Cycloastragenol Confers Cerebral Protection after Subarachnoid Hemorrhage by Suppressing Oxidative Insults and Neuroinflammation via the SIRT1 Signaling Pathway

Abstract

Subarachnoid hemorrhage (SAH) is an acute cerebral vascular disease featured by oxidative insults and neuroinflammation. Cycloastragenol (CAG), the major active component of Astragalus radix, has a wide range of biological functions. However, the potential beneficial effects and the underlying molecular mechanisms of CAG on SAH remain obscure. In the current study, the cerebroprotective effects and mechanism of CAG on SAH were evaluated both in vivo and in vitro. Our results indicated that CAG significantly suppressed SAH-triggered oxidative insults, inflammatory mediators production, microglia activation, and the neutrophil infiltration in the brain. In addition, CAG improved neurological function and ameliorated neuronal apoptosis and degeneration after SAH. In vitro results also revealed the therapeutic effects of CAG on neurons and microglia co-culture system. Mechanistically, CAG treatment upregulated sirtuin 1 (SIRT1) expression, inhibited the levels of FoxO1, nuclear factor-kappa B, and p53 acetylation, and suppressed the subsequent oxidative, inflammatory, and apoptotic pathways. In contrast, inhibiting SIRT1 by pretreatment with Ex527 abrogated the protective actions of CAG both in vivo and in vitro models of SAH. Collectively, our findings indicated that CAG could be a promising and effective drug candidate for SAH.

Inflammation and immune cell abnormalities in intracranial aneurysm subarachnoid hemorrhage (SAH): Relevant signaling pathways and therapeutic strategies

“…The increased expression of SIRT1 has been reported to have a neuroprotective effect on brain edema and endogenous protection against DCI after SAH, as well as inducing the attenuation of neurovascular dysfunction following SAH ( 226 – 228 ), and the p53 pathway regulated by endogenous SIRT1 can crucially affect BBB permeability and brain edema after SAH ( 226 ). Concomitant with FOXO1, NF-кB, and p53 decreased acetylation, activation of SIRT1 pathways after SAH markedly reduced the levels of IL-1β, IL-6, and TNF-α; decreased Bax and cleaved caspase-3 levels and microglial activation; and increased Bcl-2 expression ( 229 , 230 ). In EBI after SAH, pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) and neural apoptosis were also suppressed by resveratrol (RSV) via the AMPK/SIRT1 cascade ( 157 ).…”

Peripheral extracellular vesicle-derived miR-150-3p exacerbates acute kidney injury following acute pancreatitis by promoting ferroptosis through FTH1 signaling

“…Further experiments showed that MDA and Fe 2+ were increased in the AP-AKI group, and GSH levels were decreased, which indicated that EVs could aggravate renal ferroptosis and lipid peroxidation (Figure 2B). As shown in a previous study, TECs are damaged by AP-AKI [7]. GPX4 and COX-2 are the essential regulators and the most important ferroptosis markers [33,35].…”

“…Tubular epithelial cells (TECs) account for 90% of the kidney volume and are damaged by AP-AKI [7]. Recent studies have shown that several forms of regulated cell death (RCD), including apoptosis, necrosis (Toll-like receptor/ZBP1-RIPK3 mediated), mitochondrial permeability transition-mediated regulated necrosis (MPT-RN), pyroautophagy (PARP1-dependent), pyroptosis (caspase1-IL-18/IL-1β mediated) and ferroptosis (GPX4 mediated), all participate in AKI [8][9][10][11][12][13][14][15].…”

Heat-Killed Staphylococcus aureus Induces Bone Mass Loss through Telomere Erosion

“…In order to further confirm that telomere erosion is the mechanism of bone loss caused by HKSA, the most recognized telomere protector, CAG [ 33 ], was used to rescue telomere damage caused by HKSA. The results showed that the telomere length of HKSA + CAG mice was significantly longer than that of HKSA mice, and the TIF signal was the opposite, suggesting that CAG improved HKSA-induced telomere damage.…”