Immunopharmacology and Immunotoxicology最新文献

Background: The anesthetic sevoflurane can cause cognitive dysfunction and may be involved in mediating DeoxyriboNucleic Acid (DNA) methylation. In this study, we dig into the mechanism of sevoflurane inducing cognitive dysfunction via DNA methylation pathway.

Methods: In vivo and in vitro experiments were performed in sevoflurane-induced rat models and microglia. In vivo experiments included Morris water maze, Western blot, methylation analysis and immunofluorescence, while in vitro experiments consisted of quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot. MK2206 was used as a protein kinase B (AKT) inhibitor.

Results: Sevoflurane induced cognitive dysfunction in rats, promoted levels of nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3), Interleukin (IL)-18, IL-1β, and ionized calcium-binding adapter molecule 1 (Iba-1) proteins, and inhibited Period2 (PER2) expression by enhancing methylation modification. PER2 was found to be located in microglia. Sevoflurane activated DNA methyltransferases (DNMTs) expression and suppressed PER2 in vitro. PER2 overexpression reduced NLRP3 inflammasomes-related protein expressions and restored AKT activation in sevoflurane-treated cells. Furthermore, MK2206 reversed the inhibitory effect of PER2 overexpression on cellular inflammation and AKT pathway activation.

Conclusion: Sevoflurane affects AKT pathway-suppressed NLRP3 inflammasomes in microglia by modulating PER2 methylation, thereby contributing to cognitive dysfunction.

Background: Ferroptosis-associated insults play a critical role in the pathological development of septic cardiomyopathy. Fenofibrate (Feno) is a fibrate drug used to treat high triglycerides and high cholesterol, however its pharmacological function in septic cardiomyopathy is not well understood.

Materials and methods: We allocated 36 male C57BL/6J mice into four groups (n = 9/group): Vehicle, Feno, LPS, and LPS+Feno. Techniques included hematoxylin-eosin (HE) staining, LDH assay, ELISA, echocardiography, measurement of MDA, GSH, Fe2⁺, real-time PCR, and western blot analysis.

Results: Administration of Feno significantly mitigated myocardial injury by reducing serum CK-MB levels from 963.8 U/L to 512.5 U/L, cTnI from 0.65 g/L to 0.36 g/L, and LDH from 552.4 U/L to 372.1 U/L. Feno improved cardiac function by increasing ejection fraction from 65.5% to 78.5% and fractional shortening from 42.3% to 57.3%. Feno also inhibited inflammatory cytokines IL-6 and TNF-α, reduced MDA levels, increased GSH levels, and restored GPX4, FTH1, and SLC7A11 expression. The protective effects of Feno may be associated with the YAP1 signaling pathway.

Conclusion: Our findings suggest that Feno has the potential to protect against LPS-induced cardiac injury through the alleviation of ferroptosis, offering a promising therapeutic strategy for septic cardiomyopathy. However, the study is limited by the use of a single animal model and the lack of translational data in humans.

Introduction: The immunosuppressant drug cyclosporine A (CsA) demonstrates anti-inflammatory properties in numerous pathological conditions. It acts through modulating T-cell receptor signaling, reducing the expression of inflammatory cytokines, and inhibiting mitochondrial permeability, besides modulating vascular response. These features make it a potential drug to prevent or treat septic acute kidney injury (AKI).

Objective: In this study, we investigated whether CsA exerts a protective effect against hemodynamic, inflammatory, and renovascular consequences of sepsis and whether these effects are modulated by adenosine receptor signaling.

Material and methods: Cecal ligation and puncture (CLP) was utilized to induce sepsis 24 h before hemodynamic and renovascular studies were implicated. Renal vasoconstrictions and vasodilatations were induced by cumulative bolus injections of phenylephrine (PE, 0.41-900 ng) and acetylcholine (ACh, 0.01-7.29 nmol), respectively.

Results: The data showed that CsA abrogated CLP-evoked hypotension, tachycardia, and impaired renovascular responsiveness. Similarly, the elevation in kidney biomarkers together with the pro-inflammatory cytokines (Tumor necrosis factor-alpha (TNFα) and Interleukin-6 (IL-6)) were also blunted after CsA administration. Likewise, the elevation in nuclear factor kappa-light-chain enhancer of activated B cells (NFκB) and decrease in A2BRs renal tubular expression in sepsis was reversed in CsA-treated rats. These advantageous effects of CsA disappeared upon concurrent exposure to the selective A2BR antagonist, Alloxazine.

Conclusion: These results suggest a key role for functional A2BR in CsA counteracting CLP-induced hemodynamic, inflammatory, and renal dysfunction in rats.

Background: Immune checkpoint inhibitors (ICIs) have shown significant advantages in the treatment of lung cancer. Several studies have reported immune-related adverse events (irAEs) induced by ICIs. However, in clinical practice, irAEs occasionally cause lymphadenopathy, which can be mistaken for tumor progression, making it more challenging to accurately assess the patient's condition.

Case presentation: This research report documents a rare clinical case of a patient with early-stage non-small cell lung cancer (NSCLC) who developed systemic lymphadenopathy during treatment with a PD-1 ICI following surgical resection. The patient developed widespread lymphadenopathy during postoperative PD-1 antibody maintenance therapy, accompanied by a series of irAEs, including persistent low cortisol levels, sluggish responses, memory loss, and stiffness in distal limbs and shoulder joints. Given the clinical presentation, the possibility of lymph node metastasis from lung cancer could not be entirely excluded. However, lymph node biopsy revealed reactive hyperplasia. After receiving corticosteroid treatment, the enlarged lymph nodes significantly reduced in size, and the associated low cortisol symptoms disappeared. During subsequent follow-up, the patient showed significant improvement and maintained a relatively stable condition.

Results: In cases of postoperative generalized lymphadenopathy in NSCLC patients, if tumor recurrence is suspected, careful consideration is needed, especially in the era of ICI therapy. Postoperative PD-1 antibody maintenance therapy may induce reactive lymphadenopathy, including mediastinal lymph nodes. It is hypothesized that PD-1 antibodies cause T-cell activation in the lymph nodes.

Introduction: Sepsis-induced acute kidney injury (AKI) is a major cause of mortality in critically ill patients. Inflammation, oxidative stress, and apoptosis are key contributors to sepsis-related renal damage. Dapagliflozin (DPG), an SGLT2 inhibitor, has demonstrated anti-inflammatory and nephroprotective effects. This study aimed to investigate the renoprotective effects of DPG in a lipopolysaccharide (LPS)-induced sepsis model, focusing on inflammation, oxidative stress, and apoptosis in the kidneys.

Methods: Thirty-two male Wistar albino rats were divided into four equal groups: (1) Control group, which received saline for 5 days; (2) LPS group, which received oral saline for 5 days and a single intraperitoneal LPS injection (5 mg/kg on day 5); (3) LPS+DPG group, which received oral DPG (10 mg/kg/day) for 5 days and a single intraperitoneal LPS injection (5 mg/kg on day 5); (4) DPG group, which received oral DPG (10 mg/kg/day) for 5 days. At the end of the experiment, samples were collected for histopathological, immunohistochemical, biochemical, and genetic analyses.

Results: DPG significantly reduced serum urea and creatinine levels, indicating improved renal function. Histopathological analysis of the kidney tissues revealed reduced inflammation, hemorrhage, and necrosis in the LPS+DPG group compared to the LPS group. Also, DPG lowered the expression of pro-inflammatory markers (APAF-1, TNF-α, VCAM-1), reduced oxidative stress (decreased OSI), and downregulated NLRP3, caspase-1, IL-1β, and IL-18 gene expression.

Conclusion: Prophylactic DPG administration exerts notable renoprotective effects in sepsis-induced AKI by mitigating inflammation, oxidative stress, and apoptosis. These findings highlight its potential as a preventive strategy, warranting further investigation in therapeutic contexts.

Purpose: Tofacitinib, a small molecule pan-JAK inhibitor, targets key inflammatory pathways that play a pivotal role in the pathophysiology of uveitis. Its ability to inhibit multiple cytokine signaling pathways makes it a promising candidate for the treatment of ocular inflammation. This study aimed to investigate the effect of oral tofacitinib on peptide-derived S-antigen (PDSAg)-induced chronic experimental autoimmune uveitis (EAU) in rats.

Materials and methods: Nineteen albino Wistar rats were divided into five groups. Groups 1-3 (5 rats each) were immunized with 15 micrograms PDSAg to induce EAU; Group 2 received tofacitinib (5 mg/kg) by gavage twice daily. Group 3 received saline in the same manner as Group 2. Group 4 (2 rats) was a healthy control group. Group 5 (2 rats) received only tofacitinib. Uveitis development and treatment efficacy were evaluated using clinical scoring based on the the signs of anterior segment inflammation and histological scoring based on the deterioration of the retinal architectural structure.

Results: Uveitis confirmed based on histological evidence was observed in all EAU groups (Groups 1-3) compared to the healthy control group (Group 4) (p < 0.001, Mann-Whitney U test). Tofacitinib significantly delayed the onset of uveitis in Group 2 when compared with Groups 1 and 3, which did not receive tofacitinib (p < 0.001, Mann-Whitney U test). Histological scores also showed a trend toward reduction (p = 0.393, Mann-Whitney U test).

Conclusions: Oral tofacitinib delayed uveitis onset and reduced clinical and histological findings, suggesting its potential as an alternative treatment for uveitis.

Background: Camrelizumab has shown encouraging efficacy in advanced liver cancer, either as monotherapy or in combination with chemotherapy; however, there is currently insufficient empirical support for the use of camrelizumab therapy in conjunction with anti-angiogenic drugs to treat intermediate and advanced hepatocellular carcinoma.

Methods: Clinical information was gathered retrospectively from patients with intermediate- to advanced-stage hepatocellular carcinoma who were treated with camrelizumab and certain anti-angiogenic drugs at Shanghai Hospital between July 2019 and May 2023.

Results: This trial comprised 60 patients with intermediate and advanced hepatocellular carcinoma. Patients receiving first-line therapy had an objective remission rate of 25% (9/36) and a disease control rate of 58.3% (21/36), while those administered second-line therapy and beyond had rates of 12.5% (3/24) and 33.3% (8/24), respectively. Moreover, the median overall survival was 15.17 months (95% CI 12.067, 18.267) and 13 months (95% CI 11.644, 14.356), whereas the median progression-free survival was 7.1 months (95% CI 3.846, 10.354) and 4.67 months (95% CI 2.492, 6.842), respectively. The predominant treatment-emergent adverse events observed during therapy included: elevated total bilirubin in 28 cases (46.7%), proteinuria in 19 cases (31.7%), gastrointestinal reactions in 19 cases (31.7%), and thrombocytopenia in 16 cases (26.7%).

Conclusion: Based on real-world data, individuals with intermediate and advanced primary liver cancer undergoing systemic therapy may benefit from camrelizumab combined with anti-angiogenic drugs.

Introduction: Punicalagin (PCG) is a major polyphenolic component with potent anti-inflammatory, anti-atherogenic, anti-cancer, and antioxidant activities. This study aimed to investigate the impact and underlying mechanisms of PCG on lipopolysaccharide (LPS)-induced dental pulpitis.

Methods: A rat pulpitis model was constructed, and the infected pulp was covered with a PCG collagen sponge. In vitro, dental pulp cells (DPCs) were isolated, and the effects of LPS and PCG on cell viability were assessed. The expression levels of inflammation-related factors were investigated by qRT-PCR and ELISA. The Nuclear Factor kappa B (NF-κB) transcription factors and Wnt family member 5a-Receptor tyrosine kinase like Orphan Receptor 2 (Wnt5a-ROR2) levels were evaluated by immunofluorescence staining and Western blotting.

Results: We demonstrated that the PCG collagen sponge effectively reduced the infiltration of inflammatory cells in the pulp. PCG significantly alleviated the inflammatory response by reducing the mRNA expression levels of IL-1β, IL-6, IL-8, ICAM-1, and VCAM-1 and the secretion of IL-6 and IL-8 in a concentration-dependent manner. Immunofluorescence staining showed that the activation of the NF-κB pathway was hindered by PCG, which affected with the nuclear translocation of P65. PCG reduced the phosphorylation levels of P65 and IκBα and suppressed the expression levels of Wnt5a and ROR2 induced by LPS. The NF-κB inhibitor Bay11-7082 reduced the activation of the NF-κB/Wnt5a-ROR2 pathway and the inflammatory response; the application of PCG significantly augmented this inhibitory effect.

Discussion: PCG demonstrated an anti-inflammatory effect in LPS-induced DPCs by targeting the NF-κB/Wnt5a-ROR2 signaling pathway.

Background: Doxorubicin (DOX) is an anticancer commonly employed in cancer treatment. However, the clinical application of DOX is associated with hepatotoxicity. Vildagliptin is an anti-hyperglycemic agent that inhibits the dipeptidyl peptidase-4 enzyme. Besides being used in managing type-2 diabetes, vildagliptin showed potential anti-inflammatory, antioxidant, and other activities.

Objective: Our investigation targeted the hepatoprotective effects of vildagliptin against DOX-induced hepatotoxicity.

Methods: Vildagliptin was given in a dose of 30 mg/kg, once daily; p.o. for 2 weeks while DOX was injected in a single dose of 30 mg/kg, i.p.

Results: Vildagliptin effectively decreased serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, while it effectively elevated serum total protein (TP) level. Histologically, vildagliptin administration resulted in significant hepatoprotective efficacy with abundant figures of normal hepatocytes. Moreover, vildagliptin considerably decreased lipid peroxidation biomarker malondialdehyde (MDA), and the cytokines interleukin (IL)-6, tumor necrosis factor-alpha (TNF-α), and cyclooxygenase (COX)-2, while it remarkably boosted the antioxidative defenses of glutathione (GSH) and catalase (CAT). Dual antioxidant and anti-inflammatory activities were mediated by upregulating nuclear factor (erythroid-derived 2)-like 2 (Nrf2), silent information regulator 1 (SIRT1), and heme oxygenase (HO-1) and suppressing the nuclear factor kappa B (NF-κB) signals. Finally, vildagliptin alleviated apoptosis by downregulating hepatic p53 and cytochrome (Cyt)-C.

Conclusion: Our findings suggest that vildagliptin improved hepatocellular architecture and reduced hepatic oxidative injury, inflammation, and apoptosis associated with DOX treatment.