Immunopharmacology and Immunotoxicology最新文献

Background: Lebrikizumab is an interleukin-13 antagonist that has been approved for use in adults and pediatric patients aged 12 years and over who weigh at least 40 kg, for the treatment of moderate-to-severe atopic dermatitis (AD) that is inadequately controlled with topical prescription therapies, or for whom such therapies are not suitable. Due to the relatively short duration of existing clinical trials and the absence of real-world postmarketing evidence involving AD patients receiving lebrikizumab, it is crucial to comprehensively characterize its safety profile, including the potential delayed AEs.

Methods: Adverse event (AE) signals were identified using disproportionality analysis with four algorithms: the reporting odds ratio (ROR), the proportional reporting ratio, the information component, and the empirical Bayesian geometric mean. Data were analyzed from the FDA Adverse Event Reporting System, covering the period from the fourth quarter of 2024 to the third quarter of 2025.

Results: A total of 791 AEs associated with lebrikizumab were identified. Lebrikizumab was documented in a lower proportion of serious AEs, accounting for 15.68% of cases. The three most frequently reported AEs associated with lebrikizumab were injection site pain, conjunctivitis, and rash. The top three AE signals with ROR values were conjunctivitis, eyelid irritation and dermatitis exfoliative generalised. Specific AEs of lebrikizumab included hypersensitivity, eosinophilia, and injection site reactions.

Conclusion: This study provides a comprehensive overview of the safety of lebrikizumab and confirms that it has a favorable and manageable safety profile, supporting its suitability for long-term use in clinical practice.

Background: Metabolic dysfunction-associated steatohepatitis (MASH) is a widespread hepatic disorder that arises from metabolic dysfunction-associated steatotic liver disease (MASLD). It is characterized by fat deposition throughout the hepatocytes accompanied by lobular inflammation that may eventually lead to progressive fibrosis. This is driven by different metabolic disturbances including hyperglycemia, hyperlipidemia, and obesity. Thus, the disease has a growing prevalence among the general population due to the widespread occurrence of these metabolic conditions. Patients with MASH have a much higher mortality rate compared to the general population or those without this inflammatory subtype of MASLD. MASH is accompanied by a high mortality rate, so it is considered a crucial point under study.

Objective: The current review outlines MASH features, its pathogenesis which is based on 'two hits' and 'multiple hits' theories and its great rate of incidence. The review also displays detailed explanations of the invasive and noninvasive methods for diagnosis focusing on NAS scoring system. Moreover, this review offers critical presentation of the most important experimental models and their drawbacks. Additionally, a summary of the substantial emerging pathways of molecular pathogenesis, therapeutic approaches (non-pharmacological and pharmacological), and up-to-date clinical drug trials are elucidated.

Conclusion: Data presented in our review could facilitate understanding the molecular mechanisms involved in MASH development and interference by effective therapeutic modalities.

Background: Doxorubicin- (DOX-) related cardiotoxicity is a progressive degenerative loss of cardiac muscle mass and strength. This investigation aims to compare the anticipated cardioprotective effects of crocin (Cr) and dapagliflozin (DAPA) against DOX-induced cardiotoxicity, and to assess their effects on apoptosis and the Nrf-2/HO-1/NQO1 pathway.

Materials and methods: Forty Wistar male rats were randomly divided into four groups: The control group received distilled water (DW) by oral gavage. The DOX group was given DOX 3 times/week, i.p., 2.5 mg/kg for three weeks. The Cr + DOX-treated group was intraperitoneally injected with Cr daily, concomitantly with DOX, for 12 weeks. The DAPA + DOX-treated group received DAPA daily by oral gavage concomitantly with DOX for 12 weeks. Initial fasting blood glucose (FBG), body weight, vital signs, systolic blood pressure (SBP), and electrocardiography (ECG) were recorded and then repeated monthly throughout the study period. After 12 weeks, biochemical analyses were performed. Moreover, histopathological and immunohistochemical examinations of cardiac tissue were conducteed.

Results: DOX significantly affected FBG and increased oxidative stress markers and proinflammatory cytokines, with hypotension, bradycardia, ECG changes, and downregulation of antioxidant genes (Nrf-2/HO-1/NQO1) mRNA. Besides, cardiac biomarkers deteriorated. Administration of either Cr or DAPA resulted in significant improvements in all tested parameters compared with DOX. However, the DAPA + DOX group showed greater improvement, particularly in some parameters.

Conclusion: DAPA is a promising new cardioprotective medication against DOX-related cardiotoxicity. Cardiotoxicity is better controlled with DAPA than Cr by suppressing oxidative stress, apoptosis, and upregulation of the antioxidant Nrf-2/HO-1/NQO1 genes.

Objectives: Pulpitis is a dynamic condition that affects vascular and immune responses. A major driver of inflammation is the inflammasome, which regulates interleukin-1 (IL-1) family cytokines and pyroptosis. Pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) activate the inflammasome via caspase recruitment, which is essential for the inflammasome's immunomodulatory effects.

Materials: In order to synthesize evidence for this review, a comprehensive search was conducted in PubMed, Scopus, and Web of Science. Subsequently, preclinical models and clinical studies on the role of inflammasome components in dental pulp inflammation were selected and critically presented.

Results: According to recent research, factors associated with the inflammasome are dysregulated during dental pulpitis, while therapeutic targeting through computational discovery of anti-inflammasome ligands and cell-free exosome-based treatments can counteract the immunopathology of dental pulpitis.

Conclusion: Although preclinical studies were promising, comprehensive clinical trials of IL-1 family and inflammasome inhibitors are required for translating current research into viable treatments for patients with dental pulpitis. Future work should prioritize clinical validation to enable implementation in patient care.

Background: The anti-inflammatory effect of dexmedetomidine can be mediated through alpha7 nicotinic acetylcholine receptor (α7nAChR). However, it remains unknown whether α7nAChR is involved in mediating the effects of dexmedetomidine on CD4⁺T cell differentiation. The study aims to explore whether dexmedetomidine can affect CD4⁺T cell differentiation through α7nAChR.

Methods: Naïve CD4⁺T cells obtained from mouse spleens were incubated with different concentrations of dexmedetomidine for 3 days in vitro. The percentages of helper T (Th)1, Th2, Th17, and regulatory T (Treg) cells were determined by flow cytometry. The corresponding transcription factors T-bet (Th1), GATA-3 (Th2), ROR γt (Th17), and Foxp3 (Treg) were detected using quantitative real-time PCR. Mice with tibia fracture were pretreated with dexmedetomidine or methyllycaconitine (MLA, an α7nAChR antagonist) for 48 h in vivo. The percentages of Th1, Th2, Th17, and Treg cells were determined. Naïve CD4⁺T cells were incubated with dexmedetomidine and MLA in vitro and Treg cells were detected. The level of interleukin (IL)-10 secreted by Treg cells was quantified by an enzyme-linked immunosorbent assay.

Results: Dexmedetomidine administration, both in vitro and in vivo, suppressed Th1 cell differentiation along with its transcription factor T-bet, while promoting Treg cell differentiation and upregulating Foxp3. Conversely, MLA reversed these effects of dexmedetomidine on Th1 and Treg cell differentiation in vivo. In vitro, MLA also attenuated the dexmedetomidine-induced enhancement of Treg cell differentiation and the associated IL-10 secretion.

Conclusion: Dexmedetomidine promotes Treg cell differentiation while inhibiting Th1 cell differentiation. This regulatory activity on Treg cells may be mediated through the α7nAChR pathway.

Objective: This study aimed to examine the impact of riboflavin (RF) on tumor necrosis factor-alpha (TNF-α), caspase-3 (Cas-3) expression, and Sirtuin1 (SIRT1)/protein 53 (p53)/Bcl-2-associated X protein (Bax)/B-cell lymphoma gene-2 (Bcl-2) gene expressions in the diatrizoate (DTZ)-induced experimental nephropathy model.

Methods: Within the scope of the study, 32 Wistar Albino-type female rats were divided into 4 groups (n = 8). The groups were as follows: Control, DTZ (Rats were given 1 ml saline (SF) by oral gavage for three days. On the third day, intraperitoneal 10 ml/kg and 2.5-3 ml in volume of Urografin in a single dose), DTZ+RF (Rats were given 100 mg/kg RF by oral gavage for three days. On the third day, intraperitoneal 10 ml/kg and 2.5-3 ml of Urografin in a single dose) and RF (Rats were given 100 mg/kg RF by oral gavage for three days. On the third day, intraperitoneal 2.5-3 ml of SF in a single dose). Histopathological, immunohistochemical (TNF-α, Cas-3), biochemical (total antioxidant status (TAS), total oxidant status (TOS), oxidative stress index (OSI), urea and creatinine), and genetic (SIRT1, p53, Bax, Bcl-2) analyses were performed on the kidney tissues.

Results: In the DTZ group, pathologic changes, TNF-α and Cas-3 expressions, TOS, OSI, urea, and creatinine levels, p53, and Bax gene expressions increased, while biochemical TAS levels, genetic SIRT1 and Bcl-2 gene expressions decreased. It was determined that these findings observed in the DTZ group were reversed with RF treatment.

Conclusions: All these results suggest that DTZ-induced renal damage develops through oxidative stress, inflammation, and apoptosis mechanisms and that RF administration can protect renal function by suppressing these processes.

Objective: The research aimed to explore the protective effect of Nodakenin against cerebral ischemia-reperfusion (I/R) injury and its underlying mechanism, with a particular focus on the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/nuclear factor kappa B (NF-κB) signaling axis, neuroinflammation, oxidative stress and ferroptosis.

Methods: The function of Nodakenin was investigated in a rat middle cerebral artery occlusion and reperfusion (MCAO/R) model and a PC12 cell oxygen-glucose deprivation and reoxygenation (OGD/R) model. Infarct size was evaluated by 2,3,5-triphenyltetrazolium chloride (TTC) staining, brain edema was quantified using the wet-dry weight method, and histological changes were examined by hematoxylin and eosin (HE) staining. Biochemical assays and Western blotting was detected by malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase 4 (GPX4), ferritin heavy chain 1 (FTH1), tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β), and interleukin 6 (IL-6), along with PI3K/AKT-NF-κB pathway activity.

Results: Nodakenin treatment reduced infarct volume, histological damage and brain edema in cerebral I/R models. Nodakenin treatment suppressed proinflammatory cytokines, decreased MDA, restored SOD activity and attenuated ferroptosis-related alterations including Fe²⁺ accumulation and downregulation of GPX4 and FTH1. Consistent effects were observed in PC12 cells subjected to OGD/R. Mechanistically, Nodakenin activated the PI3K/AKT signaling pathway but suppressed NF-κB activation. These protective effects were abolished by PI3K inhibitor LY294002.

Conclusion: Nodakenin exerted neuroprotective effects against cerebral I/R injury by regulating the PI3K/AKT/NF-κB pathway to reduce neuroinflammation, oxidative stress and ferroptosis. These findings identify Nodakenin as a promising candidate for limiting secondary injury after ischemic stroke.

Background: Chronic respiratory diseases (CRDs) affect over 545 million individuals globally, with COPD alone causing approximately 3.2 million deaths annually. Flavonoids have shown promise in reducing lung inflammation and disease risk; however, their clinical application is hindered by poor solubility and low bioavailability. Nanocarrier-based pulmonary delivery systems offer a solution by enabling targeted, controlled release and improved solubility.

Objective: This review explores the preclinical and clinical potential of flavonoid-loaded nanocarriers in mitigating CRDs by regulating inflammation and cellular senescence, while offering sustained release and enhanced biocompatibility.

Methods: A comprehensive analysis of flavonoid mechanisms in modulating inflammatory pathways (e.g. NF-κB, Nrf2/Keap1) and enzymes (COX, 5-LOX, iNOS) was conducted using data from electronic databases (PubMed, ScienceDirect, Web of Science, TRIP, Springer). MeSH terms included 'Flavonoids,' 'Preclinical Studies,' 'Clinical Trials,' and 'Lung Health.' Taxonomy, epidemiology, and chemical data were verified using World Flora Online, WHO factsheets, and ChemSpider.

Results: Flavonoid-loaded nanocarriers demonstrated significant anti-inflammatory and antioxidant effects. PLGA-based systems reduced TNF-α and IL-6 levels by up to 80%. Lipid-based carriers (SLNs, NLCs) enhanced bioavailability 2-5 fold, while liposomes improved cell viability (40-50%) and reduced oxidative stress (>60%). Inhalable nanoformulations, such as quercetin achieved 3-fold higher lung concentration and 50% longer retention compared with oral formulations.

Conclusion: Flavonoid-loaded nanocarriers, especially liposomes, show enhanced pulmonary targeting, bioavailability, and therapeutic efficacy in CRDs. Their ability to suppress inflammation and cellular aging highlights their potential as a promising nanomedicine strategy for improving lung health.

Objective: To investigate whether vitamin D modulates gut microbiota and the colorectal cancer (CRC) immune microenvironment through the vitamin D receptor (VDR)-JAK-STAT signaling pathway.

Methods: Thirty male SD rats were randomly divided into the control group (CG), model group (MG), and vitamin D intervention group (VDG). Protein expression levels of VDR-JAK-STAT pathway (VDR, p-JAK2/JAK2, p-STAT3/STAT3), gut microbiota composition (via 16S rRNA sequencing), and immune markers (CD4⁺/CD8⁺ T cells, regulatory T cells (Treg), interleukin (IL)-6, IL-10, tumor necrosis factor (TNF)-α were compared across the groups.

Results: Compared to the CG, the MG exhibited a significant reduction in VDR expression (p < 0.05) and a marked increase in the p-JAK2/JAK2 and p-STAT3/STAT3 ratios (p < 0.05). The gut microbiota α-diversity (Shannon/Chao1 indices) was significantly reduced (p < 0.05), and microbial composition was abnormal, with a decrease in Bacteroidetes and an increase in Firmicutes/Proteobacteria (p < 0.05). Immune microenvironment imbalance was characterized by a reduction in CD4⁺ T cells (p < 0.05), an increase in Treg cells (p < 0.05), elevated pro-inflammatory cytokines IL-6/TNF-α, and decreased anti-inflammatory cytokine IL-10 (p < 0.05). Vitamin D intervention significantly reversed these abnormalities (all p < 0.05). The MG also showed a significant increase in macrophage proportion and M2 polarization, and a significant decrease in dendritic cell proportion and M1 macrophage polarization (all p < 0.01). Vitamin D intervention reversed the polarization imbalance, reducing total macrophages, increasing M1 polarization, and decreasing M2 polarization (all p < 0.05).

Conclusion: Vitamin D inhibits excessive activation of the JAK-STAT pathway through VDR activation, ameliorates gut microbiota dysbiosis, restores butyrate metabolism, and rebalances macrophage polarization.

The context of the article: Diffuse large B-cell lymphoma (DLBCL) is the most common pathological type of non-Hodgkin lymphoma. Breviscapine is an active ingredient of flavonoids extracted from breviscapus. However, the role of Breviscapine in DLBCL remains unclear.

Objective: We aimed to clarify the Breviscapine impact on DLBCL.

Materials and methods: The toxic effect of Breviscapine on GM12878 cells and DLBCL cells was verified by Cell Counting Kit-8 (CCK-8) analysis. The function of Breviscapine in DLBCL was assessed using CCK-8, Hoechst staining, Western blot, Enzyme-Linked Immunosorbent Assay (ELISA), lactate dehydrogenase (LDH) cytotoxicity analysis, and flow cytometry. Also, the role of Breviscapine in vivo was determined by hematoxylin-eosin, TUNEL staining, immunohistochemical, and Western blot in tumor xenograft model.

Results and discussion: Breviscapine was nontoxic to GM12878 cells when the Breviscapine dose was ≤200 μM. Functionally, Breviscapine weakened DLBCL cell proliferation (IC50 = 52.62 μM for U2932 cells, and IC50 = 39.74 μM for OCI-LY3 cells) and induced cell apoptosis. Also, Breviscapine repressed DLBCL cell immune escape by reducing PD-L1 expression in DLBCL cells, raising TNF-α and IFN-γ levels in DLBCL cells and CD8⁺ T cell co-culture supernatant, but decreasing CD8⁺T cell apoptosis. Mechanistically, Breviscapine inactivated JAK2/STAT3/PD-L1 in DLBCL cells. Meanwhile, Breviscapine restrained DLBCL cell growth and immune escape, but these impacts were abolished after JAK2 overexpression. Furthermore, Breviscapine reduced the tumor growth, tumor volume and weight, decreased PD-L1, p-JAK2 and p-STAT3 levels, but increased IFN-γ levels in mice.

Conclusion: Breviscapine repressed DLBCL cell growth and immune escape via inactivating JAK2/STAT3/PD-L1.