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 ... -  《-》

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 ... -  《-》

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 ... -  《-》

Ghrelin attenuates brain injury in septic mice via PI3K/Akt signaling activation.

Brain injury has been reported to occur in sepsis and can lead to high mortality among septic patients. Previous studies suggest that ghrelin is protective for the brain, but whether ghrelin protects brain from sepsis remains unclear. Therefore, the aim of this study is to investigate the protective effect of ghrelin against sepsis-induced brain injury. Cecal ligation and puncture was performed in male C57BL/6J mice to establish the sepsis model. Ghrelin was administrated intraperitoneally at a dose of 80μg/kg. The blood-brain barrier (BBB) integrity, brain water content, inflammatory cytokines (TNF-α and IL-1β), oxidative stress (SOD and MDA) and neuronal apoptosis were assessed. In addition, the expression levels of Akt, phospho-Akt (Ser473) (p-Akt), Bcl-2 and Bax were detected by Western blot. Our results suggested that ghrelin attenuated brain edema, neuronal apoptosis and enhanced BBB integrity. Ghrelin decreased the production of TNF-α and IL-1β. Ghrelin increased the activity of SOD and decreased MDA production. Additionally, ghrelin increased the expression of p-Akt and Bcl-2 and decreased the Bax expression. The protective effects of ghrelin mentioned above were abolished by LY294002 (LY), a PI3K inhibitor. In conclusion, our results demonstrate that ghrelin attenuates brain injury in sepsis via PI3K/Akt signaling activation.

Sun N ，Wang H ，Ma L ，Lei P ，Zhang Q ... -  《-》

Melatonin attenuates sepsis-induced cardiac dysfunction via a PI3K/Akt-dependent mechanism.

An R ，Zhao L ，Xi C ，Li H ，Shen G ，Liu H ，Zhang S ，Sun L ... -  《-》