Search Results (93)

Background: Punicalagin (Pg), a major ellagitannin derived from pomegranates, possesses antimicrobial, antioxidant, and immunomodulatory properties, suggesting its potential as an adjunctive therapy for sepsis. Objectives: This study investigated the synergistic effects of punicalagin and meropenem in a murine model of sublethal sepsis induced by cecal ligation and puncture (CLP). Methods: Mice were treated with punicalagin and meropenem, and multiple parameters were analyzed, including hematological indices, bacterial burden, lymphoid organ cellularity, cytokine profiles (IL-2, IL-4, IL-6, IL-10, IL-17, IFN-γ, TNF-α), nitric oxide (NO) production, and organ histopathology. Results: Punicalagin enhanced NO-mediated antimicrobial responses, increased neutrophil migration, preserved lymphoid cellularity, and significantly reduced the bacterial translocation. Combined therapy with meropenem improved systemic IL-10 levels and mitigated histopathological damage in the liver, kidney, intestine, and lung. Importantly, punicalagin did not induce thrombocytopenia. Conclusions: These results support the potential of punicalagin as an adjunctive agent to antibiotics for sepsis treatment, offering both antimicrobial and immunoregulatory benefits. Further studies are required to explore its clinical applicability. Full article

Background: Sepsis-induced acute lung injury (ALI) is a serious disease constituting a heavy burden on society due to high mortality and morbidity. Inflammation and oxidative stress constitute key pathological mechanisms in ALI caused by sepsis. LL-37 can improve the survival of septic mice. Nevertheless, its function and underlying mechanism in sepsis-evoked ALI is elusive. Methods: The human A549 alveolar epithelial cell line was treated with LL-37 or ZBP1 recombinant vector under LPS exposure. Then, the effects on cell oxidative stress injury, inflammatory response, and autophagy were analyzed. RNA-seq analysis was performed to detect the differentially expressed genes (DEGs) between the LPS and LPS/LL-37 groups. Furthermore, the effects of LL-37 on cecal ligation and the puncture (CLP)-constructed ALI model were explored. Results: LL-37 attenuated LPS-evoked oxidative injury in human alveolar epithelial cells by increasing cell viability and suppressing ROS, malondialdehyde, and lactate dehydrogenase levels and apoptosis. Moreover, LPS-induced releases of pro-inflammatory IL-18, TNF-α, and IL-1β were suppressed by LL-37. Furthermore, LPS’s impairment of autophagy was reversed by LL-37. RNA-seq analysis substantiated 1350 differentially expressed genes between the LPS and LPS/LL-37 groups. Among them was ZBP1, a significantly down-regulated gene with the largest fold change. Moreover, LL-37 suppressed LPS-increased ZBP1 expression. Importantly, ZBP1 elevation restrained LL-37-induced autophagy in LPS-treated cells and abrogated LL-37-mediated protection against LPS-evoked oxidative injury and inflammation. LL-37 ameliorated abnormal histopathological changes, tissue edema, the lung injury score, oxygenation index (PaO2/FiO2), and glycemia contents in the CLP-constructed ALI model, which were offset through ZBP1 elevation via its activator CBL0137. Additionally, LL-37 suppressed inflammation and oxidative stress in lung tissues, concomitant with autophagy elevation and ZBP1 down-regulation. Conclusions: LL-37 may alleviate the progression of sepsis-evoked ALI by attenuating pulmonary epithelial cell oxidative injury and inflammatory response via ZBP1-mediated autophagy activation, indicating a promising approach for the therapy of ALI patients. Full article

Background/Objectives: Sepsis remains one of the most serious and possibly fatal complications encountered in intensive care units. Considering the frequent use of narcotic analgesics in this setting, we investigated whether the cardiovascular and peripheral and central inflammatory features of sepsis could be modified by morphine. Methods: Rats were instrumented with femoral and intracisternal (i.c.) indwelling catheters and sepsis was induced by cecal ligation and puncture (CLP). Results: The i.v. administration of morphine (3 and 10 mg/kg) significantly and dose-dependently aggravated septic manifestations of hypotension and impaired cardiac autonomic activity, as reflected by the reductions in indices of heart rate variability (HRV). Cardiac contractility (dP/dtmax) was also reduced by morphine in septic rats. The morphine effects were mostly eliminated following (i) blockade of μ-opioid receptors by i.v. naloxone and (ii) inhibition of central PI3K, MAPK-ERK, MAPK-JNK, NADPH oxidase (NADPHox), or Rho-kinase (ROCK) by i.c. wortmannin, PD98059, SP600125, diphenyleneiodonium, and fasudil, respectively. Further, these pharmacologic interventions significantly reduced the heightened protein expression of toll-like receptor 4 (TLR4) and monocyte chemoattractant protein-1 (MCP1) in brainstem rostral ventrolateral medullary (RVLM), but not cardiac, tissues of CLP/morphine-treated rats. Conclusions: Morphine worsens cardiovascular and autonomic disturbances caused by sepsis through a mechanism mediated via μ-opioid receptors and upregulated central inflammatory, chemotactic, and oxidative signals. Clinical studies are warranted to re-affirm the adverse cardiovascular interaction between opioids and the septic challenge. Full article

Background/Objectives: This study aims to develop and evaluate neutrophil-membrane-coated nanoparticles (Siv@NMs) encapsulating sivelestat for the treatment of sepsis-induced endothelial injury. Leveraging the intrinsic chemotactic properties of neutrophil membranes, Siv@NMs are engineered to achieve site-specific delivery of sivelestat to damaged endothelia, thereby overcoming the limitations of conventional therapies in mitigating endothelial dysfunction and multiorgan failure associated with sepsis. Methods: Siv@NMs were synthesized through a combination of ultrasonication and extrusion techniques to encapsulate sivelestat within neutrophil-membrane-derived vesicles. Comprehensive physicochemical characterization included analysis of particle size distribution, zeta potential, and encapsulation efficiency. Stability profiles and controlled release kinetics were systematically evaluated under simulated conditions. In vitro investigations encompassed (1) endothelial cell biocompatibility assessment via cytotoxicity assays, (2) investigation of the targeting efficiency in suppressing endothelial neutrophil extracellular trap generation during inflammation, and (3) ROS-scavenging capacity quantification using flow cytometry with DCFH-DA fluorescent probes. In vivo therapeutic efficacy was validated using a cecal ligation and puncture (CLP) sepsis mouse model, with multiparametric monitoring of endothelial function, inflammatory markers, ROS levels, and survival outcomes. Results: The optimized Siv@NMs exhibited an average particle size of approximately 150 nm, and a zeta potential of −10 mV was achieved. Cellular studies revealed that (1) Siv@NMs selectively bound to inflammatory endothelial cells with minimal cytotoxicity, and (2) Siv@NMs significantly reduced ROS accumulation in endothelial cells subjected to septic stimuli. In vitro experiments demonstrated that Siv@NMs treatment markedly attenuated endothelial injury biomarkers’ expression (ICAM-1 and iNOS), suppressed formation of neutrophil extracellular traps, and improved survival rates compared to treatment with free sivelestat. Conclusions: The neutrophil-membrane-coated nanoparticles loaded with sivelestat present a breakthrough strategy for precision therapy of sepsis-associated endothelial injury. This bioengineered system synergistically combines targeted drug delivery with multimodal therapeutic effects, including ROS mitigation, anti-inflammatory action, and endothelial protection. These findings substantiate the clinical translation potential of Siv@NMs as a next-generation nanotherapeutic for sepsis management. Full article

Background/Objectives: Abnormal bile acid (BA) pool may play an important role in inducing liver damage in sepsis. Farnesoid X receptor (FXR) is a main negative feedback regulator of BA metabolism. This study aims to explore the protective effect and mechanism of the FXR agonist obeticholic acid (OCA) on liver dysfunction when sepsis occurs. Methods: A rat model of sepsis was induced by cecal ligation and puncture (CLP) for 24 h. Systematic inflammation, tissue injury, hepatic FXR, and BA transporter expression were investigated in the CLP rats and sham-operated control rats with and without OCA pre-treatment (10 mg/kg, gavage) at 2 h before operation. Liquid chromatography–tandem mass spectrometry (LC-MS/MS) assay was performed to access BA composition in the rats’ serum and livers. The injury and inflammatory effects of the elevated unconjugated BAs found in the CLP rats was further verified in a hepatic cell line BRL-3A in vitro. Results: Hepatic FXR was repressed in CLP rats, whereas OCA upregulated liver FXR and hepatic BA transporter expression, reduced total serum BA concentration, ameliorated the elevation of serum levels of IL-1β and IL-6, and improved liver and ileal tissue injuries. OCA administration reduced the elevated unconjugated BAs in both serum and liver, and effectively inhibited increases in cholic acid (CA), deoxycholic acid (DCA), and 7-ketoDCA concentrations in CLP rat livers. These BA fractions promoted the release of aspartate aminotransferase (AST) from BRL-3A cells and increased IL-6, CXCL2, and monocyte chemoattractant protein-1 (MCP-1) expression in the cells, along with enhanced transcription factor nuclear factor-κB activation. Conclusions: Liver inflammation and dysfunction during sepsis is attributable to significant changes in bile acid composition in the blood and liver. FXR activation reduces systemic inflammation and liver dysfunction by regulating bile acid homeostasis, especially inflammatory unconjugated bile acid components. Full article

Sepsis-associated acute kidney injury (S-AKI) is a severe complication in critically ill patients, marked by inflammation, oxidative stress, and renal dysfunction. This study aimed to evaluate the renoprotective effects of Fasudil (Fas), a Rho-associated kinase inhibitor, in a rat model of S-AKI induced by cecal ligation and puncture (CLP). Thirty-six Wistar albino rats were divided into control, CLP with saline, and Fas (100 mg/kg/day intraperitoneally) groups. Biochemical, histopathological, and molecular analyses were conducted to assess kidney function, oxidative stress, and inflammation. Fas treatment significantly decreased plasma malondialdehyde and TNF-α levels, reducing oxidative stress and systemic inflammation. Kidney function markers, including BUN and creatinine, showed marked improvement. Furthermore, Fas suppressed the expression of STAT-3 and NLRP-3 in renal tissues, highlighting its role in modulating key inflammatory pathways. Histological evaluation revealed alleviated renal damage, with less tubular necrosis and interstitial inflammation in the Fas-treated group. In conclusion, Fas demonstrates significant anti-inflammatory, antioxidant, and nephroprotective effects in S-AKI, primarily by inhibiting STAT-3 and NLRP-3 signaling. These results support its potential as a therapeutic agent in sepsis-induced kidney injury and suggest the need for further clinical evaluation. Full article

Background: Sepsis is a life-threatening condition that is characterized by systemic inflammation and organ dysfunction, with adrenal dysfunction being a significant complication. This study aimed to investigate the role of necroptosis and hydrogen sulfide (H₂S) in sepsis-induced adrenal dysfunction. Methods: A cecal ligation and puncture (CLP)-induced sepsis mouse model was employed. Adrenocortical-specific mixed lineage kinase domain-like pseudokinase (MLKL) knockout (MLKL-KO) and cystathioneine β-synthase (CBS) knockout (CBS-KO) mice were generated using Cre-loxP technology and adrenocortical-specific Cre tool mice. In vitro experiments utilized TNFα-stimulated Y1 adrenocortical cells. The treatments included the H₂S donor NaHS, TNFα inhibitor R-7050, necroptosis inhibitor NSA and CBS inhibitor AOAA. Pathological assessment involved hematoxylin–eosin (H&E) staining and a Western blot analysis of necroptosis markers (the phosphorylation of MLKL (p-MLKL) and phosphorylation of receptor-interacting protein kinases 1 (p-RIPK1)). Results: Sepsis induced adrenal congestion, elevated TNFα levels, and activated necroptosis (increased p-MLKL/p-RIPK1) in wild-type mice. H₂S treatment attenuated adrenal damage, reduced TNFα, and suppressed necroptosis. MLKL knockout reduced septic adrenal dysfunction, whereas CBS knockout exacerbated septic adrenal dysfunction. In vitro, TNFα induced Y1 cell necroptosis, which was reversed by H₂S or NSA. AOAA exacerbated TNFα-induced necroptosis in Y1 cells. Conclusions: H₂S inhibits TNFα-mediated necroptosis, thereby preserving adrenal integrity in sepsis. Targeting the TNFα–necroptosis axis and enhancing endogenous H₂S production may represent novel therapeutic strategies for sepsis-associated adrenal dysfunction. Full article

Janus kinase inhibitors (JAKis) represent a relatively new class of immunomodulatory drugs with potent effects on various cytokine signalling pathways. They have revolutionized the treatment landscape for autoimmune diseases such as rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis. However, their ability to modulate immune responses presents a dual-edged nature, influencing both protective immunity and pathological inflammation. This review explores the complex role of JAKis in infectious settings, highlighting both beneficial and detrimental effects. On the one hand, experimental models suggest that JAK inhibition can impair host defence mechanisms, increasing susceptibility to certain bacterial and viral infections. For example, tofacitinib-treated mice exhibited more severe joint erosions in Staphylococcus aureus (S. aureus) septic arthritis and showed impaired viral clearance in herpes simplex encephalitis. Additionally, clinical data confirm an increased risk of herpes zoster in patients receiving JAKis, underscoring the need for rigorous monitoring. On the other hand, JAK inhibition has demonstrated protective effects in certain infectious and hyperinflammatory conditions. In sepsis models, including cecal ligation and puncture (CLP) and S. aureus bacteraemia, tofacitinib improved survival by attenuating excessive inflammation. Furthermore, JAKis, particularly baricitinib, have shown substantial efficacy in mitigating cytokine storms during severe COVID-19 infections, leading to improved clinical outcomes and reduced mortality. These observations suggest that JAKis have a role in modulating hyperinflammatory responses in select infectious contexts. In conclusion, JAKis present a complex interplay between immunosuppression and immunomodulation. While they increase the risk of certain infections, they also show potential in managing hyperinflammatory conditions such as cytokine storms. The key challenge is determining which patients and situations benefit most from JAKis while minimizing risks, requiring a careful and personalized treatment approach. Full article

Introduction: Septic patients have low levels of high-density lipoproteins (HDLs), which is a risk factor. Replenishing HDLs with synthetic HDLs (sHDLs) has shown promise as a therapy for sepsis. This study aimed to develop a computational approach to design and test new types of sHDLs for sepsis treatment. Methods: We used a three-step computational approach to design sHDL nanoparticles based on the structure of HDLs and their binding to endotoxins. We tested the efficacy of these sHDLs in two sepsis mouse models—cecal ligation and puncture (CLP)-induced and P. aeruginosa-induced sepsis models—and assessed their impact on inflammatory signaling in cells. Results: We designed four sHDL nanoparticles: two based on the ApoA-I sequence (YGZL1 and YGZL2) and two based on the ApoE sequence (YGZL3 and YGZL4). We demonstrated that an ApoE-based sHDL nanoparticle, YGZL3, provides effective protection against CLP- and P. aeruginosa-induced sepsis. The sHDLs effectively suppressed inflammatory signaling in HEK-blue or RAW264 cells. Conclusions: Unlike earlier approaches, we developed a new approach that employs computational simulations to design a new type of sHDL based on HDL’s structure and function. We found that YGZL3, an ApoE sequence-based sHDL, provides effective protection against sepsis in two mouse models. Full article

Background/Objectives: Sepsis has been shown to depress arterial baroreceptor function, and this effect is counterbalanced by the cholinergic anti-inflammatory pathway. Considering the importance of central adenosine receptors in baroreceptor function, this study tested whether central adenosine A3 receptors (A3ARs) modulate the cholinergic-baroreflex interaction in sepsis and whether this interaction is modulated by mitogen-activated protein kinases (MAPKs) and related proinflammatory cytokines. Methods: Sepsis was induced by cecal ligation and puncture (CLP) and rats were instrumented with femoral and intracisternal (i.c.) catheters. Baroreflex sensitivity (BRS) was measured 24 h later in conscious animals using the vasoactive method, which correlates changes in blood pressure caused by i.v. phenylephrine (PE) and sodium nitroprusside (SNP) to concomitant reciprocal changes in heart rate. Results: The reduction in reflex bradycardic (BRS-PE), but not tachycardic (BRS-SNP), responses elicited by CLP was reversed by i.v. nicotine in a dose-related manner. The BRS-PE effect of nicotine was blunted following intracisternal administration of IB-MECA (A3AR agonist, 4 µg/rat). The depressant action of IB-MECA on the BRS facilitatory action of nicotine was abrogated following central inhibition of MAPK-JNK (SP 600125), PI3K (wortmannin), and TNFα (infliximab), but not MAPK-ERK (PD 98059). Additionally, the nicotine suppression of sepsis-induced upregulation of NFκB and NOX2 expression in the nucleus tractus solitarius (NTS) was negated by A3AR activation. The molecular effect of IB-MECA on NFκB expression disappeared in the presence of SP 600125, wortmannin, or infliximab. Conclusions: The central PI3K/MAPK-JNK/TNFα pathway contributes to the restraining action of A3ARs on cholinergic amelioration of sepsis-induced central neuroinflammatory responses and impairment of the baroreceptor-mediated negative chronotropism. Full article

Sepsis is a leading cause of death in hospitalized patients. The underlying pathophysiologic mechanisms of sepsis have not been fully elucidated thus far. The receptor of programmed cell death 1 (PD-1) and its ligand (PD-L1), in combination with the Toll-like receptors (TLRs), seem to contribute considerably in systematic responses during sepsis. Investigating the relationship between them and identifying potential target pathways is important in the future management of sepsis, especially in relation to acute lung injury. This study investigated the interactions between TLR-5, -6, and -9 and PD-1/PD-L1 expression in a septic mouse model. Sixty C57BL/6J mice were included and categorized in six study groups. Three sepsis (S) groups (24 h, 48 h, and 72 h) and three sham (Sh) groups (24 h, 48 h, and 72 h) were created. Cecal ligation and puncture (CLP) was utilized to simulate sepsis in the S groups. Hematological analysis and lung tissue histopathological analysis were performed after 24 h, 48 h, and 72 h. Significant decreases in S groups compared to Sh groups in WBC and lymphocyte counts at 24, 48, and 72 h were observed. Significant increases in S groups compared to Sh groups in RBC and monocyte counts, IL-6 and IL-10 levels, alveolar flooding, and alveolar collapse were demonstrated by histopathological analysis. This study suggested a strong correlation between TLR expression and PD-1/PD-L1 up-regulation in lung tissue during sepsis. These molecules, also, seem to contribute to the histopathological changes in lung tissue during sepsis, leading to acute lung injury. Full article

Background: Sepsis-induced cardiomyopathy (SIC) is a life-threatening cardiac complication of sepsis with limited therapeutic options. Dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, has demonstrated cardioprotective effects in heart failure, but its role in mitigating sepsis-related cardiac dysfunction remains unclear. Methods: A retrospective cohort analysis was conducted to assess the impact of pre-hospital dapagliflozin use on major adverse cardiovascular events (MACEs) and survival in patients with SIC. Additionally, a murine SIC model was established using cecal ligation and puncture (CLP) to evaluate the effects of dapagliflozin on cardiac function, histopathology, and biomarkers of myocardial injury. Transcriptomic and metabolomic profiling, combined with multi-omics integration, was employed to elucidate the molecular mechanisms underlying dapagliflozin’s cardioprotective effects. Results: In the clinical cohort, pre-hospital dapagliflozin use was associated with a significant reduction in the risk of MACE and improved survival outcomes. In the murine SIC model, dapagliflozin restored cardiac function, reduced biomarkers of myocardial injury, and alleviated histological damage. Multi-omics analysis revealed that dapagliflozin modulates inflammatory responses, enhances autophagy, and regulates metabolic pathways such as AMPK signaling and lipid metabolism. Key regulatory genes and metabolites were identified, providing mechanistic insights into the underlying actions of dapagliflozin. Conclusions: Dapagliflozin significantly improves cardiac outcomes in sepsis-induced cardiomyopathy through the multi-level regulation of inflammation, energy metabolism, and cellular survival pathways. These findings establish dapagliflozin as a promising therapeutic strategy for SIC, offering translational insights into the treatment of sepsis-induced cardiac dysfunction. Full article

Sepsis is a clinical condition causing tissue damage as a result of infection and an exaggerated immune response. Sepsis causes 11 million deaths annually, a third of which are associated with acute lung injury (ALI). Rapid and effective treatment is crucial to improve survival rates. Punica granatum (pomegranate) is rich in polyphenols and demonstrates strong antioxidant activity, while amifostine acts as a free radical scavenger. This study aimed to investigate the antioxidant and anti-inflammatory effects of P. granatum peel extract (PGPE) and amifostine in sepsis-related ALI. Experimental groups included Control, CLP (cecal ligation and puncture-induced sepsis), Amf (200 mg/kg amifostine, intraperitoneally), and PGPE250, and PGPE500 (250 and 500 mg/kg PGPE via oral gavage, respectively). Thiobarbituric acid reactive substances (TBARS), total thiol (TT), tumor necrosis factor-alpha (TNF-α) levels, and metalloproteinases 2 and 9 (MMP-2 and MMP-9) were assessed in the lung tissue. Biochemical analysis demonstrated that TBARS and TNF-α levels significantly decreased in both the PGPE and amifostine treatment groups compared to the CLP group, while TT levels showed notable improvement. Histopathological evaluation revealed reduced MMP-2 and MMP-9 immunopositivity in the PGPE250 and PGPE500 groups. These findings highlight the lung-protective properties of PGPE, underscoring its potential as a therapeutic agent for sepsis-induced acute lung injury. Full article

Objective: This study investigates the therapeutic efficacy of ghrelin in alleviating sepsis-induced intestinal damage, focusing on its potential to inhibit ferroptosis and protect intestinal barrier integrity. Methods: This study evaluates the therapeutic efficacy of intraperitoneal ghrelin (80 μg/kg) and Ferrostatin-1 (5 mg/kg) using a cecal ligation and puncture (CLP) model in C57BL/6 mice to determine their potential in alleviating sepsis-induced intestinal damage. The investigation focuses on the impacts of ghrelin and Ferrostatin-1 on bacterial load, intestinal morphology, systemic inflammation, oxidative stress, and ferroptosis markers. Our comprehensive methodology encompasses histopathological evaluations, cytokine profiling, oxidative stress assays, and detailed analyses of ferroptosis indicators to thoroughly assess the interventions’ efficacy. Results: Treatment with ghrelin significantly reduced bacterial proliferation, mitigated intestinal damage, and decreased systemic inflammation. Comparable outcomes were observed with Fer-1 treatment. Both interventions restored intestinal barrier functions, modulated inflammatory responses, and attenuated oxidative stress, indicating a suppression of the ferroptosis pathway. Conclusion: Ghrelin exhibits a protective role in sepsis-induced intestinal injury, likely through the inhibition of ferroptosis. This mechanism underscores ghrelin’s therapeutic potential in sepsis management, suggesting avenues for further clinical exploration. Full article

Sepsis, a life-threatening condition characterized by dysregulated host responses to infection, often leads to multi-organ dysfunction, including kidney injury. Kidney damage in sepsis can have severe consequences and is associated with high mortality rates. This study aimed to investigate the potential therapeutic effects of fosfomycin (FOS), a broad-spectrum antibiotic with immunomodulatory properties, on kidney damage induced by cecal ligation and puncture (CLP)-induced sepsis in a rodent model. In total, 24 rats were randomly divided into three groups. Group 1 (n = 8), the healthy control group (C), received a single dose of 0.9% NaCl (saline) solution via an intraperitoneal (i.p.) route. To group 2 (n = 8), the CLP group, CLP-induced sepsis was applied without medication, and a single dose of 0.9% NaCl (saline) solution was applied i.p. before induction. To group 3 (n = 8), the CLP + FOS (500 mg/kg) group, a single dose of 500 mg/kg FOS was administered i.p. before sepsis induction. The effects of fosfomycin on kidney function, histopathological changes, inflammatory markers, oxidative stress, and apoptosis were assessed. In the fosfomycin-treated group, the histological analysis results demonstrated reduction in kidney tissue damage and inflammation. Additionally, fosfomycin attenuated the upregulation of pro-inflammatory cytokines and reduced oxidative stress markers in kidney tissue. Furthermore, fosfomycin treatment was associated with a decrease in apoptotic cell death in the kidney. These findings suggest that fosfomycin may have a protective effect on kidney damage caused by CLP-induced sepsis. The potential mechanisms underlying this protection include the modulation of inflammation, reduction of oxidative stress, and inhibition of apoptosis. Full article