Immunopharmacology and Immunotoxicology最新文献

Background: Acute lung injury (ALI) represents a diverse clinical condition characterized by significant complications and death rates. Naftidrofuryl (NAF) is a vasodilator drug with reported anti-inflammatory properties.

Objective: This study aimed to explore the effects of NAF administration on lipopolysaccharide (LPS)-induced ALI through in vitro experiments using the human leukemia monocytic cell line (THP-1) and in vivo ALI-rat model, while investigating the potential underlying mechanisms.

Methodology: Inflammatory biomarkers for macrophage phenotypes were evaluated in vitro. Additionally, rats were classified into the following groups: Group I, Control, receiving daily intraperitoneal (ip) saline. Group II: NAF-treated rats (45 mg/kg/day, ip), Group III: LPS-treated rats (3 mg/kg, ip at day one), then continued with saline, Group IV: NAF+LPS-treated rats. This study lasted 28 days, after which the rats were sacrificed. Biochemical and histopathological analyses were conducted on pulmonary tissue.

Results: The in vitro results highlighted the activation of macrophages from both phenotypes following LPS administration, indicating a disrupted macrophage environment characterized by altered levels of CD11b, CD38, CD206, IL-10, and LY6G/LY6C, as assessed by western blotting. NAF incorporation into LPS-treated samples significantly regulated all measured markers. The in vivo findings indicated an activated pro-inflammatory status, evidenced by elevated levels of TNF-α, IL-1β, IL-6, and iNOS in the LPS-treated group. The NLRP3/TLR4 pathway was activated, resulting in further disruption of redox and inflammatory homeostasis. Rats in Group-IV exhibited improved regulation of assessed parameters, characterized by decreased inflammation and modulation of the NLRP3/TLR4 pathway.

Conclusion: NAF may serve as a potential pulmonary protective agent against ALI by restoring inflammatory homeostasis and modulating various inflammatory pathways.

Objective: Sepsis-induced cardiotoxicity (SIC) is a critical complication characterized by inflammation, oxidative stress, and apoptosis, leading to myocardial dysfunction. The short-acting opioid analgesic remifentanil (REMI) possesses antioxidant and anti-inflammatory properties. This study aimed to evaluate the cardioprotective effects of REMI on lipopolysaccharide (LPS)-induced SIC by examining inflammation, oxidative stress, apoptosis, and mitochondrial function.

Materials and methods: Thirty-two female Wistar albino rats were divided into four groups: control, lipopolysaccharide (LPS), LPS+REMI, and REMI. Myocardial and aortic tissues were analyzed for histopathology, immunoexpression of Caspase-3 (Cas-3), nuclear factor kappa beta (NF-κB), and tumor necrosis factor alpha (TNF-α). Oxidative stress markers, including total oxidant status (TOS), total antioxidant status (TAS), and oxidative stress index (OSI), were measured. Mitochondrial apoptosis-related gene expression of AMP-activated protein kinase (AMPK), BCL2 Associated X (BAX), B-cell lymphoma 2 (BCL-2), Sirtuin 1 (SIRT1), and Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) was assessed.

Results: LPS administration induced severe histopathological damage, increased oxidative stress (elevated TOS and OSI), and upregulated apoptotic (Cas-3, BAX/BCL-2 imbalance) and inflammatory (NF-κB, TNF-α) markers. REMI treatment significantly alleviated myocardial and aortic injury, reducing the histopathological score. It markedly decreased Cas-3, NF-κB, and TNF-α expression, lowered TOS and OSI levels, and modulated the BAX/BCL-2. Furthermore, REMI restored the expression of AMPK, SIRT1, and PGC-1α genes, indicating a protective effect on mitochondrial biogenesis and energy metabolism.

Conclusions: REMI exhibits significant cardioprotective effects in LPS-induced SIC by attenuating inflammation, oxidative stress, and apoptosis while preserving mitochondrial homeostasis.

Objectives: Cannabidiol (CBD), the primary component of Cannabis sativa, has a neuroprotective and anti-inflammatory properties. Due to its modulation of multiple molecular targets within the central nervous system, CBD holds therapeutic promise for various neurological and psychiatric disorders.

Methods: This study aimed to evaluate the potential protective effects of CBD and/or low-dose ionizing radiation (LDR) in a rat model of hepatic encephalopathy (HE) induced by thioacetamide (TAA). Male Wistar rats received two (i.p.) injections of thioacetamide (TAA) at a dose of 200 mg/kg b.w. with a one-day interval between doses. Cannabidiol was administered i.p. at a dose of 20 mg/kg b.w. for seven consecutive days. Two LDR doses were applied (0.2 Gy each) with a one-day interval between exposures. The experimental design included assessment of oxidative stress and inflammatory markers, as well as neurobehavioral and histopathological evaluations.

Results: Treatment with CBD and/or LDR significantly reduced oxidative stress and inflammation, as evidenced by modulation of nuclear factor kappa B (NF-κB), apoptosis signal-regulating kinase 1 (ASK1), and c-Jun N-terminal kinase (JNK). Additionally, notable improvements were observed in levels of nicotinamide adenine dinucleotide (NAD), serotonin (5-hydroxytryptamine, 5-HT), and liver function enzymes. Behavioral performance, assessed using the Morris water maze, revealed cognitive enhancement, which was further confirmed by histological examination of brain and liver tissues.

Conclusion: Both CBD and LDR exhibited promising protective effects against TAA-induced hepatic encephalopathy, mitigating brain and liver damage through anti-inflammatory and antioxidant mechanisms. Thus, this supporting their potential as adjunct therapies in managing HE and related neuroinflammation.

Background: Bisphenol A (BPA) and bisphenol S (BPS) are commonly used in the food industry to manufacture epoxy resins in food packaging. Both compounds are characterized as potent carcinogens and xenoestrogens. However, little is known about their effects on the immune response.

Objective: This study evaluated the immunotoxic effects of BPA and BPS (0.1 ng/mL) on human peripheral blood leukocytes.

Methods: Leukocytes isolated from human peripheral blood were exposed in vitro to 0.1 ng/mL (0.4 nM) of BPA and 0.1 ng/mL (0.4 nM) of BPS for 0.5, 4, and 24 hours. Apoptosis, mitochondrial membrane potential (ΔΨm), senescence, reactive oxygen species (ROS), and intracellular Ca²⁺ flux were subsequently assessed through flow cytometry.

Results: Data suggest that in vitro exposure to BPA or BPS does not cause leukocyte death; however, it induces loss of mitochondrial membrane potential (ΔΨm), senescence, as well as ROS production and intracellular Ca²⁺ flux.

Conclusion: These findings demonstrate that even low concentrations (0.1 ng/ml) of BPA or BPS, levels that have been reported in human blood, can cause alterations in leukocyte function.

Background: Ulcerative colitis (UC) is a persistent inflammation of the mucous membrane of the large intestine, mostly impacting the colon and rectum. Lack of secure and efficient medical treatments motivates the search for new therapeutic agents to efficiently manage UC and its associated outcomes. The objective of this study was to investigate the preventive effect of febuxostat in rats with UC caused by acetic acid (AA).

Methods: AA (2 ml, 3% v/v) was administered intrarectally to induce UC. Preceding the administration of AA, febuxostat (10 mg/kg/day) was orally administered for two weeks.

Results: Febuxostat suppressed AA-induced UC by ameliorating colonic histological alterations, including inflammation, glandular hyperplasia, goblet cell loss, and mucosal ulcerations, while simultaneously reducing colon weight, malondialdhyde, and interleukin-18 contents. Febuxostat successfully rectified the metabolic imbalance between oxidants and antioxidants induced by AA. Furthermore, febuxostat decreased the levels of caspase-1 and NOD-LRR and pyrin domain containing protein 3 and increased colon length, catalase activity, and zonula occludens-1 expression.

Conclusion: Febuxostat mitigated AA-induced UC in rats by influencing the NLRP3/caspase-1/IL-1β signaling pathway, controlling the equilibrium between oxidants and antioxidants, and improving the integrity of the barrier of the colon.

Background: Telitacicept (RC18, RemeGen, Ltd) is a novel human TACI-Fc fusion protein that combines B cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL). RC18 has recently been approved in China for the treatment of systemic lupus erythematosus (SLE), demonstrating its safety and efficacy in the majority of the target population. However, the unique pharmacological mechanism of RC18 has not yet been fully elucidated.

Methods: In this study, we tested MRL-/lpr mice (a classic SLE animal model) and in vitro LLPCs induced models after RC18 treatment to evaluate the factors contributing to treatment benefits.

Results: We found that RC18 delayed the progression of SLE mice by specifically targeting APRIL and long-lived plasma cells (LLPCs). In the SLE animal model, RC18 blocked proteinuria and splenic involvement. RC18 specifically downregulated LLPCs in the bone marrow (BM) compared to other immune cell types. Moreover, the deposition of immune complexes in the kidneys of the RC18 group was also reversed. In vitro, we constructed an LLPCs induction model and verified the direct regulatory ability of RC18 on LLPCs.

Conclusion: This study reveals the crucial role of LLPCs in the SLE treatment with RC18, providing a new explanation for the excellent efficacy in clinical practice.

Objective: Atopic dermatitis (AD) is a common chronic inflammatory skin problem. Herein, we aimed to demonstrate the efficacy of matrine (MT) on AD and to reveal its mechanism.

Material and methods: An AD model was induced via topical administration of 1-fluoro-2,4-dinitorobenzene (DNFB). H&E staining was performed to observe the histological alterations of epidermal tissue, and the expression of inflammatory cytokines were measured using ELISA assay. Cell viability was determined using MTT assay. The T cell differentiation was monitored by flow cytometry. The target interactions were detected by ChIP, dual luciferase reporter assays, RIP, and RNA pull down assays.

Results: LDH, IgE, circTNFRSF21, and STAT3 levels in the serum of AD patients were elevated, while FOXO4 was decreased. Treatment with MT improved epidermal thickness in AD models, suppressed inflammatory cell and macrophage infiltration, and reduced the dermatitis score. Additionally, MT regulated the immune imbalance of T cells to mitigate the inflammatory damage on keratinocytes induced by TNF-α/IFN-γ. FOXO4 inhibited TNFRSF21 transcription to suppress circTNFRSF21 expression. Moreover, circTNFRSF21 was found to bind to ELAVL1, thereby enhancing STAT3 mRNA stability. In addition, overexpression of circTNFRSF21 reversed the effect of MT on TNF-α/IFN-γ induced HaCat injury. WP1066 (JAK/STAT3 inhibitor) eliminated the role of circTNFRASF21 overexpression in MT treated HaCat cells.

Conclusion: MT alleviates the inflammatory response of atopic dermatitis by suppressing circTNFRSF21 expression to decrease the activity of STAT3 signaling pathway.

Background: Esophageal cancer (ESCA) is a pervasive health threat, and cancer driver genes (CDGs) are under investigation as potential biomarkers for its treatment.

Methods: This study applied univariate regression to identify CDGs affecting survival and performed clustering analysis in TCGA-ESCA samples based on CDG expression. It explored differentially expressed genes (DEGs) and immune landscapes between the subtypes, analyzed tumor mutations, and further predicted the potential small-molecule drugs. In addition, we collected ESCA-related cell lines and investigated the expression levels of CDGs that were most significantly differentially expressed and related to survival.

Results: Our research pinpointed 18 survival-associated CDGs and split TCGA-ESCA patients into cluster 1 and cluster 2 via consensus clustering. The subtypes exhibited different levels of immune cell infiltration, with lower Tumor Immune Dysfunction and Exclusion scores in cluster 1. Enrichment analysis revealed that DEGs between the two subtypes were primarily linked to the humoral immune response, receptor ligand activity, and neuroactive ligand-receptor interaction. Mutation analysis did not find significant differences in mutation rates between the subtypes. Additionally, potential small-molecule drugs targeting DEGs in ESCA were investigated, such as 3,3'-diindolylmethane, SJ-172550, aminoglutethimide, nitrazepam, actarit, and epigallocatechin. The results of qRT-PCR showed that RUNX1, NONO, and TSC2 were not only significantly associated with the survival of esophageal squamous cell carcinoma (ESCC) but also significantly overexpressed in the ESCC cell lines (KYSE150 and KYSE450).

Conclusion: This study is valuable for elucidating CDG functions in ESCA and for biomarker identification.

Background: The primary goal of the post-transplant maintenance therapy is to keep equilibrium between minimizing the drug side effects and managing the long-term graft survival. In this prospective (10 years follow-up) study, we compared the short term and long-term outcomes of two different immunosuppression regimens.

Objective: The aim of the study is to evaluate the long term outcome following renal transplantation with a combination of low dose quadruple immunosuppression.

Methods: Group I (n = 25) comprised of low dose everolimus (0.5 mg/bd) (EVR), low dose Tacrolimus (1 mg/bd), low dose mycophenolate sodium (360 mg/bd) and prednisolone. Group II (n = 29) consisted of standard triple drug regimen of tacrolimus (3 mg/bd), mycophenolate sodium (720 mg/bd) and prednisolone. Renal function, rejection episodes, adverse events, graft and patient survival were analyzed.

Results and discussion: There was an improvement in the renal function from 1-year post transplant to the end of the study period in Group I. The mean serum creatinine at 10 years was 1.54 ± 0.44 and in Group II it was 2.1 ± 0.7 mg/dl with a statistical significance of p = 0.005. Mean eGFR at 10 years in Group I was 57.8 and in Group II it was 46.7 ml/mt/1.73m² (p = < 0.05). There was no statistical difference between the two groups in rejection rates (Group I-12% Group II -17.24% (p = 0.65), graft loss (Group I-12% vs Group II-27%(p = 0.26) and the patient loss was (Group I -12% vs Group II 24%(p = 0.36). Drug related adverse events were insignificant. Proteinuria and hyperlipidemia were comparable between the groups.

Conclusion: The low dose quadruple immunosuppression protocol was a better option for long-term graft survival with fewer complications.