Alzheimer's disease (AD) is characterized by multiple pathological hallmarks, including β-amyloid aggregation, oxidative stress, and metal dys-homeostasis. In the absence of treatments addressing its multi-factorial pathology, we designed novel multi-functional adamantane-based semicarbazones and hydrazones (1-12) targeting AD hallmarks. Of these, 2-pyridinecarboxaldehyde (N-adamantan-1-yl)benzoyl-4-amidohydrazone (10) was identified as the lead compound, which demonstrated: (1) pronounced iron chelation efficacy; (2) attenuation of CuII-mediated β-amyloid aggregation; (3) low cytotoxicity; (4) inhibition of oxidative stress; and (5) favorable characteristics for effective blood-brain barrier permeation. Structure-activity relationships revealed that pyridine-derived hydrazones represent a promising pharmacophore for future design strategies due to their ability to bind critical FeII pools. Collectively, the unique multi-functional activity of these agents provides a novel therapeutic strategy for AD treatment.
Background and Purpose: Breast cancer (BRCA) is the most frequent female malignancy and is potentially life threatening. The amino acid metabolism (AAM) has been shown to be strongly associated with the development and progression of human malignancies. In turn, long noncoding RNAs (lncRNAs) exert an important influence on the regulation of metabolism. Therefore, we attempted to build an AAM-related lncRNA prognostic model for BRCA and illustrate its immune characteristics and molecular mechanism.Experimental Design: The RNA-seq data for BRCA from the TCGA-BRCA datasets were stochastically split into training and validation cohorts at a 3:1 ratio, to construct and validate the model, respectively. The amino acid metabolism-related genes were obtained from the Molecular Signature Database. A univariate Cox analysis, least absolute shrinkage and selection operator (LASSO) regression, and a multivariate Cox analysis were applied to create a predictive risk signature. Subsequently, the immune and molecular characteristics and the benefits of chemotherapeutic drugs in the high-risk and low-risk subgroups were examined.Results: The prognostic model was developed based on the lncRNA group including LIPE-AS1, AC124067.4, LINC01655, AP005131.3, AC015802.3, USP30-AS1, SNHG26, and AL589765.4. Low-risk patients had a more favorable overall survival than did high-risk patients, in accordance with the results obtained for the validation cohort and the complete TCGA cohort. The elaborate results illustrated that a low-risk index was correlated with DNA-repair–associated pathways; a low TP53 and PIK3CA mutation rate; high infiltration of CD4+ T cells, CD8+ T cells, and M1 macrophages; active immunity; and less-aggressive phenotypes. In contrast, a high-risk index was correlated with cancer and metastasis-related pathways; a high PIK3CA and TP53 mutation rate; high infiltration of M0 macrophages, fibroblasts, and M2 macrophages; inhibition of the immune response; and more invasive phenotypes.Conclusion: In conclusion, we attempted to shed light on the importance of AAM-associated lncRNAs in BRCA. The prognostic model built here might be acknowledged as an indispensable reference for predicting the outcome of patients with BRCA and help identify immune and molecular characteristics.
Background and Purpose: Alzheimer's disease (AD) is a multifactorial condition leading to cognitive decline and represents a major global health challenge in ageing populations. The lack of effective AD therapeutics led us to develop multifunctional nicotinoyl hydrazones to target several pathological characteristics of AD.Experimental Approach: We synthesised 20 novel multifunctional agents based on the nicotinoyl hydrazone scaffold, which acts as a metal chelator and a lipophilic delivery vehicle, donating a NAD + precursor to cells, to target metal dyshomeostasis, oxidative stress, β-amyloid (Aβ) aggregation, and a decrease in the NAD + /NADH ratio.Key Results: The most promising compound, 6-methoxysalicylaldehyde nicotinoyl hydrazone (SNH6), demonstrated low cytotoxicity, potent iron (Fe)-chelation efficacy, significant inhibition of copper-mediated Aβ aggregation, oxidative stress alleviation, effective donation of NAD + to NAD-dependent metabolic processes (PARP and sirtuin activity) and enhanced cellular NAD + /NADH ratios, as well as significantly increased median Caenorhabditis elegans lifespan (to 1.46-fold of the control); partly decreased BACE1 expression, resulting in significantly lower soluble amyloid precursor protein-β (sAPPβ) and Aβ 1-40 levels; and favourable blood-brain barrierpermeation properties. Structure-activity relationships demonstrated that the ability of these nicotinoyl hydrazones to increase NAD + was dependent on the electronwithdrawing or electron-donating substituents on the aldehyde-or ketone-derived moiety. Aldehyde-derived hydrazones containing the ONO donor set and electrondonating groups were required for NAD + donation and low cytotoxicity. Conclusions and Implications:The nicotinoyl hydrazones, particularly SNH6, have the potential to act as multifunctional therapeutic agents and delivery vehicles for NAD + precursors for AD treatment.Abbreviations: 59 Fe2-Tf, iron-59 labelled diferric transferrin; 8-OH-QNH, 8-hydroxy-2-quinolinecarboxaldehyde nicotinoyl hydrazone; Aβ, β-amyloid; AcNH1, 4 0 -fluoro-2 0 -hydroxyacetophenone nicotinoyl hydrazone; AcNH2, 5 0 -bromo-2 0 -hydroxyacetophenone nicotinoyl hydrazone; AD, Alzheimer's disease; APP, amyloid precursor protein; BBB, blood-brain barrier; DTPA, diethylenetriaminepentaacetic acid; InNH1, 7-hydroxy-1-indanone nicotinoyl hydrazone; InNH2, 7-hydroxy-6-methyl-1-indanone nicotinoyl hydrazone; InNH3, 4-bromo-7-hydroxy-1-indanone nicotinoyl hydrazone; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; NNH, 2-hydroxy-1-naphthaldehyde nicotinoyl hydrazone; PAMPA-BBB, parallel artificial membrane permeability assay of the blood-brain barrier; PCNH, 2-pyridinecarboxaldehyde nicotinoyl hydrazone; PNH, pyridoxal nicotinoyl hydrazone; PrNH1, 5 0 -bromo-2 0
In recent years, various breakthroughs have been made in tumor immunotherapy that have contributed to prolonging the survival of tumor patients. However, only a subset of patients respond to immunotherapy, which limits its use. One reason for this is that the tumor microenvironment (TME) hinders the migration and infiltration of T cells and affects their continuous functioning, resulting in an exhausted phenotype. Therefore, clarifying the mechanism by which T cells become exhausted is of significance for improving the efficacy of immunotherapy. Several recent studies have shown that mitochondrial dynamics play an important role in the immune surveillance function of T cells. Dynamin-related protein 1 (Drp1) is a key protein that mediates mitochondrial fission and maintains the mitochondrial dynamic network. Drp1 regulates various activities of T cells in vivo by mediating the activation of a series of pathways. In addition, abnormal mitochondrial dynamics were observed in exhausted T cells in the TME. As a potential target for immunotherapy, in this review, we describe in detail how Drp1 regulates various physiological functions of T cells and induces changes in mitochondrial dynamics in the TME, providing a theoretical basis for further research.
Purpose: Immune checkpoint and antiangiogenic inhibitors have a potentially synergistic antitumor effect. We aimed to assess the efficacy and safety of immunotherapy in combination with antiangiogenesis therapy with or without chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC).Methods: PubMed, Embase, the Cochrane library, Google Scholar, Ovid, Scopus, and Web of Science were searched for eligible trials. ClinicalTrials.gov and meeting abstracts were also searched for qualified clinical studies. The inclusion criteria were as follows: prospective studies (including single-arm studies) that evaluated efficacy and/or toxicity of immunotherapy combined with antiangiogenic agents (A + I) with or without chemotherapy (A + I + chemo) in patients with advanced or metastatic NSCLC; and primary outcome of each study reported at least one of these endpoints: progression-free survival (PFS), overall survival, objective response rate (ORR), disease control rate (DCR), or adverse events (AEs).Results: Twenty three prospective studies comprising 1,856 patients with advanced NSCLC were included. The pooled ORR, median PFS and estimated overall survival were 39%, 6.8 months [95% confidence interval (CI), 5.53–8.13], and 18.6 months in the overall group. Similar ORR and median PFS with A + I + chemo versus A + I were observed in patients treated in first-line setting [59% and 9.47 months (95% CI, 6.45–12.49) versus 52% and 10.9 months (95% CI, 1.81–19.98), respectively]. We also observed improved ORR and mPFS with A + I + chemo versus A + I in subsequent-line setting [56% and 8.1 months (95% CI, 5.00–11.26) versus 22% and 5.1 months (95% CI, 4.01–6.15), respectively]. Efficacy of A + I + chemo therapy was evident across different PD-L1 subgroups, especially in patients with EGFR mutations [ORR: 59%; mPFS: 8.13 months (95% CI: 5.00–11.26)] or baseline liver metastases. The incidence of AEs with a major grade of ≥3 in the overall, A + I, and A + I + chemo groups were 4.1% vs. 5.5% vs. 3.4% for proteinuria, 13.7% vs. 16.2% vs. 9.7% for hypertension, and 1.9% vs. 1.2% vs. 2.8% for rash, respectively. No new safety signals were identified in this pooled analysis.Conclusion: Immunotherapy combined with antiangiogenic agents with or without chemotherapy showed encouraging antitumor activity and an acceptable toxicity profile in treatment-naïve or pretreated patients with advanced NSCLC. Doublet treatment with immunotherapy and antiangiogenic agents might be a new option for patients with advanced NSCLC, especially those who are treatment-naive or cannot tolerate chemotherapy.
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