An Amino Acids and Dipeptide Injection Inhibits the TNF-α/HMGB1 Inflammatory Signaling Pathway to Reduce Pyroptosis and M1 Microglial Polarization in POCD Mice: the Gut to the Brain.

Peripheral surgery-induced neural inflammation is a key pathogenic mechanism of postoperative cognitive dysfunction (POCD). However, the mechanism underlying neuroinflammation and associated neural injury remains elusive. Surgery itself can lead to gut damage, and the occurrence of POCD is accompanied by high levels of TNF-α in the serum and blood‒brain barrier (BBB) damage. Reductions in stress, inflammation and protein loss have been emphasized as strategies for enhanced recovery after surgery (ERAS). We designed an amino acids and dipeptide (AAD) formula for injection that could provide intestinal protection during surgery. Through the intraoperative infusion of AAD based on the ERAS concept, we aimed to explore the effect of AAD injection on POCD and its underlying mechanism from the gut to the brain. Here, we observed that AAD injection ameliorated neural injury in POCD, in addition to restoring the function of the intestinal barrier and BBB. We also found that TNF-α levels decreased in the ileum, blood and hippocampus. Intestinal barrier protectors and TNF-α inhibitors also alleviated neural damage. AAD injection treatment decreased HMGB1 production, pyroptosis, and M1 microglial polarization and increased M2 polarization. In vitro, AAD injection protected the impaired gut barrier and decreased TNF-α production, alleviating damage to the BBB by stimulating cytokine transport in the body. HMGB1 and Caspase-1 inhibitors decreased pyroptosis and M1 microglial polarization and increased M2 polarization to protect TNF-α-stimulated microglia in vitro. Collectively, these findings suggest that the gut barrier-TNF-α-BBB-HMGB1-Caspase-1 inflammasome-pyroptosis-M1 microglia pathway is a novel mechanism of POCD related to the gut-brain axis and that intraoperative AAD infusion is a potential treatment for POCD.

SS-31 inhibits mtDNA-cGAS-STING signaling to improve POCD by activating mitophagy in aged mice.

BACKGROUND: Neuroinflammation is crucial in the development of postoperative cognitive dysfunction (POCD), and microglial activation is an active participant in this process. SS-31, a mitochondrion-targeted antioxidant, is widely regarded as a potential drug for neurodegenerative diseases and inflammatory diseases. In this study, we sought to explore whether SS-31 plays a neuroprotective role and the underlying mechanism. METHODS: Internal fixation of tibial fracture was performed in 18-month-old mice to induce surgery-associated neurocognitive dysfunction. LPS was administrated to BV2 cells to induce neuroinflammation. Neurobehavioral deficits, hippocampal injury, protein expression, mitophagy level and cell state were evaluated after treatment with SS-31, PHB2 siRNA and an STING agonist. RESULTS: Our study revealed that SS-31 interacted with PHB2 to activate mitophagy and improve neural damage in surgically aged mice, which was attributed to the reduced cGAS-STING pathway and M1 microglial polarization by decreased release of mitochondrial DNA (mtDNA) but not nuclear DNA (nDNA). In vitro, knockdown of PHB2 and an STING agonist abolished the protective effect of SS-31. CONCLUSIONS: SS-31 conferred neuroprotection against POCD by promoting PHB2-mediated mitophagy activation to inhibit mtDNA release, which in turn suppressed the cGAS-STING pathway and M1 microglial polarization.

Rutin prevents pyroptosis and M1 microglia via Nrf2/Mac-1/caspase-1-mediated inflammasome axis to improve POCD.

BACKGROUND: Neuroinflammation following peripheral surgery plays a key role in postoperative cognitive dysfunction (POCD) development and there is no effective therapy to inflammation-mediated cognitive impairment. Recent studies showed that rutin, a natural flavonoid compound, conferred neuroprotection. However, the effects and mechanisms of rutin on cognition of surgical and aged mice and LPS-induced BV2 need deeper exploration. METHODS: The effect of rutin in vivo and vitro were evaluated by Morris water maze test, HE stainin, Golgi-Cox staining, IF, IHC, RT-PCR, Flow Cytometer and Western blotting. In vivo, aged mice were treated with rutin and surgery. In vitro, rutin, Nrf2 knockdown, MAC-1 overexpression and VX765, a caspase-1 inhibitor, were administration on BV2 microglial cells. RESULTS: Surgery led to compensatory increase in nuclear Nrf2 and rutin could further increase it. Neural damage was accompanied with high level in MAC-1, caspase-1-mediated pyroptosis and M1 microglia, while rutin recovered the process. Nrf2 inhibition abolished the effect of rutin with the increase of MAC-1, caspase-1-mediated pyroptosis and M1 microglia. Activation of MAC-1 abrogated protection of rutin by increase in pyroptosis and M1 microglia. Finally, we found that treatment with VX765 improved injury and increased M2 microglia against overexpression of MAC-1. CONCLUSIONS: Our study indicated that rutin may be a potential therapy in POCD and exerted neural protection via Nrf2/ Mac-1/ caspase-1-mediated inflammasome axis to regulate pyroptosis and microglial polarization.

Obesity aggravated hippocampal-dependent cognitive impairment after sleeve gastrectomy in C57/BL6J mice via SIRT1/CREB/BDNF pathway.

Postoperative cognitive dysfunction (POCD) is characterized by cognitive impairments following anesthesia/surgery, but the role of obesity and the underlying mechanisms are not known. We investigated the impact of obesity on POCD. Eighty male C57BL/6 J mice were assigned randomly to two groups fed a normal chow diet (ND, n = 40) or a high-fat diet (HD, n = 40) for 20 weeks. Then, they were divided randomly into eight subgroups of 10: ND control (NDC), ND with surgery (NDS), HD control (HDC), HD with surgery (HDS); NDS + DMSO (NDS + DS), NDS + SRT1720 (NDS + SRT), HDS + DMSO (HDS + DS), and HDS + SRT1720 (HDS + SRT). Body weight, blood glucose level, and serum lipid levels were measured. Staining methods on liver tissues were used to determine hepatic steatosis. A POCD model was established by sleeve gastrectomy (SG) under isoflurane anesthesia. Cognitive function was assessed using the Morris water maze test (MWMT). Expression of sirtuin1 (SIRT1), phosphorylated cAMP-responsive element binding protein (p-CREB), CREB and brain-derived neurotrophic factor (BDNF) in the hippocampus were measured. High-fat diet-fed mice for 20 weeks could establish an obesity model with hyperlipidemia and hepatic steatosis. Cognitive impairment was significantly worse in the HDC and HDS groups than that in the NDC and NDS groups, respectively. Hippocampal expression of SIRT1, p-CREB, and BDNF in the HDS group was significantly lower than that of the HDC group. SRT1720 (SIRT1 activator) pretreatment could attenuate cognitive impairment by upregulating SIRT1 expression. These data suggest that obesity exacerbated postoperative hippocampal-dependent cognitive impairment via a SIRT1 pathway, and SRT1720 pretreatment could alleviate it.

The mitochondria-targeted antioxidant MitoQ ameliorates myocardial ischemia-reperfusion injury by enhancing PINK1/Parkin-mediated mitophagy in type 2 diabetic rats.

Type 2 diabetic hearts are more vulnerable to myocardial ischemia reperfusion (MIR) injury, which involves decreased mitophagy status with unknown mechanisms. MitoQ, a mitochondria-targeted antioxidant, has been shown to have protection against ischemia reperfusion injury through upregulating mitophagy. The aim of this study was to investigate the effects of MitoQ on myocardium during MIR injury in type 2 diabetes (T2D). Herein, this study discovered that type 2 diabetic hearts with PINK1/Parkin downregulation suffered more MIR injury accompanied by reduced mitophagy. Treatment with MitoQ significantly decreased the levels of CK-MB, LDH, myocardial infarction, myocardial pathological damage, and cardiomyocytes apoptosis, while it improved cardiac function, mitophagy status, and PINK1/Parkin pathway in vivo study. Furthermore, MitoQ significantly reduced high glucose/high fat and hypoxia/reoxygenation induced injury in H9C2 cells as evidenced by reduced cardiomyocytes apoptosis and ROS production, and increased cell viability, the level of mitochondrial membrane potential, PINK1/Parkin expression. However, mitochondrial division inhibitor (mdivi-1), an inhibitor of mitophagy, reversed the improvement and protein expression levels of PINK1/Parkin pathway in vitro models. In conclusion, MIR induced more severe damage in T2D by reduction of mitophagy. MitoQ can confer cardioprotection following MIR in T2D by mitophagy up-regulation via PINK1/Parkin pathway.

Meta-analysis of coagulation parameters associated with disease severity and poor prognosis of COVID-19.

BACKGROUND: To determine whether abnormal coagulation parameters are associated with disease severity and poor prognosis in patients with 2019 Corona Virus Disease (COVID-19). METHODS: A systematic literature search was conducted using the databases PubMed, Embase, and Web of sciences until April 25, 2020. We included a total of 15 studies with 2277 patients. Platelet count (PLT), prothrombin time (PT), activated partial thromboplastin time (APTT), D-dimer (D-D), and fibrinogen (FIB) were collected and analyzed. The statistical results were expressed as the effect measured by mean difference (MD) with the related 95% confidence interval (CI). RESULTS: The PLT level of severe cases was lower than that of mild cases, while the levels of PT, D-D, and FIB were higher than those of mild cases (P < 0.05). The level of APTT had no statistical difference between two groups (P > 0.05). PT of ICU patients was significantly longer (P < 0.05) than that of non-ICU patients. In non-survivors, PT and D-D were higher, yet PLT was lower than that of survivors (P < 0.05). There was no significant difference in APTT between survivors and non-survivors (P > 0.05). The funnel plot and Egger's regression test demonstrated that there was no publication bias. CONCLUSIONS: Our data support the notion that coagulopathy could be considered as a risk factor for disease severity and mortality of COVID-19, which may help clinicians to identify the incidence of poor outcomes in COVID-19 patients.