Recent advances in mass spectrometry-based proteomics and metabolomics in chronic rhinosinusitis with nasal polyps.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a complex and heterogeneous disease, typically diagnosed through endoscopy and computed tomography and treated with glucocorticoid or surgery. There is an urgent need to develop molecular-level diagnostic or prognostic tools to better understand the pathophysiology of CRSwNP. Proteomics and metabolomics, emerging fields, offer significant potential in elucidating the mechanisms underlying CRSwNP. Mass spectrometry, a powerful and sensitive tool for trace substance detection, is broadly applied for proteomics and metabolomics analysis in CRSwNP research. While previous literature has summarized the advancement of mass spectrometry-based CRSwNP proteomics from 2004 to 2018, recent years have seen new advances in this field, particularly about non-invasive samples and exosomes. Furthermore, mass spectrometry-based CRSwNP metabolomics research has opened new avenues for inquiry. Therefore, we present a comprehensive review of mass spectrometry-based proteomics and metabolomics studies on CRSwNP conducted between 2019 and 2022. Specifically, we highlight protein and metabolic biomarkers that have been utilized as diagnostic or prognostic markers for CRSwNP. Lastly, we conclude with potential directions for future mass spectrometry-based omics studies of CRSwNP.

Study on the interaction of polyamine transport (PAT) and 4-Chloro-naphthalimide-homospermidine conjugate (4-ClNAHSPD) by molecular docking and dynamics.

Polyamine transporter (PAT) is a protein that can deliver "drug-polyamine" conjugates to tumor cells. 4-Chloro-naphthalimide- homospermidine (4-ClNAHSPD) displayed good antitumor activity and excellent cell selectivity via PAT pathway. In this paper, 4-ClNAHSPD and spermidine (SPD) were docked against PAT. The results showed that 4-ClNAHSPD could bind to PAT through hydrogen bond, Van der Waals, salt bridge or attractive charge and hydrophobic interaction. The interaction of SPD and PAT, however, was hydrogen bond and Van der Waals interaction. Moreover, their binding sites were also different. The primary binding sites of 4-ClNAHSPD with PAT are the residues of VAL59, HIS222, ASP61, ASP179 and GLU64, while SPD interacts with PAT in the sites of ASP37, ASP244, APS275 and SER36. The docked ligand-protein complexes were simulated for 5000ps. In simulations, various binding sites further resulted in the diverse root-mean-square deviation (RMSD) and root-mean-square deviation fluctuation (RMSF) values. The RMSD and RMSF values of 4-ClNAHSPD-PAT indicated that 4-ClNAHSPD caused a weak conformational change of PAT in a different style from SPD. More importantly, the interaction force numbers of 4-ClNAHSPD-PAT were also changed after the simulation. These results supported that 4-ClNAHSPD harnesses PAT pathway for cellular entrance.Communicated by Ramaswamy H. Sarma.

Applications of spatially resolved omics in the field of endocrine tumors.

Endocrine tumors derive from endocrine cells with high heterogeneity in function, structure and embryology, and are characteristic of a marked diversity and tissue heterogeneity. There are still challenges in analyzing the molecular alternations within the heterogeneous microenvironment for endocrine tumors. Recently, several proteomic, lipidomic and metabolomic platforms have been applied to the analysis of endocrine tumors to explore the cellular and molecular mechanisms of tumor genesis, progression and metastasis. In this review, we provide a comprehensive overview of spatially resolved proteomics, lipidomics and metabolomics guided by mass spectrometry imaging and spatially resolved microproteomics directed by microextraction and tandem mass spectrometry. In this regard, we will discuss different mass spectrometry imaging techniques, including secondary ion mass spectrometry, matrix-assisted laser desorption/ionization and desorption electrospray ionization. Additionally, we will highlight microextraction approaches such as laser capture microdissection and liquid microjunction extraction. With these methods, proteins can be extracted precisely from specific regions of the endocrine tumor. Finally, we compare applications of proteomic, lipidomic and metabolomic platforms in the field of endocrine tumors and outline their potentials in elucidating cellular and molecular processes involved in endocrine tumors.

Investigation of the interaction of a polyamine-modified flavonoid with bovine serum albumin (BSA) by spectroscopic methods and molecular simulation.

The interaction between BSA and compound 1 was studied by UV-vis, fluorescence and circular dichroism spectroscopy under physiological conditions (pH = 7.4). Molecular docking and molecular dynamics analyses were also performed. The results showed that compound 1 could bind to BSA. When compound 1 bound to BSA, there were a series of changes in the spectral properties of BSA, which were an enhancement effect of the UV-Vis spectrum of BSA, fluorescence quenching and a weak conformational change in the CD spectrum. The results of the fluorescence experiments at 298, 303 and 310 K showed that fluorescence quenching caused by the addition of compound 1 to BSA was generally static quenching accompanied by a dynamic quenching process, which was shown by the quenching constants of 2.010 × 104 L∙M-1, 1.850 × 104 L∙M-1, and 1.970 × 104 L∙M-1 at the three different temperatures, respectively. From the obtained binding constants and thermodynamic parameters, it was found that hydrophobic forces played an important role in the binding process of 1 to BSA. The results of synchronous fluorescence and three-dimensional fluorescence showed that compound 1 caused a weak conformational change in BSA. Docking results showed that compound 1 was located at binding site II of bovine serum albumin protease. In addition, the flavonoid moiety of compound 1 contributes to the hydrophobic binding of compound 1 to BSA. The results of molecular dynamics, including the root-mean-square deviation (RMSD) and RMS fluctuation (RMSF) values, showed that the binding of compound 1 to BSA did not cause a significant conformational change in BSA.

A Polyamine-Based Dinitro-Naphthalimide Conjugate as Substrates for Polyamine Transporters Preferentially Accumulates in Cancer Cells and Minimizes Side Effects in vitro and in vivo.

Naphthalimides, such as amonafide and mitonafide in clinical trials, have been developed as antitumor agents for orthotopic tumor. However, the serious side effects in cancer patients limit their applications. Herein, a new class of polyamine-based naphthalimide conjugates 5a-5c, 7a-7b, and 11a-11b with and without the alkylation of the distant nitrogen in the polyamine chain were synthesized and the mechanism was determined. Compared with amonafide, dinitro-naphthalimide conjugate 5c with a 4,3-cyclopropyl motif preferentially accumulates in cancer cells and minimizes side effects in vitro and in vivo. More importantly, 5c at the dosage of as low as 3 mg/kg (57.97%) displays better antitumor effects than the positive control amonafide (53.27%) at 5 mg/kg in vivo. And a remarkably elevated antitumor activity and a reduced toxicity are also observed for 5c at 5 mg/kg (65.90%). The upregulated p53 and the apoptotic cells (73.50%) indicate that the mechanism of 5c to induce apoptosis may result from its enhanced DNA damage. Further investigation indicates that in addition to target DNA, 5c can modulate the polyamine homeostasis by upregulating polyamine oxidase (PAO) in a different way from that of amonafide. And also by targeting PTs overexpressed in most of cancer cells, 5c downregulates the contents of Put, Spd, and Spm, which are in favor of suppressing fast-growing tumor cells. Our study implies a promising strategy for naphthalimide conjugates to treat hepatic carcinoma with notable activities and reduced toxicities at a low dosage.

Polyamine-Based Pt(IV) Prodrugs as Substrates for Polyamine Transporters Preferentially Accumulate in Cancer Metastases as DNA and Polyamine Metabolism Dual-Targeted Antimetastatic Agents.

Diverse platinum drug candidates have been designed to improve inhibitory potency and overcome resistance for orthotopic tumors. However, the antimetastatic properties have rarely been reported. We herein report that homospermidineplatin (4a), a polyamine-Pt(IV) prodrug, can potently inhibit tumor growth in situ and reverse cisplatin resistance as expected, and more importantly, 4a displays remarkably elevated antimetastatic activity in vivo (65.7%), compared to those of cisplatin (27.0%) and oxaliplatin (19.6%). The underlying molecular mechanism indicates that in addition to targeting nuclear DNA, 4a can modulate polyamine metabolism and function in a manner different from that of cisplatin. By upregulating SSAT and PAO, 4a downregulates the concentrations of Put, Spd, and Spm, which favors the suppression of fast-growing tumor cells. Moreover, the p53/SSAT/ß-catenin and PAO/ROS/GSH/GSH-Px pathways are involved in the inhibition of 4a-induced tumor metastasis. Our study implies a promising strategy for the design of platinum drugs for the treatment of terminal cancer.