SIRT1 activation by butein attenuates sepsis-induced brain injury in mice subjected to cecal ligation and puncture via alleviating inflammatory and oxidative stress.

Sepsis-induced brain injury is frequently encountered in critically ill patients with severe systemic infection. Butein (3,4,2',4'-tetrahydroxychalcone) has been demonstrated as the neuro-protective agent via reducing inflammation and oxidative stress on neurons. Moreover, activation of silent information regulator 1 (SIRT1) inhibits apoptosis, oxidation and inflammation thus alleviating sepsis-induced multiorgan injuries. In present study, we show that butein administrated intraperitoneally (10 mg/kg) saved mice from sepsis-induced lethality by increasing 7-day survival rate after cecal ligation and puncture (CLP) surgery. Additionally, butein treatment enhanced SIRT1 signaling thus decreasing the Ac-NF-κB, Ac-FOXO1 and Ac-p53 levels, thus attenuating the brain injury of mice after CLP surgery by decreasing cerebral edema, maintaining the blood-brain barrier integrity, inhibiting neuronal apoptosis, and decreasing pro-inflammatory cytokines production (IL-6, TNF-α and IL-1β) and oxidative stress (downregulation of MDA, and upregulation of SOD and CAT) in both serum and cerebral cortex tissues. Moreover, butein treatment attenuated LPS induced neurological function loss. However, all above mentioned neuro-protective actions of butein were partially inhibited by EX527 co-treatment, one standard SIRT1 inhibitor. Collectively, butein attenuates sepsis-induced brain injury through alleviation of cerebral inflammation, oxidative stress and apoptosis by SIRT1 signaling activation.

Zhu Y ，Wang K ，Ma Z ，Liu D ，Yang Y ，Sun M ，Wen A ，Hao Y ，Ma S ，Ren F ，Xin Z ，Li Y ，Di S ，Liu J ... -  《-》

Melatonin alleviates brain injury in mice subjected to cecal ligation and puncture via attenuating inflammation, apoptosis, and oxidative stress: the role of SIRT1 signaling.

Sepsis is a systemic inflammatory response to infection that causes severe neurological complications. Previous studies have suggested that melatonin is protective during sepsis. Additionally, silent information regulator 1 (SIRT1) was reported to be beneficial in sepsis. However, the role of SIRT1 signaling in the protective effect of melatonin against septic encephalopathy remains unclear. This study aimed to investigate the role of SIRT1 in the protective effect of melatonin. EX527, a SIRT1 inhibitor, was used to reveal the role of SIRT1 in melatonin's action. Cecal ligation and puncture or sham operation was performed in male C57BL/6J mice. Melatonin was administrated intraperitoneally (30 mg/kg). The survival rate of mice was recorded for the 7-day period following the sham or CLP operation. The blood-brain barrier (BBB) integrity, brain water content, levels of inflammatory cytokines (TNF-α, IL-1β, and HMGB1), and the level of oxidative stress (superoxide dismutase (SOD), catalase (CAT), and malondialdehyde (MDA)) and apoptosis were assessed. The expression of SIRT1, Ac-FoxO1, Ac-p53, Ac-NF-κB, Bcl-2, and Bax was detected by Western blot. The results suggested that melatonin improved survival rate, attenuated brain edema and neuronal apoptosis, and preserved BBB integrity. Melatonin decreased the production of TNF-α, IL-1β, and HMGB1. Melatonin increased the activity of SOD and CAT and decreased the MDA production. Additionally, melatonin upregulated the expression of SIRT1 and Bcl-2 and downregulated the expression of Ac-FoxO1, Ac-p53, Ac-NF-κB, and Bax. However, the protective effects of melatonin were abolished by EX527. In conclusion, our results demonstrate that melatonin attenuates sepsis-induced brain injury via SIRT1 signaling activation.

Zhao L ，An R ，Yang Y ，Yang X ，Liu H ，Yue L ，Li X ，Lin Y ，Reiter RJ ，Qu Y ... -  《-》

Tetrahydrocurcumin protects against sepsis-induced acute kidney injury via the SIRT1 pathway.

Li L ，Liu X ，Li S ，Wang Q ，Wang H ，Xu M ，An Y ... -  《-》

Salvianolic acid B attenuates apoptosis and inflammation via SIRT1 activation in experimental stroke rats.

Silent information regulator 1 (SIRT1), a histone deacetylase, has been suggested to be effective in ischemic brain diseases. Salvianolic acid B (SalB) is a polyphenolic and one of the active components of Salvia miltiorrhiza Bunge. Previous studies suggested that SalB is protective against ischemic stroke. However, the role of SIRT1 in the protective effect of SalB against cerebral ischemia has not been explored. In this study, the rat brain was subjected to middle cerebral artery occlusion (MCAO). Before this surgery, rats were intraperitoneally administrated SalB with or without EX527, a specific SIRT1 inhibitor. The infarct volume, neurological score and brain water content were assessed. In addition, levels of TNF-α and IL-1β in the brain tissues were detected by commercial ELISA kits. And the expression levels of SIRT, Ac-FOXO1, Bcl-2 and Bax were detected by Western blot. The results suggested that SalB exerted a cerebral-protective effect, as shown by reduced infarct volume, lowered brain edema and increased neurological scores. SalB also exerted anti-inflammatory effects as indicated by the decreased TNF-α and IL-1β levels in the brain tissue. Moreover, SalB upregulated the expression of SIRT1 and Bcl-2 and downregulated the expression of Ac-FOXO1 and Bax. These effects of SalB were abolished by EX527 treatment. In summary, our results demonstrate that SalB treatment attenuates brain injury induced by ischemic stoke via reducing apoptosis and inflammation through the activation of SIRT1 signaling.

Lv H ，Wang L ，Shen J ，Hao S ，Ming A ，Wang X ，Su F ，Zhang Z ... -  《-》

Pterostilbene alleviates polymicrobial sepsis-induced liver injury: Possible role of SIRT1 signaling.

Liver injury occurs frequently during sepsis. Pterostilbene (Pte), a natural dimethylated analog of resveratrol from blueberries, exerts anti-inflammatory and anti-apoptotic effects in various diseases. However, the role of Pte in sepsis-induced liver injury and its underlying mechanisms remain unknown. The current study aimed to evaluate the protective effects of Pte on sepsis-induced liver injury and its potential mechanisms. Sepsis was induced using cecal ligation and puncture (CLP) in C57BL/6 mice. Mice were administered Pte (5, 10, 15mg/kg, i.p.) at 0.5h, 2h, and 8h after CLP induction. The pathological changes of the liver were evaluated using hematoxylin and eosin (H&E) staining. The serum levels of alanine transaminase (ALT) and aspartate aminotransferase (AST) were measured. The levels of tumor necrosis factor-alpha (TNF-α), interleukin (IL-6), myeloperoxidase (MPO), p38 mitogen-activated protein kinase (p38MAPK), Bax, and B-cell lymphoma 2 (Bcl-2) were also evaluated. Pte treatment attenuated the CLP-induced liver injury, as evidenced by the attenuated histopathologic injuries and the decreased serum aminotransferase levels. Pte reduced the serum inflammatory cytokine (TNF-α and IL-6) levels and hepatic mRNA levels of TNF-α and IL-6. Pte also reduced MPO activity and p38MAPK activation in the liver. Additionally, Pte significantly inhibited Bax expression and increased Bcl-2 expression. Moreover, Pte increased the expression of sirtuin-1 (SIRT1) and reduced the expression of acetylated forkhead box O1 (Ac-FoxO1), acetylated Ac-p53, and acetylated nuclear factor-kappa beta (Ac-NF-κB). However, SIRT1 small interfering RNA (siRNA) abolished Pte's effects on the expression levels of those protein. Notably, Pte improved the survival rate in septic mice. In conclusion, Pte alleviates sepsis-induced liver injury by reducing inflammatory response and inhibiting hepatic apoptosis, and the potential mechanism is associated with SIRT1 signaling activation.

Liu X ，Yang X ，Han L ，Ye F ，Liu M ，Fan W ，Zhang K ，Kong Y ，Zhang J ，Shi L ，Chen Y ，Zhang X ，Lin S ... -  《-》