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Sepsis-associated encephalopathy (SAE), one of the common complications of sepsis, is associated with higher ICU mortality, prolonged hospitalization, and long-term cognitive decline. Sepsis can induce neuroinflammation, which negatively affects hippocampal neurogenesis. Dexmedetomidine has been shown to protect against SAE. However, the potential mechanism remains unclear. In this study, we added lipopolysaccharide (LPS)-stimulated astrocytes-conditioned media (LPS-CM) to neural stem cells (NSCs) culture, which were pretreated with dexmedetomidine in the presence or absence of the α2-adrenoceptor antagonist yohimbine or the α2A-adrenoceptor antagonist BRL-44408. LPS-CM impaired the neurogenesis of NSCs, characterized by decreased proliferation, enhanced gliogenesis, and declined viability. Dexmedetomidine alleviated LPS-CM-induced impairment of neurogenesis in a dose-dependent manner. Yohimbine, as well as BRL-44408, reversed the effects of dexmedetomidine. We established a mouse model of SAE via cecal ligation and perforation (CLP). CLP-induced astrocyte-related neuroinflammation and hippocampal neurogenesis deficits, accompanied by learning and memory decline, which were reversed by dexmedetomidine. The effect of dexmedetomidine was blocked by BRL-44408. Collectively, our findings support the conclusion that dexmedetomidine can protect against SAE, likely mediated by the combination of inhibiting neuroinflammation via the astrocytic α2A-adrenoceptor with attenuating neuroinflammation-induced hippocampal neurogenesis deficits via NSCs α2A-adrenoceptor.

Sepsis-associated encephalopathy is a common neurological complication of sepsis that is characterized by neuroinflammation, oxidative stress and apoptosis, which results in cognitive impairments in septic survivors. Despite numerous treatment options for this condition, none of them are definite. Therefore, this study aimed to investigate the impact of morin, a flavone known for its neuroprotective and anti-inflammatory effects, against lipopolysaccharides-induced sepsis-associated encephalopathy in albino mice for 7 days. Mice were divided into 4 groups: Negative control, morin, septic, and septic morin-treated mice. Sepsis was induced by a single injection of lipopolysaccharides (5 mg/kg, intraperitoneally), morin (50 mg/kg b. wt.) was given orally, starting from 5 h after sepsis induction, then daily for 4 other days. Morin ameliorated septic structural and functional alternations as manifested by improving the survival rate, the behavioral functions, in addition to preserving and protecting the brain tissue. This was accompanied with the augmentation of the total antioxidant capacity, as well as the suppression of tissue levels of the lipid peroxidation marker malondialdehyde, apoptosis (cleaved-caspase-3), glial fibrillary acidic protein, and the proinflammatory cytokine tumor necrosis factor. In conclusion, morin has a promising ameliorative effect to counteract the sepsis-associated encephalopathy via its anti-inflammatory and antioxidant effects and to prevent the associated cognitive impairments., Competing Interests: Declarations Competing Interests The authors declare no competing interests., (© 2024. The Author(s).)

Objectives: Delirium is a prominent symptom of sepsis-associated encephalopathy (SAE) and is highly prevalent in septic patients hospitalized in the intensive care unit, being closely connected with raised mortality rates. Acute hyperglycemia (AH) has been recognized as a separate risk factor for delirium and a worse prognosis in critically sick patients. Nevertheless, the exact contribution of AH to the advancement of SAE is still unknown., Methods: This research retrospectively evaluated the connection between blood glucose levels (BGLs) and the incidence of delirium and death rates in septic patients in the ICU of a tertiary comprehensive hospital. In addition, a septic rat model was induced through cecal ligation and puncture (CLP), after which continuous glucose infusion was promptly initiated via a central venous catheter post-surgery to evaluate the potential implications of AH on SAE. Next, septic rats were assigned to four groups based on target BGLs: high glucose group (HG, ≥ 300 mg/dL), moderate glucose group (MG, 200-300 mg/dL), normal glucose group (NG, < 200 mg/dL), and a high glucose insulin-treated group (HI, 200-300 mg/dL) receiving recombinant human insulin treatment (0.1 IU/kg/min). The sham group (SG) received an equivalent volume of saline infusion and denoted the NG group. The effects of AH on neuroinflammation and cognitive function in septic rats were evaluated using behavioral tests, histopathological examination, TUNEL staining, ELISA, and Western blot. The effects of glucose levels on microglial activation and glucose metabolism following lipopolysaccharide (LPS, 1 μg/mL) exposure were assessed using CCK8 assay, qRT-PCR, Western blot, and ELISA., Results: Our findings revealed that AH during sepsis was a separate risk factor for delirium and assisted in predicting delirium occurrence. AH raised the levels of systemic and central inflammatory cytokines in septic rats, promoting neuronal apoptosis, blood-brain barrier disruption, and cognitive impairment. In addition, both in vivo and in vitro, an elevated glucose challenge increased the ChREBP, HIF-1α, glycolytic enzymes, and inflammatory cytokines expressions in microglia after exposure to CLP or LPS., Conclusions: These results collectively suggest that hyperglycemia can exacerbate neuroinflammation and delirium by enhancing microglial glycolysis under septic conditions, potentially mediated by upregulation of the ChREBP/HIF-1α signaling pathway., Competing Interests: Declarations Ethics approval and consent to participate All animal experimental protocols were conducted in strict adherence to the ethical guidelines established by the Animal Care and Use Committee of Nanchang University and adhered to the standards outlined by the National Institutes of Health for the ethical care and use of laboratory animals. All methods are reported following ARRIVE guidelines for the reporting of animal experiments. Competing interests All authors confirm that they have no competing interests., (© 2024. The Author(s).)

Previous studies have demonstrated the roles of both microglia homeostasis and RNA editing in sepsis-associated encephalopathy (SAE), yet their relationship remains to be elucidated. In this study, we analyzed bulk and single-cell RNA-seq (scRNA) datasets containing 107 brain tissue and microglia samples from mice with microglial depletion and repopulation to explore canonical RNA editing associated with microglia homeostasis and evaluate its role in SAE. Analysis of mouse brain RNA-Seq revealed hallmarks of microglial repopulation, including peak expressions of Apobec1 and Apobec3 at Day 5 of repopulation and dramatically altered B2m RNA editing. Significant time-dependent changes in brain RNA editing during microglial depletion and repopulation were primarily observed in synapse-related genes, such as Tbc1d24 and Slc1a2. ScRNA-Seq revealed heterogeneous RNA editing among microglia subpopulations and their distinct changes associated with microglia homeostasis. Moreover, repopulated microglia from lipopolysaccharide (LPS)-induced sepsis mice exhibited intensified up-regulation of Apobec1 and Apobec3, with distinct RNA editing responses to LPS, mainly involved in immune-related pathways. The hippocampus from sepsis mice induced by peritoneal contamination and infection showed upregulated Apobec1 and Apobec3 expression, and altered RNA editing in immune-related genes, such as B2m and Mier1, and nervous-related lncRNA Meg3 and Snhg11, both of which were repressed by microglial depletion. Furthermore, the expression of complement-related genes, such as C4b and Cd47, was substantially correlated with RNA editing activity in microglia homeostasis and SAE. Our study demonstrates canonical RNA editing associated with microglia homeostasis and provides new insights into its potential role in SAE., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 International Brain Research Organization (IBRO). Published by Elsevier Inc. All rights reserved.)

Neuroinflammation and oxidative stress contribute to the progression of sepsis-associated encephalopathy (SAE). Angiotensin-converting enzyme 2 (ACE2) is considered to be a neuroprotective factor due to its anti-inflammatory and antioxidant properties. However, the role of ACE2 on myeloid cells in regulating SAE and the underlying mechanism warrants further exploration. SAE was induced in ACE2 transgenic (TG), knockout (KO), and bone marrow (BM) chimeric mice by cecal ligation and puncture (CLP). The expression levels of apoptosis-, oxidation- and neuroinflammation-associated mediators and morphological changes were monitored by quantitative real-time PCR analyses and histological examinations in the cortex of septic mice. The contents of angiotensin (Ang) II and Ang-(1-7) along with the activity of ACE2 were examined with commercial kits. The expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and Sestrin2 was detected by immunoblotting analysis. Our results indicated that the expression of cortical ACE2 was significantly reduced in the early phase of CLP-induced sepsis. Moreover, ACE2 overexpression in TG mice conferred neuroprotection against sepsis, as evidenced by alleviated neuronal apoptosis, oxidative stress, and proinflammatory M1-like microglial polarization, accompanied by upregulation of the Ang-(1-7), Nrf2, and Sestrin2 protein levels. Conversely, ACE2 deficiency in KO mice exacerbated SAE. The neuroprotective effects of ACE2 were further confirmed in wild-type mice transplanted with ACE2-TG and KO BM cells. Therefore, our data suggest that myeloid ACE2 exerts a protective role in the pathogenesis of SAE, potentially by activating Ang-(1-7)-Nrf2/sestrin2 signaling pathway, and highlight that upregulating ACE2 expression and activity may represent a promising approach for the treatment of SAE in patients with sepsis., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Sepsis-associated encephalopathy (SAE) is a severe complication of sepsis, characterized by neuroinflammation, mitochondrial dysfunction, and oxidative stress, leading to cognitive decline and high mortality. The effectiveness of dichloroacetate (DCA) in modulating mitochondrial function provides a novel therapeutic strategy for SAE. In this study, we evaluated the neuroprotective effects of DCA in a rat model of SAE induced by cecal ligation and puncture (CLP). Rats treated with DCA exhibited significant improvements in neurological function and survival, as evidenced by less neuron loss from histopathologic analysis, restored neurologic deficit scores, improved Y-maze alternation percentages, and enhanced recognition index performance. Biochemical analyses showed that DCA administration at 25 mg/kg and 100 mg/kg reduced astrocyte and microglial activation, indicating reduced neuroinflammation. Furthermore, DCA simultaneously reduced the production of circulating and cerebral inflammatory cytokines (including TNF-α, IL-1β, and IL-10), concomitant with mitigating oxidative stress through down-regulating expression of 8-Hydroxy-2'-deoxyguanosine (8-OHdG) and reactive oxygen species (ROS) in the brain. Mechanistically, DCA modulated mitochondrial dynamics by suppressing Drp1 and pDrp1 expression, which are indicators of mitochondrial fission. This was corroborated by transmission electron microscopy, quantification of mitochondrial area, and Western blot analyses. Furthermore, DCA treatment improved ATP levels, mitochondrial complex I activity, and NAD + /NADH ratio, indicating a significant attenuation of brain mitochondrial dysfunction. In conclusion, our findings suggest that DCA confers neuroprotection in SAE by curtailing neuroinflammation and mitochondrial fission, outlining a promising therapeutic strategy for treating SAE in critically ill patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Sepsis-associated encephalopathy (SAE) is a devastating complication of sepsis, affecting approximately 70% of patients with sepsis in intensive care units (ICU). Although the pathophysiological mechanisms remain elusive, sepsis is typically accompanied by systemic inflammatory response syndrome (SIRS) and hyper-oxidative conditions. Here, we introduce a biomimetic nanomodulator (mAOI NP) that specifically targets inflammation site and simultaneously regulates oxidative and inflammatory stresses. mAOI NPs are constructed using metal-coordinated polyphenolic antioxidants (tannic acid) and flavonoid quercetin, which are then coated with macrophage membrane to enhance pharmacokinetics and enable SAE targeting. In a cecal ligation and puncture (CLP)-induced severe sepsis model, mAOI NPs effectively mitigate oxidative stress by purging reactive oxygen species, repairing mitochondrial damage and activating the Nrf2/HO-1 signaling pathway; while polarizing M1 macrophages or microglia toward anti-inflammatory M2 subtype. mAOI NPs potently inhibit sepsis progress, prolong overall survival from 25 to 66% and enhance learning and memory capabilities in SAE mice. Further proteomics analysis reveals that mAOI NPs modulate neurodevelopment processes related to learning and memory formation while also exerting anti-inflammatory and antioxidative effects on brain tissue responses associated with SAE pathology. This study offers significant potential for improving patient outcomes and revolutionizing the treatment landscape for this devastating complication of sepsis.

Sepsis-associated encephalopathy (SAE) is a serious neurological complication accompanied by acute and long-term cognitive dysfunction. Ferroptosis is a newly discovered type of cell death that is produced by iron-dependent lipid peroxidation. As a key transcriptional coactivator in the Hippo signalling pathway, Yes-associated protein 1 (YAP1) could target ferroptosis-related genes. This study was aimed to determine whether Yap1 protects against SAE and inhibits ferroptosis via maintaining mitochondrial dynamic homeostasis. Caecal ligation puncture (CLP) was used to establish the SAE model, and LPS was applied in hippocampal cells to mimic the inflammatory model in vitro. The results showed that Yap1 conditional knockout in hippocampal caused lower survival in SAE mice and cognitive dysfunction, as proved by Morri's water maze (MWM) task, tail suspension test (TST), open field test (OFT) and elevated plus maze test (EPMT). After Yap1 knockout, the production of ROS, MDA and Fe 2+ and proinflammatory cytokines in the hippocampus were increased, indicating that Yap1 deficiency exacerbates CLP-induced brain injury and hippocampus ferroptosis. Meanwhile, GPX4, SLC7A11, ferritin (FTH1) and GSH levels were decreased in the Yap1 knockout group. In vitro, Yap1 overexpression mitigated LPS-induced hippocampal cell ferroptosis and improved mitochondrial function by inhibiting mitochondrial fission, as evidenced by lower mitochondrial ROS, cell viability, Fe 2+ and the expression of Fis1 and Drp1. Further, the present study suggested that Yap1 could inhibit ferritinophagy-mediated ferroptosis in the hippocampus via inhibiting mitochondrial fission, thus reducing cognitive dysfunction in SAE mice., (© 2024 The Author(s). Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Aims: Adipose-derived stem cell (ADSC)-derived exosomes have been recognized for their neuroprotective effects in various neurological diseases. This study investigates the potential neuroprotective effects of ADSC-derived exosomes in sepsis-associated encephalopathy (SAE)., Methods: Behavioral cognitive functions were evaluated using the open field test, Y-maze test, and novel object recognition test. Brain activity was assessed through functional magnetic resonance imaging (fMRI). Pyroptosis was measured using immunofluorescence staining and western blotting., Results: Our findings indicate that ADSC-derived exosomes mitigate cognitive impairment, improve survival rates, and prevent weight loss in SAE mice. Additionally, exosomes protect hippocampal function in SAE mice, as demonstrated by fMRI evaluations. Furthermore, SAE mice exhibit neuronal damage and infiltration of inflammatory cells in the hippocampus, conditions which are reversed by exosome treatment. Moreover, our study highlights the downstream regulatory role of the NLRP3/caspase-1/GSDMD signaling pathway as a crucial mechanism in alleviating hippocampal inflammation., Conclusion: ADSC-derived exosomes confer neuroprotection in SAE models by mediating the NLRP3/caspase-1/GSDMD pathway, thereby ameliorating cognitive impairment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Sepsis-associated encephalopathy (SAE) is associated with increased risk of long-term cognitive impairment. SAE is driven, at least in part, by brain endothelial dysfunction in response to systemic cytokine signaling. However, the mechanisms driving SAE and its consequences remain largely unknown. Here, we performed translating ribosome affinity purification and RNA-sequencing (TRAP-seq) from the brain endothelium to determine the transcriptional changes after an acute endotoxemic (LPS) challenge. LPS induced a strong acute transcriptional response in the brain endothelium that partially correlates with the whole brain transcriptional response and suggested an endothelial-specific hypoxia response. Consistent with a crucial role for IL-6, loss of the main regulator of this pathway, SOCS3, leads to a broadening of the population of genes responsive to LPS, suggesting that an overactivation of the IL-6/JAK/STAT3 pathway leads to an increased transcriptional response that could explain our prior findings of severe brain injury in these mice. To identify any potential sequelae of this acute response, we performed brain TRAP-seq following a battery of behavioral tests in mice after apparent recovery. We found that the transcriptional response returns to baseline within days post-challenge, but reductions in gene expression regulating protein translation and respiratory electron transport remained. We observed that mice that recovered from the endotoxemic shock showed mild, sex-dependent cognitive impairment, suggesting that the acute brain injury led to sustained effects. A better understanding of the transcriptional and non-transcriptional changes in response to shock is needed in order to prevent and/or revert the devastating consequences of septic shock., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 International Brain Research Organization (IBRO). Published by Elsevier Inc. All rights reserved.)

Sepsis-associated encephalopathy (SAE) is a severe complication of sepsis, however, its exact mechanism remains unknown. This study aimed to evaluate whether clusterin is essential to the development of SAE during the aging process of astrocytes. In the study, septic mice were established with cecal ligation and puncture (CLP) and lipopolysaccharides were applied to astrocytes in vitro. Evan's blue dye was used in vivo to show blood-brain barrier (BBB) permeability. A morris water maze test was conducted to assess cognitive functions of the mice. Clusterin-knockout mice were used to examine the effect of clusterin on sepsis. The astrocytes were transfected with lentivirus expressing clusterin cDNA for clusterin overexpression or pYr-LV-clusterin small hairpin RNA for clusterin knockdown in vitro . The expression of clusterin, p-p53, p21, GDNF, and iNOS was detected. he CLP mice exhibited a higher clusterin expression in hippocampus tissue, aging astrocytes, lower GDNF expression and higher iNOS expression, accompanied with BBB damage and cognitive deficiency. Following clusterin knockout, this pathological process was further enhanced. In vitro , following lipopolysaccharides treatment, astrocytes exhibited increased clusterin, p-p53, p21, iNOS and decreased GDNF. Following clusterin knockdown, the cells exhibited a further increase in p-p53, p21, and iNOS and decrease in GDNF. Clusterin overexpression, however, helped inhibit astrocytes aging and neuroinflammation evidenced by decreased p-p53, p21, iNOS and increased GDNF. The present study has revealed that clusterin may exert its neuroprotective effect by preventing aging in astrocytes, suppressing the secretion of iNOS and promoting GNDF release., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Sepsis-associated encephalopathy (SAE) is a critical neurological complication of sepsis and represents a crucial factor contributing to high mortality and adverse prognosis in septic patients. This study explored the contribution of NAT10-mediated messenger RNA (mRNA) acetylation in cognitive dysfunction associated with SAE, utilizing a cecal ligation and puncture (CLP)-induced SAE mouse model. Our findings demonstrate that CLP significantly upregulates NAT10 expression and mRNA acetylation in the excitatory neurons of the hippocampal dentate gyrus (DG). Notably, neuronal-specific Nat10 knockdown improved cognitive function in septic mice, highlighting its critical role in SAE. Proteomic analysis, RNA immunoprecipitation, and real-time qPCR identified GABA B R1 as a key downstream target of NAT10. Nat10 deletion reduced GABA B R1 expression, and subsequently weakened inhibitory postsynaptic currents in hippocampal DG neurons. Further analysis revealed that microglia activation and the release of inflammatory mediators lead to the increased NAT10 expression in neurons. Microglia depletion with PLX3397 effectively reduced NAT10 and GABA B R1 expression in neurons, and ameliorated cognitive dysfunction induced by SAE. In summary, our findings revealed that after CLP, NAT10 in hippocampal DG neurons promotes GABA B R1 expression through mRNA acetylation, leading to cognitive dysfunction., Competing Interests: Competing interests statement:The authors declare no competing interest.

Background: Sepsis-associated encephalopathy (SAE) is a diffuse brain dysfunction activated by microglia. The potential pathological changes of SAE are complex, and the cellular pathophysiological characteristics remains unclear. This study aims to explore the ROS/TXNIP/NLRP3 pathway mediated lipopolysaccharide (LPS)-induced inflammatory response in microglia., Methods: BV-2 cells were pre-incubated with 10 μM N-acetyl-L-cysteine (NAC) for 2 h, which were then reacted with 1 μg/mL LPS for 24 h. Western blot assay examined the protein levels of IBA1, CD68, TXNIP, NLRP3, ASC, and Cleaved Caspase-1 in BV-2 cells. The contents of inflammatory factor were detected by ELISA assay. The co-immunoprecipitation assay examined the interaction between TXNIP and NLRP3., Results: LPS was confirmed to promote the positive expressions of IBA1 and CD68 in BV-2 cells. The further experiments indicated that LPS enhanced ROS production and NLRP3 inflammasome activation in BV-2 cells. Moreover, we also found that NAC partially reversed the facilitation of LPS on the levels of ROS, IL-1β, IL-18, TXNIP, NLRP3, ASC, and Cleaved Caspase-1 in BV-2 cells. NAC treatment also notably alleviated the interaction between TXNIP and NLRP3 in BV-2 cells., Conclusion: ROS inhibition mediated NLRP3 signaling inactivation by decreasing TXNIP expression., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Sepsis-related brain injury (SRBI) refers to brain dysfunction and structural damage caused by sepsis, which is characterized by inflammation, oxidative stress, and destruction of the blood-brain barrier. Pioglitazone is a PPAR-γ agonist in which PPAR-γ acts as an inflammatory modulator, determining the relationship between PPAR-γ and SRBI and inflammatory state is critical for the disease. This study aimed to construct a drug-target-disease network for SRBI and Pioglitazone based on network pharmacology, and to investigate the therapeutic effect and potential mechanism of Pioglitazone in SRBI induced by lipopolysaccharide (LPS) in rats through transcriptomics. To establish a rat Model of SRBI by intraperitoneal injection of LPS (10 mg/kg): SD rats were divided into Control, Model (LPS), Pioglitazone, (LPS + Pioglitazone) and GW9662 group (LPS+GW9662). The effects and potential mechanisms of Pioglitazone in the treatment of SRBI were studied using biochemical indexes, pathological changes and transcriptome-sequencing (RNA-seq). RNA-seq results showed 620 DEGs between the Model and the Pioglitazone groups. Enrichment analysis involved multiple inflammatory response processes and chemokine receptor binding functions. TLR4 and CXCL10 in the Toll signaling pathway may play an important role in SRBI as important targets. Pioglitazone may ameliorate SRBI through the PPAR-γ/TLR4/CXCL10 pathway., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Sepsis-associated encephalopathy (SAE) is a serious neurological complication accompanied with acute and long-term cognitive dysfunction. Ferroptosis is a newly discovered type of cell death that is produced by iron-dependent lipid peroxidation. Emerging evidence suggests that ferroptosis is involved in SAE. The nuclear factor erythroid 2-related factor 2 (Nrf2) is a mitochondria related gene involved in ferroptosis. However, the role of Nrf2 in SAE and the mechanisms remains elusive. In this study, we found that Nrf2 knockout aggravated cognitive and emotional dysfunction and promoted caecal ligation and puncture (CLP)-induced brain injury and hippocampus ferroptosis as indicated by the increase of ROS, Fe 2+ and the levels of proinflammatory cytokines. Meanwhile, the levels of glutathione peroxidase 4 (GPX4), SLC7A11 and glutathionewere downregulatedin Nrf2 knockout group. In vitro experiments showed that mitochondrial ROS, Fe 2+ and the expression of Fis1 and Drp1 decreased, and the level of Mfn1 and Opa-1 increased after Nrf2 overexpression. The silence of Nrf2 increased the expression of ROS, MDA and Fe 2+ , while decreased glutathione, mitochondrial membrane potential (MMP) and cell viability in vitro, indicating Nrf2 improved LPS-induced mitochondrial dysfunction and mitigated hippocampal cells ferroptosis. These results suggest that Nrf2 could inhibit ferroptosis and neuroinflammation in hippocampus and reduce cognitive dysfunction in SAE mice, making it a potential therapeutic target in the treatment of SAE. The protective effects of Nrf2 on the brain may be mediated by maintaining mitochondrial dynamic homeostasis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Paeonol, a phenolic acid compound extracted from the Cortex Moutan, exhibits significant anti-inflammatory, antioxidant, and anti-apoptotic properties. This study aimed to investigate the effects of paeonol on neuroinflammation and depressive-like symptoms, and the underlying mechanisms in a mouse model of sepsis-associated encephalopathy (SAE) induced by lipopolysaccharide (LPS). To assess the therapeutic potential of paeonol in mice treated with LPS, behavioral assessments were conducted using the open-field test (OFT), tail suspension test (TST), and forced swimming test (FST), and quantitative PCR (qPCR), Western blot, and immunofluorescent staining were utilized to determine the expression levels of inflammatory molecules in the hippocampus in vivo and microglial cells in vitro. Our results revealed that paeonol significantly alleviated anxiety and depressive-like symptoms, as evidenced by improved activity in OFT, reduced immobility time in TST and FST, and decreased levels of inflammatory markers such as IL6, TNFα, and PFKFB3. Further in vitro experiments confirmed that paeonol downregulated the expression of pro-inflammatory molecules. A network pharmacology-based strategy combined with molecular docking and cellular thermal shift assay highlighted HIF1A as a potential target for paeonol. Similar anti-inflammatory effects of a HIF1A inhibitor were also observed in microglia treated with LPS. Furthermore, these effects were reversed by CoCl 2 , a HIF1A agonist, indicating the critical role of the HIF1A signaling pathway in mediating the therapeutic effects of paeonol. These findings highlight the potential of paeonol in modulating the HIF1A pathway, offering a promising therapeutic strategy for neuroinflammation in SAE., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Sepsis-associated encephalopathy (SAE) is a severe complication of sepsis. Reduced glutathione (GSH) has antioxidant properties and is used as a neuroprotective agent in some studies. However, research on the application of exogenous GSH in the treatment of SAE is limited. This study aimed to determine the effects of exogenous GSH in pediatric SAE patients and mice. We evaluated clinical parameters, inflammatory factors, and oxidative stress before and after GSH treatment. The clinical trials demonstrated that GSH treatment improved brain damage markers (S-100 beta protein, brain fatty acid-binding protein), increased neurological status scores (Glasgow coma scale), and reduced Pediatric Risk of Mortality III scores in children with SAE. GSH treatment also significantly reduced the levels of inflammatory factors (interleukin-6, tumor necrosis factor-α) and decreased lipid peroxidation (superoxide dismutase). Additionally, GSH reduced lipid peroxidation resulting from abnormal lipid metabolism, as indicated by the levels of acyl-CoA synthetase long-chain family member 4, lysophosphatidylcholine acyltransferase 3, and glutathione peroxidase 4. In-vivo experiments showed that the neuroprotective effect of GSH was dose-dependent, with better effects observed at medium and high doses. Furthermore, GSH alleviated brain damage, suppressed the release of inflammatory factors, and inhibited lipid peroxidation in SAE mice. The animal experiments also showed that GSH reduces lipid peroxidation through the 15-lipoxygenase/phosphatidylethanolamine binding protein 1/glutathione peroxidase 4 pathway. Our study suggests that exogenous GSH has neuroprotective effects in pediatric SAE. These findings provide a basis for the potential use of GSH as a therapeutic method for SAE., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: In sepsis-associated encephalopathy (SAE), the activation of microglial cells and ensuing neuroinflammation are important in the underlying pathological mechanisms. Increasing evidence suggests that the protein Piezo1 functions as a significant regulator of neuroinflammation. However, the influence of Piezo1 on microglial cells in the context of SAE has not yet been determined. This study aims to investigate the role of Piezo1 in microglial cells in the context of SAE., Methods: By inducing cecal ligation and puncture (CLP), a mouse model of SAE was established, while the control group underwent a sham surgery in which the cecum was exposed without ligation and puncture. Piezo1 knockout mice were employed in this study. Morris water maze tests were conducted between Days 14 and 18 postop to assess both the motor activity and cognitive function. A proteomic analysis was conducted to assess the SAE-related pathways, whereas a Mendelian randomization analysis was conducted to identify the pathways associated with cognitive impairment. Dual-label immunofluorescence and flow cytometry were used to assess the secretion of inflammatory factors, microglial status, and oligodendrocyte development. Electron microscopy was used to evaluate axonal myelination. A western blot analysis was conducted to evaluate the influence of Piezo1 on oligodendrocyte ferroptosis., Results: The results of the bioinformatics analysis have revealed the significant involvement of CCL25 in the onset and progression of SAE-induced cognitive impairment. SAE leads to cognitive dysfunction by activating the microglial cells. The release of CCL25 by the activated microglia initiates the demyelination of oligodendrocytes in the hippocampus, resulting in ferroptosis and the disruption of hippocampal functional connectivity. Of note, the genetic knockout of the Piezo1 gene mitigates these changes. The treatment with siRNA targeting Piezo1 effectively reduces the secretion of inflammatory mediators CCL25 and IL-18 by inhibiting the p38 pathway, thus preventing the ferroptosis of oligodendrocytes through the modulation of the CCL25/GPR78 axis., Conclusion: Piezo1 is involved in the activation of microglia and demyelinating oligodendrocytes in the animal models of SAE, resulting in cognitive impairment. Consequently, targeting Piezo1 suppression can be a promising approach for therapeutic interventions aimed at addressing cognitive dysfunction associated with SAE., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Sepsis-associated encephalopathy (SAE) is a common and severe clinical feature of sepsis; however, therapeutic approaches are limited because of the unclear pathogenesis. Adiponectin receptor agonist (AdipoRon) is a small-molecule agonist of the adiponectin receptor that exhibits anti-inflammatory and memory-improving effects in various diseases. In the present study, we established lipopolysaccharide (LPS)-induced mice models of SAE and found that Adiponectin receptor 1 (AdipoR1) was significantly decreased in the hippocampus. Administration of AdipoRon improves memory impairment, mitigates synaptic damage, and alleviates neuronal death. Furthermore, AdipoRon reduces the number of microglia. More importantly, AdipoRon promotes the phosphorylation of adenosine 5 '-monophosphate activated protein kinase (pAMPK). In conclusion, AdipoRon is protective against SAE-induced memory decline and brain injury in the SAE models via activating the hippocampal adenosine 5 '-monophosphate activated protein kinase (AMPK)., Competing Interests: Competing interests The authors declare that they have no competing interests., (Copyright © 2024. Published by Elsevier B.V.)

Sepsis-associated encephalopathy (SAE) is a severe complication that affects the central nervous system and is a leading cause of increased morbidity and mortality in intensive care units. Psoralidin (PSO), a coumarin compound isolated from the traditional Chinese medicine Psoralea corylifolia L., can penetrate the blood-brain barrier and has various pharmacological activities, including anti-inflammation, anti-oxidation and anti-depression. This study aims to explore whether PSO alleviates SAE and delve into the underlying mechanisms. We found that PSO treatment significantly reduced sepsis scores, aspartate transaminase (AST) and aspartate transaminase (LDH), while increased anal temperature and neurological scores in CLP-injured mice. Moreover, PSO treatment ameliorated sepsis-associated cognitive impairment, mood, anxiety disorders, inhibited inflammatory responses, as well as attenuated endoplasmic reticulum stress (ERS). These results were also validated in vitro experiments, PSO treatment reduced ROS, inflammation response, and attenuated ERS in LPS-injured N2a cells. Importantly, tunicamycin (TUN), as ERS agonist, significantly reversed the protective effect of PSO on LPS-injured N2a cells, as evidenced by increased expression levels of IL-6, NLRP3, CHOP, and ATF6. Likewise, ATF6 overexpression also reversed the protective effect of PSO. In conclusion, these results confirmed that PSO has a protective effect on SAE, which was largely attributed to neuroinflammation and ERS. These findings provide new insights into the neuroprotective role of PSO and suggest that PSO is a new therapeutic intervention of SAE., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: We aim to deal with the Hub-genes and signalling pathways connected with Sepsis-associated encephalopathy (SAE)., Methods: The raw datasets were acquired from the Gene Expression Omnibus (GEO) database (GSE198861 and GSE167610). R software filtered the differentially expressed genes (DEGs) for hub genes exploited for Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Hub genes were identified from the intersection of DEGs via protein-protein interaction (PPI) network. And the single-cell dataset (GSE101901) was used to authenticate where the hub genes express in hippocampus cells. Cell-cell interaction analysis and Gene Set Variation Analysis (GSVA) analysis of the whole transcriptome validated the interactions between hippocampal cells., Results: A total of 161 DEGs were revealed in GSE198861 and GSE167610 datasets. Biological function analysis showed that the DEGs were primarily involved in the phagosome pathway and significantly enriched. The PPI network extracted 10 Hub genes. The M2 Macrophage cell decreased significantly during the acute period, and the hub gene may play a role in this biological process. The hippocampal variation pathway was associated with the MAPK signaling pathway., Conclusion: Hub genes (Pecam1, Cdh5, Fcgr, C1qa, Vwf, Vegfa, C1qb, C1qc, Fcgr4 and Fcgr2b) may paticipate in the biological process of SAE., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Sepsis-associated encephalopathy (SAE) is a collection of clinical syndromes resulting from sepsis and characterized by widespread brain dysfunction. The high prevalence of SAE has adverse outcomes on the clinical management and prognosis of sepsis patients. However, currently, there are no effective treatments to ameliorate SAE. The pathogenesis of SAE is complex, including neuroinflammation and microglia activation, destruction of the blood-brain barrier (BBB), neurotransmitter dysfunction, cerebral metabolism and mitochondrial impairment, accumulation of amyloid beta and tauopathy, complement activation, among others. Furthermore, these mechanisms intertwine with each other, further complicating the comprehension of SAE. Among them, neuroinflammation mediated by hyperactivated microglia is considered the primary etiology of SAE. This instigates a detrimental cycle wherein BBB permeability escalates, facilitating direct damage to the central nervous system (CNS) by various neurotoxic substances. Activation of the NLRP3 inflammasome, situated within microglia, can be triggered by diverse danger signals, leading to cell pyroptosis, apoptosis, and tauopathy. These complex processes intricately regulate the onset and progression of neuroinflammation. In this review, we focus on elucidating the inhibitory regulatory mechanism of the NLRP3 inflammasome in microglia, which ultimately manifests as suppression of the inflammatory response. Our ultimate objective is to augment comprehension regarding the role of microglial NLRP3 inflammasome as we explore potential targets for therapeutic interventions against SAE., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Sepsis-associated encephalopathy (SAE) is characterized by high incidence and mortality rates, with limited treatment options available. The underlying mechanisms and pathogenesis of SAE remain unclear. Annexin A1 (ANXA1), a membrane-associated protein, is involved in various in vivo pathophysiological processes. This study aimed to explore the neuroprotective effects and mechanisms of a novel bioactive ANXA1 tripeptide (ANXA1sp) in SAE. Forty Sprague-Dawley rats were randomly divided into four groups (n = 10 each): control, SAE (intraperitoneal injection of lipopolysaccharide), vehicle (SAE + normal saline), and ANXA1sp (SAE + ANXA1sp) groups. Changes in serum inflammatory factors (interleukin-6 [IL-6], tumor necrosis factor-α [TNF-α]), hippocampal reactive oxygen species (ROS), mitochondrial membrane potential (MMP), and adenosine triphosphate (ATP) levels were measured. The Morris water maze and Y maze tests were used to assess learning and memory capabilities in the rats. Further, changes in peroxisome proliferator-activated receptor-gamma (PPAR-γ) and apoptosis-related protein expression were detected using western blot. The IL-6, TNF-α, and ROS levels were significantly increased in the SAE group compared with the levels in the control group. Intraperitoneal administration of ANXA1sp led to a significant decrease in the IL-6, TNF-α, and ROS levels (p < 0.05). Compared with the SAE group, the ANXA1sp group exhibited reduced escape latency on day 5, a significant increase in the number of platform crossings and the percent spontaneous alternation, and significantly higher hippocampal MMP and ATP levels (p < 0.05). Meanwhile, the expression level of PPAR-γ protein in the ANXA1sp group was significantly increased compared with that in the other groups (p < 0.05). The expressions of apoptosis-related proteins (nuclear factor-kappa B [NF-κB], Bax, and Caspase-3) in the SAE and vehicle groups were significantly increased, with a noticeable decrease in Bcl-2 expression, compared with that noted in the control group. Moreover, the expressions of NF-κB, Bax, and Caspase-3 were significantly decreased in the ANXA1sp group, and the expression of Bcl-2 was markedly increased (p < 0.05). ANXA1sp can effectively reverse cognitive impairment in rats with SAE. The neuroprotective effect of ANXA1sp may be attributed to the activation of the PPAR-γ pathway, resulting in reduced neuroinflammatory response and inhibition of apoptosis., (© 2024 International Union of Biochemistry and Molecular Biology, Inc.)

Background: Sepsis-associated encephalopathy (SAE) develops in 30-70% of hospitalized patients with sepsis. In intensive care units (ICUs), propofol is often administered to ensure an appropriate level of sedation in mechanically ventilated patients. Ferroptosis is a newly identified mode of cellular death characterized by the peroxidation of membrane lipids and excessive iron. This study was conducted to explore the interplay between propofol, sepsis, and ferroptosis., Methods: An acute systemic inflammatory model was constructed via the intraperitoneal administration of lipopolysaccharide (LPS). Nissl and Fluoro-Jade C (FJC) staining were employed to display neuronal damage and degeneration. Western blotting and immunofluorescence (IF) staining of Bax and Bcl-2 were used to confirm the neural apoptosis. QPCR of cytokines and DHE staining were used to indicate neuroinflammation. To validate ferroptosis, we assessed the content of malondialdehyde (MDA), GSH, and tissue iron, accompanied by transcription level of CHAC1, PTGS2 and GPX4. Additionally, we examined the content of acyl-CoA synthetase long-chain family member 4 (ACSL4), xCT (SLC7A11, solute carrier family 7 member 11), and glutathione peroxidase 4 (GPX4). The IF staining of Iba1-labeled microglia and GFAP-marked astrocytes were used to measure the gliosis. Erastin was pre-pretreated to confirm the anti-ferroptotic capability of propofol. ML385 was preconditioned to explore the role of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) in propofol-repressed ferroptosis., Results: Propofol dose-dependently inhibited the decrease of Nissl-positive neurons and the increase of FJC-stained neurons in septic hippocampus and cortex. Neural cytokines, oxidative stress, apoptosis and gliosis were reduced by propofol. Propofol repressed the level of MDA, iron, CHAC1, PTGS2, ACLS4 and restored the content of GSH, GPX4, xCT, Nrf2 and HO-1, thus inhibiting sepsis-induced ferroptosis. All protections from propofol could be reversed by eratsin and ML385 pretreatment., Conclusion: Propofol protected against sepsis-induced brain damage, neuroinflammation, neuronal apoptosis and gliosis through the activation of the Nrf2/HO-1 axis to combat ferroptosis., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Sepsis-associated encephalopathy (SAE) is a disease characterized by neuroinflammation and cognitive dysfunction caused by systemic infection. Inflammation-induced microglial activation is closely associated with neuroinflammation in SAE. It is widely understood that melatonin has strong anti-inflammatory and immunomodulatory properties beneficial for sepsis-related brain damage. However, the mechanism of melatonin action in SAE has not been fully elucidated., Methods: The SAE cell model and SAE mouse model were induced by lipopolysaccharide (LPS). Behavioral tests were performed to analyze cognitive function. Microglial markers and M1/M2 markers were measured by immunofluorescence. Mitophagy was assessed by western blot, mt-Keima and transmission electron microscopy experiments. Immunoprecipitation and co-immunoprecipitation assays investigated the interactions between AMP-activated protein kinase α2 (AMPKα2) and PTEN-induced putative kinase 1 (PINK1)., Results: Melatonin suppresses LPS-induced microglia M1 polarization by enhancing mitophagy, thereby attenuating LPS-induced neuroinflammation and behavioral deficits. However, inhibition or knockdown of AMPKα2 can inhibit the enhancement of melatonin on mitophagy, then weaken its promotion of microglia polarization towards M2 phenotype, and eliminate its protective effect on brain function. Furthermore, melatonin enhances mitophagy through activating AMPKα2, promotes PINK1 Ser495 site phosphorylation, and ultimately regulates microglial polarization from M1 to M2., Conclusions: Our findings demonstrate that melatonin facilitates microglia polarization towards M2 phenotype to alleviate LPS-induced neuroinflammation, primarily through AMPKα2-mediated enhancement of mitophagy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Molecular pathways mediating systemic inflammation entering the brain parenchyma to induce sepsis-associated encephalopathy (SAE) remain elusive. Here, we report that in mice during the first 6 hours of peripheral lipopolysaccharide (LPS)-evoked systemic inflammation (6 hpi), the plasma level of adenosine quickly increased and enhanced the tone of central extracellular adenosine which then provoked neuroinflammation by triggering early astrocyte reactivity. Specific ablation of astrocytic Gi protein-coupled A1 adenosine receptors (A1ARs) prevented this early reactivity and reduced the levels of inflammatory factors (e.g., CCL2, CCL5, and CXCL1) in astrocytes, thereby alleviating microglial reaction, ameliorating blood-brain barrier disruption, peripheral immune cell infiltration, neuronal dysfunction, and depression-like behaviour in the mice. Chemogenetic stimulation of Gi signaling in A1AR-deficent astrocytes at 2 and 4 hpi of LPS injection could restore neuroinflammation and depression-like behaviour, highlighting astrocytes rather than microglia as early drivers of neuroinflammation. Our results identify early astrocyte reactivity towards peripheral and central levels of adenosine as an important pathway driving SAE and highlight the potential of targeting A1ARs for therapeutic intervention., (© 2024. The Author(s).)

Background: Understanding the mechanism behind sepsis-associated encephalopathy (SAE) remains a formidable task. This study endeavors to shed light on the complex cellular and molecular alterations that occur in the brains of a mouse model with SAE, ultimately unraveling the underlying mechanisms of this condition., Methods: We established a murine model using intraperitoneal injection of lipopolysaccharide (LPS) in wild type and Anxa1 -/- mice and collected brain tissues for analysis at 0-hour, 12-hour, 24-hour, and 72-hour post-injection. Utilizing advanced techniques such as single-nucleus RNA sequencing (snRNA-seq) and Stereo-seq, we conducted a comprehensive characterization of the cellular responses and molecular patterns within the brain., Results: Our study uncovered notable temporal differences in the response to LPS challenge between Anxa1 -/- (annexin A1 knockout) and wild type mice, specifically at the 12-hour and 24-hour time points following injection. We observed a significant increase in the proportion of Astro-2 and Micro-2 cells in these mice. These cells exhibited a colocalization pattern with the vascular subtype Vas-1, forming a distinct region known as V1A2M2, where Astro-2 and Micro-2 cells surrounded Vas-1. Moreover, through further analysis, we discovered significant upregulation of ligands and receptors such as Timp1-Cd63, Timp1-Itgb1, Timp1-Lrp1, as well as Ccl2-Ackr1 and Cxcl2-Ackr1 within this region. In addition, we observed a notable increase in the expression of Cd14-Itgb1, Cd14-Tlr2, and Cd14-C3ar1 in regions enriched with Micro-2 cells. Additionally, Cxcl10-Sdc4 showed broad upregulation in brain regions containing both Micro-2 and Astro-2 cells. Notably, upon LPS challenge, there was an observed increase in Anxa1 expression in the mouse brain. Furthermore, our study revealed a noteworthy increase in mortality rates following Anxa1 knockdown. However, we did not observe substantial differences in the types, numbers, or distribution of other brain cells between Anxa1 -/- and wildtype mice over time. Nevertheless, when comparing the 24-hour post LPS injection time point, we observed a significant decrease in the proportion and distribution of Micro-2 and Astro-2 cells in the vicinity of blood vessels in Anxa1 -/- mice. Additionally, we noted reduced expression levels of several ligand-receptor pairs including Cd14-Tlr2, Cd14-C3ar1, Cd14-Itgb1, Cxcl10-Sdc4, Ccl2-Ackr1, and Cxcl2-Ackr1., Conclusions: By combining snRNA-seq and Stereo-seq techniques, our study successfully identified a distinctive cellular colocalization, referred to as a special pathological niche, comprising Astro-2, Micro-2, and Vas-1 cells. Furthermore, we observed an upregulation of ligand-receptor pairs within this niche. These findings suggest a potential association between this cellular arrangement and the underlying mechanisms contributing to SAE or the increased mortality observed in Anxa1 knockdown mice., (© 2024. The Author(s).)

Sepsis-associated encephalopathy (SAE) is a frequent complication of severe systemic infection resulting in delirium, premature death, and long-term cognitive impairment. We closely mimicked SAE in a murine peritoneal contamination and infection (PCI) model. We found long-lasting synaptic pathology in the hippocampus including defective long-term synaptic plasticity, reduction of mature neuronal dendritic spines, and severely affected excitatory neurotransmission. Genes related to synaptic signaling, including the gene for activity-regulated cytoskeleton-associated protein (Arc/Arg3.1) and members of the transcription-regulatory EGR gene family, were downregulated. At the protein level, ARC expression and mitogen-activated protein kinase signaling in the brain were affected. For targeted rescue we used adeno-associated virus-mediated overexpression of ARC in the hippocampus in vivo. This recovered defective synaptic plasticity and improved memory dysfunction. Using the enriched environment paradigm as a non-invasive rescue intervention, we found improvement of defective long-term potentiation, memory, and anxiety. The beneficial effects of an enriched environment were accompanied by an increase in brain-derived neurotrophic factor (BDNF) and ARC expression in the hippocampus, suggesting that activation of the BDNF-TrkB pathway leads to restoration of the PCI-induced reduction of ARC. Collectively, our findings identify synaptic pathomechanisms underlying SAE and provide a conceptual approach to target SAE-induced synaptic dysfunction with potential therapeutic applications to patients with SAE., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Sepsis-associated encephalopathy (SAE) is an acute cerebral dysfunction secondary to infection, and the severity can range from mild delirium to deep coma. Disorders of iron metabolism have been proven to play an important role in a variety of neurodegenerative diseases by inducing cell damage through iron accumulation in glial cells and neurons. Recent studies have found that iron accumulation is also a potential mechanism of SAE. Systemic inflammation can induce changes in the expression of transporters and receptors on cells, especially high expression of divalent metal transporter1 (DMT1) and low expression of ferroportin (Fpn) 1, which leads to iron accumulation in cells. Excessive free Fe 2+ can participate in the Fenton reaction to produce reactive oxygen species (ROS) to directly damage cells or induce ferroptosis. As a result, it may be of great help to improve SAE by treatment of targeting disorders of iron metabolism. Therefore, it is important to review the current research progress on the mechanism of SAE based on iron metabolism disorders. In addition, we also briefly describe the current status of SAE and iron metabolism disorders and emphasize the therapeutic prospect of targeting iron accumulation as a treatment for SAE, especially iron chelator. Moreover, drug delivery and side effects can be improved with the development of nanotechnology. This work suggests that treating SAE based on disorders of iron metabolism will be a thriving field., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Sepsis-associated encephalopathy, which manifests in severe cognitive and depressive symptoms, is directly linked to neuroinflammation. Our study investigates the efficacy of 25H-NBOMe, a phenethylamine, in alleviating these symptoms, potentially offering an innovative treatment for post-sepsis depression. Wistar rats, weighing between 250-300 g, were subjected to cecal ligation and puncture (CLP) surgery to induce sepsis. Depressive-like behaviors were assessed using the forced swim test (FST) on either day 7 or 14 post-surgery, to establish the presence of depressive symptoms. The impact of 25H-NBOMe treatment was then evaluated, focusing on the head-twitch response (HTR), performance in the FST, and GFAP expression in the prefrontal cortex. Treatment with 25H-NBOMe resulted in significant behavioral changes, demonstrated by decreased immobility and increased swimming times in the FST, along with a rise in the HTR. These outcomes indicate a reduction in depressive-like symptoms post-sepsis and the psychoactive effects of the compound. Furthermore, a notable decrease in GFAP expression in the study highlights the compound's impact on mitigating sepsis-induced astrogliosis. This study demonstrates the effectiveness of 25H-NBOMe, a psychedelic in the phenethylamine class, in treating post-sepsis depression and reducing astrogliosis. However, the psychedelic nature of 25H-NBOMe calls for further investigation into similar compounds with less psychoactive impact, crucial for advancing treatment options for neuropsychiatric symptoms following sepsis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Sepsis-associated encephalopathy (SAE) presents a significant clinical challenge, associated with increased mortality and healthcare expenses. Hyperbaric oxygen therapy (HBOT), involving inhaling pure or highly concentrated oxygen under pressures exceeding one atmosphere, has demonstrated neuroprotective effects in various conditions. However, the precise mechanisms underlying its protective actions against sepsis-associated brain injury remain unclear. This study aimed to determine whether HBOT protects against SAE and to elucidate the impact of the hypoxia-inducible factor-1α (HIF-1α) signaling pathway on SAE., Methods: The experiment consisted of two parts. In the first part, C57BL/6 J male mice were divided into five groups using a random number table method: control group, sham surgery group, sepsis group, HBOT + sepsis group, and HBOT + sham surgery group. In the subsequent part, C57BL/6 J male mice were divided into four groups: sepsis group, HBOT + sepsis group, HIF-1α + HBOT + sepsis group, and HIF-1α + sepsis group. Sepsis was induced via cecal ligation and puncture (CLP). Hyperbaric oxygen therapy was administered at 1 h and 4 h post-CLP. After 24 h, blood and hippocampal tissue were collected for cytokine measurements. HIF-1α, TNF-α, IL-1β, and IL-6 expression were assessed via ELISA and western blotting. Microglial expression was determined by immunofluorescence. Blood-brain barrier permeability was quantified using Evans Blue. Barnes maze and fear conditioning were conducted 14 days post-CLP to evaluate learning and memory., Results: Our findings reveal that CLP-induced hippocampus-dependent cognitive deficits coincided with elevated HIF-1α and increased TNF-α, IL-1β, and IL-6 levels in both blood and hippocampus. Observable activation of microglial cells in the hippocampus and increased blood-brain barrier (BBB) permeability were also evident. HBOT mitigated HIF-1α, TNF-α, IL-1β, and IL-6 levels, attenuated microglial activation in the hippocampus, and significantly improved learning and memory deficits in CLP-exposed mice. Additionally, these outcomes were corroborated by injecting a lentivirus that overexpressed HIF-1α into the hippocampal region of the mice., Conclusion: HIF-1α escalation induced peripheral and central inflammatory factors, promoting microglial activation, BBB impairment, and cognitive dysfunction. However, HBOT ameliorated these effects by reducing HIF-1α levels in Sepsis-Associated Encephalopathy., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective To elucidate the role of chaperone-mediated autophagy (CMA) in alleviating emotional dysfunction in mice with sepsis-associated encephalopathy (SAE). Methods The SAE mouse model was established by cecal ligation and perforation (CLP). The severity of sepsis was assessed using the sepsis severity score (MSS). Emotional function in SAE mice was assessed by the open-field test and elevated plus-maze. The expression levels of cognitive heat shock cognate protein 70 (HSC70), lysosomal-associated membrane protein 2A (LAMP2A) and high mobility group box 1 protein B1 (HMGB1) were detected using Western blotting. Co-localization of LAMP2A in the hippocampal neurons was observed by immunofluorescence. The release of inflammatory factors interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α) was measured using ELISA. Following 12 hours post-CLP, mice were orally administered resveratrol at a dose of 30 mg/kg once daily until day 14. Results The mortality rate of CLP mice was 45.83% 24 days post CLP, and all surviving mice exhibited emotional disturbances. 24 hours after CLP, a significant decrease in HSC70 and LAMP2A expression in hippocampal neurons was observed, indicating impaired CMA activity. Meanwhile, HMGB1 and inflammatory cytokines (IL-6 and TNF-α) levels increased. After resveratrol treatment, an increase of HSC70 and LAMP2A expression, and a decrease of HMGB1 expression and inflammatory cytokine release were observed, suggesting enhanced CMA activity and reduced neuroinflammation. Behavioral tests showed that emotional dysfunction was improved in SAE mice after resveratrol treatment. Conclusion CMA activity of hippocampal neurons in SAE mice is significantly reduced, leading to emotional dysfunction. Resveratrol can alleviate neuroinflammation and emotional dysfunction in SAE mice by promoting CMA and inhibiting the expression of HMGB1 and the release of inflammatory factors.

The gut-brain axis is a bidirectional communication network linking the gut and the brain, overseeing digestive functions, emotional responses, body immunity, brain development, and overall health. Substantial research highlights a connection between disruptions of the gut-brain axis and various psychiatric and neurological conditions, including depression and Alzheimer's disease. Given the impact of the gut-brain axis on behavior, cognition, and brain diseases, some studies have started to pay attention to the role of the axis in sepsis-associated encephalopathy (SAE), where cognitive impairment is the primary manifestation. SAE emerges as the primary and earliest form of organ dysfunction following sepsis, potentially leading to acute cognitive impairment and long-term cognitive decline in patients. Notably, the neuronal damage in SAE does not stem directly from the central nervous system (CNS) infection but rather from an infection occurring outside the brain. The gut-brain axis is posited as a pivotal factor in this process. This review will delve into the gut-brain axis, exploring four crucial pathways through which inflammatory signals are transmitted and elevate the incidence of SAE. These pathways encompass the vagus nerve pathway, the neuroendocrine pathway involving the hypothalamic-pituitary-adrenal (HPA) axis and serotonin (5-HT) regulation, the neuroimmune pathway, and the microbial regulation. These pathways can operate independently or collaboratively on the CNS to modulate brain activity. Understanding how the gut affects and regulates the CNS could offer the potential to identify novel targets for preventing and treating this condition, ultimately enhancing the prognosis for individuals with SAE., Competing Interests: Declaration of competing interest The authors have no competing interests to declare., (Copyright © 2024. Published by Elsevier Inc.)

Background: Sepsis refers to a systemic inflammatory response caused by infection, involving multiple organs. Sepsis-associated encephalopathy (SAE), as one of the most common complications in patients with severe sepsis, refers to the diffuse brain dysfunction caused by sepsis without central nervous system infection. However, there is no clear diagnostic criteria and lack of specific diagnostic markers., Methods: The main active ingredients of coptidis rhizoma(CR) were identified from TCMSP and SwissADME databases. SwissTargetPrediction and PharmMapper databases were used to obtain targets of CR. OMIM, DisGeNET and Genecards databases were used to explore targets of SAE. Limma differential analysis was used to identify the differential expressed genes(DEGs) in GSE167610 and GSE198861 datasets. WGCNA was used to identify feature module. GO and KEGG enrichment analysis were performed using Metascape, DAVID and STRING databases. The PPI network was constructed by STRING database and analyzed by Cytoscape software. AutoDock and PyMOL software were used for molecular docking and visualization. Cecal ligation and puncture(CLP) was used to construct a mouse model of SAE, and the core targets were verified in vivo experiments., Results: 277 common targets were identified by taking the intersection of 4730 targets related to SAE and 509 targets of 9 main active ingredients of CR. 52 common DEGs were mined from GSE167610 and GSE198861 datasets. Among the 25,864 DEGs in GSE198861, LCN2 showed the most significant difference (logFC = 6.9). GO and KEGG enrichment analysis showed that these 52 DEGs were closely related to "inflammatory response" and "innate immunity". A network containing 38 genes was obtained by PPI analysis, among which LCN2 ranked the first in Degree value. Molecular docking results showed that berberine had a well binding affinity with LCN2. Animal experiments results showed that berberine could inhibit the high expression of LCN2,S100A9 and TGM2 induced by CLP in the hippocampus of mice, as well as the high expression of inflammatory factors (TNFα, IL-6 and IL-1β). In addition, berberine might reduce inflammation and neuronal cell death by partially inhibiting NFκB/LCN2 pathway in the hippocampus of CLP models, thereby alleviating SAE., Conclusion: Overall, Berberine may exert anti-inflammatory effects through multi-ingredients, multi-targets and multi-pathways to partially rescue neuronal death and alleviate SAE., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Survivors of sepsis may encounter cognitive impairment following their recovery from critical condition. At present, there is no standardized treatment for addressing sepsis-associated encephalopathy. Lactobacillus rhamnosus GG (LGG) is a prevalent bacterium found in the gut microbiota and is an active component of probiotic supplements. LGG has demonstrated to be associated with cognitive improvement. This study explored whether LGG administration prior to and following induced sepsis could ameliorate cognitive deficits, and explored potential mechanisms., Methods: Female C57BL/6 mice were randomly divided into three groups: sham surgery, cecal ligation and puncture (CLP), and CLP+LGG. Cognitive behavior was assessed longitudinally at 7-9d, 14-16d, and 21-23d after surgery using an open field test and novel object recognition test. The impact of LGG treatment on pathological changes, the expression level of brain-derived neurotrophic factor (BDNF), and the phosphorylation level of the TrkB receptor (p-TrkB) in the hippocampus of mice at two weeks post-CLP (16d) were evaluated using histological, immunofluorescence, immunohistochemistry, and western blot analyses., Results: The CLP surgery induced and sustained cognitive impairment in mice with sepsis for a minimum of three weeks following the surgery. Compared to mice subjected to CLP alone, the administration of LGG improved the survival of mice with sepsis and notably enhanced their cognitive functioning. Moreover, LGG supplementation significantly alleviated the decrease in hippocampal BDNF expression and p-TrkB phosphorylation levels caused by sepsis, preserving neuronal survival and mitigating the pathological changes within the hippocampus of mice with sepsis. LGG supplementation mitigates sepsis-related cognitive impairment in mice and preserves BDNF expression and p-TrkB levels in the hippocampus., Competing Interests: The authors declare there are no competing interests., (©2024 Wang et al.)

Sepsis-associated encephalopathy (SAE) is a significant cause of mortality in patients with sepsis. Despite extensive research, its exact cause remains unclear. Our previous research indicated a relationship between non-hepatic hyperammonemia (NHH) and SAE. This study aimed to investigate the relationship between NHH and SAE and the potential mechanisms causing cognitive impairment. In the in vivo experimental results, there were no significant abnormalities in the livers of mice with moderate cecal ligation and perforation (CLP); however, ammonia levels were elevated in the hippocampal tissue and serum. The ELISA study suggest that fecal microbiota transplantation in CLP mice can reduce ammonia levels. Reduction in ammonia levels improved cognitive dysfunction and neurological impairment in CLP mice through behavioral, neuroimaging, and molecular biology studies. Further studies have shown that ammonia enters the brain to regulate the expression of aquaporins-4 (AQP4) in astrocytes, which may be the mechanism underlying brain dysfunction in CLP mice. The results of the in vitro experiments showed that ammonia up-regulated AQP4 expression in astrocytes, resulting in astrocyte damage. The results of this study suggest that ammonia up-regulates astrocyte AQP4 expression through the gut-brain axis, which may be a potential mechanism for the occurrence of SAE., (© 2024. The Author(s).)

Background: Sepsis-associated encephalopathy (SAE) causes acute and long-term cognitive deficits. However, information on the prevention and treatment of cognitive dysfunction after sepsis is limited. The neuropeptide orexin-A (OXA) has been shown to play a protective role against neurological diseases by modulating the inflammatory response through the activation of OXR1 and OXR2 receptors. However, the role of OXA in mediating the neuroprotective effects of SAE has not yet been reported., Methods: A mouse model of SAE was induced using cecal ligation perforation (CLP) and treated via intranasal administration of exogenous OXA after surgery. Mouse survival, in addition to cognitive and anxiety behaviors, were assessed. Changes in neurons, cerebral edema, blood-brain barrier (BBB) permeability, and brain ultrastructure were monitored. Levels of pro-inflammatory factors (IL-1β, TNF-α) and microglial activation were also measured. The underlying molecular mechanisms were investigated by proteomics analysis and western blotting., Results: Intranasal OXA treatment reduced mortality, ameliorated cognitive and emotional deficits, and attenuated cerebral edema, BBB disruption, and ultrastructural brain damage in mice. In addition, OXA significantly reduced the expression of the pro-inflammatory factors IL-1β and TNF-α, and inhibited microglial activation. In addition, OXA downregulated the expression of the Rras and RAS proteins, and reduced the phosphorylation of P-38 and JNK, thus inhibiting activation of the MAPK pathway. JNJ-10,397,049 (an OXR2 blocker) reversed the effect of OXA, whereas SB-334,867 (an OXR1 blocker) did not., Conclusion: This study demonstrated that the intranasal administration of moderate amounts of OXA protects the BBB and inhibits the activation of the OXR2/RAS/MAPK pathway to attenuate the outcome of SAE, suggesting that OXA may be a promising therapeutic approach for the management of SAE., (© 2024. The Author(s).)

MiRNAs in mesenchymal stem cells (MSCs)-derived exosome (MSCs-exo) play an important role in the treatment of sepsis. We explored the mechanism through which MSCs-exo influences cognitive impairment in sepsis-associated encephalopathy (SAE). Here, we show that miR-140-3p targeted Hmgb1. MSCs-exo plus miR-140-3p mimic (Exo) and antibiotic imipenem/cilastatin (ABX) improve survival, weight, and cognitive impairment in cecal ligation and puncture (CLP) mice. Exo and ABX inhibit high mobility group box 1 (HMGB1), IBA-1, interleukin (IL)-1β, IL-6, iNOS, TNF-α, p65/p-p65, NLRP3, Caspase 1, and GSDMD-N levels. In addition, Exo upregulates S-lactoylglutathione levels in the hippocampus of CLP mice. Our data further demonstrates that Exo and S-lactoylglutathione increase GSH levels in LPS-induced HMC3 cells and decrease LD and GLO2 levels, inhibiting inflammatory responses and pyroptosis. These findings suggest that MSCs-exo-mediated delivery of miR-140-3p ameliorates cognitive impairment in mice with SAE by HMGB1 and S-lactoylglutathione metabolism, providing potential therapeutic targets for the clinical treatment of SAE., (© 2024. The Author(s).)

Sepsis-associated encephalopathy (SAE), a common neurological complication of sepsis, is a heterogenous complex clinical syndrome caused by the dysfunctional response of a host to infection. This dysfunctional response leads to excess mortality and morbidity worldwide. Despite clinical relevance with high incidence, there is a lack of understanding for its both its acute/chronic pathogenesis and therapeutic management. A better understanding of the molecular mechanisms behind SAE may provide tools to better enhance therapeutic efficacy. Mounting evidence indicates that some types of non-apoptotic regulated cell death (RCD), such as ferroptosis, pyroptosis, and autophagy, contribute to SAE. Targeting these types of RCD may provide meaningful targets for future treatments against SAE. This review summarizes the core mechanism by which non-apoptotic RCD leads to the pathogenesis of SAE. We focus on the emerging types of therapeutic compounds that can inhibit RCD and delineate their beneficial pharmacological effects against SAE. Within this review we suggest that pharmacological inhibition of non-apoptotic RCD may serve as a potential therapeutic strategy against SAE., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Aims: Sepsis-associated encephalopathy (SAE) is manifested as a spectrum of disturbed cerebral function ranging from mild delirium to coma. However, the pathogenesis of SAE has not been clearly elucidated. Astrocytes play important roles in maintaining the function and metabolism of the brain. Most recently, it has been demonstrated that disorders of lipid metabolism, especially lipid droplets (LDs) dyshomeostasis, are involved in a variety of neurodegenerative diseases. The aim of this study was to investigate whether LDs are involved in the underlying mechanism of SAE., Methods: The open field test, Y-maze test, and contextual fear conditioning test (CFCT) were used to test cognitive function in SAE mice. Lipidomics was utilized to investigate alterations in hippocampal lipid metabolism in SAE mice. Western blotting and immunofluorescence labeling were applied for the observation of related proteins., Results: In the current study, we found that SAE mice showed severe cognitive dysfunction, including spatial working and contextual memory. Meanwhile, we demonstrated that lipid metabolism was widely dysregulated in the hippocampus by using lipidomic analysis. Furthermore, western blotting and immunofluorescence confirmed that LDs accumulation in hippocampal astrocytes was involved in the pathological process of cognitive dysfunction in SAE mice. We verified that LDs can be inhibited by specifically suppress hypoxia-inducible lipid droplet-associated protein (HILPDA) in astrocytes. Meanwhile, cognitive dysfunction in SAE was ameliorated by reducing A1 astrocyte activation and inhibiting presynaptic membrane transmitter release., Conclusion: The accumulation of astrocytic lipid droplets plays a crucial role in the pathological process of SAE. HILPDA is an attractive therapeutic target for lipid metabolism regulation and cognitive improvement in septic patients., (© 2024 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Background: Sepsis-associated encephalopathy (SAE) refers to the widespread impairment of brain function caused by noncentral nervous system infection mediated by sepsis. Lipid peroxidation-induced ferroptosis contributes to the occurrence and course of SAE. This study aimed to investigate the relationship between neuronal injury and lipid peroxidation-induced ferroptosis in SAE., Methods: Baseline data were collected from pediatric patients upon admission, and the expression levels of various markers related to lipid peroxidation and ferroptosis were monitored in the serum and peripheral blood mononuclear cells (PBMCs) of patients with SAE as well as SAE model mice. The hippocampal phosphatidylethanolamine-binding protein (PEBP)-1/15-lysine oxidase (LOX)/ glutathione peroxidase 4 (GPX4) pathway was assessed for its role on the inhibitory effect of ferroptosis in SAE treatment., Results: The results showed elevated levels of S100 calcium-binding protein beta (S-100β), glial fibrillary acidic protein, and malondialdehyde in the serum of SAE patients, while superoxide dismutase levels were reduced. Furthermore, analysis of PBMCs revealed increased transcription levels of PEBP1, LOX, and long-chain fatty acyl-CoA synthetase family member 4 (ACSL4) in SAE patients, while the transcription levels of GPX4 and cystine/glutamate transporter xCT (SLC7A11) were decreased. In comparison to the control group, the SAE mice exhibited increased expression of S-100β and neuron-specific enolase (NSE) in the hippocampus, whereas the expression of S-100β and NSE were reduced in deferoxamine (DFO) mice. Additionally, iron accumulation was observed in the hippocampus of SAE mice, while the iron ion levels were reduced in the DFO mice. Inhibition of ferroptosis alleviated the mitochondrial damage (as assessed by transmission electron microscopy, hippocampal mitochondrial ATP detection, and the JC-1 polymer-to-monomer ratio in the hippocampus) and the oxidative stress response induced by SAE as well as attenuated neuroinflammatory reactions. Further investigations revealed that the mechanism underlying the inhibitory effect of ferroptosis in SAE treatment is associated with the hippocampal PEBP-1/15-LOX/GPX4 pathway., Conclusion: These results offer potential therapeutic targets for the management of neuronal injury in SAE and valuable insights into the potential mechanisms of ferroptosis in neurological disorders., (© 2024. The Author(s).)

Sepsis-associated encephalopathy (SAE) refers to diffuse brain dysfunction caused by sepsis, which is characterized by decreased attention, directional impairment, being prone to irritation, and in severe cases the patient will experience drowsiness and coma. The pathogenesis of SAE mainly includes neuroinflammation, damage of blood-brain barrier, cerebral vascular dysfunction, and neurometabolic changes, among which neuroinflammation is the core pathological process. Microglia are considered to be important immune cells of the central nervous system and play an important role in neuroinflammation. This article systematically describes the role of microglia in the development of SAE, and discusses the phenotype and related signaling pathways of microglia, in order to clarify the role of microglia in SAE and provide a theoretical basis for clinical treatment of SAE.

Background: Gasdermin D (GSDMD)-mediated pyroptotic cell death is implicated in the pathogenesis of cognitive deficits in sepsis-associated encephalopathy (SAE), yet the underlying mechanisms remain largely unclear. Dynamin-related protein 1 (Drp1) facilitates mitochondrial fission and ensures quality control to maintain cellular homeostasis during infection. This study aimed to investigate the potential role of the GSDMD/Drp1 signaling pathway in cognitive impairments in a mouse model of SAE., Methods: C57BL/6 male mice were subjected to cecal ligation and puncture (CLP) to establish an animal model of SAE. In the interventional study, mice were treated with the GSDMD inhibitor necrosulfonamide (NSA) or the Drp1 inhibitor mitochondrial division inhibitor-1 (Mdivi-1). Surviving mice underwent behavioral tests, and hippocampal tissues were harvested for histological analysis and biochemical assays at corresponding time points. Haematoxylin-eosin staining and TUNEL assays were used to evaluate neuronal damage. Golgi staining was used to detect synaptic dendritic spine density. Additionally, transmission electron microscopy was performed to assess mitochondrial and synaptic morphology in the hippocampus. Local field potential recordings were conducted to detect network oscillations in the hippocampus., Results: CLP induced the activation of GSDMD, an upregulation of Drp1, leading to associated mitochondrial impairment, neuroinflammation, as well as neuronal and synaptic damage. Consequently, these effects resulted in a reduction in neural oscillations in the hippocampus and significant learning and memory deficits in the mice. Notably, treatment with NSA or Mdivi-1 effectively prevented these GSDMD-mediated abnormalities., Conclusions: Our data indicate that the GSDMD/Drp1 signaling pathway is involved in cognitive deficits in a mouse model of SAE. Inhibiting GSDMD or Drp1 emerges as a potential therapeutic strategy to alleviate the observed synaptic damages and network oscillations abnormalities in the hippocampus of SAE mice., (© 2024. The Author(s).)

Objective To investigate the impact of the cannabinoid receptor agonist arachidonyl-2'-chloroethylamide (ACEA) on cognitive function in mice with sepsis-associated encephalopathy (SAE). Methods C57BL/6 mice were randomly divided into artificial cerebrospinal fluid (ACSF) and lipopolysaccharide (LPS) groups. The SAE model was established by intraventricular injection of LPS. The severity of sepsis in mice was assessed by sepsis severity score (MSS) and body mass changes. Behavioral paradigms were used to evaluate motor ability (open field test) and cognitive function (contextual fear conditioning test, Y-maze test). To evaluate the effects of ACEA intervention on SAE, mice were randomly assigned to ACSF group, ACEA intervention combined with ACSF group, LPS group, and ACEA intervention combined with LPS group. The dosage of ACEA intervention was 1.5 mg/kg. Real-time quantitative PCR was used to measure the mRNA expression levels of interleukin 1β (IL-1β), IL-6, and tumor necrosis factor α (TNF-α) in mouse hippocampal tissues. Western blot analysis was used to assess the protein levels of IL-6 and TNF-α in the hippocampus. Nissl staining was performed to examine neuronal damage in the CA1 region of the mouse hippocampus. Behavioral paradigms were again employed to evaluate motor ability and cognitive function. Results Three days after intraventricular LPS injection, mice exhibited significant cognitive dysfunction, confirming SAE modeling. Compared to the control group, the LPS group showed significant increases in mRNA of inflammatory factors such as IL-6, TNF-α, and IL-1β, together with significant increases in IL-6 and TNF-α protein levels in the hippocampus, a decrease in Nissl bodies in the CA1 region, and significant cognitive dysfunction. Compared to the LPS group, the ACEA intervention group showed a significant decrease in the mRNA of IL-6, TNF-α, and IL-1β, a significant reduction in IL-6 and TNF-α protein levels, an increase in Nissl bodies, and improved cognitive function. Conclusion ACEA improves cognitive function in SAE mice by inhibiting the expression levels of inflammatory factors IL-6 and TNF-α.

Sepsis is a life-threatening condition induced by a deregulated host response to infection. Post-sepsis injury includes long-term cognitive impairment, whose neurobiological mechanisms and effective treatment remain unknown. The present study was designed to determine the potential effects of cannabidiol (CBD) in a sepsis-associated encephalopathy (SAE) model and explore if peroxisome proliferator activated receptor gamma (PPARγ) is the putative mechanism underpinning the beneficial effects. SAE was induced in Wistar rats by cecal ligation and puncture (CLP) or sham (control). CLP rats received vehicle, CBD (10 mg/kg), PPARγ inhibitor (GW9662 - 1 mg/kg), or GW9662 (1 mg/kg) + CBD (10 mg/kg) intraperitoneally for ten days. During this period, the survival rate was recorded, and at the end of 10 days, a memory test was performed, and the prefrontal cortex and hippocampus were removed to verify brain-derived neurotrophic factor (BDNF), cytokines (IL-1β, IL-6 and IL-10), myeloperoxidase activity, nitrite nitrate concentration, and lipid and protein carbonylation and catalase activity. Septic rats presented cognitive decline and an increase in mortality following CLP. Only CBD alone improved the cognitive impairment, which was accompanied by restoration of BDNF, reduced neuroinflammation, and oxidative stress, mainly in the hippocampus. This study shows that CLP induces an increase in brain damage and CBD has neuroprotective effects on memory impairment and neurotrophins, as well as against neuroinflammation and oxidative stress, and is mediated by PPARγ activation., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Sepsis-associated encephalopathy (SAE) is a serious complication of sepsis. The tumour necrosis factor receptor superfamily member 6 (TNFRSF6) gene encodes the Fas protein, and it participates in apoptosis induced in different cell types. This study aimed to explore TNFRSF6 function in SAE. The SAE mouse model was established by intraperitoneal injection of LPS in TNFRSF6-/- mice and C57BL/6J mice. Microglia were treated with LPS to establish the cell model. The learning, memory and cognitive functions in mice were tested by behavioral tests. Nissl staining was utilized for determining neuronal injury. Microglial activation was tested by immunofluorescence assay. ELISA was utilized for determining TNF-α, IL-1β, IL-6, and IL-10 contents. Mitochondrial dysfunction was measured by mitochondrial oxygen consumption, ATP content, ROS production, and JC-1 assay. TNFRSF6 was upregulated in the LPS-induced mouse model and cell model. TNFRSF6 deficiency notably alleviated the impaired learning, memory and cognitive functions in SAE mice. Furthermore, we found that TNFRSF6 deficiency could alleviate neuronal injury, microglial activation, and inflammation in SAE mice. Additionally, mitochondrial dysfunction in the SAE mice was improved by TNFRSF6 depletion. In the LPS-induced microglia, we also proved that TNFRSF6 knockdown reduced inflammatory response inhibited ROS production, and alleviated mitochondrial dysfunction. TNFRSF6 induced mitochondrial dysfunction and microglia activation in the in vivo and in vitro models of SAE.

Sepsis-associated encephalopathy (SAE) is a diffuse brain dysfunction secondary to body infection without overt central nervous system infection. Dysregulation of miRNA expression in the transcriptome can spread through RNA transfer in exosomes, providing an early signal of impending neuropathological changes in the brain. Here, we comprehensively analyzed brain-derived exosomal miRNA profiles in SAE rats (n = 3) and controls (n = 3). We further verified the differential expression and correlation of brain tissue, cerebrospinal fluid, and plasma exosomal miRNAs in SAE rats. High-throughput sequencing of brain-derived exosomal miRNAs identified 101 differentially expressed miRNAs, of which 16 were downregulated and 85 were upregulated. Four exosomal miRNAs (miR-127-3p, miR-423-3p, mR-378b, and miR-106-3p) were differentially expressed and correlated in the brain tissue, cerebrospinal fluid, and plasma, revealing the potential use of miRNAs as SAE liquid brain biopsies. Understanding exosomal miRNA profiles in SAE brain tissue and exploring the correlation with peripheral exosomal miRNA can contribute to a comprehensive understanding of miRNA changes in the SAE pathological process and provide the possibility of establishing early diagnostic assays., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Previous studies have reported that puerarin possesses cardioprotective, vasodilatory, anti-inflammatory, anti-apoptotic, and hypoglycemic properties. However, the impact of puerarin on sepsis-associated encephalopathy (SAE) remains unexplored. In this study, we explored whether puerarin can modulate microglia-mediated neuroinflammation for the treatment of SAE and delved into the underlying mechanisms., Methods: We established a murine model of SAE through intraperitoneal injection of lipopolysaccharide (LPS). The puerarin treatment group received pretreatment with puerarin. For in vitro experiments, BV2 cells were pre-incubated with puerarin for 2 h before LPS exposure. We employed network pharmacology, the Morris Water Maze (MWM) test, Novel Object Recognition (NOR) test, immunofluorescence staining, enzyme-linked immunosorbent assay (ELISA), Western blotting, and quantitative real-time PCR (qRT-PCR) to elucidate the molecular mechanism of underlying puerarin's effects in SAE treatment., Results: Our findings demonstrate that puerarin significantly reduced the production of inflammatory cytokines (TNF-α and IL-6) in the peripheral blood of LPS-treated mice. Moreover, puerarin treatment markedly ameliorated sepsis-associated cognitive impairment. Puerarin also exhibited inhibitory effects on the release of TNF-α and IL-6 from microglia, thereby preventing hippocampal neuronal cell death. Network pharmacology analysis identified AKT1 as a potential therapeutic target for puerarin in SAE treatment. Subsequently, we validated these results in both in vitro and in vitro experiments. Our study conclusively demonstrated that puerarin reduced LPS-induced phosphorylation of AKT1, with the AKT activator SC79 reversing puerarin's anti-inflammatory effects through the activation of the AKT1 signaling pathway., Conclusion: Puerarin exerts an anti-neuroinflammatory effect against SAE by modulating the AKT1 pathway in microglia., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023. Published by Elsevier GmbH.)

Anxiety manifestations and cognitive dysfunction are common sequelae in patients with sepsis-associated encephalopathy (SAE). Microglia-mediated inflammatory signaling is involved in anxiety, depression, and cognitive dysfunction during acute infection with bacterial lipopolysaccharide (LPS). However, the molecular mechanisms underlying microglia activation and behavioral and cognitive deficits in sepsis have not been in fully elucidated. Based on previous research, we speculated that the CD137 receptor/ligand system modulates microglia function during sepsis to mediate classical neurological SAE symptoms. A murine model of SAE was established by injecting male C57BL/6 mice with LPS, and cultured mouse BV2 microglia were used for in vitro assays. RT-qPCR, immunofluorescence staining, flow cytometry, and ELISA were used to assess microglial activation and the expression of CD137L and inflammation-related cytokines in the mouse hippocampus and in cultured BV2 cells. In addition, behavioral tests were conducted in assess cognitive performance and behavioral distress. Immunofluorescence and RT-qPCR analyses showed that hippocampal expression of CD137L was upregulated in activated microglia following LPS treatment. Pre-treatment with the CD137L neutralizing antibody TKS-1 significantly reduced CD137L levels, attenuated the expression of M1 polarization markers in microglia, and inhibited the production of TNF-α, IL-1β, and IL-6 in both LPS-treated mice and BV2 cells. Conversely, stimulation of CD137L signaling by recombinant CD137-Fc fusion protein activated the synthesis and release of pro-inflammatory cytokines in cultures BV2 microglia. Importantly, open field, elevated plus maze, and Y-maze spontaneous alternation test results indicated that TKS-1 administration alleviated anxiety-like behavior and spatial memory decline in mice with LPS-induced SAE. These findings suggest that CD137L upregulation in activated microglia critically contributes to neuroinflammation, anxiety-like behavior, and cognitive dysfunction in the mouse model of LPS-induced sepsis. Therefore, therapeutic modulation of the CD137L/CD137 signaling pathway may represent an effective way to minimize brain damage and prevent cognitive and emotional deficits associated with SAE., (© 2023. The Author(s).)

Patients with sepsis-associated delirium (SAD) show severe neurological impairment, often require an intensive care unit (ICU) stay and have a high risk of mortality. Hence, useful biomarkers for early detection of SAD are urgently needed. Extracellular vesicles (EVs) and their cargo are known to maintain normal physiology but also have been linked to numerous disease states. Here, we sought to identify differentially expressed proteins in plasma EVs from SAD patients as potential biomarkers for SAD. Plasma EVs from 11 SAD patients and 11 age-matched septic patients without delirium (non-SAD) were isolated by differential centrifugation, characterized by nanoparticle tracking analysis, transmission electron microscopy and Western blot analysis. Differential EV protein expression was determined by mass spectrometry and the resulting proteomes were characterized by Gene Ontology term and between-group statistics. As preliminary results because of the small group size, five distinct proteins showed significantly different expression pattern between SAD and non-SAD patients ( p ≤ 0.05). In SAD patients, upregulated proteins included paraoxonase-1 (PON1), thrombospondin 1 (THBS1), and full fibrinogen gamma chain (FGG), whereas downregulated proteins comprised immunoglobulin (IgHV3) and complement subcomponent (C1QC). Thus, plasma EVs of SAD patients show significant changes in the expression of distinct proteins involved in immune system regulation and blood coagulation as well as in lipid metabolism in this pilot study. They might be a potential indicator for to the pathogenesis of SAD and thus warrant further examination as potential biomarkers, but further research is needed to expand on these findings in longitudinal study designs with larger samples and comprehensive polymodal data collection.