👤 Yoo KC

The aim of the UniProt Knowledgebase (UniProtKB; https://www.uniprot.org/) is to provide users with a comprehensive, high-quality and freely accessible set of protein sequences annotated with functional information. In this publication, we describe ongoing changes to our production pipeline to limit the sequences available in UniProtKB to high-quality, non-redundant reference proteomes. We continue to manually curate the scientific literature to add the latest functional data and use machine learning techniques. We also encourage community curation to ensure key publications are not missed. We provide an update on the automatic annotation methods used by UniProtKB to predict information for unreviewed entries describing unstudied proteins. Finally, updates to the UniProt website are described, including a new tab linking protein to genomic information. In recognition of its value to the scientific community, the UniProt database has been awarded Global Core Biodata Resource status. Show less

A series of iridium(iii) complexes (Ir1-Ir3) with the formula [Ir(F₂ppy)₂(L)] (F₂ppy = 2-(2,4-difluoro-phenyl)pyridine, L = pyridine-2-aldoxime, 2-pyridylamidoxime and di-2-pyridylketoxime) were synthesized through the reaction of [(F₂ppy)₂Ir(μ-Cl)₂Ir(F₂ppy)₂] (SM1) and the respective ancillary ligands (L). All the complexes were characterised by FT-IR, ¹H & ¹⁹F-NMR analysis, electronic absorption-emission spectroscopy and cyclic voltammetric studies. Molecular structures of complexes Ir1 and Ir3 were determined by interpreting single crystal X-ray data. All the complexes were found to be luminescent with low quantum yields. Anticancer studies on cancer cell lines MDAMB, HT-29 and LN-229 revealed their effectiveness as antiproliferative agents. The cytotoxicity of the complexes was evaluated using the MTT assay and complex Ir2 showed activity similar to that of cisplatin towards the three cancer cells. The elevated level of reactive oxygen species (ROS) in the iridium complex-treated cancer cells further supported the antiproliferation efficacy of Ir1-Ir3. Further, the effectiveness of Ir1-Ir3 on cancer cells was established through a cell migration study and apoptotic induction assay on LN-229 and a colony formation assay on HT-29 cancer cells. Immunocytochemistry analysis of LN-229 cancer cells revealed apoptosis through the p53-dependent pathway. Show less

For decades, great strides have been made in the field of immunometabolism. A plethora of evidence ranging from basic mechanisms to clinical transformation has gradually embarked on immunometabolism to the center stage of innate and adaptive immunomodulation. Given this, we focus on changes in immunometabolism, a converging series of biochemical events that alters immune cell function, propose the immune roles played by diversified metabolic derivatives and enzymes, emphasize the key metabolism-related checkpoints in distinct immune cell types, and discuss the ongoing and upcoming realities of clinical treatment. It is expected that future research will reduce the current limitations of immunotherapy and provide a positive hand in immune responses to exert a broader therapeutic role. Show less

The β-diketone scaffold is a commonly used synthetic intermediate, and is a functional group found in natural products such as curcuminoids. This core structure can also act as a chelating ligand for a variety of metals. In order to assess the potential of this scaffold for medicinal inorganic chemistry, seven different κ²-O,O'-chelating ligands were used to construct Ru(II) complexes with polypyridyl co-ligands, and their biological activity was evaluated. The complexes demonstrated promising structure-dependent cytotoxicity. Three complexes maintained high activity in a tumor spheroid model, and all complexes demonstrated low in vivo toxicity in a zebrafish model. From this series, the best compound exhibited a ~ 30-fold window between cytotoxicity in a 3-D tumor spheroid model and potential in vivo toxicity. These results suggest that κ²-O,O'-ligands can be incorporated into Ru(II)-polypyridyl complexes to create favorable candidates for future drug development. Show less

Ruthenium(II) complexes developed for photodynamic therapy (PDT) are almost exclusively tris-bidentate systems with C₂ or D₃ symmetry. This is due to the fact that this structural framework commonly produces long-lived excited states, which, in turn, allow for the generation of large amounts of singlet oxygen (¹O₂) and other reactive oxygen species. Complexes containing tridentate ligands would be advantageous for biological applications as they are generally achiral (D_2d or C_2v symmetry), which eliminates the possibility of multiple isomers which could exhibit potentially different interactions with chiral biological entities. However, Ru(II) complexes containing tridentate ligands are rarely studied as candidates for photobiological applications, such as PDT, since they almost exclusively exhibit low quantum yields and very short excited-state lifetimes and, thus, are not capable of generating sufficient ¹O₂ or engaging in electron transfer reactions. Here, we report a proof-of-concept approach to make bis-tridentate Ru(II) complexes useful for PDT applications by altering their photophysical properties through the inclusion of N-heterocyclic carbene (NHC) ligands. Three NHC and two terpyridine ligands were studied to evaluate the effects of structural and photophysical modulations of bis-substituted Ru(II) complexes. The NHC complexes were found to have superior excited-state lifetimes, ¹O₂ production, and photocytotoxicity. To the best of our knowledge, these complexes are the most potent light-activated bis-tridentate complexes reported. Show less

A panel of iridium(iii) porphyrin complexes containing axial N-heterocyclic carbene (NHC) ligand(s) were synthesized and characterized. X-ray crystal structures of the bis-NHC complexes [Ir^III(ttp)(IMe)₂]⁺ (2a), [Ir^III(oep)(BIMe)₂]⁺ (2d), [Ir^III(oep)(I ⁱ Pr)₂]⁺ (2e) and [Ir^III(F₂₀tpp)(IMe)₂]⁺ (2f) display ruffled porphyrin rings with mesocarbon displacements of 0.483-0.594 Å and long Ir-C_NHC bonds of 2.100-2.152 Å. Variable-temperature ¹H NMR analysis of 2a reveals that the macrocycle porphyrin ring inversion takes place in solution with an activation barrier of 40 ± 1 kJ mol^-1. The UV-vis absorption spectra of Ir^III(por)-NHC complexes display split Soret bands. TD-DFT calculations and resonance Raman experiments show that the higher-energy Soret band is derived from the ¹MLCT dπ(Ir) → π*(por) transition. The near-infrared phosphorescence of Ir^III(por)-NHC complexes from the porphyrin-based ³(π, π*) state features broad emission bands at 701-754 nm with low emission quantum yields and short lifetimes (Φ _em < 0.01; τ < 4 μs). [Ir^III(por)(IMe)₂]⁺ complexes (por = ttp and oep) are efficient photosensitizers for ¹O₂ generation (Φ _so = 0.64 and 0.88) and are catalytically active in the light-induced aerobic oxidation of secondary amines and arylboronic acid. The bis-NHC complexes exhibit potent dark cytotoxicity towards a panel of cancer cells with IC₅₀ values at submicromolar levels. The cytotoxicity of these complexes could be further enhanced upon light irradiation with IC₅₀ values as low as nanomolar levels in association with the light-induced generation of reactive oxygen species (ROS). Bioimaging of [Ir^III(oep)(IMe)₂]⁺ (2c) treated cells indicates that this Ir complex mainly targets the endoplasmic reticulum. [Ir^III(oep)(IMe)₂]⁺ catalyzes the photoinduced generation of singlet oxygen and triggers protein oxidation, cell cycle arrest, apoptosis and the inhibition of angiogenesis. It also causes pronounced photoinduced inhibition of tumor growth in a mouse model of human cancer. Show less

Reactive oxygen species (ROS) are well known to be involved in oncogene-mediated cellular transformation. However, the regulatory mechanisms underlying ROS generation in oncogene-transformed cells are unclear. In the present study, we found that oncogenic K-Ras induces ROS generation through activation of NADPH oxidase 1 (NOX1), which is a critical regulator for the K-Ras-induced cellular transformation. NOX1 was activated by K-Ras-dependent translocation of p47(phox), a subunit of NOX1 to plasma membrane. Of note, PKCδ, when it was activated by PDPK1, directly bound to the SH3-N domain of p47(phox) and catalyzed the phosphorylation on Ser348 and Ser473 residues of p47(phox) C-terminal in a K-Ras-dependent manner, finally leading to its membrane translocation. Notably, oncogenic K-Ras activated all MAPKs (JNK, ERK and p38); however, only p38 was involved in p47(phox)-NOX1-dependent ROS generation and consequent transformation. Importantly, K-Ras-induced activation of p38 led to an activation of PDPK1, which then signals through PKCδ, p47(phox) and NOX1. In agreement with the mechanism, inhibition of p38, PDPK1, PKCδ, p47(phox) or NOX1 effectively blocked K-Ras-induced ROS generation, anchorage-independent colony formation and tumor formation. Taken together, our findings demonstrated that oncogenic K-Ras activates the signaling cascade p38/PDPK1/PKCδ/p47(phox)/NOX1 for ROS generation and consequent malignant cellular transformation. Show less