Immunopharmacology and Immunotoxicology最新文献

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.

Background: WHIM syndrome is a rare primary immune deficiency and chronic neutropenia caused by overactivation of the C-X-C motif chemokine receptor 4/C-X-C motif chemokine ligand 12 (CXCR4/CXCL12) signaling pathway. On April 26th, 2024, Xolremdi (mavorixafor) capsules received its approval from US FDA, is the first targeted treatment specifically for patients aged ≥12 years with WHIM syndrome. Mavorixafor, as a selective CXCR4 antagonist, is able to increase the number of mature neutrophils and lymphocytes in the blood.

Objective: This review is to describe the pharmacological properties of mavorixafor and evaluate its clinical efficacy and safety profile.

Methods: A literature search was conducted using keywords mavorixafor, XOLREMDI, AMD070, AMD11070, X4P-001, WHIM Syndrome, and CXCR4/CXCL12 on Web of Science, Google Scholar, and PubMed. Drug information was obtained from the FDA website.

Results: In the pivotal 52-week phase III trial, time above absolute neutrophil count threshold (TAT_ANC) values in the mavorixafor group were higher than those in the placebo group at 4 different time points (15.04 h vs 2.75 h; p < 0.0001), and mavorixafor group had lower infection frequency, severity and duration. The most common adverse events are thrombocytopenia, pityriasis, rash, rhinitis, epistaxis, vomiting, and dizziness.

Conclusion: Mavorixafor 400mg daily effectively increases WBC count, reduces disease symptoms and infection burden in WHIM syndrome patients ≥12 years. Future clinical programs will continue to evaluate the safety and efficacy of mavorixafor in patients with chronic neutropenic disease.

Introduction: Nitric oxide (NO) plays a crucial role in the induction of neuropathic pain by stimulating the production of inflammatory cytokines. Additionally, research indicates that amitriptyline can inhibit nitric oxide production. In this study, we examined the inhibitory role of the nitric oxide signaling pathway through the administration of amitriptyline in the treatment of neuropathic pain.

Methods: Forty rats were randomly assigned to five groups, with eight animals in each group: (1) Sham-operated, (2) Chronic constriction injury (CCI), (3) CCI plus amitriptyline, (4) CCI plus amitriptyline and L-arginine, and (5) CCI plus amitriptyline and L-NAME. Behavioral tests, including thermal hyperalgesia, cold allodynia, and mechanical allodynia, were conducted on the fourth, seventh, and fourteenth days following CCI induction. On the final day, spinal cord samples were collected to assess the levels of inflammatory cytokines. Additionally, the sciatic nerve was isolated on the same day for histological examination.

Results: The results indicated that the administration of amitriptyline can reduce levels of inflammatory cytokines and improve symptoms of neuropathic pain. It should be noted that the simultaneous use of L-NAME and amitriptyline increases the therapeutic impacts of amitriptyline. However, the beneficial effects of amitriptyline are reduced by the nitric oxide stimulation induced by L-arginine.

Conclusion: It was determined that one of the mechanisms by which amitriptyline ameliorates neuropathic pain is the inhibition of the nitric oxide signaling pathway. In this study, this effect was associated with a reduction in the release of inflammatory cytokines and a decrease in inflammation surrounding the nerve.

Background: The pathophysiology of cognitive impairment has recently focused on 1,2-Diacetylbenzene (DAB), B vitamins, tau hyperphosphorylation, and neuroinflammation. While past evidence shows that vitamin B6 influences the immune system, the molecular processes behind DAB-induced neuroinflammation and cognitive impairment remain largely unknown. This study aimed to assess the protective roles of vitamin B6 against DAB-induced toxicity in BV2 microglial and SH-SY5Y cells.

Methods: In vitro approaches included Western blot, qRT-PCR, cell viability assays, immunocytochemistry, reactive oxygen species, and nitrite assays. For in silico analysis, we utilized Metascape, Cytoscape, MIENTURNET, and molecular docking.

Results: Vitamin B6 suppressed the TLR4/NF-κB pathway and the TREM-1/DAP12/NLRP3/caspase-1/IL1B pathway in DAB-activated BV2 cells. Additionally, it reduced reactive oxygen species and nitric oxide levels while increasing Nrf2 and IL10 production. In SH-SY5Y cells, vitamin B6 inhibited GSK-3β Tyr216, tau hyperphosphorylation, and β-amyloid production. The in silico analysis identified 'positive regulation of NF-κB transcription factor activity,' 'regulation of IL-6 production,' and 'positive regulation of adaptive immune response' as key molecular mechanisms linked with DAB-induced cognitive impairment and targeted by vitamin B6. Core genes, miRNAs, and transcription factors included IL1β, IL6, IL10, TNF, hsa-miR-155-5p, hsa-miR-203a-3p, hsa-miR-106a-5p, hsa-miR-26a-5p, CEBPB, and PXR.

Conclusion: Our findings indicate that vitamin B6 may protect against DAB-induced cognitive impairment by attenuating key inflammatory pathways, reducing oxidative stress, and inhibiting tau hyperphosphorylation, β-amyloid production, and GSK-3β Tyr216 phosphorylation. This highlights its potential as a therapeutic agent for cognitive impairment.

Objective: Oxidative stress and neuroinflammation are crucial factors in the pathogenesis of Parkinson's disease (PD). Vitamin D (Vit D) and canagliflozin (CAN) are known to have anti-inflammatory and antioxidant properties. Together, they target key molecular pathways involved in PD, including oxidative stress and neuroinflammation, specifically, the small GTPase protein (RAC1)/nuclear factor-kappa B (NF-κB)/nuclear factor erythroid 2-related factor 2 (Nrf2) signaling, which regulates brain's oxidative stress and inflammation. This study investigates the effects of Vit D and CAN alone and in combination in a rat model of PD.

Materials and methods: Fifty male Wistar rats were assigned to five groups (n = 10), including control, rotenone (ROT), Vit D + ROT, CAN + ROT, and Vit D + CAN + ROT. We assessed weight changes, brain weight, neurobehavioral functions, biochemical markers, and immunohistopathology of brain tissues.

Results: The results showed that Vit D treatment was more effective than CAN in alleviating PD symptoms, with the combination of Vit D and CAN offering the best therapeutic outcome. This combination therapy significantly improved serum Vit D, striatal dopamine (DA) levels, antioxidant status (reduced glutathione (GSH) and catalase (CAT), reduced oxidative stress (malondialdehyde (MDA)), and ameliorated inflammation (tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), and interleukin 10 (IL-10)). Additionally, the combination therapy modulated the expression of RAC1, NF-κB, Nrf2, vitamin D receptors (VDR), and vitamin D-binding protein (DBP) and immunoexpression of tyrosine hydroxylase (TH), and α-synuclein (α-SYN).

Conclusion: These findings suggest that Vit D and CAN synergistically modulate the RAC1/NF-κB/Nrf2 pathway, leading to improved neuroprotection in PD.