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关键词： adverse drug reaction   DRESS syndrome   HLA-B*53   pharmacogenetics   raltegravir  

摘要： Introduction: Raltegravir, an HIV integrase inhibitor, although generally well tolerated, may cause severe reactions such as drug reaction with eosinophilia and systemic symptoms (DRESS). This syndrome has been associated with impaired drug metabolism, viral reactivation and genetic factors including HLA-B*53:01. We describe two cases of DRESS in a raltegravir-treated cohort and review the relevant literature. Methodology: Medical records from Hospital Universitario de La Princesa (2008–2020) were retrospectively reviewed to identify patients genotyped for HLA-B*53 who received raltegravir. Suspected DRESS cases were assessed using the RegiSCAR scoring system and Naranjo algorithm. A structured literature search was conducted to identify additional published cases. Results: Among 109 patients treated with raltegravir, three (2.8%) were HLA-B*53 carriers. Two developed DRESS, while no events occurred in non-carriers. One presented with fever, rash, lymphadenopathy, hepatitis and HHV-6 reactivation (RegiSCAR 6). The second developed eosinophilia, rash and pulmonary symptoms (RegiSCAR 4). The third carrier remained asymptomatic. A continuity correction yielded a RR of 133.9. Nine additional cases were identified in the literature and summarized according to clinical features and HLA-B*53 status. Conclusion: Findings support a potential genetic predisposition involving HLA-B*53:01 in raltegravir-induced DRESS. Screening in high-prevalence populations may help prevent severe reactions. Further research should refine diagnostic and management strategies. © 2025 The Author(s). Basic & Clinical Pharmacology & Toxicology published by John Wiley & Sons Ltd on behalf of Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

关键词： IL-11 signaling   Macrophage-TEC crosstalk   Renal fibrosis   STAT3/ERK pathway   Neutralizing antibodies  

摘要： Aims: To investigate the pathogenic role of Interleukin-11 (IL-11) in chronic kidney disease (CKD) progression and evaluate the therapeutic potential of IL-11 neutralizing antibodies in attenuating renal inflammation and fibrosis. Materials and methods: We conducted systematic molecular and cellular analyses to characterize IL-11-mediated signaling pathways in CKD models. The effects of IL-11 on macrophage polarization, cellular transitions, and stress responses were examined. Preclinical efficacy studies were performed using selective IL-11 neutralizing antibodies to assess their impact on renal pathology. Key findings: IL-11 orchestrates renal injury through immune crosstalk between macrophages and tubular epithelial cells (TECs) via STAT3 signaling activation. IL-11 promotes M1 macrophage polarization, facilitates the macrophage-to-myofibroblast transition (MMT), and triggers epithelial-to-mesenchymal transition (EMT) in TECs. Additionally, IL-11 amplifies oxidative and endoplasmic reticulum stress responses. Treatment with IL-11 neutralizing antibodies effectively interrupted IL-11/IL-11R alpha 1 interaction and downstream STAT3/ERK1/2mediated metadherin activation, resulting in reduced pro-fibrotic extracellular matrix deposition, enhanced TEC regenerative capacity, and improved renal parenchymal repair. Significance: These findings establish the IL-11 signaling axis as a promising therapeutic target in CKD. The demonstrated efficacy of antibody-based interventions presents a novel precision medicine approach for CKD treatment, offering significant potential for clinical translation in nephrology.

关键词： ADC   Antibody-drug conjugate   AML   Acute myeloid leukemia   ALL   Acute lymphoblastic leukemia   Allo-HSCT   Allogeneic hematopoietic stem cell transplantation   BCL-2   B-cell lymphoma 2   BH   BCL-2 homology   BiTEs   Bispecific T-cell engagers   BiKEs   Bispecific killer-cell engagers   BPDCN   Blastic plasmacytoid dendritic cell neoplasm   CBL   Cbl proto-oncogene   CLL   Chronic lymphocytic leukemia   CR   Complete remission   CRh   Complete remission with partial hematologic recovery   CRi   Complete remission with incomplete hematologic recovery   CTLA-4   Cytotoxic T-lymphocyte-associated protein 4   DOT1L   Disruptor of telomeric silencing 1-like   EFS   Event-free survival   FGF2   Fibroblast growth factor 2   FL   FLT3 ligand   FLT3   FMS-related tyrosine kinase receptor 3   G-CSF   Granulocyte colony-stimulating factor   GO   Gemtuzumab ozogamicin   HDAC   Histone deacetylase   2-HG   2-Hydroxyglutarate   HLA   Human leukocyte antigen   HMA   Hypomethylating agent   HSC   Hematopoietic stem cell   HSP90   Heat shock protein 90   HSPC   Hematopoietic stem and progenitor cell   ICs   Immune checkpoints   IDH1/2   Isocitrate dehydrogenase 1/2   IDO1   Indoleamine 2,3-dioxygenase 1   IL-3Rα   Interleukin-3 receptor alpha chain   IRAK1/IRAK4   IL-1 receptor-associated kinases   ITD   Internal tandem duplication   α-KG   α-Ketoglutarate   LAG-3   Lymphocyte activation gene-3   LDAC   Low-dose cytarabine   LILRB4   Leukocyte immunoglobulin-like receptor B4   LSC   Leukemia stem cell   mAb   Monoclonal antibody   MDR   Multidrug resistance   MDS   Myelodysplastic syndromes   MDSC   Myeloid-derived suppressor cells   MHC   Major histocompatibility complex   NK   Natural killer   ORR   Overall response rate   OS   Overall survival   OxPHOS   Oxidative phosphorylation   PARP   Poly-ADP-ribose-polymerase   PBD   Pyrrolobenzodiazepine   PD-1   Programmed cell death protein 1   PD-L1   Programmed death-ligand 1   PFS   Progression-free survival   P-gp   P-glycoprotein   PI3K   Phosphatidylinositol 3-kinase   PROTAC   Proteolysis-targeting chimeras   PTCH1   Patched-1   RFS   Relapse-free survival   ROS   Reactive oxygen species   R/R AML   Refractory or relapsed AML   RTK   Receptor tyrosine kinase   RSK   Ribosomal S6 kinase   SIRPα   Signal regulatory protein  

摘要：

关键词： demethylation   inflammation   lung injury   PM2.5   TET1  

摘要： PM2.5 has been linked to a variety of lung diseases. The objective of this study was to investigate the mechanism of lung inflammation caused by acute exposure to PM2.5 from the perspective of DNA methylation. Sprague-Dawley male rats were exposed to different concentrations of PM2.5 by non-exposure intratracheal instillation every other day for 3 times. Chemically modified si-Foxa1, si-Tet1, and si-NC were administered via the intratracheal instillation, followed by exposure to a medium concentration of PM2.5. Fourteen days following the final exposure, serum, bronchoalveolar lavage fluid (BALF), and lung tissues were collected for the appropriate tests. Acute exposure to PM2.5 resulted in infiltration of inflammatory cells and destruction of the alveolar structure. The levels of IL-4 and eotaxin-1 in serum and BALF were increased, while the levels of interferon-gamma (IFN-gamma) were decreased. In lung tissues, there was a decrease in the whole genome 5-mC and an increase in 5-hmC. The methylation level of the interleukin-4 (IL-4) DNA promoter CpG islands decreased, accompanied by an increase in the mRNA level. The protein expression of Forkhead box A1 (FOXA1) and ten-eleven translocation methylcytosine dioxygenase 1 (TET1) was upregulated. Downregulation of FOXA1 and TET1 levels reversed those changes. PM2.5 induced the upregulation of FOXA1 and TET1 protein expression, which subsequently affected the DNA methylation levels of IL-4. This, in turn, promoted the release of IL-4 and led to pulmonary inflammation. This study provides insights into the potential DNA methylation regulatory mechanisms underlying lung inflammation induced by acute PM2.5 exposure.

关键词： DNA damage   iNKT cells   AML   NF-kappa B   LncRNA   CD1d  

摘要： Acute myeloid leukemia (AML) is the most common and deadly type of leukemia with the high recurrence rates and poor prognosis. Despite extensive exploration of therapeutic strategies, there is currently no effective remedy for AML. Recently, there has been a growing focus on immunotherapeutic approaches for treating hematologic malignancies. CD1d-restricted invariant Natural Killer T (iNKT) cells have been recognized for their significant role in antitumor immunity. This study identified a potential therapeutic strategy based on the iNKT cells and demonstrated that treating AML cells with DNA damage agents can enhance iNKT cell-mediated cytotoxicity in vitro. Research has also demonstrated that DNA damage regulates CD1d gene transcription activity by specifically activating NF-kappa B/RELA. Additionally, lncRNA-HLA-DRB6 is involved in the targeted regulation of CD1d by RELA, thus promoting the stability of CD1d mRNA in the cytoplasm. The activation of the RELA/lncRNA-HLADRB6/CD1d pathway by DNA damage contributes to sensitizing AML cells to killing by iNKT cells. Furthermore, combination treatment with alpha-galactosylceramide (alpha-GalCer;which is an activator of iNKT cells) and DNA damage agents exhibited synergistic antitumor effects in vivo, which may be beneficial for alleviating the progression of AML. In conclusion, these findings provide information on the mechanism by which DNA damage in AML cells regulates iNKT cell activity, thus suggesting that the development of immune therapeutic strategies based on iNKT cells during chemotherapy may represent a potential avenue for AML treatment.

关键词： ADDE   Aqueous-deficient dry eye   BALB/c   BALB/C wildtype (mice)   CI   confidence interval   CXL   Corneal cross-linking   DED   Dry eye disease   DEQ-5   5-Item Dry Eye Questionnaire   DEWS   Dry Eye Workshops   DNA   Deoxyribonucleic acid   EDE   Evaporative dry eye   FDA   Food and drug administration   (f)MRI   (Functional) magnetic resonance imaging   GVHD   Graft-versus-host disease   HLA   Human leukocyte antigen   HPMC   Hydroxypropyl methylcellulose   ICAM-1   Intercellular Adhesion Molecule 1   IL   Interleukin   IGF   Insulin-like growth factor   IVCM   In vivo confocal microscopy   LASIK   Laser-assisted in situ keratomileusis   LIPCOF   Lid-parallel conjunctival folds   LLT   Lipid layer thickness   MGD   Meibomian gland dysfunction   MGYLS   Meibomian glands yielding liquid secretion   MMP   Matrix metalloproteinase   MUC4   Mucin 4   NGF   Nerve growth factor   NIBUT   Non-invasive tear film breakup time   NF-kB   Nuclear factor kappa-light-chain-enhancer of activated B cells   NRS   Numerical rating scale   OCT   Optical coherence tomography   OR   Odds ratio   OSDI   Ocular Surface Disease Index   PRK   Photorefractive keratectomy   QoL   Quality of Life   SANDE   Symptom Assessment iN Dry Eye questionnaire   SPEED   Standard Patient Evaluation of Eye Dryness questionnaire   TBUT   Tear film breakup time   TED   Thyroid eye disease   TFOS   Tear Film & Ocular Surface Society   TRPM8   Transient Receptor Potential cation channel subfamily M member 8   VAS   Visual analogue scale  

摘要： This digest summarizes the interdisciplinary research in dry eye disease (DED) published since the 2017 TFOS DEWS II reports. It comprises 7 topics including Sex, Gender, and Hormones;Epidemiology;Pathophysiology;Tear Film;Pain and Sensation;Iatrogenic Dry Eye;and Clinical Trial Design and explores how each of these inform diagnostic methodology, disease subtype, and management of DED. Sex-and gender-related differences significantly influence the ocular surface due to hormones, sex chromosomes, sex-specific autosomal factors, epigenetics, care-seeking behaviors, and service use. Epidemiologic data reveal that DED prevalence varies by age and sex, influenced by diagnostic criteria and the multifactorial nature of the disease. New risk factors for DED include environmental, iatrogenicity, systemic diseases, and lifestyle domains. Pathophysiological distinctions between aqueous deficient and more evaporative forms of DED have been clarified, with the latter most commonly characterized by a muted inflammatory response at the ocular surface, meibomian gland dysfunction, and conceivably phenotypic changes in corneal epithelial cells. There is an expanding role for metabolic, hormonal, physical, neural and cellular stresses, including hyperosmolarity, mitochondrial stress, and neurogenic inflammation. Advancements in tear film research recommend new approaches to understanding DED pathogenesis and identifying biomarkers, such as microRNAs. Ocular pain perception is linked to structural integrity of corneal nerves, functional capacities of neurons, and activity of the central and peripheral nervous systems. Iatrogenic DED can result from medications, contact lenses, and surgical procedures. Clinical trials now emphasize aligning design and end points with DED subtypes and therapeutic mechanisms, with new therapeutics and trial designs under consideration. (Am J Ophthalmol 2025;279: 451-553. (c) 2025 The Author(s). Published by Elsevier Inc. This is an open access article u

关键词： Ulcerative colitis   Human neonatal Fc receptor   Targeted therapy   Anti-tumor necrosis factor-alpha   Bispecific antibody  

摘要： Ulcerative colitis (UC), a chronic inflammatory bowel disease (IBD), is characterized by disruption of intestinal barrier function and complex inflammatory manifestations locally and systemically. Although anti-tumor necrosis factor-alpha (TNF-alpha) agents such as Infliximab (IFX) are effective in treating IBD, their intestinal tissue concentration has been regarded as determinant of therapeutic efficacy while was restrained by the large molecular weight. Considering the enhanced expression of human neonatal Fc receptor (hFcRn) in UC tissues, we attempted to deliver the therapeutic entity of IFX into UC tissues by developing a novel dual-acting IFX Fab-F8 (IFX-F8) fusion protein for UC treatment. The IFX Fab was fused to the hFcRn-binding scFv F8, generating a bispecific FabscFv protein with half the molecular weight of full-length IgG. IFX-F8 maintained independent high-affinity binding to both TNF-alpha and hFcRn, conferring prolonged serum half-life and enhanced intestinal epithelial retention through hFcRn-mediated recycling. In DSS-induced UC hFcRn mice, intraperitoneal IFX-F8 administration significantly attenuated the weight loss and improved survival and ZO-1 of the experimental animals compared to IFX. The fusion protein exhibited preferential accumulation in inflamed colonic tissues and superior therapeutic efficacy over IFX or IFX Fab monotherapy. Mechanistically, IFX-F8 more effectively suppressed pathogenic Th17 cells and IL-17 signaling than IFX, leading to sustained disease remission. Collectively, our findings suggest that the IFX-F8 fusion protein is a potential UC therapeutic agent and deserves further study.

关键词： Orange-spotted grouper   MHC-I alpha   Polymorphism   Singapore grouper iridovirus (SGIV)   Red-spotted grouper nerve necrosis virus   RGNNV   Apoptosis  

摘要： The Major Histocompatibility Complex (MHC) is a group of tightly linked, highly polymorphic genes that play a critical role in vertebrate immune responses. MHC is closely associated with various diseases, including autoimmune disorders, antigen invasion, and inflammation. Notably, MHC class I (MHC-I) molecules exhibit extensive polymorphism and have the ability to specifically bind to a diverse array of viral antigens, which is crucial for antigen presentation and antiviral immunity. However, studies on the differential functions of different MHC-I genotypes in response to fish viral diseases are still scarce. In our previous research, we cloned three novel MHC-I alpha genotypes-EcMHC-IA*01, EcMHC-IA*02, and EcMHC-IA*03 based on transcriptomic data from SGIV-infected grouper spleen cells. It has been established that the EcMHC-IA*01 gene contributes to the resistance against SGIV infection. In this study, we investigated the differences in antiviral functions and apoptotic effects of EcMHC-IA*02 and EcMHC-IA*03. The full-length sequence homology of these two genotypes was 73.66 %, while the homology of the signal peptide was only 2.09 %. The polymorphism of domains may directly contribute to the functional differences among genotypes. Molecular characterization analysis revealed that EcMHC-IA*02 and EcMHC-IA*03 encoded 366-amino-acid and 357-amino-acid proteins, respectively, both containing typical domains of MHC class I molecules, including a signal peptide, MHC-I (alpha 1, alpha 2, alpha 3) domains, and a transmembrane region. Based on their conserved structural features, domain organization, and overall sequence similarity to known classical MHC-I molecules in other species, these two genotypes are presumed to be classical MHC class I genes. Subcellular localization analysis showed that EcMHC-IA*02 and EcMHC-IA*03 were distributed throughout the cytoplasm. Functional studies demonstrated that overexpression of EcMHC-IA*02 enhanced cytopathic effects (CPE), cell

关键词： Optical biosensor   Multi-resonance analysis   IL-6   IL-8   OSCC   Point-of-care diagnostics   Semi-distributed interferometer   Biomarker detection   Surface functionalization  

摘要： Biomarker-based diagnostics offer a promising approach for early cancer detection, while simultaneous analysis of multiple biomarkers can further improve disease diagnosis by enhancing sensitivity and specificity of the detection. This work presents a multi-resonance analysis strategy for the simultaneous detection of oral cancer biomarkers interleukin-6 and interleukin-8 in artificial saliva with a Fiber-Bragg grating-assisted semi-distributed interferometer-based probe. The analysis of the sensor response takes advantage of the entire spectral feature, which enhances the robustness and reliability of the detection results. Unlike single-feature approaches, multi-resonance analysis ensures greater resilience to spectral distortions, since the spectral features of the proposed sensor exhibit varying sensitivity to biomolecular interactions. The sensor demonstrated a limit of detection (LoD) of 480 aM for IL-6 and 23.4 fM for IL-8 in artificial saliva with high specificity to target proteins.

关键词： Hydroxychloroquine   IgA nephropathy   network pharmacology   TNF   toll-like receptor signaling pathway  

摘要： Background IgA nephropathy (IgAN) is the most prevalent primary glomerulonephritis globally and has a high propensity to develop into end-stage renal disease (ESRD). Hydroxychloroquine has been proven to reduce proteinuria in IgAN patients, but the precise mechanism remains unclear. Therefore, network pharmacology was used to investigate the *** PubChem and SwissADME databases were utilized to acquire the structure of hydroxychloroquine. The SwissTargetPrediction, PharmMapper, DrugBank, TargetNet, and BATMAN-TCM databases were then utilized to obtain the targets. The target genes related to IgAN were then gathered from the databases, which included GeneCards, PHARMGKB, DrugBank, OMIM, and DisGeNET. Common targets were obtained by UniProt. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to define the main molecular mechanisms and pathways. Furthermore, a protein-protein interaction (PPI) network was constructed using the STRING tool, and the core targets were obtained by Cytoscape. Finally, molecular docking between the core targets and hydroxychloroquine was *** 167 common target genes were acquired by overlapping. The core targets were TNF, ALB, IL1B, JUN, FOS, SRC, and MMP9. The GO and KEGG results showed the targets to be related to the production of inflammatory cytokines and chemokines and were engaged in the toll-like receptor (TLR) signaling pathway. At the same time, the molecular docking results showed that the core targets all combined with hydroxychloroquine *** This study proved that hydroxychloroquine may treat IgAN through the TLR signaling pathway, and the restraint of TNF, TLR, IL1B, and JUN may be essential for the treatment.