Bakuchiol Attenuates Oxidative Stress and Neuron Damage by Regulating Trx1/TXNIP and the Phosphorylation of AMPK After Subarachnoid Hemorrhage in Mice

Abstract

Subarachnoid hemorrhage (SAH) is a fatal cerebrovascular condition with complex pathophysiology that reduces brain perfusion and causes cerebral functional impairments. An increasing number of studies indicate that early brain injury (EBI), which occurs within the first 72 h of SAH, plays a crucial role in the poor prognosis of SAH. Bakuchiol (Bak) has been demonstrated to have multiorgan protective effects owing to its antioxidative and anti-inflammatory properties. The present study was designed to investigate the effects of Bak on EBI after SAH and its underlying mechanisms. In this study, 428 adult male C57BL/6J mice weighing 20 to 25 g were observed to investigate the effects of Bak administration in an SAH animal model. The neurological function and brain edema were assessed. Content of MDA/3-NT/8-OHdG/superoxide anion and the activity of SOD and GSH-Px were tested. The function of the blood-brain barrier (BBB) and the protein levels of claudin-5, occludin, zonula occludens-1, and matrix metalloproteinase-9 were observed. TUNEL staining and Fluoro-Jade C staining were conducted to evaluate the death of neurons. Ultrastructural changes of the neurons were observed under the transmission electron microscope. Finally, the roles of Trx, TXNIP, and AMPK in the protective effect of Bak were investigated. The data showed that Bak administration 1) increased the survival rate and alleviated neurological functional deficits; 2) alleviated BBB disruption and brain edema; 3) attenuated oxidative stress by reducing reactive oxygen species, MDA, 3-NT, 8-OHdG, gp91 phox , and 4-HNE; increased the activities of SOD and GSH-Px; and alleviated the damage to the ultrastructure of mitochondria; 4) inhibited cellular apoptosis by regulating the protein levels of Bcl-2, Bax, and cleaved caspase-3; and 5) upregulated the protein levels of Trx1 as well as the phosphorylation of AMPK and downregulated the protein levels of TXNIP. Moreover, the protective effects of Bak were partially reversed by PX-12 and compound C. To summarize, Bak attenuates EBI after SAH by alleviating BBB disruption, oxidative

Tilianin Ameliorates Cognitive Dysfunction and Neuronal Damage in Rats with Vascular Dementia via p‐CaMKII/ERK/CREB and ox‐CaMKII‐Dependent MAPK/NF‐κB Pathways

“…GSH and SOD are among the most important physiological antioxidants against free radicals, preventing subsequent lipid peroxidation and protein oxidation [ 44 ]. When ROS and membrane lipids undergo lipid peroxidation reaction, a large quantity of lipid peroxidation products is produced, including MDA and 4-HNE, which are the markers that indicate the degree of lipid peroxidation [ 45 ]. ROS reacts with protein amino acid residues to produce protein oxidation products, among which 3-NT is a commonly used detection indicator [ 46 ].…”

Role of Thioredoxin-Interacting Protein in Diseases and Its Therapeutic Outlook

“…Other drugs, such as allopurinol and quercetin, have been found to prevent the overexpression of TXNIP in the rat liver and activation of the NLRP3 inflammasome, and upregulation of sterol-regulatory element–binding protein 1c (SREBP-1c), SREBP-2, liver X receptor α (LXRα), fatty acid synthase, and ROS while downregulating PPARα [ 146 ]. Moreover, several other small-molecule drugs, for example, telmisartan [ 172 ], bakuchiol [ 173 ], vorinostat (SAHA) [ 147 ], trichostatin A (TSA) [ 149 , 174 ], imatinib [ 150 ], taurine [ 151 ], and troglitazone [ 153 ] can inhibit the expression of TXNIP. Thielen L.A. et al recently identified a small-molecule inhibitor, SRI-37330, that effectively suppresses TXNIP expression in rats, mice, and human pancreatic islets.…”

Effect of chronic administration with human thioredoxin‐1 transplastomic lettuce on diabetic mice

“…Trx‐1 may participate in NLRP6‐mediated signaling. The inhibition of the TXNIP expression through the activation of the AMPK pathway induces protective effects against diabetes following treatment with bakuchiol or sulforaphane, which induces the Trx protein (Groschwitz & Hogan, 2009 ; Han et al., 2016 ; Huang et al., 2015 ; Liu et al., 2020 ; Lv et al., 2020 ; Tanito et al., 2005 ). In addition, metformin, an oral antihyperglycemic agent, exerts a gastroprotective effect through increased mucus production, which is possibly related to the activation of the AMPK pathway (Noleto et al., 2019 ).…”

“…Another natural compound, bakuchiol, exhibits multiorgan protective properties owing to its antioxidative and anti‐inflammatory activities. It exerts antidiabetic, antiaging, and anticancer effects by downregulating TXNIP protein levels, upregulating phosphorylation of AMPK, and increasing the levels of Trx‐1 protein and the tight junction protein, occluding, which regulates intestinal mucosal barrier function (Groschwitz & Hogan, 2009 ; Han et al., 2016 ; Huang et al., 2015 ; Liu et al., 2020 ). Moreover, metformin, which is known as an oral antihyperglycemic agent, has a gastroprotective effect that causes increased mucus production, possibly related to the activation of the AMPK pathway (Noleto et al., 2019 ).…”