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关键词： ferroptosis   IL-9   intestinal mucosal barrier   sepsis  

摘要： Background:Interleukin-9 (IL-9) is an emerging pro-inflammatory cytokine that promotes intestinal barrier injury (IBI) in sepsis. The specific mechanisms of IL-9-induced IBI still need to be clarified. As a newly discovered form of programmed cell death, ferroptosis was demonstrated to be involved in sepsis-related organ dysfunction, yet its role in IL-9-induced IBI in sepsis remains ***:Serum levels of IL-9, D-lactate, intestinal fatty acid binding protein (iFABP), glutathione (GSH), and glutathione peroxidase 4 (GPX4) were tested in septic patients and control subjects. Biomarkers reflecting barrier function in serum and intestinal tissue were tested in treated rats. Rats underwent sepsis induction, IL-9, IL-9 inhibition (IL-9i), and ferroptosis inhibition (Fei) treatment were selected to examine the severity of IBI and survival ***:Significantly elevated levels of IL-9, D-lactate, iFABP, GSH, and GPX4 were observed in septic patients and rats. IL-9 levels showed a negative correlation with GSH and GPX4 levels, while GSH or GPX4 levels showed an inverse correlation with D-lactate and iFABP levels. Serum GSH and GPX4 levels demonstrated strong predictive value for acute gastrointestinal injury of grade II and above in septic patients. IL-9 administration increased levels of transferrin receptor, Fe2+, and iFABP in serum and intestinal tissue of septic rats, while decreasing GSH, GPX4, and zonula occludens 1 levels. Inhibition of ferroptosis reversed these biomarkers alterations. Intestinal permeability, transmission electron microscopy, histopathology, and apoptosis assays confirmed exacerbated IBI following IL-9 upregulation and its attenuation upon ferroptosis ***:Ferroptosis was implicated in the IL-9-induced intestinal barrier injury in sepsis.

摘要： Objectives: Antimelanoma differentiation-associated gene 5-positive dermatomyositis (anti-MDA5(+) DM) is a rare subtype of myositis with a poor prognosis and insufficient genetic understanding. Our study aimed to identify risk variants associated with anti-MDA5(+) DM and to assess their correlation with clinical outcomes. Methods: We enrolled 231 anti-MDA5(+) DM patients, 127 anti-MDA5(-) DM patients, 1468 patients with non-DM rheumatic disease, and 1027 healthy controls, with an additional 51 anti-MDA5(+) DM patients for validation. Whole-exome sequencing was used to identify human leukocyte antigen (HLA) alleles, amino acids, and single nucleotide polymorphisms (SNPs) in major histocompatibility complex (MHC) and non-MHC regions. Association studies were performed to identify genetic variants associated with anti-MDA5(+) DM by comparing different sets of control groups. A clinical association study was conducted to further explore the influence of genetic factors on clinical manifestations. Results: Two novel genetic risks, HLA-DQA1*06:01 and HLA-DQB1*06:09, were significantly associated with anti-MDA5(+) DM in both the discovery and validation cohorts. HLA-DQA1*06:01 was particularly prevalent in anti-MDA5(+) DM (20.4%) compared with anti-MDA5(-) DM (6.69%) and non-DM rheumatic disease (5.93%). Besides, the strongest associated amino acid was HLA-DQ alpha 1:69 (P = 3.27 x 10(-11)), and 1 SNP in the ARHGAP22 gene (rs76208937) showed suggestive significance (P = 7.99 x 10(-6)). In addition, HLA-DQA1*06:01 was linked to acute rapidly progressive interstitial lung disease (P < .001), elevated levels of lactate dehydrogenase (P = .026), and death (P = .049) in patients with anti-MDA5(+) DM. Conclusions: HLA-DQA1*06:01 is a new genetic and prognostic factor for anti-MDA5(+) DM, potentially serving as a biomarker for early diagnosis and intervention.

关键词： PARP inhibitors   NK cells   Tumor immune evasion   HLA-G   TFEB  

摘要： Resistance to poly(ADP-ribose) polymerase inhibitors (PARPi) poses a significant challenge to enhancing the efficacy of cancer treatments. Beyond the cellular mechanisms intrinsic to tumor cells, the modulation of the tumor immune microenvironment is crucial in dictating the responsiveness to pharmacological interventions. Thus, there is a pressing need to elucidate the intricate interplay between PARPi and antitumor immune responses and to develop an optimized combinatorial therapeutic approach. In this study, using matched tumor samples before and after neoadjuvant monotherapy with the PARPi niraparib in a prospective clinical trial (NCT04507841), we observed a significant increase in natural killer (NK) cell infiltration post-treatment. However, this was not accompanied by the expected enhancement in their cytotoxic functions. This observation underscores the necessity to optimize the antitumor potential of NK cells by enhancing their cytotoxic capabilities. Upon exposure to niraparib, tumor cells, particularly those with wild-type EGFR, exhibited a pronounced upregulation of human leukocyte antigen G (HLA-G), an immune checkpoint impeding NK cell functions. Niraparib promotes EGFR internalization, which in turn diminishes AKT/mTOR signaling, leading to the increased transcriptional activity of the transcription factor EB (TFEB) and subsequent enhancement of HLA-G expression. The combination of niraparib with HLA-G blockade not only augmented NK cell-mediated tumor lysis in vitro but also synergistically inhibited tumor growth in humanized patient-derived xenograft models. Collectively, our results shed light on a previously unrecognized immune evasion mechanism and offer a compelling argument for the integration of HLA-G blockade with PARPi in cancer therapy.

关键词： anastomotic leakage   rectal cancer   IL-17   intraoperative hypothermia   risk factor  

摘要： Objective: In this prospective observational cohort study, we aim to investigate the risk factors for early postoperative anastomotic leakage (AL) in patients undergoing rectal cancer resection. Methods:This study included 459 patients with rectal cancer who underwent treatment at our hospital from January 2021 to October 2022. All patients were hospitalized for 1 week postoperatively and observed for the occurrence of AL. Fasting venous blood samples (5 mL) were collected from all cases 1 day before surgery and 1, 2, and 3 days after surgery, and serum levels of interleukins (IL)-17, IL-6, IL-1 beta, tumor necrosis factor-alpha, and C-reactive protein (CRP) were determined using enzyme-linked immunosorbent assay. Demographic, clinical data, intraoperative hypothermia, and nutritional indicators were collected for all patients. Statistical analysis was performed using SPSS 25.0 software. Results: AL patients had significantly lower hemoglobin, albumin (ALB) levels, and a higher proportion of intraoperative hypothermia compared to patients in the non-AL group (P < .05). On the first, second, and third days after surgery, patients in the AL group had significantly higher levels of serum CRP, IL-1 beta, and IL-17 compared to the non-AL group. Pearson's correlation analysis showed a positive correlation between serum IL-17 levels and CRP levels. Serum IL-17 had the highest predictive value for early AL, with an area under the curve (AUC) of 0.755 cutoff value of 94.77 pg/mL, a sensitivity of 70.1%, and a specificity of 66.0%. Moreover, logistic regression analysis indicated that intraoperative hypothermia, decreased ALB levels, and increased CRP, IL-1 beta, and IL-17 levels on the first day after surgery were identified as risk factors for early AL in rectal cancer patients. Conclusions:This study found a significant elevation of IL-17 levels in the serum of patients who experienced early postoperative AL. Furthermore, intraoperative hypothermia and elevated IL-17 level

关键词： Pt(IV) prodrug   Gramine   TGF-beta targeting   Immune regulation  

摘要： Platinum(II) (Pt(II)) drugs, such as cisplatin and oxaliplatin, played critical roles in cancer therapy;however, their efficacy is often limited by significant toxicity and the development of drug resistance. Recently, multi-target platinum(IV) (Pt(IV)) complexes, particularly those optimized with axial ligands, have emerged as promising alternatives enhancing tumor selectivity and drug stability. In this study, we synthesized a series of novel platinum(IV) prodrugs, gramine-platinum(IV), by incorporating gramine-a natural indole alkaloid that antagonizes TGF-beta receptors I and II to inhibit the TGF-beta signaling pathway-as an axial ligand. Among them, compound 8 (referred to as GP) was screened out to have the best antitumor activity. GP not only enhances the therapeutic efficacy of platinum(II) drugs but also targets TGF-beta signaling. Our findings demonstrate that GP rapidly enters cells and preferentially accumulates in critical subcellular compartments, such as the nucleus and mitochondria, significantly amplifying its therapeutic impact. Notably, GP exhibits great tumor accumulation compared to cisplatin and oxaliplatin, with minimal uptake in normal tissues, highlighting its superior tumor specificity with reduced systemic toxicity. This unique characteristic enables GP to enhance therapeutic efficiency through multiple modalities, including strengthening DNA damage, reducing mitochondrial membrane potential, promoting apoptosis, and arresting cell cycle in the S phase. Moreover, GP activates the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling (cGAS-STING) pathway, enhancing antigen presentation and fostering robust anti-tumor immune responses. In mouse models of pancreatic and breast cancer, GP significantly inhibits tumor growth and triggers strong innate immune activation. By combining GP with anti-PD-1 therapy, immunotherapy-resistant tumors are rendered responsive, leading to a pronounced suppression of tumor growth. O

关键词： Endometriosis   SCM-198   IFN-gamma T+ cells   CCR5(+)T cells   CCL5  

摘要： Endometriosis is a common gynecological disease that causes severe pain and infertility. However, the available treatments for EMS are limited. SCM-198, a synthetic form of leonurine, possesses various abilities, including anti-inflammatory, immunomodulatory, antioxidant, anti-fibrotic, and anti-proliferative effects. Previous studies have shown that SCM-198 can inhibit the growth of ectopic lesions, but the specific mechanism remains unknown. The results of our studies indicate that SCM-198 significantly suppresses the endometriotic growth of EMS mice. Enrichment analysis of RNA-seq indicates that SCM-198 is involved in T cell differentiation, activation, cytokine production, stimulation of chemotaxis, and migration. Flow cytometry reveals that SCM-198 reverses the decreased proportions of IFN-gamma T+ cells and CCR5 + T cells in ectopic lesions. RNA-seq analysis shows that SCM-198 enhances the expression of CCL5 in the ectopic lesions, and western blot is conducted to verify this conclusion both in vivo and in vitro. These findings demonstrate that SCM-198 reverses the decreased proportions of IFN-gamma + T cells and CCR5 + T cells, alleviating the growth of mouse ectopic lesions, and the changes in CCR5 + T cells are likely due to the reduced expression of CCL5.

关键词： allergic rhinitis   indolepropionic acid   immune modulation   AKT/CCAAT enhancer binding protein beta/IL-10 pathway   inflammatory response  

摘要： Allergic rhinitis (AR) is a common inflammatory disorder of the nasal mucosa, usually triggered by environmental allergens. Indolepropionic acid (IPA) can influence immune responses;however, the specific mechanisms underlying the effects of IPA on immune regulation in AR remain largely unexplored. In the present study, an experimental mouse model of AR was established by sensitizing and exposing the mice to allergens, followed by the administration of IPA via gavage. Nasal symptoms were assessed through behavioral scoring, histological examinations were conducted to evaluate changes in nasal mucosa, and cytokine levels were quantified using ELISA. The expression of key signaling molecules was analyzed by immunohistochemistry, reverse transcription-quantitative PCR and western blotting. Additionally, the effects of IPA combined with an AKT inhibitor (HY-10355) on signaling pathway-related proteins in human nasal epithelial cells were evaluated using cellular immunofluorescence and western blotting. The results revealed that IPA treatment significantly reduced nasal inflammation, as indicated by decreased sneezing and mucus secretion. Histological analysis showed reduced inflammatory cell infiltration and epithelial damage in IPA-treated mice compared to controls. Furthermore, cytokine analysis revealed reduced levels of the pro-inflammatory cytokines IL-4, IL-5, IL-13 and immunoglobulin E, along with increased levels of the anti-inflammatory cytokine IL-10. Molecular investigations demonstrated that IPA can activate the AKT/CCAAT enhancer binding protein beta pathway, leading to increased IL-10 expression and reduced inflammation. In conclusion, these findings suggested that IPA may serve as a promising therapeutic strategy for managing AR, pending further clinical validation.

关键词： Aβ   amyloid β peptide   Aβ   40   amyloid β peptide 40   Aβ   42   amyloid β peptide 42   ABC   ammonium bicarbonate   AD   Alzheimer’s disease   ADAM10   a disintegrin and metalloproteinase 10   ADAM17   a disintegrin and metalloproteinase 17   AGC   automatic gain control   APLP1   amyloid β precursor like protein 1   APP   amyloid-β precursor protein   ATV   antibody transport vehicle   BACE1   β-site APP cleaving enzyme 1   BACE2   β-site APP cleaving enzyme 2   BSG   basigin   CACHD1   VWFA and cache domain-containing protein 1   CHL1   neural cell adhesion molecule L1-like protein   CNTN2   contactin-2   CSF   cerebrospinal fluid   DDA   data-dependent acquisition   DIA   data-independent acquisition   DTT   dithiothreitol   FDR   false discovery rate   IAA   iodoacetamide   IL6ST   interleukin-6 receptor subunit β   ITGA4   integrin α-4   L1CAM   neural cell adhesion molecule L1   LC-MS/MS   liquid chromatography-coupled tandem mass spectrometry   LFQ   label-free quantification   LRRN1   leucine-rich repeat neuronal protein 1   NHP   non-human primate   PASEF   parallel accumulation-serial fragmentation   QARIP   quantitative analysis of regulated intramembrane proteolysis   RSV   respiratory syncytial virus   sAPPα   soluble APPα   sAPPβ   soluble APPβ   SEZ6   seizure protein 6 homolog   SEZ6L   seizure 6-like protein   SP3   single-pot, solid-phase-enhanced sample preparation   sVCAM-1   soluble VCAM-1   TfR   transferrin receptor   TMEM27   transmembrane protein 27   TNF   tumor necrosis factor   VCAM1   vascular cell adhesion protein 1 (gene name)   VCAM-1   vascular cell adhesion protein 1 (protein name)   VEGFR3   vascular endothelial growth factor receptor 3   VLA-4   very late antigen-4  

摘要： The beta-secretase beta-site APP cleaving enzyme 1 (BACE1) is a major drug target for Alzheimer's disease (AD). Clinically tested BACE1 inhibitors induced unexpected cognitive side effects that may stem from their cross-inhibition of the homologous protease BACE2. Yet, little is known about BACE2 functions and substrates in vivo, and no biomarker is available to monitor the extent of BACE2 inhibition in vivo, particularly in cerebrospinal fluid (CSF). To identify a potential CSF biomarker for monitoring BACE2 activity, we analyzed the CSF proteome changes in nonhuman primates after treatment with a BACE1-selective inhibitor (a brain-targeted monoclonal antibody) in comparison to verubecestat, a clinically tested small-molecule drug inhibiting both BACE1 and BACE2. Acute treatment with either the antibody or verubecestat similarly reduced CSF abundance of the cleavage products of several known BACE1 substrates, including SEZ6, gp130, and CACHD1, demonstrating similar target engagement in vivo. One CSF protein, vascular cell adhesion protein 1 (VCAM-1), was only reduced upon inhibition with verubecestat, but not upon BACE1-selective inhibition with the antibody. We conclude that VCAM-1 is a promising biomarker candidate for monitoring BACE2 inhibition in CSF, which is instrumental for the development of BACE1-selective inhibitors for the prevention of AD.

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.

关键词： Dermatophytoses   ILC3   Mycoses   T cells  

摘要： Fungal skin infections significantly contribute to the global human disease burden, yet our understanding of cutaneous immunity against dermatophytes remains limited. Previously, we developed a model of epicutaneous infection with Microsporum canis in C57BL/6 mice, which highlighted the critical role of IL-17RA signaling in antidermatophyte defenses. In this study, we expanded our investigation to the human pathogen Nannizzia gypsea and demonstrated that skin yBTCRint and CD8/CD4 double-negative (3TCR+ T cells are the principal producers of IL-17A during dermatophytosis. These IL-17A+ T cells exhibited an activated/memory phenotype, including a subset of proliferating tissue-resident cells. Notably, restriction of lymphocyte trafficking after fingolimod administration in infected mice did not lead to increased susceptibility, indicating that local antifungal defenses are independent of T-cell priming in lymph nodes. In addition, Rag1-/- mice lacking T and B lymphocytes effectively controlled infection and exhibited increased IL-17A production by innate lymphoid cells. Furthermore, Rag2-/-Il2rg-/- mice, devoid of T, B, and innate lymphoid cells, were highly susceptible to dermatophytosis compared with Rag2-/-or wild-type mice, demonstrating that innate lymphoid cells are sufficient to antifungal defenses in T-cell-deficient mice. In conclusion, our study underscores the coordinated interplay between skin yBT, a(3T, and innate lymphoid cell subsets in controlling primary N gypsea dermatophytosis.