课程文献中心 更多>>

关键词： PONV   AP   NLRP3   MCC950   IL-1 beta  

摘要： Background: Postoperative nausea and vomiting (PONV) are common complication following surgical procedures, which can significantly impair the quality of patient care, delay discharge, and hinder the resumption of daily activities. In clinical practice, the incidence of PONV after thyroid surgery is approximately 30 %, with a higher prevalence among female patients. Although existing studies have identified various risk factors, treatment methods, and preventive strategies for PONV, research progress in this field has been relatively slow in recent years. Given that rodents lack a functional emetic reflex, precluding direct observation of vomiting, there remains a paucity of suitable animal models for studying PONV. Prior studies have been confined to anatomical and pharmacological investigations, while research on the molecular, cellular, and neural circuit mechanisms of post-thyroidectomy PONV remains scarce. In the existing research, some scientists have defined the behavior of mice opening their mouths as the occurrence of nausea and vomiting in mice. Here, we aim to establish a rodent model of thyroidectomy-induced retching-like behavior (TIRB) in mice to mimic PONV, thereby enabling systematic characterization of its neural and molecular regulatory pathways. Methods: In this study, a mouse model of retching-like behavior was established using thyroidectomy. Using transcriptomics, we explored the up-regulated genes after TIRB, focusing on finding feasible targets for TIRB treatment. Meanwhile, we used immunofluorescence and qPCR to verify the expression of up-regulated genes. Results: Our screening revealed that IL-1 beta, an inflammatory factor associated with NLRP3, was significantly up-regulated after TIRB. In addition, immunofluorescence revealed a significant increase in NLRP3 expression in area postrema, and treatment with MCC950, a specific NLRP3 inhibitor, decreased retching-like behavior incidence in mice. Conclusion: These results suggest that NLRP3-r

关键词： Interferon   Oncolytic adenoviruses   Combination therapy   Melanoma  

摘要： Melanoma is an aggressive malignancy originating from melanocytes, marked by its high metastatic potential, severe malignancy, and poor prognosis. The primary clinical approach involves surgical resection, complemented by adjuvant therapies such as radiotherapy, chemotherapy, targeted therapies, and immunotherapies. In recent years, high-dose IFN alpha 2b has emerged as a pivotal adjuvant therapy following surgery. However, the clinical remission rate of IFN alpha 2b as a standalone treatment remains limited, prompting deeper exploration into novel immune combination therapies to improve response rate. Oncolytic adenoviruses (OA) selectively target and destroy cancer cells, activate localized immunity, and synergize with other tumor inhibitors, offering a promising new avenue to cancer treatment. In light of this, we investigated the combination of IFN alpha 2b and OA for melanoma treatment. The combination therapy showed excellent tumor inhibition effects in a melanoma mouse model. Importantly, the combination of IFN alpha 2b and OA significantly induced immunogenic tumor cell death and improved tumor antigen presentation compared to either therapy alone. This enhancement bolstered the activation and proliferation of CD8+ T cells, driving a more potent anti-tumor immune response.

关键词： TSLP   Nanobody   Asthma   Komagataella phaffii  

摘要： Thymic stromal lymphopoietin (TSLP) is an epithelial cell-derived cytokine that plays a crucial role in the pathophysiology of asthma, initiating multiple allergic cascade responses. Tezepelumab is the only monoclonal antibody currently approved for marketing, which acts by blocking TSLP binding to TSLPR. However, it is reported that a TSLP trap which simultaneously block TSLP binding with TSLPR and IL-7R alpha has better efficiency in the repression of TSLP signal pathway. In this study, we identified two monovalent nanobodies targeting TSLP through immunization of alpacas and phage display screening. They could block TSLP binding with the TSLPR and IL-7R alpha receptors, respectively. Then, various protein linkers were designed between these two monovalent nanobodies to form different biparatopic nanobodies. We found that the affinity and biological activity of biparatopic nanobodies are related to the length of the linkers and the tandem order of the nanobodies. We screened a biparatopic nanobody CRNB909, which exhibits extremely high binding affinity for human TSLP with a KD < 1E-12 M, demonstrating approximately 40-fold greater potency compared to the Tezepelumab antibody (KD = 3.98E-11 M). Furthermore, it shows superior functional activity in biological assays, displaying 9.2-fold enhanced inhibition of TSLP-mediated JAK-STAT signaling pathway activation and 4.3-fold greater suppression of TSLP-induced BAF3 cell proliferation relative to Tezepelumab. Finally, CRNB909 was successfully secretory expressed in Komagataella phaffii with reduced production costs. This study provides a biparatopic nanobody that could bind TSLP to simultaneously block TSLPR and IL-7R alpha, which might be a promising therapeutant for TSLP related diseases.

关键词： Periapical periodontitis   Lysosomal membrane protein   Dental cementum   Cell death   Autophagy   Signal transduction  

摘要： Apical periodontitis (AP) is globally prevalent and characterized by inflammatory infiltration and periapical bone loss. The systemic RNA interference deficient-1 transmembrane family member 2 (Sidt2) is a nucleic acid transporter that plays essential roles in apoptosis and inflammatory response. However, the effect of Sidt2 on AP remains unknown. In this study, we established an AP mouse model and treated MC3T3-E1 cells and OCCM-30 cells with tumor necrosis factor-alpha (TNF-alpha). Compared to the control groups, the results of Western blot and quantitative real-time polymerase chain reaction (qRT-PCR) analysis confirmed that Sidt2 expression was downregulated in the AP mouse model and TNF-alpha-treated cells, in parallel with increased apoptosis and the production of inflammatory molecules, as evaluated by hematoxylin and eosin staining and immunohistochemistry staining. Furthermore, knockdown of Sidt2 reduced autophagic flux, aggravated TNF-alpha-induced apoptosis and inflammation in vitro, as detected by flow cytometry, Western blot, enzyme-linked immunosorbent assay, and qRT-PCR, and overexpression of Sidt2 yielded the opposite results. In addition, the autophagy inhibitors Chloroquine or 3-Methyladenine could reverse TNF-alpha-induced effects after overexpression of Sidt2. Moreover, knockdown of Sidt2 activated the TNF-alpha-induced p65 signaling, while blocking it with Pyrrolidinedithiocarbamate ammonium suppressed TNF-alpha-induced effects and autophagy. Taken together, our results suggest that Sidt2 ameliorates TNF-alpha-induced apoptosis and inflammation by enhancing autophagic flux via the downregulation of p65 signaling. These results demonstrate that Sidt2 functions as a negative regulator in the apoptosis and inflammatory response of AP, and it may contribute to the development of novel diagnostic and therapeutic approaches for the disease.

关键词： Stress   Depressive   Neutrophils   Lymphocytes   Machine learning   Bone marrow  

摘要： Environmental stress contributes to the development of depression through neuro-immune interactions, yet the underlying molecular mechanisms and associated clinical diagnostic biomarkers remain unclear. We established a psychosocial stress mouse model and systematically investigated the immune dysregulation induced by stress through integrated analysis of blood cell profiles, leukocyte transcriptomics, protein-protein interaction networks, single-cell RNA sequencing, and targeted pharmacological intervention. Additionally, we constructed and validated a depression predictive model using multiparametric peripheral blood data and machine learning, and assessed feature importance using the SHapley Additive exPlanations (SHAP) analysis. The results show that stressed mice exhibited increased neutrophils and decreased lymphocytes, which were positively correlated with depressive-like behaviors. Differential expression analysis identified 127 differentially genes enriched in pathways related to immune response, inflammation regulation, and hematopoietic dysfunction. Hub-genes (Rel, Cd274, Icam1, Tnf, Maff, Nfkbia) were upregulated and drove leukocyte redistribution via inflammatory cascades and adhesion mechanisms, whereas TNF/NF-kappa B pathway inhibition (Etanercept/Infliximab) reversed bone marrow immune imbalance and ameliorated depressive-like behavior. The random forest (RF) model trained with RF-mean features and random oversampling resampling based on blood cell parameters achieved 91.60 % accuracy and an AUC of 0.65. SHAP analysis identified RDW, MOPCT, PLTSI, SII, and NPR as biomarkers. In short, this study elucidates the regulatory role of bone marrow immune remodeling in stress-induced depression and proposes a feasible predictive strategy based on multiparametric peripheral blood profiling.

关键词： Alzheimer's disease   Ferroptosis   IL-17 pathway   TNF pathway   Single-cell sequencing   Network pharmacology  

摘要： Alzheimer's Disease (AD) is a neurodegenerative condition marked by cognitive decline and memory loss, with ferroptosis, an iron-dependent form of regulated cell death, emerging as a contributing factor. This study explored the potential modulatory effects of key components of the traditional Chinese medicine (TCM) formula Linggui Zhugan Decoction (LZD) on microglial ferroptosis in AD, focusing on IL-17 and TNF signaling pathways. Using single-cell RNA sequencing, we observed alterations in microglial populations and ferroptosis-related gene expression in AD mice. Network pharmacology and in vitro experiments indicated that LZD components might influence ferroptosis-related pathways, coinciding with reduced IL-17 and TNF levels in A beta 1-42-treated microglia. In vivo, LZD administration was associated with improved behavioral outcomes and modulation of ferroptosis markers. Although our findings suggest a correlation between LZD treatment and attenuation of ferroptosis-associated pathology, further mechanistic validation is necessary to establish causal links. This study provides preliminary evidence supporting the therapeutic potential of TCM in AD via inflammatory pathway modulation.

关键词： Malaria   Self-assembling protein nanoparticle (SAPN) FluoroSpot   T cells   Epitope   HLA  

摘要：

关键词： Psoriasis   Relapse psoriasis   mRNA   LNP   TNF-alpha  

摘要： Psoriasis is an autoimmune skin disease that substantially impairs patients' quality of life and presents clinical challenges due to frequent relapses and adverse effects associated with conventional therapies, including glucocorticoids and immunosuppressants. Although tumor necrosis factor-alpha (TNF-alpha) inhibitors are widely used as front-line treatments, safer alternatives remain imperative. Here, RET-1-mRNA-LNP, a novel mRNA-based TNF-alpha inhibitor, was developed and comprehensively evaluated for its therapeutic efficacy in imiquimod (IMQ)-induced psoriasis and relapse mouse model. RET-1-mRNA-LNP demonstrated superior efficacy in reducing erythema, scaling, and epidermal hyperplasia, along with a significant suppression of Th17 cell activity and other immune cell infiltration into lesional skin. Mechanistically, RET-1-mRNA-LNP delayed psoriasis recurrence by suppressing IL-15 production and generation of tissue-resident memory T (TRM) cells. These findings provide novel insights and a theoretical foundation for developing TNF-alpha-targeting mRNA-based therapeutics for psoriasis treatment, evoking potential applications in other autoimmune diseases characterized by excessive TNF-alpha production.

关键词： HT22 hippocampal neurons   Mitophagy   Propofol   p-Tau   TNF-alpha  

摘要： Background: Tau protein is a soluble microtubule-binding protein expressed in neurons. Abnormal posttranslational modifications, such as hyperphosphorylation, are closely related to central nervous system inflammation and may lead to neuronal damage. Propofol has been shown to exert neuroprotective effects. In this study, we investigated the effects of propofol on TNF-alpha-induced p-Tau increase in hippocampal neurons and explored the underlying mechanisms. Methods: HT22 hippocampal neurons were pretreated with propofol, and then stimulated with TNF-alpha. Cell viability was measured by cell counting kit-8 (CCK-8). The expression and phosphorylation of Tau, AMPK, AKT and the expression of SIRT3 were detected by Western blot. Mitophagy was detected through the mitophagy detection kit and confocal imaging of LC3B localization. Results: TNF-alpha enhanced Tau phosphorylation in a time- and dose-dependent manner, and significant effects were observed at 10 ng/mL for 2 h. Pretreatment with 25 mu M propofol for 1 h effectively reduced TNF-alpha-induced Tau phosphorylation. TNF-alpha activated the phosphorylation of AMPK and AKT, which was attenuated by propofol pretreatment and by AMPK inhibitor (Compound C) or AKT inhibitor (MK2206). Meanwhile, TNF-alpha promoted mitophagy and upregulated the expression of SIRT3, which was inhibited by propofol and by SIRT3 inhibitor (3TYP). Conclusions: Propofol may attenuate TNF-alpha-induced p-Tau expression in HT22 cells through modulation of the AMPK/AKT signaling pathway, and may inhibit TNF-alpha-enhanced mitophagy by affecting the AMPK/SIRT3 signaling pathway.

关键词： Immuno-radiotherapy   Spatiotemporal drug release   Interleukin-12 (IL-12)   Bilayer nanofiber stent   In situ vaccination effect  

摘要： Internal radiation (IR), utilizing iodine-125 (125I) seeds as a radiation source, is a clinically established modality for targeted treatment of malignant tumors. In addition to inducing DNA damage in tumor cells, IR therapy can trigger systemic antitumor immune responses, known as the abscopal effect, through immunogenic cell death (ICD). However, the gradual decline in radioactive output and the inherently limited immunogenicity of IR therapy compromise its overall efficacy, with the abscopal effect rarely observed in clinical settings. To overcome these challenges, we developed a bilayer nanofiber-coated stent integrating 125I seed-based brachytherapy with sustained, spatiotemporally controlled delivery of interleukin-12 (IL-12). Utilizing FDA-approved PLGA and PEO polymers, the inner layer was engineered for IL-12 loading, while the outer layer acted as a regulatory barrier, achieving a biphasic release profile with sustained cytokine delivery for up to 14 days. In vivo studies demonstrated that the IL-12@IRS (IL-12-loaded 125I internal radiation stent) effectively enhanced antigen presentation and elicited a tumor in situ vaccination effect, thereby promoting durable local and systemic antitumor immunity. This immuno-radiotherapeutic platform not only improves local tumor control but also offers a promising strategy for overcoming immune resistance and inducing robust systemic antitumor effects.