Immunopharmacology and Immunotoxicology最新文献

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.

Background: Autoimmune hepatitis (AIH) is a chronic autoimmune liver disease whose pathogenesis is closely related to the imbalance between regulatory T (Treg) and T helper 17 (Th17) cells. Rebuilding the Treg/Th17 balance provides a potential therapeutic approach for AIH patients. All-trans retinoic acid (atRA) sustains Treg cell function while inhibiting pathogenic Th17 cell differentiation. This study explored the potential of atRA for treating experimental AIH (EAH).

Methods: S100-induced EAH was established in mice, which were intraperitoneally injected with 25 mg/kg atRA every other day. Biochemical and histomorphological parameters were measured and liver histopathological changes were assessed. Hepatic CD4⁺ T cells were detected using immunofluorescence staining, and the ratios of splenic Tregs and Th17 cells were evaluated using flow cytometry. The expression levels of Rorγt and Foxp3 in the liver were assessed using real-time quantitative polymerase chain reaction (RT-qPCR) and immunoblotting. Changes in IL-6/STAT3 signaling were detected via enzyme-linked immunosorbent assay (ELISA), RT-qPCR, and immunoblotting.

Results: atRA attenuated liver inflammation in S100-induced EAH mice. Additionally, atRA decreased the infiltration of CD4⁺ T cells in the liver, increased the proportion of splenic Tregs, decreased the proportion of splenic Th17 cells, and restored the Treg/Th17 ratio. atRA also significantly reduced serum IL-6 levels and inhibited the activation of STAT3.

Conclusions: Our findings suggest that atRA ameliorated S100-induced EAH likely by suppressing the IL-6/STAT3 signaling pathway to restore the Treg/Th17 balance. Therefore, atRA may be a promising therapeutic drug for treating AIH.

Background: Microglia are brain resident cells that control neural network maintenance, damage healing, and brain development. Microglia undergo apoptosis, cytokine production, and reactive free radicals of oxygen (ROS) in response to lipopolysaccharide (LPS) stimulation. TRPM2 is activated by LPS-induced oxidative stress, but it is inhibited by carvacrol (CARV) and N-(p-amylcinnamoyl)anthranilic acid (ACA). Morphine (MRP), an opioid ligand, has the potential to be both an anesthetic and an antioxidant.

Objective: We investigated how MRP changed the TRPM2 signaling pathways to protect murine BV-2 microglia cells from LPS-induced ROS, cytokine production, and death.

Materials and methods: We generated five primary groups in the cultured BV-2 cells: Control, MRP (50 μM for 24h), LPS (1 μg/ml for 24h), LPS + MRP, and LPS + TRPM2 blockers (ACA or CARV).

Results: The incubation of LPS increased the amounts of apoptosis, cell death (propidium iodide positive cell number), oxidants (ROS and lipid peroxidation), mitochondrial dysfunction, apoptotic markers (caspase -3, -8, and -9), cytokines (TNF-α, IL-1β, and IL-6), death cell waste (debris), cytosolic free Ca²⁺, Zn²⁺, and ADP-ribose-induced TRPM2 current densities, while the treatments of MRP and TRPM2 blockers reduced their amounts. The LPS-induced reductions in BV-2 viability percentage, BV-2 number, glutathione peroxidase activity, and glutathione levels were increased by the treatments.

Conclusions: MRP reduced the levels of LPS-induced oxidative stress, inflammatory cytokines, and apoptosis via inhibiting TRPM2 in the BV-2 cells. One possible treatment option for oxidative microglia damage and neurological disorders induced by LPS could be the MRP.

Background: Combination therapy for cancer using oncolytic viruses and anticancer drugs/agents has better therapeutic effects through direct destructive effects on cancer defence. Direct destructive effects of both factors and triggering an enhanced immune response can augment the anticancer effect in a synergistic manner. e. This study aimed to evaluate the efficacy of ammonium metavanadate (NH4VO3) as an anticancer agent combined with oncolytic reovirus serotype 3, Dearing strain (ReoT3D), in the induction of cytotoxic effect in a murine colorectal cancer cell line (CT26 cells).

Methods: The impact of NH4VO3, ReoT3D, and their synergistic effect on the viability of CT26 cells was assessed using the MTT assay. The rate of apoptosis induction and cell cycle arrest by NH4VO3 and ReoT3D was evaluated by flow cytometry and real-time PCR.

Results: The results showed that cell viability decreased with increasing NH4VO3 dosage, viral titer, and treatment time. Regarding the induction of apoptosis by oncolytic reovirus and NH4VO3, apoptosis was increased because of the synergism of NH4VO3 and ReoT3D, and the cell cycle was arrested with the combined treatment. Caspase 3, 8, and p53 gene expression increased and bcl-2 gene expression decreased.

Conclusion: Combination therapy using oncolytic ReoT3D and NH4VO3 increases apoptosis in cancer cells and can be used as a promising platform for scientific studies and research in cancer treatment.

Objective: Immune checkpoint inhibitors (ICIs) made a big change in the treatment of hepatocellular carcinoma (HCC), thereby bringing fresh hope in terms of treatment to patients with few options until that time.

Methods: However, ICIs still encounter resistance mechanisms in a substantial number of patients, either in primary or secondary forms. This phenomenon of resistance occurs due to various reasons that comprise but are not restricted to epigenetic alterations, immunosuppressive tumor microenvironments, and activation of TGF-β and VEGF signaling pathways.

Results: In this study, we will discuss the mechanisms of ICI resistance in HCC and these emerging avenues of therapy as an approach to circumvent the resistance. The rationale and current status of ongoing trials to combine ICIs with anti-angiogenic agents, epigenetic modulating agents, and local therapies will be discussed.

Discussion: In a nutshell, we indicate an immediate need for reliable predictive biomarkers and personalized treatment approaches to improve clinical outcomes. Therefore, by managing challenges and knowledge gaps, this review presents a futurist outlook while charting a course for subsequent clinical trials designed to optimize immunotherapeutic results in HCC.

Objective: Atopic dermatitis (AD) is a chronic skin disease marked by immune dysregulation such as upregulated T helper (Th) 2 responses. While Th2-targeted therapies for AD are under development, their application is limited by side effects such as hypereosinophilia and arthritis. Amygdalin is a glucoside known for its anti-inflammatory and antioxidant effects. It is an essential component of bitter apricot kernel, traditionally utilized to alleviate inflammatory skin diseases such as boils and acne. This study focused on investigating the therapeutic effects of amygdalin on AD.

Materials and methods: Its effectiveness was evaluated both in vivo, using the AD mouse model induced by 2,4-dinitrochlorobenzene (DNCB) and Dermatophagoides farinae extract (DFE), and in vitro, using activated leukemia T lymphoblasts and keratinocytes.

Results: Amygdalin was shown to reduce the infiltration of immune cells in lesions and both total and DFE-specific immunoglobulin E (IgE) levels in mouse serum. Of note, it explicitly suppressed the expression of Th2 cytokines including interleukin (IL)-4, IL-5, and IL-13, as well as tumor necrosis factor (TNF)-α in ear tissues with AD induced by DNCB/DFE. These phenomena were corroborated by observations in CCRF-CEM cells, where amygdalin notably reduced the levels of IL-4 and TNF-α by inhibiting nuclear translocation of nuclear factor of activated T cells 1 and nuclear factor-κB.

Conclusion: These findings suggest that amygdalin effectively alleviates allergic skin inflammation by suppressing the Th2 and inflammatory responses, making it a promising candidate for AD treatment.

Objective: Glucocorticoids (GC) play a critical role in managing inflammatory conditions and have gained attention in cancer immunotherapy due to their immunosuppressive properties. This review explores the relationship between GC and immune checkpoint inhibitors (ICI) in cancer progression and therapy, and most importantly, synthesizes updated evidence linking GC-induced upregulation of inhibitory checkpoint molecules leading to ICI therapy failure in some cases.

Methods: This review examines the role of co-inhibitory molecules (CIMs) like programmed cell death protein-1 (PD-1), cytotoxic T-lymphocyte antigen 4 (CTLA-4), and lymphocyte activation gene-3 (LAG-3) in modulating immune responses and enabling tumor evasion. It also considers immune-related adverse events (irAEs) associated with ICI therapy, which are often mitigated using GCs. While GCs manage irAEs effectively, their influence on therapeutic outcomes remains controversial. Preclinical and clinical evidence shows that GCs may activate CIMs, potentially undermining the efficacy of immunotherapy.

Results: Preclinical studies indicate that both synthetic and endogenous GC upregulate CIMs like PD-1 and LAG-3 on immune cells, impairing immune activation and anti-tumor responses. Pharmacologic inhibition of GCs signaling, such as 11β-HSD1 inhibitors, has shown promise in enhancing ICI efficacy. GCs timing and dosage are critical; early GC use often correlates with poorer treatment responses, while later use may improve clinical outcomes.

Conclusions: This review highlights the dual role of GCs as potential immunomodulators of immune responses in cancer immunotherapy. A deeper understanding of GC-ICI interactions is vital to optimize treatment strategies. Future studies are needed to refine therapeutic approaches and individualized patient outcomes.