative effects against a human neuroblastoma cell line [ 101 , 103 ].…”

Network Pharmacology/Metabolomics‐Based Validation of AMPK and PI3K/AKT Signaling Pathway as a Central Role of Shengqi Fuzheng Injection Regulation of Mitochondrial Dysfunction in Cancer‐Related Fatigue

“…AMPK and SIRT1 have overlapping effects in the promotion of muscle mitochondrial biogenesis and oxidative stress. However, SIRT1 activation requires AMPK phosphorylation, further affecting PGC1α deacetylation [32,33]. Since the activation of AMPK/SIRT1 is closely related to biogenesis and the function of the muscle mitochondria, it is likely that AMPK/SIRT1 is a key target for the prevention and treatment of CRF and its related metabolic effects.…”