ABSTRACT
Lactylation, an emerging post-translational modification, plays a pivotal role in the initiation and progression of digestive system tumors. This study presents a comprehensive review of lactylation in digestive system tumors, underscoring its critical involvement in tumor development and progression. By focusing on metabolic reprogramming, modulation of the tumor microenvironment, and the molecular mechanisms regulating tumor progression, the potential of targeting lactylation as a therapeutic strategy is highlighted. The research reveals that lactylation participates in gene expression regulation and cell signaling by affecting the post-translational states of histones and non-histone proteins, thereby influencing metabolic pathways and immune evasion mechanisms in tumor cells. Furthermore, this study assesses the feasibility of lactylation as a therapeutic target, providing insights for clinical treatment of gastrointestinal cancers. Future research should concentrate on elucidating the mechanisms of lactylation, developing efficient lactylation inhibitors, and validating their therapeutic efficacy in clinical trials, which could transform current cancer treatment and immunotherapy approaches. In summary, this review emphasizes the crucial role of lactylation in tumorigenesis and progression through a detailed analysis of its molecular mechanisms and clinical significance.
ABSTRACT
Immunotherapy is a promising strategy for nasopharyngeal carcinoma (NPC), a common and aggressive malignancy with poor prognosis. However, the literature lacks a comprehensive and objective overview of the current research status and trends of immunotherapy-related fields in NPC. We performed a bibliometric analysis of 513 original articles and reviews in English on immunotherapy for NPC from the Web of Science Core Collection database, using CiteSpace and Bibliometrix software tools. We visualized the development trend of publications, the distribution of countries/regions, the co-occurrence of keywords, the collaboration and citation of authors, the citation of journals, the evolution of topics, and the thematic map. We found that the publication volume increased sharply after 2017, with China as the main contributor and leader, the US as an important partner, and the Netherlands as a potential innovator. The research focused on immune checkpoint inhibitors and cell therapy, which were also the hotspots of clinical trials. Tumor microenvironment, immune infiltration, multicenter studies, and novel immunotherapy were the frontier topics and the key challenges for future research. CD137l-DC, lymphoma, and chimeric antigen receptor were emerging topics with good prospects. Our study provides a valuable insight into the research status and trends of immunotherapy for NPC, which may guide future research directions and clinical applications.
Subject(s)
Bibliometrics , Immunotherapy , Nasopharyngeal Carcinoma , Nasopharyngeal Neoplasms , Tumor Microenvironment , Humans , Nasopharyngeal Carcinoma/therapy , Nasopharyngeal Carcinoma/immunology , Immunotherapy/methods , Immunotherapy/trends , Nasopharyngeal Neoplasms/therapy , Tumor Microenvironment/immunology , Immune Checkpoint Inhibitors/therapeutic use , China/epidemiology , Cell- and Tissue-Based Therapy/methods , Cell- and Tissue-Based Therapy/trendsABSTRACT
Bis-(10-deoxydihydroartemisinin)-phloroglucinol (9), has been synthesized in a one-step reaction and has demonstrated strong inhibition to cancer cell proliferation and immunosuppressive activity. The structure modification of the compound reduced its cytotoxicity, and among the analogs, bis-(10-deoxydihydroartemisinin)-phloroglucinol phenyl decanoate (16) showed significant reduction of ear swelling in a mouse model for DNFB-induced delayed-type hypersensitivity without observable toxicity in a dose-dependent manner.
Subject(s)
Antineoplastic Agents , Artemisinins , Mice , Animals , Structure-Activity Relationship , Phloroglucinol , Artemisinins/chemistry , Immunosuppressive Agents/pharmacology , Cell Proliferation , Antineoplastic Agents/chemistryABSTRACT
BACKGROUND: A novel artemisinin derivative, dihydroartemisinin-ursodeoxycholic acid conjugate (4), was found to exhibit strong immunosuppressive activity. Various methods were used to evaluate the immunosuppressive activity and mechanism of action of the compound to explore its potential applications. METHODS: T cell proliferation, mixed lymphocyte reaction (MLR), and Th1/Th17 differentiation assays were used to evaluate the immunosuppressive activity of the compound. Differentially expressed genes from RNA sequencing were analysed with Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, while enriched signalling pathways were further validated by western blotting (WB). In vivo efficacy was validated with delayed-type hypersensitivity (DTH) mouse models and dextran sodium sulphate (DSS)-induced inflammatory bowel disease (IBD) mouse model. RESULTS: Compound 4 inhibited concanavalin A -induced mouse splenic T cell proliferation (IC50 = 15 nM) and anti-CD3/CD28-induced human primary T cell proliferation (IC50 = 30 nM) while also reducing the secretion of hIFN-γ. Compound 4 exhibited similar inhibitory activity in MLR assay. Compound 4 dose-dependently inhibited human Th1/Th17 differentiation. The KEGG pathway enrichment analysis indicated that the genes related to T cell activation signalling pathways PI3K-AKT, MAPK, and NF-κB were significantly enriched. WB confirmed that compound 4 inhibited the AKT/MAPK and NF-κB signalling pathways. Compound 4 dose-dependently inhibited ear and foot pad swelling in DTH mouse models. In the DSS-induced IBD mouse model, compound 4 significantly decreased the disease activity index and colon density, and inhibited splenomegaly of the mice. CONCLUSION: The in vitro and in vivo results indicated that compound 4 has the potential to be developed into an anti-IBD drug.
Subject(s)
Colitis , Inflammatory Bowel Diseases , Mice , Humans , Animals , NF-kappa B/metabolism , Ursodeoxycholic Acid/therapeutic use , Proto-Oncogene Proteins c-akt/metabolism , Phosphatidylinositol 3-Kinases , Inflammatory Bowel Diseases/drug therapy , Immunosuppressive Agents/therapeutic use , Dextran Sulfate , Mice, Inbred C57BLABSTRACT
A series of dihydroartemisinin derivatives was synthesized, and their anti-proliferation activity against cancer cells was evaluated. Structure-activity relationship studies led to the discovery of dihydroartemisinin-bile acid conjugates that exhibit broad-spectrum anti-proliferation activities. Among them, the dihydroartemisinin-ursodeoxycholic acid conjugate (49) was the most potent, with IC50 values between 0.04 and 0.96 µM when tested to determine its inhibitory properties against 15 various cancer cell lines. In vivo experiments showed that compound 49 effectively suppressed tumor growth in an A549 cell xenograft model at the dosage of 10 mg/kg body weight and in Lewis lung cancer cell transplant model at the dosage of 12 mg/kg body weight.
Subject(s)
Antineoplastic Agents/pharmacology , Artemisinins/pharmacology , Bile Acids and Salts/pharmacology , Drug Discovery , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Artemisinins/chemistry , Bile Acids and Salts/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Female , Humans , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Nude , Molecular Structure , Neoplasms, Experimental/drug therapy , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
Eight new dihydroartemisinin-O-glycosides were synthesized with their relative configurations were determined based on NMR spectrum. In vitro immunosuppressive assay showed that 10α-dihydroartemisinin-ß-O-d-mannoside (19a) demonstrate 88% inhibition towards T cells proliferation and 98% reduction in IFN-γ levels in cell media. These results suggest that dihydroartemisinin-O-glycoside as a potential lead for further in vivo evaluation.