Startseite Glutathione attenuates sepsis-associated encephalopathy via dual modulation of NF-κB and PKA/CREB pathways
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Glutathione attenuates sepsis-associated encephalopathy via dual modulation of NF-κB and PKA/CREB pathways

  • Cailin Wang , Yong Liu , Xiangru Wen EMAIL logo und Hui Lu EMAIL logo
Veröffentlicht/Copyright: 20. September 2025
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Open Medicine
Aus der Zeitschrift Open Medicine Band 20 Heft 1

Abstract

Background

Sepsis-associated encephalopathy (SAE) remains a major unmet clinical need, due to the lack of effective treatments. Although glutathione (GSH) is known for its antioxidant properties, its specific neuroprotective role via modulation of inflammatory pathways in SAE remains poorly understood.

Methods

Using a lipopolysaccharide (LPS)-induced murine sepsis model, we examined GSH’s effects through comprehensive behavioral assessments, histopathological analysis, and molecular profiling. Mice were pretreated with GSH prior to LPS challenge, and outcomes were assessed across multiple parameters.

Key results

This study reveals that GSH pretreatment significantly improved survival rates by 10% (p < 0.01) and significantly alleviates neurological deficits in a murine model of sepsis. Behaviorally, GSH reversed depression-like symptoms, boosting locomotor activity (p = 0.009) and reducing immobility (p < 0.05). Histopathological analysis showed that GSH preserved hippocampal structure, maintaining 40% more viable neurons in CA1/DG regions (p < 0.05). Mechanistically, GSH exerts dual neuroprotective actions: it robustly suppresses NF-κB signaling via inhibition of p65 nuclear translocation and downregulation of IL-1β and IL-6, while simultaneously activating the PKA/CREB pathway revealing a previously unrecognized mechanism of action.

Conclusion

This study provides the first evidence of GSH’s dual mechanism action in SAE, establishing it as a promising multi-target therapeutic candidate. These findings open new avenues for developing effective SAE interventions targeting both inflammatory and neuroprotective pathways.

Keywords: sepsis; SAE; GSH; PKA; NF-κB

1 Introduction

Sepsis-associated encephalopathy (SAE) is a critical complication affecting the central nervous system in patients with sepsis, characterized by diffuse or multifocal brain dysfunction secondary to systemic infection [1]. Notably, SAE can develop even in the absence of direct brain infection, rendering its pathophysiology particularly complex [2]. SAE is common among critically ill patients in the intensive care unit (ICU), affecting up to 70% of individuals with severe systemic infections [3]. Its clinical manifestations range from mild disturbances, such as confusion and attention deficits, to profound coma, with patients often experiencing behavioral, cognitive, arousal, and consciousness impairments [4]. Furthermore, many patients develop long-term cognitive deficits [5]. Despite its high prevalence in ICU settings, the pathogenesis of SAE remains poorly understood, and there are no effective treatments currently available [6]. Thus, SAE represents a significant clinical challenge, drawing increasing attention from the global medical community.

In addition to cognitive dysfunction, depression is one of the most debilitating complications of sepsis-induced brain dysfunction, contributing to increased morbidity and mortality [7]. Depression in this context remains a major therapeutic challenge, as current treatments primarily alleviate symptoms without addressing the underlying causes. This underscores the urgent need to elucidate the mechanisms underlying sepsis-induced depression and to identify novel therapeutic strategies targeting these behavioral impairments [8].

Inflammatory mediators – including cytokines, the complement system, and disrupted intracellular signaling pathways – are believed to play key roles in the pathogenesis of SAE. Neuroinflammation, characterized by activation of microglia, astrocytes, and neurons, leads to a dysregulated balance between pro- and anti-inflammatory responses [9]. Moreover, activation of the NF-κB signaling pathway and excessive generation of reactive oxygen species (ROS) have been implicated in SAE development [10]. Glutathione (GSH), a crucial endogenous antioxidant, is essential for counteracting oxidative stress during sepsis [11].

GSH, a naturally occurring tripeptide, contributes to immune regulation, redox homeostasis, apoptosis, and modulation of intracellular signaling cascades [12]. Previous studies suggest that GSH improves outcomes in sepsis, particularly in organ systems such as the lungs, liver, and kidneys [13]. However, its specific role in protecting the brain during sepsis – particularly regarding neuroinflammation and neuronal damage – remains underexplored.

Taken together, we hypothesize that GSH may attenuate neuroinflammation and hippocampal neuronal injury by enhancing the cAMP/PKA signaling pathway and inhibiting NF-κB activation, thereby alleviating depressive-like behavior associated with SAE. This study aims to investigate the therapeutic potential of GSH in sepsis-induced brain injury, offering novel insights into its application as a candidate treatment for SAE.

2 Methods

2.1 Reagents

Lipopolysaccharide (LPS) and GSH were purchased from Sigma-Aldrich (St Louis, MO, USA). The following primary antibodies were used: anti-PKA, polyclonal anti-p-PKA (Thr198), anti-IL-1β, anti-IL-6, anti-NF-κB, mouse monoclonal anti-Caspase-3 (CASP3), and goat monoclonal anti-IL-10, all obtained from Santa Cruz Biotechnology (Santa Cruz, CA, USA). A rabbit polyclonal anti-cleaved-Caspase-3 (Cleaved-CASP3) antibody was purchased from Cell Signaling Technology (Beverly, MA, USA). The secondary antibodies used in this study were also purchased from Sigma-Aldrich.

2.2 Animal model

Male C57BL/6 mice (2–3 months, 20 ± 5 g) were obtained from the Experimental Animal Center of Xuzhou Medical College. They were housed under standard conditions with free access to food and water at 21°C on a 12 h light/dark cycle. All procedures were approved by the Institutional Animal Care and Use Committee (IACUC) of Xuzhou Medical University. Sepsis model: sepsis was induced by a single intraperitoneal (i.p.) injection of LPS (25 mg/kg) dissolved in normal saline. Mice in the control (CON) group received an equivalent volume of saline. GSH treatment: mice in the GSH treatment group received daily i.p. injections of GSH (100 mg/kg) for 4 days before LPS administration (details in Figure S1).

2.3 Pathological behavioral scoring

Pathological behavioral scoring was conducted to assess the effects of LPS injection on mice, focusing on piloerection, ptosis, and activity level. Piloerection was scored as 0 (no piloerection), 1 (moderate piloerection), or 2 (extensive piloerection). Ptosis was scored as 0 (normal or >50% open), 1 (slight ptosis, 1/3–1/2 closed), or 2 (severe ptosis, <1/3 open). Activity was scored as 0 (active behavior), 1 (inactivity), or 2 (lethargy or curled up). This scoring was used to evaluate the impact of LPS and treatments, minimizing external disturbances during assessment (Table S1).

2.4 Open-field (OFT) and closed-field test (CFT)

Depression-like behavior was assessed using the OFT and CFT based on the method of Prut and Belzung. OFT: mice were placed at the center of an open-field apparatus (50 × 50 × 30 cm) and allowed to acclimate for 3 min. Their free-moving behavior was then recorded for 5 min using an open-field tracking system. Activity was quantified in terms of total movement time, total distance traveled, distance in the central area, and time spent in the central area. CFT: following the OFT, mice were placed in a dark, closed-box of the same size, and behavior was recorded as in the OFT. The experiment was conducted in a quiet environment to minimize disturbances [14].

2.5 Elevated plus maze (EPM) test

The EPM, used to assess depression-like behavior, consists of a cross-shaped elevated platform (64 × 64 cm) with two open arms and two closed arms. Mice were acclimated to the test room for 1 h before being placed at the center of the maze, facing the open arm. They were allowed to explore for 5 min while their behavior was recorded. The system tracked entries into the open and closed arms and time spent in the open arms. Parameters calculated included the percentage of time spent in the open arms and total entries into both arms. After each trial, the maze was cleaned with 75% ethanol and allowed to dry before the next test. The experiment was conducted in a quiet environment to minimize disturbances [15].

2.6 Tail suspension test

In the tail suspension test, the tip of the mouse’s tail (1.0–1.5 cm) was affixed to a metallic surface using medical adhesive tape, and the mouse was suspended 30 cm above the surface for 6 min under 100 lux illumination. During the test, two parameters were recorded: immobility, defined as the total time the mouse remained immobile for more than 2 s, and latency, the time taken for the mouse to first exhibit immobility after being suspended [16].

2.7 Nissl staining and HE staining

Mice were transcardially perfused with 200 mL ice-cold phosphate-buffered saline (PBS), followed by 300 mL of 10% formalin. After 48 h of fixation, brains were dehydrated, embedded in paraffin, and sectioned into 10 µm slices. Hippocampal sections were stained with Nissl stain (Solarbio, China) following the manufacturer’s instructions. Surviving pyramidal neurons in the CA1–CA3 and dentate gyrus (DG) regions were counted at ×400 magnification. For HE staining, 5 µm brain sections were prepared to assess hippocampal cell damage [17].

2.8 Immunohistochemistry

Frozen mouse brain sections (30 μm) were washed 3–4 times with 0.1 M PBS for 5 min each, and then incubated in blocking solution containing 5% bovine serum albumin for 2 h at room temperature. After blocking, sections were incubated overnight at 4°C with primary antibodies: anti-GFAP (1:100; Abcam) and either anti-NeuN or anti-BrdU (1:150) in 10% goat serum diluted in PBS. The next day, sections were washed 3–4 times with PBS for 5 min each and incubated with appropriate anti-rabbit secondary antibodies for 2 h at room temperature. After washing, the sections were counterstained with DAPI (1:2,000; Sigma) for 3 min to label the nuclei. Finally, sections were mounted and observed under a fluorescence microscope.

2.9 Western blot analysis

Hippocampal tissues from each group of ten mice were homogenized in RIPA lysis buffer containing 1% PMSF. After adding SDS loading buffer, samples were boiled for 5 min and proteins were separated by SDS-PAGE. Following electrophoresis, proteins were transferred to a membrane, which was blocked with skimmed milk to reduce nonspecific binding. The membrane was incubated overnight at 4°C with primary antibodies (PI3K, P-PI3K, Pan-AKT, AKT1, caspase-3, and cleaved caspase-3). After washing with buffer, the membrane was incubated with a secondary antibody (1:200) for 2 h. Protein bands were scanned and analyzed using Quantity One software (BIO-RAD, USA) [18].

2.10 Statistical analysis

Densitometric analysis of immunofluorescence and western blot bands was performed using ImageJ software (National Institutes of Health, Bethesda, MD, USA). Data were analyzed with GraphPad Prism 7 (GraphPad Software, CA, USA) and images were processed using Photoshop CS6. Statistical analyses were conducted using SPSS version 13.0 for Windows. Data are presented as mean ± SEM. One-way ANOVA followed by the Newman–Keuls test was used for statistical comparisons, with P < 0.05 considered significant. In behavioral tests, all animals were treated as independent samples.

  1. Ethical approval: All animal experiments were conducted in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals (8th edition, 2011) and approved by the Institutional Animal Care and Use Committee (IACUC) of People’s Hospital of Suzhou New District (Approval No. L2022603).

3 Result

3.1 GSH significantly improves mortality and pathological behavior in LPS-induced sepsis model

To assess the effect of GSH pretreatment on sepsis-associated mortality, mortality within 6 days of LPS injection were recorded (Figure 1a). Survival analysis showed that 24 h after LPS injection, the survival rate in the LPS group was 50%, whereas the LPS + GSH group exhibited a higher survival rate of 60%. Significant differences were observed between the groups (NS vs LPS: p < 0.01; LPS vs LPS + GSH: p < 0.01). Pathological scoring on Day 12 revealed functional impairments in both LPS and LPS + GSH groups, but no deficits in saline and GSH groups. The LPS group exhibited significantly higher pathological scores than the saline group (p < 0.001), and the scores were also significantly higher than those in the LPS + GSH group (p < 0.001), indicating a protective effect of GSH (Figure 1b).

Figure 1 Survival curve and neurological scores (a) survival curve showing the survival rates of mice from four groups over 4 days post-LPS injection: Saline (blue), LPS (red), LPS + GSH (green), and GSH (yellow). (b) Neurological scores over time for the four groups: saline (●, purple), LPS (■, red), LPS + GSH (▲, blue), and GSH (▼, green). Data are presented as mean ± SEM (n = 12). *P < 0.05 vs saline, # P < 0.05 vs LPS.
Figure 1

Survival curve and neurological scores (a) survival curve showing the survival rates of mice from four groups over 4 days post-LPS injection: Saline (blue), LPS (red), LPS + GSH (green), and GSH (yellow). (b) Neurological scores over time for the four groups: saline (●, purple), LPS (■, red), LPS + GSH (▲, blue), and GSH (▼, green). Data are presented as mean ± SEM (n = 12). *P < 0.05 vs saline, # P < 0.05 vs LPS.

3.2 Effect of GSH on depression-like behavior of LPS-induced SAE model

To assess the protective effect of GSH against LPS-induced depression-like behavior, a battery of behavioral tests was performed, including the OFT, CFT, elevated plus maze, and tail suspension test. In the OFT and CFT, LPS-treated mice exhibited reduced locomotion and fewer crossings compared to controls (total distance: P = 0.008; number of crossings: P < 0.001). GSH pretreatment significantly restored spontaneous activity, as evidenced by increased total distance traveled in the open field (P = 0.009) and more crossings compared to the LPS group (P < 0.001) (Figure 2a–c). In the elevated plus maze, LPS-treated mice spent less time in the open arms (P = 0.001) and made fewer entries (P = 0.046), indicative of anxiety-like behavior. GSH treatment increased both the time spent (P = 0.143) and the number of entries (P < 0.001) into the open arms (Figure 2d–f). The tail suspension test further confirmed GSH’s impact. LPS-treated mice showed increased immobility (P < 0.05), a hallmark of depression-like behavior, which was significantly reduced following GSH treatment (P < 0.05). These findings demonstrate that GSH effectively alleviates depression-like and sickness behaviors in the LPS-induced sepsis model (Figure 2g–i).

Figure 2 Behavioral test. (a) The autonomous trajectory map of mice in the open and closed fields after 14 days of LPS (i.p.) injection. (b) Total distance traveled by mice in open and closed fields. (c) Number of crossings in the open and closed fields. (d) Autonomous trajectory map of mice in the cross maze 24 h after LPS (i.p.) injection. (e) Percentage of time spent in the open arm. (f) Percentage of time spent in the open arm during the median time. (g) The mobile and immobile behaviors of mice during suspension tests. (h) Time spent still. (i) Number of times the mouse remained still. Data are expressed as mean ± SEM (n = 20). *P < 0.05 vs saline group, # P < 0.05 vs LPS group.
Figure 2

Behavioral test. (a) The autonomous trajectory map of mice in the open and closed fields after 14 days of LPS (i.p.) injection. (b) Total distance traveled by mice in open and closed fields. (c) Number of crossings in the open and closed fields. (d) Autonomous trajectory map of mice in the cross maze 24 h after LPS (i.p.) injection. (e) Percentage of time spent in the open arm. (f) Percentage of time spent in the open arm during the median time. (g) The mobile and immobile behaviors of mice during suspension tests. (h) Time spent still. (i) Number of times the mouse remained still. Data are expressed as mean ± SEM (n = 20). *P < 0.05 vs saline group, # P < 0.05 vs LPS group.

3.3 GSH improves the damage of neurons

GSH treatment markedly attenuated hippocampus neuronal damage in the LPS-induced sepsis model. Nissl and HE staining revealed pronounced neuronal degeneration in the CA1 region following LPS injection, characterized by disorganized neurons, blurred Nissl bodies, and irregular cellular structures. However, GSH pretreatment alleviated neuronal degeneration, preserved neuron morphology, and enhanced cell survival. Compared to the LPS group, the GSH-treated group exhibited fewer signs of cellular damage, with more intact pyramidal neurons and less nuclear shrinkage (Figures 3 and 4). Immunofluorescence staining for NeuN further confirmed these results, showing a notable increase in the number of surviving neurons in the GSH-treated group compared to the LPS group. Although neuronal survival in the GSH group did not reach control levels, it was significantly higher than that in the LPS group, underscoring the neuroprotective effect of GSH against LPS-induced hippocampal damage (Figure 5).

Figure 3 Nissl staining of hippocampal CA1 and DG regions. (a)–(c) Saline group: sections of the hippocampal CA1 and DG regions. (d)–(f) LPS group: Sections of the hippocampal CA1 and DG regions. (g)–(i) LPS + GSH group: Sections of the hippocampal CA1 and DG regions. (j)–(l) GSH group: Sections of the hippocampal CA1 and DG regions. (m) Quantification of apoptotic cells in the CA1 region. (n) Quantification of apoptotic cells in the DG region. Images were acquired at ×40 magnification. Data are expressed as mean ± SEM (n = 6). *P < 0.05 vs saline group, # P < 0.05 vs LPS group.
Figure 3

Nissl staining of hippocampal CA1 and DG regions. (a)–(c) Saline group: sections of the hippocampal CA1 and DG regions. (d)–(f) LPS group: Sections of the hippocampal CA1 and DG regions. (g)–(i) LPS + GSH group: Sections of the hippocampal CA1 and DG regions. (j)–(l) GSH group: Sections of the hippocampal CA1 and DG regions. (m) Quantification of apoptotic cells in the CA1 region. (n) Quantification of apoptotic cells in the DG region. Images were acquired at ×40 magnification. Data are expressed as mean ± SEM (n = 6). *P < 0.05 vs saline group, # P < 0.05 vs LPS group.

Figure 4 HE staining of hippocampal CA1 and DG regions. (a)–(c) Saline group: Sections of the hippocampal CA1 and DG regions. (d)–(f) LPS group: Sections of the hippocampal CA1 and DG regions. (g)–(i) LPS + GSH group: Sections of the hippocampal CA1 and DG regions. (j)–(l) GSH group: Sections of the hippocampal CA1 and DG regions. (m) Quantification of apoptotic cells in the CA1 region. (n) Quantification of apoptotic cells in the DG region. Images were acquired at ×40 magnification. Data are expressed as mean ± SEM (n = 6). *P < 0.05 vs saline group, # P < 0.05 vs LPS group.
Figure 4

HE staining of hippocampal CA1 and DG regions. (a)–(c) Saline group: Sections of the hippocampal CA1 and DG regions. (d)–(f) LPS group: Sections of the hippocampal CA1 and DG regions. (g)–(i) LPS + GSH group: Sections of the hippocampal CA1 and DG regions. (j)–(l) GSH group: Sections of the hippocampal CA1 and DG regions. (m) Quantification of apoptotic cells in the CA1 region. (n) Quantification of apoptotic cells in the DG region. Images were acquired at ×40 magnification. Data are expressed as mean ± SEM (n = 6). *P < 0.05 vs saline group, # P < 0.05 vs LPS group.

Figure 5 Immunofluorescence staining. (A) Representative photomicrographs of the saline group. Panels (a–d) show NEUN, BRDU, DAPI, and merged staining of the hippocampal CA1 region (×40). Panels (e–h) show fluorescent staining of NEUN, BRDU, DAPI, and merge of the hippocampal DG region. (B) Representative photomicrographs of the LPS group. Panels (i–l) show NEUN, BRDU, DAPI, and merged staining of the hippocampal CA1 region (×40). Panels (m–p) show fluorescent staining of NEUN, BRDU, DAPI, and merge of the hippocampal DG region. (C) Representative photomicrographs of the LPS + GSH group. Panels (q–t) show NEUN, BRDU, DAPI, and merged staining of the hippocampal CA1 region (×40). Panels (u–x) show fluorescent staining of NEUN, BRDU, DAPI, and merge of the hippocampal DG region. (D) Quantitative analysis of the number of BrdU-positive cells per unit area in the hippocampal DG. (E) Quantitative analysis of NEUN and DAPI ratio per unit area of the hippocampal CA1. (F) Quantitative analysis of NEUN and DAPI ratio per unit area of the hippocampal DG. Data are expressed as mean ± SEM (n = 6). *P < 0.05 vs saline group, # P < 0.05 vs LPS group.
Figure 5

Immunofluorescence staining. (A) Representative photomicrographs of the saline group. Panels (a–d) show NEUN, BRDU, DAPI, and merged staining of the hippocampal CA1 region (×40). Panels (e–h) show fluorescent staining of NEUN, BRDU, DAPI, and merge of the hippocampal DG region. (B) Representative photomicrographs of the LPS group. Panels (i–l) show NEUN, BRDU, DAPI, and merged staining of the hippocampal CA1 region (×40). Panels (m–p) show fluorescent staining of NEUN, BRDU, DAPI, and merge of the hippocampal DG region. (C) Representative photomicrographs of the LPS + GSH group. Panels (q–t) show NEUN, BRDU, DAPI, and merged staining of the hippocampal CA1 region (×40). Panels (u–x) show fluorescent staining of NEUN, BRDU, DAPI, and merge of the hippocampal DG region. (D) Quantitative analysis of the number of BrdU-positive cells per unit area in the hippocampal DG. (E) Quantitative analysis of NEUN and DAPI ratio per unit area of the hippocampal CA1. (F) Quantitative analysis of NEUN and DAPI ratio per unit area of the hippocampal DG. Data are expressed as mean ± SEM (n = 6). *P < 0.05 vs saline group, # P < 0.05 vs LPS group.

3.4 Protective effects of GSH against LPS-induced neuronal damage and inflammation in sepsis

To investigate the protective effects of GSH on the LPS-induced sepsis model, we focused on its impact on neuronal damage, inflammation, and key cellular signaling pathways. Our findings demonstrated that GSH significantly reduced neuronal apoptosis in the hippocampus. This was evidenced by decreased levels of caspase-3 and cleaved caspase-3 in the LPS + GSH group compared to the LPS group (P < 0.05), suggesting that GSH contributes to neuronal preservation in the context of sepsis (Figure 6a and b).

Figure 6 Western blot. (a) and (b) Activation of Caspase 3 and Cleaved Caspase 3 in the hippocampus 14 days after LPS injection was analyzed by immunoblot. (a) Scanning immunoblot bands. (b) The intensity of the bands is expressed as optical density (OD). (c) and (d) Expression changes in P65 in the cytoplasm and phosphorylation levels of IKKβ 14 days after LPS injection, analyzed by immunoblot. (c) Scanning immunoblot bands. (d) The intensity of the bands is expressed as OD. (e) and (f) Immunoblot analysis of PKA and p-PKA levels in the hippocampus 14 days after LPS injection. (e) Scanning immunoblot bands. (f) The intensity of the bands is expressed as O.D. (g)–(n) Expression of IL-1β, IL-6, IL-10, and TNF-α in the hippocampus 4 days after LPS injection was analyzed by immunoblot. (d) Scanning immunoblot bands. (d) The intensity of the bands is expressed as OD. (Data are expressed as mean ± SEM, n = 6. *P < 0.05 vs saline group, # P < 0.05 vs LPS group).
Figure 6

Western blot. (a) and (b) Activation of Caspase 3 and Cleaved Caspase 3 in the hippocampus 14 days after LPS injection was analyzed by immunoblot. (a) Scanning immunoblot bands. (b) The intensity of the bands is expressed as optical density (OD). (c) and (d) Expression changes in P65 in the cytoplasm and phosphorylation levels of IKKβ 14 days after LPS injection, analyzed by immunoblot. (c) Scanning immunoblot bands. (d) The intensity of the bands is expressed as OD. (e) and (f) Immunoblot analysis of PKA and p-PKA levels in the hippocampus 14 days after LPS injection. (e) Scanning immunoblot bands. (f) The intensity of the bands is expressed as O.D. (g)–(n) Expression of IL-1β, IL-6, IL-10, and TNF-α in the hippocampus 4 days after LPS injection was analyzed by immunoblot. (d) Scanning immunoblot bands. (d) The intensity of the bands is expressed as OD. (Data are expressed as mean ± SEM, n = 6. *P < 0.05 vs saline group, # P < 0.05 vs LPS group).

Beyond its anti-apoptotic effects, GSH also attenuated the inflammatory response. GSH treatment significantly reduced the hippocampal expression of pro-inflammatory cytokines, including TNF-α (Figure 6m and n), IL-1β (Figure 6g and h), and IL-6 (Figure 6i and j, P < 0.05), further supporting its anti-inflammatory effects. These effects are likely mediated by inhibition of the NF-κB pathway. GSH pretreatment lowered the phosphorylation of IKKβ in the cytoplasm and prevented the nuclear translocation of p65, indicating suppression of NF-κB activation (Figure 6e and f, P < 0.05).

Moreover, GSH activated the PKA signaling pathway, which is implicated in regulating cellular responses to inflammation. Phosphorylation levels of PKA and CREB were significantly higher in the LPS + GSH group compared to the LPS group (P < 0.05), suggesting that GSH may also exert its protective effects through the activation of this pathway (Figure 6c and d).

Overall, GSH protects against LPS-induced neuronal damage and inflammation, likely through the modulation of multiple signaling pathways, including NF-κB and PKA. These findings highlight GSH’s potential as a therapeutic agent in sepsis-related brain injury.

4 Discussion

SAE is a frequent and severe complication of sepsis, often leading to cognitive decline and affective disorders in survivors. Despite its clinical relevance, the pathophysiological mechanisms underlying SAE remain incompletely understood, and effective targeted therapies are lacking [19]. In this study, we investigated the neuroprotective potential of GSH in a murine model of LPS-induced sepsis and our findings reveal that GSH exerts both anti-inflammatory and neuroprotective effects in the context of SAE.

We first demonstrated that prophylactic administration of GSH significantly improved the survival rate of septic mice, with a 10% increase compared to the untreated LPS group. This enhancement in survival suggests that GSH mitigates systemic inflammation and potentially reduces sepsis-induced multi-organ dysfunction [20]. In addition to improving survival, GSH treatment mitigated behavioral abnormalities and reduced neurological deficits in septic mice. These observations support the hypothesis that GSH confers protection against sepsis-induced brain injury, especially those associated with hippocampal damage – a region critically involved in memory and emotional regulation [21].

Behavioral assessments revealed that GSH significantly alleviated depression-like symptoms in septic mice. Compared to the LPS group, GSH-treated mice exhibited increased locomotor activity and reduced immobility in both OFT and CFTs, indicating improved motivation and exploratory behavior. These behavioral improvements were accompanied by histological evidence of preserved neuronal structure in the hippocampal CA1 and DG regions. These findings strongly suggest that GSH supports hippocampal structural integrity and confers resilience to SAE-related neurodegeneration [22].

At the molecular level, we observed that GSH significantly reduced the hippocampal expression of key pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-6. These cytokines are key mediators of neuroinflammation and have been strongly implicated in SAE pathogenesis [23]. By downregulating these inflammatory mediators, GSH may directly counteract the neurotoxic inflammatory cascade triggered by systemic sepsis. Moreover, our results suggest that the anti-inflammatory effects of GSH are, at least in part, mediated by inhibition of the NF-κB signaling pathway. NF-κB is a well-established transcriptional regulator of inflammatory gene expression. We found that GSH suppressed the phosphorylation and nuclear translocation of the p65 subunit of NF-κB, thereby reducing the transcriptional activation of pro-inflammatory genes [24]. This mechanism likely contributes to the observed reduction in cytokine levels and neuronal injury in GSH-treated mice.

In addition to its anti-inflammatory effects, GSH is also recognized as a key intracellular antioxidant. Although we did not directly measure oxidative stress markers – such as ROS, lipid peroxidation, or the GSH/GSSG ratio – it is reasonable to consider that its antioxidant properties may have played a role in the neuroprotection observed in this study. Previous reports have highlighted the importance of GSH in limiting oxidative damage in neuroinflammatory conditions, including LPS-induced brain injury [25,26]. Future work involving the assessment of oxidative stress parameters will be important to clarify how much of GSH’s protective effect is driven by redox regulation versus inflammation control.

We also found that GSH treatment led to increased phosphorylation of CREB in the hippocampus, suggesting activation of the PKA/CREB signaling pathway, which is known to support neuronal survival and plasticity. However, we were not able to examine downstream CREB-regulated genes such as BDNF or c-fos in the current study. Given the well-established role of BDNF in maintaining cognitive function and synaptic health  [27], it is possible that this pathway contributed to the observed benefits. Further studies using gene expression or protein analysis will be needed to explore this mechanism in more detail.

One important limitation of this study is the use of a prophylactic treatment strategy, where GSH was administered before sepsis induction. While this approach allowed us to assess its potential protective effects under controlled experimental conditions, it does not fully reflect clinical situations in which treatment typically begins after the onset of infection. This limits the direct translational relevance of our findings. Nonetheless, prophylactic models remain a common and useful tool in early-stage research for identifying promising therapeutic targets. Future studies should evaluate the effectiveness of GSH when given after sepsis onset to better understand its potential for clinical use.

5 Conclusions

In summary, this study demonstrates that GSH pre-treatment offers significant neuroprotection in a murine model of sepsis. By attenuating neuroinflammation and preserving hippocampal neurons, GSH improves behavioral outcomes and survival in septic mice. These findings highlight the therapeutic potential of GSH for the prevention or treatment of SAE. Future studies are needed to explore the translational applicability of these findings in clinical settings and to further elucidate the molecular pathways through which GSH exerts its protective effects. Given its dual antioxidant and anti-inflammatory properties, GSH represents a promising candidate for therapeutic intervention in sepsis-associated neurological dysfunction.

# These authors contributed equally.

  1. Funding information: The People’s Hospital of SND (SGY2021A01) and Suzhou people’s Livelihood Science and technology guidance project under grant (SKJYD2021060).

  2. Author contributions: All authors made a significant contribution to the work reported, whether that is in the study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising, or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

  3. Conflict of interest: All authors state that there is no conflict of interest.

  4. Data availability statement: The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Received: 2025-05-23
Revised: 2025-07-27
Accepted: 2025-08-07
Published Online: 2025-09-20

© 2025 the author(s), published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

Artikel in diesem Heft

  1. Research Articles
  2. Network pharmacological analysis and in vitro testing of the rutin effects on triple-negative breast cancer
  3. Impact of diabetes on long-term survival in elderly liver cancer patients: A retrospective study
  4. Knockdown of CCNB1 alleviates high glucose-triggered trophoblast dysfunction during gestational diabetes via Wnt/β-catenin signaling pathway
  5. Risk factors for severe adverse drug reactions in hospitalized patients
  6. Analysis of the effect of ALA-PDT on macrophages in footpad model of mice infected with Fonsecaea monophora based on single-cell sequencing
  7. Development and validation of headspace gas chromatography with a flame ionization detector method for the determination of ethanol in the vitreous humor
  8. CMSP exerts anti-tumor effects on small cell lung cancer cells by inducing mitochondrial dysfunction and ferroptosis
  9. Predictive value of plasma sB7-H3 and YKL-40 in pediatric refractory Mycoplasma pneumoniae pneumonia
  10. Antiangiogenic potential of Elaeagnus umbellata extracts and molecular docking study by targeting VEGFR-2 pathway
  11. Comparison of the effectiveness of nurse-led preoperative counseling and postoperative follow-up care vs standard care for patients with gastric cancer
  12. Comparing the therapeutic efficacy of endoscopic minimally invasive surgery and traditional surgery for early-stage breast cancer: A meta-analysis
  13. Adhered macrophages as an additional marker of cardiomyocyte injury in biopsies of patients with dilated cardiomyopathy
  14. Association between statin administration and outcome in patients with sepsis: A retrospective study
  15. Exploration of the association between estimated glucose disposal rate and osteoarthritis in middle-aged and older adults: An analysis of NHANES data from 2011 to 2018
  16. A comparative analysis of the binary and multiclass classified chest X-ray images of pneumonia and COVID-19 with ML and DL models
  17. Lysophosphatidic acid 2 alleviates deep vein thrombosis via protective endothelial barrier function
  18. Transcription factor A, mitochondrial promotes lymph node metastasis and lymphangiogenesis in epithelial ovarian carcinoma
  19. Serum PM20D1 levels are associated with nutritional status and inflammatory factors in gastric cancer patients undergoing early enteral nutrition
  20. Hydromorphone reduced the incidence of emergence agitation after adenotonsillectomy in children with obstructive sleep apnea: A randomized, double-blind study
  21. Vitamin D replacement therapy may regulate sleep habits in patients with restless leg syndrome
  22. The first-line antihypertensive nitrendipine potentiated the therapeutic effect of oxaliplatin by downregulating CACNA1D in colorectal cancer
  23. Health literacy and health-related quality of life: The mediating role of irrational happiness
  24. Modulatory effects of Lycium barbarum polysaccharide on bone cell dynamics in osteoporosis
  25. Mechanism research on inhibition of gastric cancer in vitro by the extract of Pinellia ternata based on network pharmacology and cellular metabolomics
  26. Examination of the causal role of immune cells in non-alcoholic fatty liver disease by a bidirectional Mendelian randomization study
  27. Clinical analysis of ten cases of HIV infection combined with acute leukemia
  28. Investigating the cardioprotective potential of quercetin against tacrolimus-induced cardiotoxicity in Wistar rats: A mechanistic insights
  29. Clinical observation of probiotics combined with mesalazine and Yiyi Baitouweng Decoction retention enema in treating mild-to-moderate ulcerative colitis
  30. Diagnostic value of ratio of blood inflammation to coagulation markers in periprosthetic joint infection
  31. Sex-specific associations of sex hormone binding globulin and risk of bladder cancer
  32. Core muscle strength and stability-oriented breathing training reduces inter-recti distance in postpartum women
  33. The ERAS nursing care strategy for patients undergoing transsphenoidal endoscopic pituitary tumor resection: A randomized blinded controlled trial
  34. The serum IL-17A levels in patients with traumatic bowel rupture post-surgery and its predictive value for patient prognosis
  35. Impact of Kolb’s experiential learning theory-based nursing on caregiver burden and psychological state of caregivers of dementia patients
  36. Analysis of serum NLR combined with intraoperative margin condition to predict the prognosis of cervical HSIL patients undergoing LEEP surgery
  37. Commiphora gileadensis ameliorate infertility and erectile dysfunction in diabetic male mice
  38. The correlation between epithelial–mesenchymal transition classification and MMP2 expression of circulating tumor cells and prognosis of advanced or metastatic nasopharyngeal carcinoma
  39. Tetrahydropalmatine improves mitochondrial function in vascular smooth muscle cells of atherosclerosis in vitro by inhibiting Ras homolog gene family A/Rho-associated protein kinase-1 signaling pathway
  40. A cross-sectional study: Relationship between serum oxidative stress levels and arteriovenous fistula maturation in maintenance dialysis patients
  41. A comparative analysis of the impact of repeated administration of flavan 3-ol on brown, subcutaneous, and visceral adipose tissue
  42. Identifying early screening factors for depression in middle-aged and older adults: A cohort study
  43. Perform tumor-specific survival analysis for Merkel cell carcinoma patients undergoing surgical resection based on the SEER database by constructing a nomogram chart
  44. Unveiling the role of CXCL10 in pancreatic cancer progression: A novel prognostic indicator
  45. High-dose preoperative intraperitoneal erythropoietin and intravenous methylprednisolone in acute traumatic spinal cord injuries following decompression surgeries
  46. RAB39B: A novel biomarker for acute myeloid leukemia identified via multi-omics and functional validation
  47. Impact of peripheral conditioning on reperfusion injury following primary percutaneous coronary intervention in diabetic and non-diabetic STEMI patients
  48. Clinical efficacy of azacitidine in the treatment of middle- and high-risk myelodysplastic syndrome in middle-aged and elderly patients: A retrospective study
  49. The effect of ambulatory blood pressure load on mitral regurgitation in continuous ambulatory peritoneal dialysis patients
  50. Expression and clinical significance of ITGA3 in breast cancer
  51. Single-nucleus RNA sequencing reveals ARHGAP28 expression of podocytes as a biomarker in human diabetic nephropathy
  52. rSIG combined with NLR in the prognostic assessment of patients with multiple injuries
  53. Toxic metals and metalloids in collagen supplements of fish and jellyfish origin: Risk assessment for daily intake
  54. Exploring causal relationship between 41 inflammatory cytokines and marginal zone lymphoma: A bidirectional Mendelian randomization study
  55. Gender beliefs and legitimization of dating violence in adolescents
  56. Effect of serum IL-6, CRP, and MMP-9 levels on the efficacy of modified preperitoneal Kugel repair in patients with inguinal hernia
  57. Effect of smoking and smoking cessation on hematological parameters in polycythemic patients
  58. Pathogen surveillance and risk factors for pulmonary infection in patients with lung cancer: A retrospective single-center study
  59. Necroptosis of hippocampal neurons in paclitaxel chemotherapy-induced cognitive impairment mediates microglial activation via TLR4/MyD88 signaling pathway
  60. Celastrol suppresses neovascularization in rat aortic vascular endothelial cells stimulated by inflammatory tenocytes via modulating the NLRP3 pathway
  61. Cord-lamina angle and foraminal diameter as key predictors of C5 palsy after anterior cervical decompression and fusion surgery
  62. GATA1: A key biomarker for predicting the prognosis of patients with diffuse large B-cell lymphoma
  63. Influencing factors of false lumen thrombosis in type B aortic dissection: A single-center retrospective study
  64. MZB1 regulates the immune microenvironment and inhibits ovarian cancer cell migration
  65. Integrating experimental and network pharmacology to explore the pharmacological mechanisms of Dioscin against glioblastoma
  66. Trends in research on preterm birth in twin pregnancy based on bibliometrics
  67. Four-week IgE/baseline IgE ratio combined with tryptase predicts clinical outcome in omalizumab-treated children with moderate-to-severe asthma
  68. Single-cell transcriptomic analysis identifies a stress response Schwann cell subtype
  69. Acute pancreatitis risk in the diagnosis and management of inflammatory bowel disease: A critical focus
  70. Effect of subclinical esketamine on NLRP3 and cognitive dysfunction in elderly ischemic stroke patients
  71. Interleukin-37 mediates the anti-oral tumor activity in oral cancer through STAT3
  72. CA199 and CEA expression levels, and minimally invasive postoperative prognosis analysis in esophageal squamous carcinoma patients
  73. Efficacy of a novel drainage catheter in the treatment of CSF leak after posterior spine surgery: A retrospective cohort study
  74. Comprehensive biomedicine assessment of Apteranthes tuberculata extracts: Phytochemical analysis and multifaceted pharmacological evaluation in animal models
  75. Relation of time in range to severity of coronary artery disease in patients with type 2 diabetes: A cross-sectional study
  76. Dopamine attenuates ethanol-induced neuronal apoptosis by stimulating electrical activity in the developing rat retina
  77. Correlation between albumin levels during the third trimester and the risk of postpartum levator ani muscle rupture
  78. Factors associated with maternal attention and distraction during breastfeeding and childcare: A cross-sectional study in the west of Iran
  79. Mechanisms of hesperetin in treating metabolic dysfunction-associated steatosis liver disease via network pharmacology and in vitro experiments
  80. The law on oncological oblivion in the Italian and European context: How to best uphold the cancer patients’ rights to privacy and self-determination?
  81. The prognostic value of the neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and prognostic nutritional index for survival in patients with colorectal cancer
  82. Factors affecting the measurements of peripheral oxygen saturation values in healthy young adults
  83. Comparison and correlations between findings of hysteroscopy and vaginal color Doppler ultrasonography for detection of uterine abnormalities in patients with recurrent implantation failure
  84. The effects of different types of RAGT on balance function in stroke patients with low levels of independent walking in a convalescent rehabilitation hospital
  85. Causal relationship between asthma and ankylosing spondylitis: A bidirectional two-sample univariable and multivariable Mendelian randomization study
  86. Correlations of health literacy with individuals’ understanding and use of medications in Southern Taiwan
  87. Correlation of serum calprotectin with outcome of acute cerebral infarction
  88. Comparison of computed tomography and guided bronchoscopy in the diagnosis of pulmonary nodules: A systematic review and meta-analysis
  89. Curdione protects vascular endothelial cells and atherosclerosis via the regulation of DNMT1-mediated ERBB4 promoter methylation
  90. The identification of novel missense variant in ChAT gene in a patient with gestational diabetes denotes plausible genetic association
  91. Molecular genotyping of multi-system rare blood types in foreign blood donors based on DNA sequencing and its clinical significance
  92. Exploring the role of succinyl carnitine in the association between CD39⁺ CD4⁺ T cell and ulcerative colitis: A Mendelian randomization study
  93. Dexmedetomidine suppresses microglial activation in postoperative cognitive dysfunction via the mmu-miRNA-125/TRAF6 signaling axis
  94. Analysis of serum metabolomics in patients with different types of chronic heart failure
  95. Diagnostic value of hematological parameters in the early diagnosis of acute cholecystitis
  96. Pachymaran alleviates fat accumulation, hepatocyte degeneration, and injury in mice with nonalcoholic fatty liver disease
  97. Decrease in CD4 and CD8 lymphocytes are predictors of severe clinical picture and unfavorable outcome of the disease in patients with COVID-19
  98. METTL3 blocked the progression of diabetic retinopathy through m6A-modified SOX2
  99. The predictive significance of anti-RO-52 antibody in patients with interstitial pneumonia after treatment of malignant tumors
  100. Exploring cerebrospinal fluid metabolites, cognitive function, and brain atrophy: Insights from Mendelian randomization
  101. Development and validation of potential molecular subtypes and signatures of ocular sarcoidosis based on autophagy-related gene analysis
  102. Widespread venous thrombosis: Unveiling a complex case of Behçet’s disease with a literature perspective
  103. Uterine fibroid embolization: An analysis of clinical outcomes and impact on patients’ quality of life
  104. Discovery of lipid metabolism-related diagnostic biomarkers and construction of diagnostic model in steroid-induced osteonecrosis of femoral head
  105. Serum-derived exomiR-188-3p is a promising novel biomarker for early-stage ovarian cancer
  106. Enhancing chronic back pain management: A comparative study of ultrasound–MRI fusion guidance for paravertebral nerve block
  107. Peptide CCAT1-70aa promotes hepatocellular carcinoma proliferation and invasion via the MAPK/ERK pathway
  108. Electroacupuncture-induced reduction of myocardial ischemia–reperfusion injury via FTO-dependent m6A methylation modulation
  109. Hemorrhoids and cardiovascular disease: A bidirectional Mendelian randomization study
  110. Cell-free adipose extract inhibits hypertrophic scar formation through collagen remodeling and antiangiogenesis
  111. HALP score in Demodex blepharitis: A case–control study
  112. Assessment of SOX2 performance as a marker for circulating cancer stem-like cells (CCSCs) identification in advanced breast cancer patients using CytoTrack system
  113. Risk and prognosis for brain metastasis in primary metastatic cervical cancer patients: A population-based study
  114. Comparison of the two intestinal anastomosis methods in pediatric patients
  115. Factors influencing hematological toxicity and adverse effects of perioperative hyperthermic intraperitoneal vs intraperitoneal chemotherapy in gastrointestinal cancer
  116. Endotoxin tolerance inhibits NLRP3 inflammasome activation in macrophages of septic mice by restoring autophagic flux through TRIM26
  117. Lateral transperitoneal laparoscopic adrenalectomy: A single-centre experience of 21 procedures
  118. Petunidin attenuates lipopolysaccharide-induced retinal microglia inflammatory response in diabetic retinopathy by targeting OGT/NF-κB/LCN2 axis
  119. Procalcitonin and C-reactive protein as biomarkers for diagnosing and assessing the severity of acute cholecystitis
  120. Factors determining the number of sessions in successful extracorporeal shock wave lithotripsy patients
  121. Development of a nomogram for predicting cancer-specific survival in patients with renal pelvic cancer following surgery
  122. Inhibition of ATG7 promotes orthodontic tooth movement by regulating the RANKL/OPG ratio under compression force
  123. A machine learning-based prognostic model integrating mRNA stemness index, hypoxia, and glycolysis‑related biomarkers for colorectal cancer
  124. Glutathione attenuates sepsis-associated encephalopathy via dual modulation of NF-κB and PKA/CREB pathways
  125. Review Articles
  126. The effects of enhanced external counter-pulsation on post-acute sequelae of COVID-19: A narrative review
  127. Diabetes-related cognitive impairment: Mechanisms, symptoms, and treatments
  128. Microscopic changes and gross morphology of placenta in women affected by gestational diabetes mellitus in dietary treatment: A systematic review
  129. Review of mechanisms and frontier applications in IL-17A-induced hypertension
  130. Research progress on the correlation between islet amyloid peptides and type 2 diabetes mellitus
  131. The safety and efficacy of BCG combined with mitomycin C compared with BCG monotherapy in patients with non-muscle-invasive bladder cancer: A systematic review and meta-analysis
  132. The application of augmented reality in robotic general surgery: A mini-review
  133. The effect of Greek mountain tea extract and wheat germ extract on peripheral blood flow and eicosanoid metabolism in mammals
  134. Neurogasobiology of migraine: Carbon monoxide, hydrogen sulfide, and nitric oxide as emerging pathophysiological trinacrium relevant to nociception regulation
  135. Plant polyphenols, terpenes, and terpenoids in oral health
  136. Laboratory medicine between technological innovation, rights safeguarding, and patient safety: A bioethical perspective
  137. End-of-life in cancer patients: Medicolegal implications and ethical challenges in Europe
  138. The maternal factors during pregnancy for intrauterine growth retardation: An umbrella review
  139. Intra-abdominal hypertension/abdominal compartment syndrome of pediatric patients in critical care settings
  140. PI3K/Akt pathway and neuroinflammation in sepsis-associated encephalopathy
  141. Screening of Group B Streptococcus in pregnancy: A systematic review for the laboratory detection
  142. Giant borderline ovarian tumours – review of the literature
  143. Leveraging artificial intelligence for collaborative care planning: Innovations and impacts in shared decision-making – A systematic review
  144. Cholera epidemiology analysis through the experience of the 1973 Naples epidemic
  145. Risk factors of frailty/sarcopenia in community older adults: Meta-analysis
  146. Case Reports
  147. Delayed graft function after renal transplantation
  148. Semaglutide treatment for type 2 diabetes in a patient with chronic myeloid leukemia: A case report and review of the literature
  149. Diverse electrophysiological demyelinating features in a late-onset glycogen storage disease type IIIa case
  150. Giant right atrial hemangioma presenting with ascites: A case report
  151. Laser excision of a large granular cell tumor of the vocal cord with subglottic extension: A case report
  152. EsoFLIP-assisted dilation for dysphagia in systemic sclerosis: Highlighting the role of multimodal esophageal evaluation
  153. Rapid Communication
  154. Biological properties of valve materials using RGD and EC
  155. Letter to the Editor
  156. Role of enhanced external counterpulsation in long COVID
  157. Expression of Concern
  158. Expression of concern “A ceRNA network mediated by LINC00475 in papillary thyroid carcinoma”
  159. Expression of concern “Notoginsenoside R1 alleviates spinal cord injury through the miR-301a/KLF7 axis to activate Wnt/β-catenin pathway”
  160. Expression of concern “circ_0020123 promotes cell proliferation and migration in lung adenocarcinoma via PDZD8”
  161. Corrigendum
  162. Corrigendum to “Empagliflozin improves aortic injury in obese mice by regulating fatty acid metabolism”
  163. Corrigendum to “Comparing the therapeutic efficacy of endoscopic minimally invasive surgery and traditional surgery for early-stage breast cancer: A meta-analysis”
  164. Corrigendum to “The progress of autoimmune hepatitis research and future challenges”
  165. Retraction
  166. Retraction of “miR-654-5p promotes gastric cancer progression via the GPRIN1/NF-κB pathway”
  167. Special Issue Advancements in oncology: bridging clinical and experimental research - Part II
  168. Unveiling novel biomarkers for platinum chemoresistance in ovarian cancer
  169. Lathyrol affects the expression of AR and PSA and inhibits the malignant behavior of RCC cells
  170. The era of increasing cancer survivorship: Trends in fertility preservation, medico-legal implications, and ethical challenges
  171. Bone scintigraphy and positron emission tomography in the early diagnosis of MRONJ
  172. Meta-analysis of clinical efficacy and safety of immunotherapy combined with chemotherapy in non-small cell lung cancer
  173. Special Issue Computational Intelligence Methodologies Meets Recurrent Cancers - Part IV
  174. Exploration of mRNA-modifying METTL3 oncogene as momentous prognostic biomarker responsible for colorectal cancer development
  175. Special Issue The evolving saga of RNAs from bench to bedside - Part III
  176. Interaction and verification of ferroptosis-related RNAs Rela and Stat3 in promoting sepsis-associated acute kidney injury
  177. The mRNA MOXD1: Link to oxidative stress and prognostic significance in gastric cancer
  178. Special Issue Exploring the biological mechanism of human diseases based on MultiOmics Technology - Part II
  179. Dynamic changes in lactate-related genes in microglia and their role in immune cell interactions after ischemic stroke
  180. A prognostic model correlated with fatty acid metabolism in Ewing’s sarcoma based on bioinformatics analysis
  181. Special Issue Diabetes
  182. Nutritional risk assessment and nutritional support in children with congenital diabetes during surgery
  183. Correlation of the differential expressions of RANK, RANKL, and OPG with obesity in the elderly population in Xinjiang
  184. A discussion on the application of fluorescence micro-optical sectioning tomography in the research of cognitive dysfunction in diabetes
  185. A review of brain research on T2DM-related cognitive dysfunction
  186. Special Issue Biomarker Discovery and Precision Medicine
  187. CircASH1L-mediated tumor progression in triple-negative breast cancer: PI3K/AKT pathway mechanisms
https://doi.org/10.1515/med-2025-1282
Schlagwörter für diesen Artikel
sepsis; SAE; GSH; PKA; NF-κB
Creative Commons
BY 4.0

Artikel in diesem Heft

  1. Research Articles
  2. Network pharmacological analysis and in vitro testing of the rutin effects on triple-negative breast cancer
  3. Impact of diabetes on long-term survival in elderly liver cancer patients: A retrospective study
  4. Knockdown of CCNB1 alleviates high glucose-triggered trophoblast dysfunction during gestational diabetes via Wnt/β-catenin signaling pathway
  5. Risk factors for severe adverse drug reactions in hospitalized patients
  6. Analysis of the effect of ALA-PDT on macrophages in footpad model of mice infected with Fonsecaea monophora based on single-cell sequencing
  7. Development and validation of headspace gas chromatography with a flame ionization detector method for the determination of ethanol in the vitreous humor
  8. CMSP exerts anti-tumor effects on small cell lung cancer cells by inducing mitochondrial dysfunction and ferroptosis
  9. Predictive value of plasma sB7-H3 and YKL-40 in pediatric refractory Mycoplasma pneumoniae pneumonia
  10. Antiangiogenic potential of Elaeagnus umbellata extracts and molecular docking study by targeting VEGFR-2 pathway
  11. Comparison of the effectiveness of nurse-led preoperative counseling and postoperative follow-up care vs standard care for patients with gastric cancer
  12. Comparing the therapeutic efficacy of endoscopic minimally invasive surgery and traditional surgery for early-stage breast cancer: A meta-analysis
  13. Adhered macrophages as an additional marker of cardiomyocyte injury in biopsies of patients with dilated cardiomyopathy
  14. Association between statin administration and outcome in patients with sepsis: A retrospective study
  15. Exploration of the association between estimated glucose disposal rate and osteoarthritis in middle-aged and older adults: An analysis of NHANES data from 2011 to 2018
  16. A comparative analysis of the binary and multiclass classified chest X-ray images of pneumonia and COVID-19 with ML and DL models
  17. Lysophosphatidic acid 2 alleviates deep vein thrombosis via protective endothelial barrier function
  18. Transcription factor A, mitochondrial promotes lymph node metastasis and lymphangiogenesis in epithelial ovarian carcinoma
  19. Serum PM20D1 levels are associated with nutritional status and inflammatory factors in gastric cancer patients undergoing early enteral nutrition
  20. Hydromorphone reduced the incidence of emergence agitation after adenotonsillectomy in children with obstructive sleep apnea: A randomized, double-blind study
  21. Vitamin D replacement therapy may regulate sleep habits in patients with restless leg syndrome
  22. The first-line antihypertensive nitrendipine potentiated the therapeutic effect of oxaliplatin by downregulating CACNA1D in colorectal cancer
  23. Health literacy and health-related quality of life: The mediating role of irrational happiness
  24. Modulatory effects of Lycium barbarum polysaccharide on bone cell dynamics in osteoporosis
  25. Mechanism research on inhibition of gastric cancer in vitro by the extract of Pinellia ternata based on network pharmacology and cellular metabolomics
  26. Examination of the causal role of immune cells in non-alcoholic fatty liver disease by a bidirectional Mendelian randomization study
  27. Clinical analysis of ten cases of HIV infection combined with acute leukemia
  28. Investigating the cardioprotective potential of quercetin against tacrolimus-induced cardiotoxicity in Wistar rats: A mechanistic insights
  29. Clinical observation of probiotics combined with mesalazine and Yiyi Baitouweng Decoction retention enema in treating mild-to-moderate ulcerative colitis
  30. Diagnostic value of ratio of blood inflammation to coagulation markers in periprosthetic joint infection
  31. Sex-specific associations of sex hormone binding globulin and risk of bladder cancer
  32. Core muscle strength and stability-oriented breathing training reduces inter-recti distance in postpartum women
  33. The ERAS nursing care strategy for patients undergoing transsphenoidal endoscopic pituitary tumor resection: A randomized blinded controlled trial
  34. The serum IL-17A levels in patients with traumatic bowel rupture post-surgery and its predictive value for patient prognosis
  35. Impact of Kolb’s experiential learning theory-based nursing on caregiver burden and psychological state of caregivers of dementia patients
  36. Analysis of serum NLR combined with intraoperative margin condition to predict the prognosis of cervical HSIL patients undergoing LEEP surgery
  37. Commiphora gileadensis ameliorate infertility and erectile dysfunction in diabetic male mice
  38. The correlation between epithelial–mesenchymal transition classification and MMP2 expression of circulating tumor cells and prognosis of advanced or metastatic nasopharyngeal carcinoma
  39. Tetrahydropalmatine improves mitochondrial function in vascular smooth muscle cells of atherosclerosis in vitro by inhibiting Ras homolog gene family A/Rho-associated protein kinase-1 signaling pathway
  40. A cross-sectional study: Relationship between serum oxidative stress levels and arteriovenous fistula maturation in maintenance dialysis patients
  41. A comparative analysis of the impact of repeated administration of flavan 3-ol on brown, subcutaneous, and visceral adipose tissue
  42. Identifying early screening factors for depression in middle-aged and older adults: A cohort study
  43. Perform tumor-specific survival analysis for Merkel cell carcinoma patients undergoing surgical resection based on the SEER database by constructing a nomogram chart
  44. Unveiling the role of CXCL10 in pancreatic cancer progression: A novel prognostic indicator
  45. High-dose preoperative intraperitoneal erythropoietin and intravenous methylprednisolone in acute traumatic spinal cord injuries following decompression surgeries
  46. RAB39B: A novel biomarker for acute myeloid leukemia identified via multi-omics and functional validation
  47. Impact of peripheral conditioning on reperfusion injury following primary percutaneous coronary intervention in diabetic and non-diabetic STEMI patients
  48. Clinical efficacy of azacitidine in the treatment of middle- and high-risk myelodysplastic syndrome in middle-aged and elderly patients: A retrospective study
  49. The effect of ambulatory blood pressure load on mitral regurgitation in continuous ambulatory peritoneal dialysis patients
  50. Expression and clinical significance of ITGA3 in breast cancer
  51. Single-nucleus RNA sequencing reveals ARHGAP28 expression of podocytes as a biomarker in human diabetic nephropathy
  52. rSIG combined with NLR in the prognostic assessment of patients with multiple injuries
  53. Toxic metals and metalloids in collagen supplements of fish and jellyfish origin: Risk assessment for daily intake
  54. Exploring causal relationship between 41 inflammatory cytokines and marginal zone lymphoma: A bidirectional Mendelian randomization study
  55. Gender beliefs and legitimization of dating violence in adolescents
  56. Effect of serum IL-6, CRP, and MMP-9 levels on the efficacy of modified preperitoneal Kugel repair in patients with inguinal hernia
  57. Effect of smoking and smoking cessation on hematological parameters in polycythemic patients
  58. Pathogen surveillance and risk factors for pulmonary infection in patients with lung cancer: A retrospective single-center study
  59. Necroptosis of hippocampal neurons in paclitaxel chemotherapy-induced cognitive impairment mediates microglial activation via TLR4/MyD88 signaling pathway
  60. Celastrol suppresses neovascularization in rat aortic vascular endothelial cells stimulated by inflammatory tenocytes via modulating the NLRP3 pathway
  61. Cord-lamina angle and foraminal diameter as key predictors of C5 palsy after anterior cervical decompression and fusion surgery
  62. GATA1: A key biomarker for predicting the prognosis of patients with diffuse large B-cell lymphoma
  63. Influencing factors of false lumen thrombosis in type B aortic dissection: A single-center retrospective study
  64. MZB1 regulates the immune microenvironment and inhibits ovarian cancer cell migration
  65. Integrating experimental and network pharmacology to explore the pharmacological mechanisms of Dioscin against glioblastoma
  66. Trends in research on preterm birth in twin pregnancy based on bibliometrics
  67. Four-week IgE/baseline IgE ratio combined with tryptase predicts clinical outcome in omalizumab-treated children with moderate-to-severe asthma
  68. Single-cell transcriptomic analysis identifies a stress response Schwann cell subtype
  69. Acute pancreatitis risk in the diagnosis and management of inflammatory bowel disease: A critical focus
  70. Effect of subclinical esketamine on NLRP3 and cognitive dysfunction in elderly ischemic stroke patients
  71. Interleukin-37 mediates the anti-oral tumor activity in oral cancer through STAT3
  72. CA199 and CEA expression levels, and minimally invasive postoperative prognosis analysis in esophageal squamous carcinoma patients
  73. Efficacy of a novel drainage catheter in the treatment of CSF leak after posterior spine surgery: A retrospective cohort study
  74. Comprehensive biomedicine assessment of Apteranthes tuberculata extracts: Phytochemical analysis and multifaceted pharmacological evaluation in animal models
  75. Relation of time in range to severity of coronary artery disease in patients with type 2 diabetes: A cross-sectional study
  76. Dopamine attenuates ethanol-induced neuronal apoptosis by stimulating electrical activity in the developing rat retina
  77. Correlation between albumin levels during the third trimester and the risk of postpartum levator ani muscle rupture
  78. Factors associated with maternal attention and distraction during breastfeeding and childcare: A cross-sectional study in the west of Iran
  79. Mechanisms of hesperetin in treating metabolic dysfunction-associated steatosis liver disease via network pharmacology and in vitro experiments
  80. The law on oncological oblivion in the Italian and European context: How to best uphold the cancer patients’ rights to privacy and self-determination?
  81. The prognostic value of the neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and prognostic nutritional index for survival in patients with colorectal cancer
  82. Factors affecting the measurements of peripheral oxygen saturation values in healthy young adults
  83. Comparison and correlations between findings of hysteroscopy and vaginal color Doppler ultrasonography for detection of uterine abnormalities in patients with recurrent implantation failure
  84. The effects of different types of RAGT on balance function in stroke patients with low levels of independent walking in a convalescent rehabilitation hospital
  85. Causal relationship between asthma and ankylosing spondylitis: A bidirectional two-sample univariable and multivariable Mendelian randomization study
  86. Correlations of health literacy with individuals’ understanding and use of medications in Southern Taiwan
  87. Correlation of serum calprotectin with outcome of acute cerebral infarction
  88. Comparison of computed tomography and guided bronchoscopy in the diagnosis of pulmonary nodules: A systematic review and meta-analysis
  89. Curdione protects vascular endothelial cells and atherosclerosis via the regulation of DNMT1-mediated ERBB4 promoter methylation
  90. The identification of novel missense variant in ChAT gene in a patient with gestational diabetes denotes plausible genetic association
  91. Molecular genotyping of multi-system rare blood types in foreign blood donors based on DNA sequencing and its clinical significance
  92. Exploring the role of succinyl carnitine in the association between CD39⁺ CD4⁺ T cell and ulcerative colitis: A Mendelian randomization study
  93. Dexmedetomidine suppresses microglial activation in postoperative cognitive dysfunction via the mmu-miRNA-125/TRAF6 signaling axis
  94. Analysis of serum metabolomics in patients with different types of chronic heart failure
  95. Diagnostic value of hematological parameters in the early diagnosis of acute cholecystitis
  96. Pachymaran alleviates fat accumulation, hepatocyte degeneration, and injury in mice with nonalcoholic fatty liver disease
  97. Decrease in CD4 and CD8 lymphocytes are predictors of severe clinical picture and unfavorable outcome of the disease in patients with COVID-19
  98. METTL3 blocked the progression of diabetic retinopathy through m6A-modified SOX2
  99. The predictive significance of anti-RO-52 antibody in patients with interstitial pneumonia after treatment of malignant tumors
  100. Exploring cerebrospinal fluid metabolites, cognitive function, and brain atrophy: Insights from Mendelian randomization
  101. Development and validation of potential molecular subtypes and signatures of ocular sarcoidosis based on autophagy-related gene analysis
  102. Widespread venous thrombosis: Unveiling a complex case of Behçet’s disease with a literature perspective
  103. Uterine fibroid embolization: An analysis of clinical outcomes and impact on patients’ quality of life
  104. Discovery of lipid metabolism-related diagnostic biomarkers and construction of diagnostic model in steroid-induced osteonecrosis of femoral head
  105. Serum-derived exomiR-188-3p is a promising novel biomarker for early-stage ovarian cancer
  106. Enhancing chronic back pain management: A comparative study of ultrasound–MRI fusion guidance for paravertebral nerve block
  107. Peptide CCAT1-70aa promotes hepatocellular carcinoma proliferation and invasion via the MAPK/ERK pathway
  108. Electroacupuncture-induced reduction of myocardial ischemia–reperfusion injury via FTO-dependent m6A methylation modulation
  109. Hemorrhoids and cardiovascular disease: A bidirectional Mendelian randomization study
  110. Cell-free adipose extract inhibits hypertrophic scar formation through collagen remodeling and antiangiogenesis
  111. HALP score in Demodex blepharitis: A case–control study
  112. Assessment of SOX2 performance as a marker for circulating cancer stem-like cells (CCSCs) identification in advanced breast cancer patients using CytoTrack system
  113. Risk and prognosis for brain metastasis in primary metastatic cervical cancer patients: A population-based study
  114. Comparison of the two intestinal anastomosis methods in pediatric patients
  115. Factors influencing hematological toxicity and adverse effects of perioperative hyperthermic intraperitoneal vs intraperitoneal chemotherapy in gastrointestinal cancer
  116. Endotoxin tolerance inhibits NLRP3 inflammasome activation in macrophages of septic mice by restoring autophagic flux through TRIM26
  117. Lateral transperitoneal laparoscopic adrenalectomy: A single-centre experience of 21 procedures
  118. Petunidin attenuates lipopolysaccharide-induced retinal microglia inflammatory response in diabetic retinopathy by targeting OGT/NF-κB/LCN2 axis
  119. Procalcitonin and C-reactive protein as biomarkers for diagnosing and assessing the severity of acute cholecystitis
  120. Factors determining the number of sessions in successful extracorporeal shock wave lithotripsy patients
  121. Development of a nomogram for predicting cancer-specific survival in patients with renal pelvic cancer following surgery
  122. Inhibition of ATG7 promotes orthodontic tooth movement by regulating the RANKL/OPG ratio under compression force
  123. A machine learning-based prognostic model integrating mRNA stemness index, hypoxia, and glycolysis‑related biomarkers for colorectal cancer
  124. Glutathione attenuates sepsis-associated encephalopathy via dual modulation of NF-κB and PKA/CREB pathways
  125. Review Articles
  126. The effects of enhanced external counter-pulsation on post-acute sequelae of COVID-19: A narrative review
  127. Diabetes-related cognitive impairment: Mechanisms, symptoms, and treatments
  128. Microscopic changes and gross morphology of placenta in women affected by gestational diabetes mellitus in dietary treatment: A systematic review
  129. Review of mechanisms and frontier applications in IL-17A-induced hypertension
  130. Research progress on the correlation between islet amyloid peptides and type 2 diabetes mellitus
  131. The safety and efficacy of BCG combined with mitomycin C compared with BCG monotherapy in patients with non-muscle-invasive bladder cancer: A systematic review and meta-analysis
  132. The application of augmented reality in robotic general surgery: A mini-review
  133. The effect of Greek mountain tea extract and wheat germ extract on peripheral blood flow and eicosanoid metabolism in mammals
  134. Neurogasobiology of migraine: Carbon monoxide, hydrogen sulfide, and nitric oxide as emerging pathophysiological trinacrium relevant to nociception regulation
  135. Plant polyphenols, terpenes, and terpenoids in oral health
  136. Laboratory medicine between technological innovation, rights safeguarding, and patient safety: A bioethical perspective
  137. End-of-life in cancer patients: Medicolegal implications and ethical challenges in Europe
  138. The maternal factors during pregnancy for intrauterine growth retardation: An umbrella review
  139. Intra-abdominal hypertension/abdominal compartment syndrome of pediatric patients in critical care settings
  140. PI3K/Akt pathway and neuroinflammation in sepsis-associated encephalopathy
  141. Screening of Group B Streptococcus in pregnancy: A systematic review for the laboratory detection
  142. Giant borderline ovarian tumours – review of the literature
  143. Leveraging artificial intelligence for collaborative care planning: Innovations and impacts in shared decision-making – A systematic review
  144. Cholera epidemiology analysis through the experience of the 1973 Naples epidemic
  145. Risk factors of frailty/sarcopenia in community older adults: Meta-analysis
  146. Case Reports
  147. Delayed graft function after renal transplantation
  148. Semaglutide treatment for type 2 diabetes in a patient with chronic myeloid leukemia: A case report and review of the literature
  149. Diverse electrophysiological demyelinating features in a late-onset glycogen storage disease type IIIa case
  150. Giant right atrial hemangioma presenting with ascites: A case report
  151. Laser excision of a large granular cell tumor of the vocal cord with subglottic extension: A case report
  152. EsoFLIP-assisted dilation for dysphagia in systemic sclerosis: Highlighting the role of multimodal esophageal evaluation
  153. Rapid Communication
  154. Biological properties of valve materials using RGD and EC
  155. Letter to the Editor
  156. Role of enhanced external counterpulsation in long COVID
  157. Expression of Concern
  158. Expression of concern “A ceRNA network mediated by LINC00475 in papillary thyroid carcinoma”
  159. Expression of concern “Notoginsenoside R1 alleviates spinal cord injury through the miR-301a/KLF7 axis to activate Wnt/β-catenin pathway”
  160. Expression of concern “circ_0020123 promotes cell proliferation and migration in lung adenocarcinoma via PDZD8”
  161. Corrigendum
  162. Corrigendum to “Empagliflozin improves aortic injury in obese mice by regulating fatty acid metabolism”
  163. Corrigendum to “Comparing the therapeutic efficacy of endoscopic minimally invasive surgery and traditional surgery for early-stage breast cancer: A meta-analysis”
  164. Corrigendum to “The progress of autoimmune hepatitis research and future challenges”
  165. Retraction
  166. Retraction of “miR-654-5p promotes gastric cancer progression via the GPRIN1/NF-κB pathway”
  167. Special Issue Advancements in oncology: bridging clinical and experimental research - Part II
  168. Unveiling novel biomarkers for platinum chemoresistance in ovarian cancer
  169. Lathyrol affects the expression of AR and PSA and inhibits the malignant behavior of RCC cells
  170. The era of increasing cancer survivorship: Trends in fertility preservation, medico-legal implications, and ethical challenges
  171. Bone scintigraphy and positron emission tomography in the early diagnosis of MRONJ
  172. Meta-analysis of clinical efficacy and safety of immunotherapy combined with chemotherapy in non-small cell lung cancer
  173. Special Issue Computational Intelligence Methodologies Meets Recurrent Cancers - Part IV
  174. Exploration of mRNA-modifying METTL3 oncogene as momentous prognostic biomarker responsible for colorectal cancer development
  175. Special Issue The evolving saga of RNAs from bench to bedside - Part III
  176. Interaction and verification of ferroptosis-related RNAs Rela and Stat3 in promoting sepsis-associated acute kidney injury
  177. The mRNA MOXD1: Link to oxidative stress and prognostic significance in gastric cancer
  178. Special Issue Exploring the biological mechanism of human diseases based on MultiOmics Technology - Part II
  179. Dynamic changes in lactate-related genes in microglia and their role in immune cell interactions after ischemic stroke
  180. A prognostic model correlated with fatty acid metabolism in Ewing’s sarcoma based on bioinformatics analysis
  181. Special Issue Diabetes
  182. Nutritional risk assessment and nutritional support in children with congenital diabetes during surgery
  183. Correlation of the differential expressions of RANK, RANKL, and OPG with obesity in the elderly population in Xinjiang
  184. A discussion on the application of fluorescence micro-optical sectioning tomography in the research of cognitive dysfunction in diabetes
  185. A review of brain research on T2DM-related cognitive dysfunction
  186. Special Issue Biomarker Discovery and Precision Medicine
  187. CircASH1L-mediated tumor progression in triple-negative breast cancer: PI3K/AKT pathway mechanisms
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Heruntergeladen am 22.9.2025 von https://www.degruyterbrill.com/document/doi/10.1515/med-2025-1282/html
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