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关键词： attention mechanism   differential learning   T cell receptor   neoantigen   pMHC-I binding   TCR-pMHC-I recognition  

摘要： The identification of neoantigens is crucial for advancing vaccines, diagnostics, and immunotherapies. Despite this importance, a fundamental question remains: how to model the presentation of neoantigens by major histocompatibility complex class I molecules and the recognition of the peptide-MHC-I (pMHC-I) complex by T cell receptors (TCRs). Accurate prediction of pMHC-I binding and TCR recognition remains a significant computational challenge in immunology due to intricate binding motifs and the long-tail distribution of known binding pairs in public databases. Here, we propose an attention-aware framework comprising TranspMHC for pMHC-I binding prediction and TransTCR for TCR-pMHC-I recognition prediction. Leveraging the attention mechanism, TranspMHC surpasses existing algorithms on independent datasets at both pan-specific and allele-specific levels. For TCR-pMHC-I recognition, TransTCR incorporates transfer learning and a differential learning strategy, demonstrating superior performance and enhanced generalization on independent datasets compared to existing methods. Furthermore, we identify key amino acids associated with binding motifs of peptides and TCRs that facilitate pMHC-I and TCR-pMHC-I binding, indicating the potential interpretability of our proposed framework.

关键词： Caerin 1.1/1.9   IFNAR-1/STAT1   alpha-PD-1   Anti-CD47  

摘要： Previously, we demonstrated that natural host-defence peptide caerin 1.1/caerin 1.9 (F1/F3) increases the efficacy of anti-PD-1 and therapeutic vaccine, in a HPV16 + TC-1 tumour model, but the anti-tumor mechanism of F1/F3 is still unclear. In this study, we explored the impact of F1/F3 on the tumor microenvironment in a transplanted B16 melanoma model, and further investigated the mechanism of action of F1/F3 using monoclonal antibodies to deplete relevant cells, gene knockout mice and flow cytometry. We show that F1/F3 is able to inhibit the growth of melanoma B16 tumour cells both in vitro and in vivo. Depletion of macrophages, blockade of IFN alpha receptor, and Stat1 inhibition each abolishes F1/F3-mediated antitumor responses. Subsequent analysis reveals that F1/F3 increases the tumour infiltration of inflammatory macrophages, upregulates the level of IFN alpha receptor, and promotes the secretion of IFN alpha by macrophages. Interestingly, F1/F3 upregulates CD47 level on tumour cells;and blocking CD47 increases F1/F3-mediated antitumor responses. Furthermore, F1/F3 intratumor injection, CD47 blockade, and therapeutic vaccination significantly increases the survival time of B16 tumour-bearing mice. These results indicate that F1/F3 may be effective to improve the efficacy of ICB and therapeutic vaccine-based immunotherapy for human epithelial cancers and warrants consideration for clinical trials.

关键词： Saffron   Colorectal cancer   IL-17   Immunotherapy  

摘要： Ethnopharmacological relevance: Saffron is one of the traditional medicinal herbs, which contains various active ingredients, such as safranal, crocin, saffron acid, etc. It has anti-inflammatory, antioxidant, and anti-cancer properties, and is widely used in clinical practice. The anti-cancer efficacy of saffron has been previously confirmed, but its anti-cancer mechanism in colorectal cancer remains unclear. Objective: We investigated the effect of active compounds of saffron on the efficacy of immunotherapy for colorectal cancer. Methods: TCMSP and liquid chromatography-mass spectrometry analysis (LC-MS), GeneCards, and DisGeNET databases were used to identify the active compounds of saffron, drug targets and the disease targets of colorectal cancer. They were then subjected to Gene Ontology Enrichment (GO) and Signalling Pathway Enrichment (KEGG) analyses. The core targets and corresponding compounds were selected for molecular docking. The effect of active components of saffron on the proliferation of CT26 and HCT116 cells was investigated using the cell counting kit-8 (CCK-8). In vitro experiments were conducted by subcutaneous injection of CT26 cells to establish a colon cancer model. Enzyme-linked immunosorbent assay (ELISA), western blotting (WB), real-time polymerase chain reaction (RT-PCR), immunohistochemistry (IHC), and flow cytometry (FCM) were employed to validate the effects of saffron on colorectal cancer immunotherapy. Results: 1. LC-MS analysis revealed that the main active component of saffron extract was crocin. The active chemicals of saffron intersected with 170 colorectal cancer targets, with 17 predicting targets for saffron treatment. GO and KEGG enrichment analyses revealed that the active components of saffron can prevent colorectal cancer development by enhancing Th17 cell differentiation and the IL-17 signaling pathway. 2. In vitro studies revealed that saffron alcohol extract, crocin, and safranal can suppress the proliferation of CT26

关键词： periodontitis   smoking   TMAO   TNF-alpha  

摘要： Aims Trimethylamine N-oxide (TMAO) is a compound involved in the pathogenesis of various systemic inflammatory diseases, including cardiovascular conditions. The aim of this study was to determine differences in saliva and serum levels of TMAO between periodontitis and healthy patients according to smoking status. Methods The study included four systemically healthy groups: periodontally healthy non-smokers (NS-Control;n = 25), non-smokers with Stage-III-Grade-B periodontitis (NS-Periodontitis;n = 25), periodontally healthy smokers (S-Control;n = 25), and smokers with Stage-III Grade-C periodontitis (S-Periodontitis;n = 25). Periodontal parameters were recorded. TMAO levels were determined in saliva and serum samples using liquid chromatography-mass spectrometry (LC-MS/MS). TNF-alpha levels were measured by the ELISA method. Results Salivary TNF-alpha and TMAO levels were significantly elevated in the smoking periodontitis group compared to other groups (p < 0.001 and p = 0.003, respectively). Serum TMAO levels were also significantly higher in the smoking periodontitis group compared to non-smoking controls and non-smoking periodontitis. TMAO/SFR ratios were notably higher in the smoking periodontitis group compared to other groups, and a strong positive correlation was observed between salivary TMAO and TNF-alpha levels (r = 0.892, p < 0.001). Conclusion The data suggested that TMAO and TNF-alpha are associated with inflammatory mechanisms of periodontitis in cases where periodontitis coexists with smoking.

摘要： Inflammation plays a central role in the progression of kidney injury induced by ischemia/reperfusion (IR). Meprin metalloproteinases have been implicated in the pathophysiology of IR-induced kidney injury. Existing data from in vitro and in vivo studies show that meprins modulate interleukin-6 (IL-6)-mediated inflammation via proteolytic processing of IL-6 and its receptor. IL-6 trans-signaling induces proliferation through either MAPK/ERK or PI3K/AKT pathway or in crosstalk with AKT/ERK. We previously showed that meprin β modulates cellular survival (BCL-2) through IL-6/JAK/STAT signaling pathway in IR-induced kidney injury. However, it's not known how meprin β modulation of the IL-6 signaling pathway impacts the cellular proliferation in IR-induced acute kidney injury. The goal of the current study was to determine how meprin β modulation of the IL-6 signaling pathway impacts downstream cellular proliferation in IR-induced kidney injury. We used the unilateral IR as a model of renal inflammation in wild-type (WT) and meprin β knockout (βKO) mice, with the contralateral kidneys serving as controls. The mice were sacrificed at 96 h post-IR, and kidney tissue processed for evaluation by RT-PCR and immunohistochemistry. Statistical analysis utilized two-way ANOVA. RT-PCR data showed a significant increase in mRNA levels for IL-6 and proliferating cell nuclear antigen (PCNA) in WT and βKO mice at 96 h-post IR when compared to WT control kidneys. However, the baseline mRNA levels for PCNA were significantly higher in βKO when compared to WT kidneys. Immunohistochemical data showed significant increases in IL-6, PCNA, p-AKT and p-ERK in select tubules in both genotypes at 96 h post-IR when compared to control kidneys for each genotype. Data from immunofluorescence counterstaining of kidney tissues revealed that at 96 hours post-IR, IL-6, PCNA, p-AKT, and p-ERK were primarily expressed in meprin β-expressing proximal tubules (PTs), where meprins are abundantly present. H

关键词： Shaoyao decoction   Ulcerative colitis   IL-17a   M1 macrophage polarization   PPAR/NF-kappa B pathway  

摘要： Ethnopharmacological relevance: The efficacy of Shaoyao decoction (SYD), a traditional Chinese medicine prescription, in alleviating colonic mucosal inflammation in ulcerative colitis (UC) has been established. However, the specific mechanism underlying the therapeutic effects of SYD on UC is not clear. Aim of study: In this study, we demonstrated the therapeutic effect of SYD on the polarization of M1 macrophages and elucidated the underlying mechanism. Materials and methods: UC mice were induced with 3% DSS for one week and subsequently treated with SYD for another week. The composition of SYD was determined by HPLC. To assess the therapeutic efficacy of SYD, key parameters, including body weight changes, DAI scores, colon length, and histological alterations in colonic tissues, were monitored. ELISA was performed to quantify inflammatory cytokines, while Western blotting and immunofluorescence analyses were performed to quantify tight junction protein expression and M1 macrophage infiltration, respectively. Functional assessments focused on lysosomal activity and glucose oxidation in primary macrophages and RAW 264.7 cells exposed to LPS, IL-17a, and SYD using dedicated kits. To elucidate the mechanisms underlying the action of SYD, the data derived from TMT-based proteomics were analyzed to screen and predict its potential targets and regulated pathways. Results: After treatment for seven days, SYD significantly mitigated colitis symptoms in mice, as determined by a decrease in body weight loss, an increase in colon length, and a decrease in disease activity index (DAI) score. The results of histopathological analysis showed substantial improvements in the integrity of colonic tissue. Additionally, SYD treatment significantly decreased the levels of proinflammatory cytokines, including IL-17a, IL-6, IL-1 beta, and TNF-alpha. This effect was accompanied by a reduction in the infiltration of CD86+ macrophages and restoration of occludin and ZO-1 levels, thus impro

关键词： Alzheimer disease   neuroinflammation   interleukin-6   C-X-C Motif Chemokine Ligand 8   cell viability   apoptosis   A beta particles  

摘要： Background Alzheimer disease (AD) is a progressive neurodegenerative disorder primarily affecting the elderly, characterized by severe cognitive impairment and memory loss. Emerging evidence suggests that neuroinflammation plays a significant role in AD pathogenesis, with cytokines like interleukin-6 (IL-6) and C-X-C motif chemokine ligand 8 (CXCL8) contributing to the disease *** We utilized Gene Expression Omnibus datasets to identify IL-6 and CXCL8 as pivotal inflammatory markers in AD. In vitro experiments were conducted using SK-N-BE(2)-M17 and THP-1 cell lines treated with IL-6 and CXCL8 to model AD. Additionally, in vivo tests on Amyloid Precursor Protein/Presenilin 1 (APP/PS1) AD mouse models were performed to assess the impact of these cytokines on cognitive functions and brain *** The results indicated a significant decrease in cell viability, increased apoptosis, and elevated inflammatory factor secretion following IL-6 and CXCL8 treatment in vitro. In vivo, AD mouse models treated with these cytokines exhibited exacerbated emotional distress, decreased social interaction, impaired cognitive functions, and increased amyloid protein deposition in neural *** The study highlights the detrimental effects of IL-6 and CXCL8 on neuronal health and cognitive functions in AD. These findings suggest that targeting these cytokines could offer potential therapeutic interventions for improving patient outcomes in Alzheimer disease.

关键词： advanced metastatic pancreatic cancer   3rd line therapy   orchestrated   multi-modal   N-803   PD-L1 t-haNK cells   low dose chemotherapy  

摘要： Background Metastatic pancreatic cancer (mPC) is an aggressive form of cancer with a poor prognosis and few therapeutic options after failure of the second-line treatment. Induction of immunogenic cell death (ICD) by use of relatively low-dose chemo- or radiation therapy, enhancement of immune responses by the IL-15 superagonist N-803 (Anktiva (R)), and targeting of programmed death receptor ligand 1 (PD-L1)-expressing cells may offer a therapeutic approach to refractory mPC with the potential to increase overall survival (OS).Methods From late 2019 to 2021, single-patient Investigational New Drug (spIND) protocols for five mPC patients were designed and approved that generally comprised combined Abraxane (nab-paclitaxel) and gemcitabine therapy with experimental therapeutics N-803, PD-L1-targeted high-affinity natural killer (PD-L1 t-haNK) cells, and aldoxorubicin, a serum albumin-binding doxorubicin prodrug. Some patients also received stereotactic body radiation therapy (SBRT), cyclophosphamide, pembrolizumab, nivolumab, and/or experimental ETBX-051 (brachyury) and/or ETBX-061 (MUC1) vaccines. Duration of spIND treatment and responses, for some patients including imaging and carbohydrate antigen 19-9 (CA19-9) levels, and OS from initial diagnosis and the start of spIND therapy were *** The line/duration of spIND therapy was, for patients 1 through 5, respectively, second line/6.4 months, sixth line/3.5 months, third line/25.4 months, third line/7.4 months, and fourth line/23.2 months. OS from the commencement of spIND therapy was 13, 4.8, 26.9, 9, and 23.2 months, and OS from diagnosis was 22, 21, 42, 13, and 33 months for patients 1 through 5, *** The OS from the initiation of spIND for all patients exceeded the reported OS for the greater-than-second-line mPC patients and, for four of five patients, second-line therapy. The OS of 13, 26.9, and 23.2 months for three patients is particularly notable. The findings here support th

关键词： Acute kidney injury   Inflammation   Oxidative stress   Rats  

摘要： The kidneys have a regulatory role in many diseases with their diuresis function and capacity to maintain electrolyte balance. In case of extensive damage, the kidney's filtration capacity is impaired and cannot fulfill its functions. Fluvoxamine (FLV), an antidepressant agent, has antioxidant and anti-inflammatory effects. This study aimed to investigate the protective effects of FLV against renal tissue damage in the lipopolysaccharide (LPS) induced systemic inflammation model. Thirty-two Wistar Albino rats were divided into four equal groups: control, LPS, LPS + FLV, and FLV alone. Six hours after LPS administration, rats were sacrificed and kidney tissues were removed. Histopathological examination of kidney tissues, immunohistochemical expression of the ACE-1, Cas-9, and interleukin-10 (IL-10), as well as spectrophotometric assessment of total oxidant status (TOS), total antioxidant status (TAS), oxidative stress index (OSI), urea, creatinine levels, and zonulin-1 (ZO-1), claudin-5 (CL-5), aquaporins 2 and 4 (AQ-2, AQ-4) were evaluated. TOS, OSI, urea, creatinine levels, and Cas-9 expressions were significantly increased, and TAS levels, ACE-1, IL-10, AQ-2, AQ-4, ZO-1, and CL-5 expressions significantly decreased in the LPS group compared with the control group. In addition, marked hyperemia, slight-to-moderate hemorrhages, and degeneration of the tubule epithelial cells were observed in kidney sections in the LPS group, in addition to the inflammatory cell infiltrations. FLV treatment significantly improved all these findings. FLV treatment ameliorates renal tissues against inflammatory scenes and protects renal function by enhancing IL-10 and ACE-1 expressions and preserving AQ-2, AQ-4, CL-5, and ZO-1 expressions.