Effects of Vitamin E on Redox balance in regulating thiol/disulfide homeostasis in sepsis: An antioxidant therapy perspective

Veli Fahri Pehlivan; Başak Pehlivan; Erdogan Duran; Abdullah Taskın; Ismail Koyuncu; Yusuf Çakmak

doi:10.1371/journal.pone.0336334

Abstract

Background

Sepsis, a life-threatening condition resulting from a dysregulated host response to infection, is associated with high mortality and remains a major global health burden. Sepsis is characterized by an imbalance between oxidative stress and inflammation, leading to disruption of thiol–disulfide homeostasis, hematological abnormalities, cytokine dysregulation, and widespread tissue injury.

Methods

An experimental sepsis model was established in thirty-two male Balb-C mice using lipopolysaccharide administration. Animals were randomized into four groups: control, vitamin E, sepsis, and sepsis plus vitamin E. Serum oxidative stress markers, thiol-disulfide parameters, and inflammatory mediators, including C-reactive protein, interleukin-40, and tumor necrosis factor-alpha, were measured. Hematological indices of systemic inflammation were evaluated (Neutrophil-to-Lymphocyte Ratio, Platelet-to-Lymphocyte Ratio), and lung, liver, and kidney tissues were examined histologically using a semi-quantitative scoring system.

Results

Lipopolysaccharide-induced sepsis caused marked disruption of thiol-disulfide balance, characterized by reduced native and total thiol levels, elevated disulfide levels, increased cytokine release, and severe histopathological injury. Vitamin E supplementation restored thiol-disulfide homeostasis, decreased oxidative stress, and attenuated systemic inflammation. In the sepsis plus vitamin E group, serum thiol levels increased significantly, while disulfide levels declined. Interleukin-40 showed a 24.2% reduction and tumor necrosis factor-alpha a 9.8% reduction compared with untreated septic animals. Histopathological analyses confirmed reduced inflammatory cell infiltration, vascular congestion, and tissue degeneration, particularly in the lungs.

Conclusions

Vitamin E demonstrated significant protective effects against sepsis-induced oxidative and inflammatory injury by preserving thiol-disulfide homeostasis and reducing cytokine production. The more pronounced effect on interleukin-40 compared with tumor necrosis factor-alpha suggests selective modulation of inflammatory pathways and highlights interleukin-40 as a potential biomarker and therapeutic target. These findings support vitamin E as a promising adjunctive therapy in sepsis, although further studies are required to define optimal dosing strategies and assess clinical applicability.

Citation: Pehlivan VF, Pehlivan B, Duran E, Taskın A, Koyuncu I, Çakmak Y (2025) Effects of Vitamin E on Redox balance in regulating thiol/disulfide homeostasis in sepsis: An antioxidant therapy perspective. PLoS One 20(11): e0336334. https://doi.org/10.1371/journal.pone.0336334

Editor: Cagri Cakici, Massachusetts General Hospital, UNITED STATES OF AMERICA

Received: March 14, 2025; Accepted: October 23, 2025; Published: November 6, 2025

Copyright: © 2025 Pehlivan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the manuscript and its Supporting Information files.

Funding: The author(s) received no specific funding for this work.

Competing interests: The authors have declared that no competing interests exist.

Introduction

Sepsis is a critical medical condition characterized by a systemic inflammatory response to infection, leading to widespread organ dysfunction and high mortality rates [1,2]. The pathophysiology of sepsis involves a complex cascade of events, including uncontrolled inflammation, oxidative stress, and immune dysregulation [3,4]. Oxidative stress, defined as an imbalance between the production of reactive oxygen species (ROS) and the body’s ability to detoxify them, plays a pivotal role in the progression of sepsis by causing cellular damage and exacerbating the inflammatory response [3,5,6].

Thiol-disulfide homeostasis, a crucial redox balance system, is significantly disrupted during sepsis. Thiols, particularly protein thiols, are vital for maintaining cellular integrity and function, acting as potent antioxidants. The oxidation of thiols to disulfides is a reversible process, and an imbalance in this system reflects increased oxidative stress and impaired antioxidant defense mechanisms [3,7].

Interleukin-40 (IL-40), a newly identified cytokine secreted by activated B cells, has emerged as an important mediator in sepsis pathophysiology. Recent studies have demonstrated that IL-40 modulates sepsis-induced inflammation by blocking NETosis (Neutrophil Extracellular Trap formation) and may serve as both a prognostic biomarker and therapeutic target [8,9]. The ability of IL-40 to prevent multi-organ damage during sepsis highlights its potential significance in understanding and treating this complex condition.

Tumor necrosis factor-alpha (TNF-α), a central mediator of sepsis produced by macrophages and other immune cells, induces endothelial dysfunction, coagulopathy, and organ failure through inflammatory cascades [10,11]. TNF-α can reproduce all clinical signs of sepsis when administered systemically, underscoring its pivotal role in sepsis pathogenesis. Notably, vitamin E, particularly δ-tocotrienol, exerts anti-inflammatory effects by inhibiting TNF-α-induced NF-κB activation and enhancing anti-inflammatory A20 protein expression [12]. These insights emphasize the complex interplay of oxidative stress, thiol-disulfide homeostasis, and key inflammatory mediators such as IL-40 and TNF-α in sepsis pathogenesis.

In clinical practice, hemogram parameters are essential for assessing sepsis severity and the inflammatory response [13,14]. Recently, derived ratios such as neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and neutrophil/lymphocyte × platelet ratio (NLPR) have gained importance as prognostic markers [15,16]. These indices are also thought to reflect oxidative stress through their association with thiol-disulfide homeostasis. Disruptions in both redox balance and hemogram-derived markers suggest a link between oxidative stress and inflammation in sepsis [7,14,17,18].

Vitamin E is a family of fat-soluble compounds consisting of tocopherols and tocotrienols (α, β, γ, δ), all of which possess strong antioxidant properties. Although α-tocopherol is the most common and biologically active form, recent studies have demonstrated that δ-tocotrienol may exert stronger effects, particularly in inflammatory processes [12]. Vitamin E mitigates oxidative stress by scavenging free radicals, protecting cell membranes against lipid peroxidation, and supporting the regeneration of other antioxidants such as vitamin C [11,19,20]. Moreover, its immunomodulatory effects are associated with the regulation of cytokine production, suppression of the NF-κB signaling pathway, and improvement of T-cell functions [12]. Collectively, these properties render vitamin E a potential therapeutic agent in clinical conditions characterized by pronounced oxidative stress and inflammation, such as sepsis.

The primary aim of this study is to comprehensively investigate the effects of vitamin E on redox balance, specifically focusing on thiol-disulfide homeostasis, and its impact on inflammatory markers including IL-40 and TNF-α, as well as hemogram parameters in an experimental LPS-induced sepsis model. This research seeks to clarify whether vitamin E administration can effectively restore redox balance and attenuate the systemic inflammatory response in sepsis.

This study advances current knowledge by providing detailed insights into the specific mechanisms through which vitamin E exerts its protective effects in sepsis, particularly concerning its influence on thiol-disulfide homeostasis and novel inflammatory mediators. While previous studies have explored the general antioxidant properties of vitamin E, our work uniquely highlights its direct role in maintaining critical redox balance during sepsis and its differential effects on emerging biomarkers like IL-40 compared to classical inflammatory mediators like TNF-α. Furthermore, by correlating these biochemical changes with alterations in hemogram parameters and histopathological findings, we offer a more holistic understanding of vitamin E’s therapeutic potential in sepsis management.

Methods

Study design and animals

This experimental study was conducted using an LPS-induced sepsis model in male Balb-C mice. A total of thirty-two male Balb-C mice, weighing 25–30 g and aged 8–10 weeks, were obtained from the Experimental Animal Laboratory of Harran University (HDAM, Sanliurfa, Turkey). The animals were housed under controlled environmental conditions (22 ± 2°C, 12-hour light/dark cycle) with free access to standard rodent chow and water. All experimental procedures were approved by the Harran University Animal Experiments Ethics Committee (Approval No: 2024/006/003) and conducted in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals. Efforts were made to minimize animal suffering and reduce the number of animals used.

Sample size determination

The sample size was determined using G*Power 3.1.9.7 software based on effect sizes reported in previous experimental studies (Cohen’s d = 1.2). With α = 0.05 and β = 0.20 (power = 0.80), a minimum of six animals per group was required [21]. To account for potential attrition, eight animals per group (n = 8) were included. This sample size was considered sufficient to detect significant differences in key biochemical and inflammatory parameters, consistent with both preliminary experimental data and published literature, while adhering to ethical guidelines for animal research.

Experimental groups and treatment protocol

Mice were randomly divided into four experimental groups (n = 8 per group):

1. Control Group (DMSO): Mice in this group received an intraperitoneal (i.p.) injection of Dimethyl Sulfoxide (DMSO), which served as the vehicle for vitamin E.
2. Sepsis Group (LPS): Mice in this group received a single i.p. injection of Lipopolysaccharide (LPS) (Escherichia coli O111:B4, Sigma-Aldrich, USA) at a dose of 10 mg/kg to induce sepsis.
3. Vitamin E Group (Vit E): Mice in this group received a single i.p. injection of vitamin E (alpha-tocopherol, Sigma-Aldrich, USA) at a dose of 100 mg/kg.
4. LPS + Vit E Group: Mice in this group received an i.p. injection of vitamin E (100 mg/kg) 30 minutes prior to the LPS injection (10 mg/kg). This protocol was designed to investigate the prophylactic/preconditioning effects of vitamin E against LPS-induced sepsis.

The vitamin E dose (100 mg/kg) was selected based on previous experimental studies demonstrating antioxidant efficacy within non-toxic ranges [22]. This dose corresponds to a human equivalent of approximately 8 mg/kg, which is considered clinically applicable. The timing of administration (30 minutes prior to LPS) was determined to allow sufficient time for cellular uptake of vitamin E and activation of antioxidant defense mechanisms.

All injections were administered in a total volume of 200 µL. Animals were monitored closely for 24 hours post-LPS injection for signs of sepsis and mortality. At the end of the experimental period, animals were humanely euthanized under deep anesthesia, and blood samples were collected via cardiac puncture for biochemical and hematological analyses. Tissue samples (e.g., liver, kidney, lung) were also collected for histopathological examination.

Biochemical analysis

Serum thiol-disulfide homeostasis parameters, including native thiol, total thiol, and disulfide levels, were evaluated using the automated colorimetric method described by Erel and Neselioglu [3]. This method is based on the reduction of disulfide bonds to thiol groups, allowing for the spectrophotometric measurement of both native and total thiols, from which disulfide levels can be calculated. Results were expressed in µmol/L.

Serum Interleukin-40 (IL-40) and tumor necrosis factor-alpha (TNF-α) levels were quantified using commercial ELISA kits (Sunlong Medical, Cat No: SL1923Ra for IL-40 and EL0013Ra for TNF-α) according to the manufacturer’s instructions. Briefly, samples were applied to 96-well microplates pre-coated with rat-specific antibodies, followed by incubation with biotinylated antibodies and streptavidin–HRP. After washing, substrate solution was added, and the reaction was stopped with an acidic solution. Absorbance was measured at 450 nm using a microplate reader (Cytation-1, BioTek). The assay sensitivities were 1.0 pg/mL for IL-40 and 5.0 pg/mL for TNF-α. All samples were analyzed in duplicate, and only results with a coefficient of variation below 10% were accepted. Calibration curves were generated for each assay, with R² values consistently above 0.99.

Hematological analysis

Hemogram parameters, including white blood cell (WBC) count, neutrophil count, lymphocyte count, platelet count, and red blood cell (RBC) count, were measured using the Alinity HQ (Abbott, USA), a next-generation fully automated hematology analyzer. From these parameters, the Neutrophil-to-Lymphocyte Ratio (NLR), Platelet-to-Lymphocyte Ratio (PLR), and Neutrophil/Lymphocyte × Platelet Ratio (NLPR) were calculated as indicators of systemic inflammation. C-reactive protein (CRP) levels were measured using an enzyme-linked immunosorbent assay (ELISA) kit (R&D Systems, USA) according to the manufacturer’s instructions.

Histopathological examination

Formalin fixed, paraffin embedded lung, liver, and kidney tissue samples were sectioned at 5 µm thickness and stained with hematoxylin and eosin (H&E) for routine histopathological examination. Microscopic evaluation was performed by a blinded, board certified pathologist using a Nikon Eclipse light microscope at ×400 magnification, and representative images were captured with a Nikon DS-Fi2 camera (Nikon, Japan).

Histopathological changes were evaluated using a semi-quantitative scoring system based on the severity and extent of tissue injury: 0 = none, 1 = mild, 2 = marked, 3 = diffuse. For lung tissue, parameters included alveolar damage, bronchial epithelial degeneration/desquamation, interstitial inflammation, emphysematous changes, and vascular congestion [23]. For liver tissue, hepatocyte vacuolar degeneration, portal inflammation, vascular congestion, and necrosis were assessed [24]. For kidney tissue, tubular degeneration/necrosis, glomerular changes, interstitial inflammation, and vascular congestion were scored [25].

Statistical analysis

Statistical analyses were performed using SPSS software (Version 26.0, IBM Corp., Armonk, NY, USA). All continuous variables, including histopathological scores, are presented as mean ± standard deviation (SD). The normality of data distribution was assessed using the Shapiro–Wilk test. For normally distributed data, differences among the four experimental groups (DMSO, Vitamin E, LPS, and LPS + Vitamin E) were analyzed using one-way analysis of variance (One-Way ANOVA). When overall differences were statistically significant, Tukey’s post-hoc test was applied for general biochemical and hematological parameters, while Bonferroni-adjusted post-hoc multiple comparisons were specifically used for histopathological scores to control for type I error.

For non-normally distributed data, the Kruskal–Wallis test was employed, followed by Dunn’s post-hoc test for pairwise comparisons. Pearson’s correlation coefficient was calculated to assess relationships between continuous variables. For histopathological evaluation, semi-quantitative scores (0 = none, 1 = mild, 2 = marked, 3 = diffuse) were assigned based on tissue-specific injury parameters, and groups sharing the same superscript letter were interpreted as not significantly different, whereas groups with different superscript letters were considered significantly different. A p-value < 0.05 was accepted as the threshold for statistical significance. The minimal dataset containing all biochemical, hematological, cytokine, and histopathological parameters used in this study is provided as Supporting Information (Minimal_dataset_thiol_disulfide_sepsis.xlsx).

Results

Vitamin E Preserves Redox Homeostasis and Attenuates Inflammatory Response in Experimental Sepsis

Vitamin E supplementation significantly modulated both redox balance and inflammatory response in the experimental sepsis model. As demonstrated in Table 1, LPS administration led to a marked disruption of thiol-disulfide homeostasis, characterized by decreased native and total thiol levels alongside increased disulfide levels compared with the Control group (p < 0.001). In contrast, treatment with Vitamin E, either alone or in combination with LPS, preserved thiol-disulfide equilibrium, resulting in significantly higher native and total thiol levels and lower disulfide levels than in the Sepsis group (p < 0.001). These findings highlight the antioxidant role of Vitamin E in maintaining redox balance under septic conditions.

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Table 1. Effects of Vitamin E on Serum Thiol–Disulfide Homeostasis Parameters in Experimental Sepsis.

https://doi.org/10.1371/journal.pone.0336334.t001

In parallel, inflammatory markers exhibited significant group differences. Serum levels of IL-40, a newly identified biomarker, and TNF-α, a classical proinflammatory cytokine, were highest in the LPS group, corroborating the successful establishment of the sepsis model and paralleling CRP elevation (p < 0.001). Both IL-40 and TNF-α levels were significantly lower in the DMSO and Vit E groups, and Vitamin E supplementation in the LPS + Vit E group exerted a significant suppressive effect compared with the LPS group (p < 0.05). Interestingly, this anti-inflammatory effect was more pronounced for IL-40 than for TNF-α, with IL-40 levels showing a 24.2% decrease compared to a 9.8% decrease in TNF-α levels, suggesting a selective modulatory action of Vitamin E on specific inflammatory pathways.

Together, these results indicate that Vitamin E supplementation not only preserves thiol-disulfide homeostasis but also attenuates the inflammatory response in sepsis, underscoring its potential as an adjunctive therapeutic agent. However, the differential effects on IL-40 and TNF-α suggest that further investigations into dose optimization, timing, and mechanistic pathways are warranted to maximize clinical efficacy.

Alterations in Hematological Indices and Inflammatory Biomarkers

Analysis of hemogram parameters and inflammatory markers revealed significant alterations in response to LPS-induced sepsis and subsequent vitamin E treatment (Table 2). The Sepsis group exhibited significantly increased NLR, PLR, and CRP levels compared to the Control group (p < 0.05). In the Vit E and LPS + Vit E groups, vitamin E administration led to a significant reduction in CRP levels compared to the Sepsis group (p < 0.05), indicating a clear anti-inflammatory effect. While NLR and PLR showed a trend towards normalization in the vitamin E-treated groups, these changes were not always statistically significant when compared directly to the Sepsis group, suggesting that while vitamin E modulates the inflammatory response, its impact on these specific ratios might be less pronounced or require higher doses/longer treatment durations to achieve statistical significance.

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Table 2. Hematological Parameters of Experimental Groups (WBC, NEU, LYM, PLT, MPV, NLR, PLR, NLPR).

https://doi.org/10.1371/journal.pone.0336334.t002

Correlation Between Antioxidant Activity and Inflammatory Markers: Effect of Vit E

Table 3 demonstrates strong correlations between redox balance markers and inflammatory mediators, highlighting the intricate interplay between oxidative stress and inflammation in sepsis. Native thiol and total thiol levels were strongly and negatively correlated with CRP (r = −0.808 and r = −0.766, respectively; p < 0.001), IL-40 (r = −0.818 and r = −0.811, respectively; p < 0.001), and TNF-α (r = −0.601 and r = −0.642, respectively; p < 0.001), reflecting the decline in antioxidant capacity under inflammatory stress. Conversely, disulfide levels correlated positively with CRP (r = 0.660, p < 0.001) and IL-40 (r = 0.518, p = 0.002), indicating oxidative stress–driven shifts in thiol–disulfide homeostasis. Importantly, the robust negative correlation between native thiol and IL-40 (r = −0.818, p < 0.001) underscores a direct link between loss of antioxidant defenses and elevation of this novel inflammatory biomarker. This finding suggests that IL-40 may not only serve as an inflammatory mediator but also as an integrative biomarker reflecting the redox inflammation axis in sepsis.

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Table 3. Correlation analysis between thiol-disulfide homeostasis parameters, inflammatory markers, and hemogram indices in the experimental groups.

https://doi.org/10.1371/journal.pone.0336334.t003

In addition, antioxidant parameters (native thiol and total thiol) showed modest but significant negative associations with hemogram-derived indices (NLR, PLR, NLPR, and MPV), while disulfide levels correlated positively with these ratios. Although hematological indices capture systemic inflammation, their weaker correlations relative to thiol–disulfide markers suggest lower sensitivity in reflecting oxidative stress.

Collectively, these findings underscore that thiol–disulfide homeostasis is intricately linked with both classical (CRP, TNF-α) and emerging (IL-40) inflammatory markers, positioning it as a critical integrative biomarker at the intersection of oxidative and inflammatory cascades in sepsis. By combining mechanistic insight with clinical applicability, thiol–disulfide homeostasis, together with established and novel cytokines, provides a comprehensive biomarker framework for assessing disease severity and progression.

Histopathological Findings

Histopathological examination of lung, liver, and kidney tissues was conducted using a validated semi-quantitative scoring system to evaluate inflammatory cell infiltration, vascular congestion, alveolar alterations, and parenchymal cellular degeneration. In the Control group (DMSO), no pathological alterations were observed; lung, liver, and kidney structures remained intact with histopathological scores consistently at zero, thereby confirming preserved tissue integrity (Table 4, Fig 1).

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Table 4. Histopathological Scoring of Sepsis-Induced Organ Damage and the Protective Role of Vitamin E: Lung, Liver, and Kidney Assessment.

https://doi.org/10.1371/journal.pone.0336334.t004

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Fig 1. Lung, liver and kidney tissue sections of the groups.

https://doi.org/10.1371/journal.pone.0336334.g001

Histopathological analysis revealed that LPS-induced sepsis produced extensive multi-organ injury, with significant pathological alterations observed in the lung, liver, and kidney. Lung tissues demonstrated emphysematous changes, epithelial desquamation, diffuse vascular congestion, and interstitial inflammation. The liver displayed pronounced vascular congestion, hepatocyte vacuolar degeneration, and coagulative necrosis, while kidneys exhibited tubular necrosis, inflammatory infiltration, and diffuse congestion. These changes were reflected in markedly elevated histopathological scores across all evaluated parameters compared with controls (p < 0.001), confirming severe sepsis-induced structural damage.

In contrast, animals treated with Vitamin E prior to LPS challenge showed attenuated pathological severity. Pulmonary sections exhibited reduced emphysematous changes and less congestion, hepatic tissues demonstrated milder hepatocellular degeneration, and kidneys displayed decreased tubular necrosis and inflammatory cell infiltration. However, post-hoc statistical analysis indicated that these improvements did not consistently reach significance, with the exception of specific pulmonary parameters where Vitamin E exerted a significant protective effect (p < 0.01). Importantly, animals receiving Vitamin E alone displayed preserved histoarchitecture without pathological alterations, similar to controls.

Overall, these results demonstrate that LPS-induced sepsis causes profound structural damage to multiple organs, while Vitamin E confers partial histological protection, particularly in lung tissue. Although a single-dose regimen provided measurable benefit, the incomplete normalization of histopathological scores suggests that optimized dosing strategies may be required to achieve robust, multi-organ protection.

Discussion

This study evaluated the protective effects of vitamin E on oxidative stress, thiol–disulfide homeostasis, and inflammatory responses in an LPS-induced experimental sepsis model. Our findings demonstrate that vitamin E supplementation preserved thiol–disulfide homeostasis, reduced oxidative stress, and attenuated systemic inflammation, thereby mitigating tissue injury in septic mice. A particularly novel aspect of this work is the observation that Interleukin-40 (IL-40), a recently identified cytokine predominantly secreted by activated B cells and involved in both B-cell activation and regulation of NETosis [9] exhibited greater responsiveness to vitamin E treatment than TNF-α. This differential modulation highlights IL-40’s potential as both an integrative biomarker of oxidative–inflammatory burden and a therapeutic target in sepsis. Consistent with recent reports showing that IL-40 inhibition prevents multi-organ injury and improves survival in sepsis models [9] our results suggest that vitamin E’s protective effects extend beyond its established antioxidant actions to include selective modulation of emerging inflammatory pathways with possible clinical relevance.

Oxidative stress remains a central driver of sepsis-related organ dysfunction [5,6]. The observed reduction in native and total thiol levels with concomitant increases in disulfide levels in septic animals confirms the disruption of thiol–disulfide homeostasis. Restoration of these parameters in the LPS + Vitamin E group underscores vitamin E’s capacity to stabilize redox balance, in line with literature emphasizing thiol–disulfide dynamics as sensitive indicators of oxidative stress in systemic inflammation [3,26]. Mechanistically, α-tocopherol protects cell membranes from lipid peroxidation, modulates protein kinase C, and suppresses NF-κB signaling, thereby reducing pro-inflammatory cytokine expression [11,12,19,20]. The decline in TNF-α observed in our model supports this mechanism, while enhanced antioxidant enzyme activities described in prior studies may further explain the preservation of thiol–disulfide homeostasis.

Systemic inflammation in sepsis involves multiple interacting pathways [2]. Clinical indices such as NLR, PLR, and CRP are widely applied prognostic tools [13–16,18,27]. In our study, vitamin E supplementation reduced CRP levels significantly, whereas improvements in NLR and PLR were modest, reflecting variable responsiveness of hematological markers to therapeutic interventions [28,29]. Importantly, vitamin E also suppressed IL-40 and TNF-α levels, reinforcing its dual antioxidant and anti-inflammatory actions. While TNF-α and IL-6 are established mediators of the septic cascade [30–33] the stronger modulation of IL-40 in our study supports its potential role as a novel biomarker of disease activity and treatment response in sepsis [9].

Histopathological analyses corroborated the biochemical findings. LPS-induced sepsis resulted in severe pulmonary, hepatic, and renal damage, including vascular congestion, alveolar and tubular injury, and hepatocellular necrosis. Vitamin E conferred partial but consistent protection, with the most significant improvements observed in pulmonary structures (p < 0.01). Although protection in liver and kidney tissues was less pronounced, overall injury severity was reduced compared to untreated septic animals. Vitamin E alone caused no pathological alterations, supporting its safety profile. These results suggest that vitamin E can mitigate, but not completely prevent, sepsis-induced multi-organ injury.

Limitations

This study has several limitations. First, only a single dose of vitamin E (100 mg/kg) was administered at one time point. Although this corresponds to a human equivalent of approximately 560 mg/day (well above typical dietary intake but within the therapeutic range [34] the effects of repeated or dose-escalated regimens remain unexplored. Determining the optimal dosing strategy and therapeutic window (e.g., preconditioning vs. therapeutic intervention) will require further investigation [19,35,36]. Second, measurement of IL-40, a cytokine highlighted in this study, is not yet routinely available in clinical laboratories, which currently limits its translational applicability. Nonetheless, our findings suggest that IL-40 holds promise as both a novel biomarker and a potential therapeutic target in sepsis. Finally, while the LPS-induced mouse model provides a reliable platform for studying acute systemic inflammation, it does not fully replicate the complexity and heterogeneity of human sepsis. Therefore, extrapolation to clinical practice should be made with caution. Carefully designed clinical studies remain essential to validate both the efficacy and safety of vitamin E as an adjunctive therapy in sepsis patients [37].

Conclusion

In conclusion, vitamin E supplementation attenuated oxidative stress, preserved thiol–disulfide homeostasis, and reduced systemic inflammation in an LPS-induced sepsis model. Notably, modulation of IL-40 a recently described cytokine involved in B-cell activation and NETosis was more pronounced than that of TNF-α, highlighting its potential as a novel biomarker and therapeutic target. Histopathological findings further confirmed partial organ protection, most evident in pulmonary tissues. These results suggest that vitamin E holds promise as an adjunctive therapy in sepsis, though clinical translation will require optimized dosing strategies and validation in human trials.

Supporting information

S1 File. The minimal dataset necessary to replicate the study findings has been uploaded as Supporting Information (Minimal dataset thiol disulfide sepsis.xlsx).

https://doi.org/10.1371/journal.pone.0336334.s001

(XLSX)

Acknowledgments

We gratefully acknowledge the guidance and support of Prof. Dr. Mehmet Emin Güldür, whose academic expertise and encouragement greatly contributed to the successful completion of this study.

References

1. Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):801–10. pmid:26903338
- View Article
- PubMed/NCBI
- Google Scholar
2. Marques A, Torre C, Pinto R, Sepodes B, Rocha J. Treatment Advances in Sepsis and Septic Shock: Modulating Pro- and Anti-Inflammatory Mechanisms. J Clin Med. 2023;12(8):2892. pmid:37109229
- View Article
- PubMed/NCBI
- Google Scholar
3. Avcioğlu G, Otal Y, Erel Ö. New markers in the etiopathogenesis of bacterial sepsis: Intracellular glutathione and extracellular thiol/disulfide homeostasis. Wiley. 2024.
- View Article
- Google Scholar
4. Angus DC, van der Poll T. Severe sepsis and septic shock. N Engl J Med. 2013;369(9):840–51. pmid:23984731
- View Article
- PubMed/NCBI
- Google Scholar
5. Pei H, Qu J, Chen J-M, Zhang Y-L, Zhang M, Zhao G-J, et al. The effects of antioxidant supplementation on short-term mortality in sepsis patients. Heliyon. 2024;10(8):e29156. pmid:38644822
- View Article
- PubMed/NCBI
- Google Scholar
6. Kumar S, Srivastava VK, Kaushik S, Saxena J, Jyoti A. Free Radicals, Mitochondrial Dysfunction and Sepsis-induced Organ Dysfunction: A Mechanistic Insight. Curr Pharm Des. 2024;30(3):161–8. pmid:38243948
- View Article
- PubMed/NCBI
- Google Scholar
7. Grassïe SS, Atakent ŞD, Şahïn kavakli H, Çetïnkaya ethemoğlu FB, Balik AR, Erel Ö. Investigation of thiol/disulfide homeostasis changes and their relationship with prognosis in sepsis patients. Anadolu Kliniği Tıp Bilimleri Dergisi. 2024;29(1):13–8.
- View Article
- Google Scholar
8. Mohammed KIA, L-Alwany AAHA, Ali SHM, Ali WM, AL-Fakhar SA, Mousa JM. Levels of Interleukin - 40 and Lipid Profile in patients with Helicobacter pylori Infection. Haya: Saudi J Life Sci. 2024;9(07):295–8.
- View Article
- Google Scholar
9. Cai S, Li X, Zhang C, Jiang Y, Liu Y, He Z, et al. Inhibition of Interleukin-40 prevents multi-organ damage during sepsis by blocking NETosis. Crit Care. 2025;29(1):29. pmid:39819454
- View Article
- PubMed/NCBI
- Google Scholar
10. Khanduja KL, Avti PK, Kumar S, Pathania V, Pathak CM. Inhibitory effect of vitamin E on proinflammatory cytokines-and endotoxin-induced nitric oxide release in alveolar macrophages. Life Sci. 2005;76(23):2669–80. pmid:15792834
- View Article
- PubMed/NCBI
- Google Scholar
11. Ungurianu A, Zanfirescu A, Nițulescu G, Margină D. Vitamin E beyond Its Antioxidant Label. Antioxidants (Basel). 2021;10(5):634. pmid:33919211
- View Article
- PubMed/NCBI
- Google Scholar
12. Yang C, Jiang Q. Vitamin E δ-tocotrienol inhibits TNF-α-stimulated NF-κB activation by up-regulation of anti-inflammatory A20 via modulation of sphingolipid including elevation of intracellular dihydroceramides. J Nutr Biochem. 2019;64:101–9. pmid:30471562
- View Article
- PubMed/NCBI
- Google Scholar
13. Gupta A, Gupta R. Study of hematological parameters in sepsis patients and its prognostic implications. Int J Res Med Sci. 2019;7(3):828.
- View Article
- Google Scholar
14. Moon D-H, Kim A, Song B-W, Kim Y-K, Kim G-T, Ahn E-Y, et al. High Baseline Neutrophil-to-Lymphocyte Ratio Could Serve as a Biomarker for Tumor Necrosis Factor-Alpha Blockers and Their Discontinuation in Patients with Ankylosing Spondylitis. Pharmaceuticals (Basel). 2023;16(3):379. pmid:36986479
- View Article
- PubMed/NCBI
- Google Scholar
15. Purwoko P, Dewi FH, Prihandana PA. Correlation between elevated neutrophil lymphocyte ratio, vasotropic inotropic score, cumulative fluid balance and level of reactive oxygen species in septic patients. Vestn anesteziol reanimatol. 2024;21(4):60–8.
- View Article
- Google Scholar
16. Zhang Y, Peng W, Zheng X. The prognostic value of the combined neutrophil-to-lymphocyte ratio (NLR) and neutrophil-to-platelet ratio (NPR) in sepsis. Sci Rep. 2024;14(1):15075. pmid:38956445
- View Article
- PubMed/NCBI
- Google Scholar
17. Singhal A, Dubey S, Khan S, Tiwari R, Das S, Ahmad R. Neutrophil-to-Lymphocyte Ratio and Procalcitonin in Sepsis Patients: Do They Have Any Prognostic Significance?. Cureus. 2024;16(6):e62360. pmid:39006695
- View Article
- PubMed/NCBI
- Google Scholar
18. Al-Osami MH, Awadh NI, Khalid KB, Awadh AI. Neutrophil/lymphocyte and platelet/lymphocyte ratios as potential markers of disease activity in patients with Ankylosing spondylitis: a case-control study. Adv Rheumatol. 2020;60(1):13. pmid:32000859
- View Article
- PubMed/NCBI
- Google Scholar
19. Miyazawa T, Burdeos GC, Itaya M, Nakagawa K, Miyazawa T. Vitamin E: Regulatory Redox Interactions. IUBMB Life. 2019;71(4):430–41. pmid:30681767
- View Article
- PubMed/NCBI
- Google Scholar
20. El-Feki MA, Amin HM, Abdalla AA, Fesal M. Immunomodulatory and anti-oxidant effects of alpha-lipoic acid and vitamin E on lipopolysaccharide-induced liver injury in rats. Middle East Journal of Applied Sciences. 2016;06:460–7.
- View Article
- Google Scholar
21. Constantino L, Galant LS, Vuolo F, Guarido KL, Kist LW, de Oliveira GMT, et al. Extracellular superoxide dismutase is necessary to maintain renal blood flow during sepsis development. Intensive Care Med Exp. 2017;5(1):15. pmid:28303482
- View Article
- PubMed/NCBI
- Google Scholar
22. Belisle SE, Leka LS, Delgado-Lista J, Jacques PF, Ordovas JM, Meydani SN. Polymorphisms at cytokine genes may determine the effect of vitamin E on cytokine production in the elderly. J Nutr. 2009;139(10):1855–60. pmid:19710156
- View Article
- PubMed/NCBI
- Google Scholar
23. Gokbulut P, Kuskonmaz SM, Koc G, Onder CE, Yumusak N, Erel O, et al. Evaluation of the effects of empagliflozin on acute lung injury in rat intestinal ischemia-reperfusion model. J Endocrinol Invest. 2023;46(5):1017–26. pmid:36495440
- View Article
- PubMed/NCBI
- Google Scholar
24. Koc G, Kuskonmaz SM, Demirel K, Koca G, Akbulut A, Yumusak N, et al. Ameliorating effects of N-acetyl cysteine against early liver damage of radioiodine in rats. Nucl Med Commun. 2021;42(11):1195–201. pmid:34149008
- View Article
- PubMed/NCBI
- Google Scholar
25. Yumusak N, Sadic M, Yucel G, Atilgan HI, Koca G, Korkmaz M. Apoptosis and cell proliferation in short-term and long-term effects of radioiodine-131-induced kidney damage: an experimental and immunohistochemical study. Nucl Med Commun. 2018;39(2):131–9. pmid:29257007
- View Article
- PubMed/NCBI
- Google Scholar
26. Hasturk D, Akturk Esen S, Sahiner ES, Erel O, Neselioglu S, Aydogan N, et al. Thiol-disulfide homeostasis and ischemia modified albumin levels in patients diagnosed with ovary carcinoma. Sci Rep. 2025;15(1):19729. pmid:40473830
- View Article
- PubMed/NCBI
- Google Scholar
27. Orfanu AE, Popescu C, Leuștean A, Negru AR, Tilişcan C, Aramă V, et al. The Importance of Haemogram Parameters in the Diagnosis and Prognosis of Septic Patients. J Crit Care Med (Targu Mures). 2017;3(3):105–10. pmid:29967880
- View Article
- PubMed/NCBI
- Google Scholar
28. Anoun J, Ajmi M, Riahi S, Dhaha Y, Mbarki D, Ben Hassine I, et al. Neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios in bacterial infections: contributions to diagnostic strategies in a tertiary care hospital in Tunisia. F1000Res. 2024;13:978. pmid:39296886
- View Article
- PubMed/NCBI
- Google Scholar
29. Adamescu A-I, Tilișcan C, Stratan LM, Mihai N, Ganea O-A, Ciobanu S, et al. Decoding Inflammation: The Role of Neutrophil-to-Lymphocyte Ratio and Platelet-to-Lymphocyte Ratio in Predicting Critical Outcomes in COVID-19 Patients. Medicina (Kaunas). 2025;61(4):634. pmid:40282925
- View Article
- PubMed/NCBI
- Google Scholar
30. Bhol NK, Bhanjadeo MM, Singh AK, Dash UC, Ojha RR, Majhi S, et al. The interplay between cytokines, inflammation, and antioxidants: mechanistic insights and therapeutic potentials of various antioxidants and anti-cytokine compounds. Biomed Pharmacother. 2024;178:117177. pmid:39053423
- View Article
- PubMed/NCBI
- Google Scholar
31. Yang Z, Gao Y, Zhao L, Lv X, Du Y. Molecular mechanisms of Sepsis attacking the immune system and solid organs. Front Med (Lausanne). 2024;11:1429370. pmid:39267971
- View Article
- PubMed/NCBI
- Google Scholar
32. Wang W, Mu S, Yan D, Qin H, Zheng Z. Comprehending toll-like receptors: pivotal element in the pathogenesis of sepsis and its complications. Front Immunol. 2025;16:1591011. pmid:40386784
- View Article
- PubMed/NCBI
- Google Scholar
33. Baddam S, Burns B. Systemic Inflammatory Response Syndrome. 2025.
34. Asbaghi O, Sadeghian M, Nazarian B, Sarreshtedari M, Mozaffari-Khosravi H, Maleki V, et al. The effect of vitamin E supplementation on selected inflammatory biomarkers in adults: a systematic review and meta-analysis of randomized clinical trials. Sci Rep. 2020;10(1):17234. pmid:33057114
- View Article
- PubMed/NCBI
- Google Scholar
35. Kim O-H, Kim TW, Kang H, Jeon TJ, Chang ES, Lee HJ, et al. Early, very high-dose, and prolonged vitamin C administration in murine sepsis. Sci Rep. 2025;15(1):17513. pmid:40394136
- View Article
- PubMed/NCBI
- Google Scholar
36. Vandervelden S, Cortens B, Fieuws S, Eegdeman W, Malinverni S, Vanhove P, et al. Early administration of vitamin C in patients with sepsis or septic shock in emergency departments: a multicenter, double-blind, randomized controlled trial: the C-EASIE trial. Crit Care. 2025;29(1):160. pmid:40269974
- View Article
- PubMed/NCBI
- Google Scholar
37. Demir O. Sepsis: An Overview of Current Therapies and Future Research. J Clin Pract Res. 2025;47(2):99–110.
- View Article
- Google Scholar

[ref1] 1. Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):801–10. pmid:26903338
View Article
PubMed/NCBI
Google Scholar

[2] View Article

[3] PubMed/NCBI

[4] Google Scholar

[ref2] 2. Marques A, Torre C, Pinto R, Sepodes B, Rocha J. Treatment Advances in Sepsis and Septic Shock: Modulating Pro- and Anti-Inflammatory Mechanisms. J Clin Med. 2023;12(8):2892. pmid:37109229
View Article
PubMed/NCBI
Google Scholar

[6] View Article

[7] PubMed/NCBI

[8] Google Scholar

[ref3] 3. Avcioğlu G, Otal Y, Erel Ö. New markers in the etiopathogenesis of bacterial sepsis: Intracellular glutathione and extracellular thiol/disulfide homeostasis. Wiley. 2024.
View Article
Google Scholar

[10] View Article

[11] Google Scholar

[ref4] 4. Angus DC, van der Poll T. Severe sepsis and septic shock. N Engl J Med. 2013;369(9):840–51. pmid:23984731
View Article
PubMed/NCBI
Google Scholar

[13] View Article

[14] PubMed/NCBI

[15] Google Scholar

[ref5] 5. Pei H, Qu J, Chen J-M, Zhang Y-L, Zhang M, Zhao G-J, et al. The effects of antioxidant supplementation on short-term mortality in sepsis patients. Heliyon. 2024;10(8):e29156. pmid:38644822
View Article
PubMed/NCBI
Google Scholar

[17] View Article

[18] PubMed/NCBI

[19] Google Scholar

[ref6] 6. Kumar S, Srivastava VK, Kaushik S, Saxena J, Jyoti A. Free Radicals, Mitochondrial Dysfunction and Sepsis-induced Organ Dysfunction: A Mechanistic Insight. Curr Pharm Des. 2024;30(3):161–8. pmid:38243948
View Article
PubMed/NCBI
Google Scholar

[21] View Article

[22] PubMed/NCBI

[23] Google Scholar

[ref7] 7. Grassïe SS, Atakent ŞD, Şahïn kavakli H, Çetïnkaya ethemoğlu FB, Balik AR, Erel Ö. Investigation of thiol/disulfide homeostasis changes and their relationship with prognosis in sepsis patients. Anadolu Kliniği Tıp Bilimleri Dergisi. 2024;29(1):13–8.
View Article
Google Scholar

[25] View Article

[26] Google Scholar

[ref8] 8. Mohammed KIA, L-Alwany AAHA, Ali SHM, Ali WM, AL-Fakhar SA, Mousa JM. Levels of Interleukin - 40 and Lipid Profile in patients with Helicobacter pylori Infection. Haya: Saudi J Life Sci. 2024;9(07):295–8.
View Article
Google Scholar

[28] View Article

[29] Google Scholar

[ref9] 9. Cai S, Li X, Zhang C, Jiang Y, Liu Y, He Z, et al. Inhibition of Interleukin-40 prevents multi-organ damage during sepsis by blocking NETosis. Crit Care. 2025;29(1):29. pmid:39819454
View Article
PubMed/NCBI
Google Scholar

[31] View Article

[32] PubMed/NCBI

[33] Google Scholar

[ref10] 10. Khanduja KL, Avti PK, Kumar S, Pathania V, Pathak CM. Inhibitory effect of vitamin E on proinflammatory cytokines-and endotoxin-induced nitric oxide release in alveolar macrophages. Life Sci. 2005;76(23):2669–80. pmid:15792834
View Article
PubMed/NCBI
Google Scholar

[35] View Article

[36] PubMed/NCBI

[37] Google Scholar

[ref11] 11. Ungurianu A, Zanfirescu A, Nițulescu G, Margină D. Vitamin E beyond Its Antioxidant Label. Antioxidants (Basel). 2021;10(5):634. pmid:33919211
View Article
PubMed/NCBI
Google Scholar

[39] View Article

[40] PubMed/NCBI

[41] Google Scholar

[ref12] 12. Yang C, Jiang Q. Vitamin E δ-tocotrienol inhibits TNF-α-stimulated NF-κB activation by up-regulation of anti-inflammatory A20 via modulation of sphingolipid including elevation of intracellular dihydroceramides. J Nutr Biochem. 2019;64:101–9. pmid:30471562
View Article
PubMed/NCBI
Google Scholar

[43] View Article

[44] PubMed/NCBI

[45] Google Scholar

[ref13] 13. Gupta A, Gupta R. Study of hematological parameters in sepsis patients and its prognostic implications. Int J Res Med Sci. 2019;7(3):828.
View Article
Google Scholar

[47] View Article

[48] Google Scholar

[ref14] 14. Moon D-H, Kim A, Song B-W, Kim Y-K, Kim G-T, Ahn E-Y, et al. High Baseline Neutrophil-to-Lymphocyte Ratio Could Serve as a Biomarker for Tumor Necrosis Factor-Alpha Blockers and Their Discontinuation in Patients with Ankylosing Spondylitis. Pharmaceuticals (Basel). 2023;16(3):379. pmid:36986479
View Article
PubMed/NCBI
Google Scholar

[50] View Article

[51] PubMed/NCBI

[52] Google Scholar

[ref15] 15. Purwoko P, Dewi FH, Prihandana PA. Correlation between elevated neutrophil lymphocyte ratio, vasotropic inotropic score, cumulative fluid balance and level of reactive oxygen species in septic patients. Vestn anesteziol reanimatol. 2024;21(4):60–8.
View Article
Google Scholar

[54] View Article

[55] Google Scholar

[ref16] 16. Zhang Y, Peng W, Zheng X. The prognostic value of the combined neutrophil-to-lymphocyte ratio (NLR) and neutrophil-to-platelet ratio (NPR) in sepsis. Sci Rep. 2024;14(1):15075. pmid:38956445
View Article
PubMed/NCBI
Google Scholar

[57] View Article

[58] PubMed/NCBI

[59] Google Scholar

[ref17] 17. Singhal A, Dubey S, Khan S, Tiwari R, Das S, Ahmad R. Neutrophil-to-Lymphocyte Ratio and Procalcitonin in Sepsis Patients: Do They Have Any Prognostic Significance?. Cureus. 2024;16(6):e62360. pmid:39006695
View Article
PubMed/NCBI
Google Scholar

[61] View Article

[62] PubMed/NCBI

[63] Google Scholar

[ref18] 18. Al-Osami MH, Awadh NI, Khalid KB, Awadh AI. Neutrophil/lymphocyte and platelet/lymphocyte ratios as potential markers of disease activity in patients with Ankylosing spondylitis: a case-control study. Adv Rheumatol. 2020;60(1):13. pmid:32000859
View Article
PubMed/NCBI
Google Scholar

[65] View Article

[66] PubMed/NCBI

[67] Google Scholar

[ref19] 19. Miyazawa T, Burdeos GC, Itaya M, Nakagawa K, Miyazawa T. Vitamin E: Regulatory Redox Interactions. IUBMB Life. 2019;71(4):430–41. pmid:30681767
View Article
PubMed/NCBI
Google Scholar

[69] View Article

[70] PubMed/NCBI

[71] Google Scholar

[ref20] 20. El-Feki MA, Amin HM, Abdalla AA, Fesal M. Immunomodulatory and anti-oxidant effects of alpha-lipoic acid and vitamin E on lipopolysaccharide-induced liver injury in rats. Middle East Journal of Applied Sciences. 2016;06:460–7.
View Article
Google Scholar

[73] View Article

[74] Google Scholar

[ref21] 21. Constantino L, Galant LS, Vuolo F, Guarido KL, Kist LW, de Oliveira GMT, et al. Extracellular superoxide dismutase is necessary to maintain renal blood flow during sepsis development. Intensive Care Med Exp. 2017;5(1):15. pmid:28303482
View Article
PubMed/NCBI
Google Scholar

[76] View Article

[77] PubMed/NCBI

[78] Google Scholar

[ref22] 22. Belisle SE, Leka LS, Delgado-Lista J, Jacques PF, Ordovas JM, Meydani SN. Polymorphisms at cytokine genes may determine the effect of vitamin E on cytokine production in the elderly. J Nutr. 2009;139(10):1855–60. pmid:19710156
View Article
PubMed/NCBI
Google Scholar

[80] View Article

[81] PubMed/NCBI

[82] Google Scholar

[ref23] 23. Gokbulut P, Kuskonmaz SM, Koc G, Onder CE, Yumusak N, Erel O, et al. Evaluation of the effects of empagliflozin on acute lung injury in rat intestinal ischemia-reperfusion model. J Endocrinol Invest. 2023;46(5):1017–26. pmid:36495440
View Article
PubMed/NCBI
Google Scholar

[84] View Article

[85] PubMed/NCBI

[86] Google Scholar

[ref24] 24. Koc G, Kuskonmaz SM, Demirel K, Koca G, Akbulut A, Yumusak N, et al. Ameliorating effects of N-acetyl cysteine against early liver damage of radioiodine in rats. Nucl Med Commun. 2021;42(11):1195–201. pmid:34149008
View Article
PubMed/NCBI
Google Scholar

[88] View Article

[89] PubMed/NCBI

[90] Google Scholar

[ref25] 25. Yumusak N, Sadic M, Yucel G, Atilgan HI, Koca G, Korkmaz M. Apoptosis and cell proliferation in short-term and long-term effects of radioiodine-131-induced kidney damage: an experimental and immunohistochemical study. Nucl Med Commun. 2018;39(2):131–9. pmid:29257007
View Article
PubMed/NCBI
Google Scholar

[92] View Article

[93] PubMed/NCBI

[94] Google Scholar

[ref26] 26. Hasturk D, Akturk Esen S, Sahiner ES, Erel O, Neselioglu S, Aydogan N, et al. Thiol-disulfide homeostasis and ischemia modified albumin levels in patients diagnosed with ovary carcinoma. Sci Rep. 2025;15(1):19729. pmid:40473830
View Article
PubMed/NCBI
Google Scholar

[96] View Article

[97] PubMed/NCBI

[98] Google Scholar

[ref27] 27. Orfanu AE, Popescu C, Leuștean A, Negru AR, Tilişcan C, Aramă V, et al. The Importance of Haemogram Parameters in the Diagnosis and Prognosis of Septic Patients. J Crit Care Med (Targu Mures). 2017;3(3):105–10. pmid:29967880
View Article
PubMed/NCBI
Google Scholar

[100] View Article

[101] PubMed/NCBI

[102] Google Scholar

[ref28] 28. Anoun J, Ajmi M, Riahi S, Dhaha Y, Mbarki D, Ben Hassine I, et al. Neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios in bacterial infections: contributions to diagnostic strategies in a tertiary care hospital in Tunisia. F1000Res. 2024;13:978. pmid:39296886
View Article
PubMed/NCBI
Google Scholar

[104] View Article

[105] PubMed/NCBI

[106] Google Scholar

[ref29] 29. Adamescu A-I, Tilișcan C, Stratan LM, Mihai N, Ganea O-A, Ciobanu S, et al. Decoding Inflammation: The Role of Neutrophil-to-Lymphocyte Ratio and Platelet-to-Lymphocyte Ratio in Predicting Critical Outcomes in COVID-19 Patients. Medicina (Kaunas). 2025;61(4):634. pmid:40282925
View Article
PubMed/NCBI
Google Scholar

[108] View Article

[109] PubMed/NCBI

[110] Google Scholar

[ref30] 30. Bhol NK, Bhanjadeo MM, Singh AK, Dash UC, Ojha RR, Majhi S, et al. The interplay between cytokines, inflammation, and antioxidants: mechanistic insights and therapeutic potentials of various antioxidants and anti-cytokine compounds. Biomed Pharmacother. 2024;178:117177. pmid:39053423
View Article
PubMed/NCBI
Google Scholar

[112] View Article

[113] PubMed/NCBI

[114] Google Scholar

[ref31] 31. Yang Z, Gao Y, Zhao L, Lv X, Du Y. Molecular mechanisms of Sepsis attacking the immune system and solid organs. Front Med (Lausanne). 2024;11:1429370. pmid:39267971
View Article
PubMed/NCBI
Google Scholar

[116] View Article

[117] PubMed/NCBI

[118] Google Scholar

[ref32] 32. Wang W, Mu S, Yan D, Qin H, Zheng Z. Comprehending toll-like receptors: pivotal element in the pathogenesis of sepsis and its complications. Front Immunol. 2025;16:1591011. pmid:40386784
View Article
PubMed/NCBI
Google Scholar

[120] View Article

[121] PubMed/NCBI

[122] Google Scholar

[ref33] 33. Baddam S, Burns B. Systemic Inflammatory Response Syndrome. 2025.

[ref34] 34. Asbaghi O, Sadeghian M, Nazarian B, Sarreshtedari M, Mozaffari-Khosravi H, Maleki V, et al. The effect of vitamin E supplementation on selected inflammatory biomarkers in adults: a systematic review and meta-analysis of randomized clinical trials. Sci Rep. 2020;10(1):17234. pmid:33057114
View Article
PubMed/NCBI
Google Scholar

[125] View Article

[126] PubMed/NCBI

[127] Google Scholar

[ref35] 35. Kim O-H, Kim TW, Kang H, Jeon TJ, Chang ES, Lee HJ, et al. Early, very high-dose, and prolonged vitamin C administration in murine sepsis. Sci Rep. 2025;15(1):17513. pmid:40394136
View Article
PubMed/NCBI
Google Scholar

[129] View Article

[130] PubMed/NCBI

[131] Google Scholar

[ref36] 36. Vandervelden S, Cortens B, Fieuws S, Eegdeman W, Malinverni S, Vanhove P, et al. Early administration of vitamin C in patients with sepsis or septic shock in emergency departments: a multicenter, double-blind, randomized controlled trial: the C-EASIE trial. Crit Care. 2025;29(1):160. pmid:40269974
View Article
PubMed/NCBI
Google Scholar

[133] View Article

[134] PubMed/NCBI

[135] Google Scholar

[ref37] 37. Demir O. Sepsis: An Overview of Current Therapies and Future Research. J Clin Pract Res. 2025;47(2):99–110.
View Article
Google Scholar

[137] View Article

[138] Google Scholar

Figures

Abstract

Background

Methods

Results

Conclusions

Introduction

Methods

Study design and animals

Sample size determination

Experimental groups and treatment protocol

Biochemical analysis

Hematological analysis

Histopathological examination

Statistical analysis

Results

Vitamin E Preserves Redox Homeostasis and Attenuates Inflammatory Response in Experimental Sepsis

Alterations in Hematological Indices and Inflammatory Biomarkers

Correlation Between Antioxidant Activity and Inflammatory Markers: Effect of Vit E

Histopathological Findings

Discussion

Limitations

Conclusion

Supporting information

S1 File. The minimal dataset necessary to replicate the study findings has been uploaded as Supporting Information (Minimal dataset thiol disulfide sepsis.xlsx).

Acknowledgments

References