Also published as: Chi, Yi, EC Yi, H Yi, Hong Yi, Huangdi Yi, J-M Yi, Jaehun Yi, Jing Yi, Kraynik YI, Litai Yi, P. Yi, Qiao-Yan Yi, S Yi, S.‐J. Yi, T Yi, Wenbin Yi, X Yi
Combining single-cell parallel profiling of genome conformation, histone modifications, chromatin accessibility and gene expression reveals dynamics and intranuclear spatial clustering of epigenome pr Show more
Combining single-cell parallel profiling of genome conformation, histone modifications, chromatin accessibility and gene expression reveals dynamics and intranuclear spatial clustering of epigenome profiles, enabling sophisticated analysis of the regulatory landscape across cell types and tissues. Show less
Nitrogen-rich energetic materials are of interest due to their potential use as high-energy-density materials in various applications. However, most compounds with a high nitrogen content show poor th Show more
Nitrogen-rich energetic materials are of interest due to their potential use as high-energy-density materials in various applications. However, most compounds with a high nitrogen content show poor thermal stabilities, which may limit their use in certain applications. In pursuit of nitrogen-rich energetic materials, this study presents the synthesis and characterization of two nitrogen rich energetic compounds, namely 3-azido-1-(1H-tetrazol-5-yl)-1H-1,2,4-triazol-5-amine (3, C3H3N11, N%: 79.78) and (E)-1,2-bis(3-azido-1-(1H-tetrazol-5-yl)-1H-1,2,4-triazol-5-yl) diazene (7, C6H2N22, N%: 80.62). Compounds 3 and 7 have high thermal stabilities of 216 and 221 °C, respectively, making them the most thermally stable among metal-free primary explosives. Additionally, they show good energetic performance (vD: 8345 m s-1; P: 25.17 GPa; vD: 8275 m s-1; P: 25.57 GPa), making them potential candidates for metal-free high energy primary explosive. The energetic salts of 3 and 7 were also investigated. Among them, hydrazinium salt 11 displays better energetic performance (vD: 9089 m s-1; P: 30.55 GPa), which was on par with those of cyclotetramethylene tetranitramine (HMX). This research contributes to the exploration of nitrogen-rich energetic materials with potential applications in various fields. 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 t Show more
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
Mitochondria are central actors in diverse physiological phenomena ranging from energy metabolism to stress signaling and immune modulation. Accumulating scientific evidence points to the critical inv Show more
Mitochondria are central actors in diverse physiological phenomena ranging from energy metabolism to stress signaling and immune modulation. Accumulating scientific evidence points to the critical involvement of specific mitochondrial-associated events, including mitochondrial quality control, intercellular mitochondrial transfer, and mitochondrial genetics, in potentiating the metastatic cascade of neoplastic cells. Furthermore, numerous recent studies have consistently emphasized the highly significant role mitochondria play in coordinating the regulation of tumor-infiltrating immune cells and immunotherapeutic interventions. This review provides a comprehensive and rigorous scholarly investigation of this subject matter, exploring the intricate mechanisms by which mitochondria contribute to tumor metastasis and examining the progress of mitochondria-targeted cancer therapies. Show less
Transition metal elements, such as copper, play diverse and pivotal roles in oncology. They act as constituents of metalloenzymes involved in cellular metabolism, function as signaling molecules to re Show more
Transition metal elements, such as copper, play diverse and pivotal roles in oncology. They act as constituents of metalloenzymes involved in cellular metabolism, function as signaling molecules to regulate the proliferation and metastasis of tumors, and are integral components of metal-based anticancer drugs. Notably, recent research reveals that excessive copper can also modulate the occurrence of programmed cell death (PCD), known as cuprotosis, in cancer cells. This modulation occurs through the disruption of tumor cell metabolism and the induction of proteotoxic stress. This discovery uncovers a mode of interaction between transition metals and proteins, emphasizing the intricate link between copper homeostasis and tumor metabolism. Moreover, they provide innovative therapeutic strategies for the precise diagnosis and treatment of malignant tumors. At the crossroads of chemistry and oncology, we undertake a comprehensive review of copper homeostasis in tumors, elucidating the molecular mechanisms underpinning cuproptosis. Additionally, we summarize current nanotherapeutic approaches that target cuproptosis and provide an overview of the available laboratory and clinical methods for monitoring this process. In the context of emerging concepts, challenges, and opportunities, we emphasize the significant potential of nanotechnology in the advancement of this field. Show less
Lung cancer is a common malignant tumor that occurs in the human body and poses a serious threat to human health and quality of life. The existing treatment methods mainly include surgical treatment, Show more
Lung cancer is a common malignant tumor that occurs in the human body and poses a serious threat to human health and quality of life. The existing treatment methods mainly include surgical treatment, chemotherapy, and radiotherapy. However, due to the strong metastatic characteristics of lung cancer and the emergence of related drug resistance and radiation resistance, the overall survival rate of lung cancer patients is not ideal. There is an urgent need to develop new treatment strategies or new effective drugs to treat lung cancer. Ferroptosis, a novel type of programmed cell death, is different from the traditional cell death pathways such as apoptosis, necrosis, pyroptosis and so on. It is caused by the increase of iron-dependent reactive oxygen species due to intracellular iron overload, which leads to the accumulation of lipid peroxides, thus inducing cell membrane oxidative damage, affecting the normal life process of cells, and finally promoting the process of ferroptosis. The regulation of ferroptosis is closely related to the normal physiological process of cells, and it involves iron metabolism, lipid metabolism, and the balance between oxygen-free radical reaction and lipid peroxidation. A large number of studies have confirmed that ferroptosis is a result of the combined action of the cellular oxidation/antioxidant system and cell membrane damage/repair, which has great potential application in tumor therapy. Therefore, this review aims to explore potential therapeutic targets for ferroptosis in lung cancer by clarifying the regulatory pathway of ferroptosis. Based on the study of ferroptosis, the regulation mechanism of ferroptosis in lung cancer was understood and the existing chemical drugs and natural compounds targeting ferroptosis in lung cancer were summarized, with the aim of providing new ideas for the treatment of lung cancer. In addition, it also provides the basis for the discovery and clinical application of chemical drugs and natural compounds targeting ferroptosis to effectively treat lung cancer. Show less
Abstract Imaging contrast agents are widely investigated in preclinical and clinical studies, among which biogenic imaging contrast agents (BICAs) are developing rapidly and playing an increasingly i Show more
Abstract Imaging contrast agents are widely investigated in preclinical and clinical studies, among which biogenic imaging contrast agents (BICAs) are developing rapidly and playing an increasingly important role in biomedical research ranging from subcellular level to individual level. The unique properties of BICAs, including expression by cells as reporters and specific genetic modification, facilitate various in vitro and in vivo studies, such as quantification of gene expression, observation of protein interactions, visualization of cellular proliferation, monitoring of metabolism, and detection of dysfunctions. Furthermore, in human body, BICAs are remarkably helpful for disease diagnosis when the dysregulation of these agents occurs and can be detected through imaging techniques. There are various BICAs matched with a set of imaging techniques, including fluorescent proteins for fluorescence imaging, gas vesicles for ultrasound imaging, and ferritin for magnetic resonance imaging. In addition, bimodal and multimodal imaging can be realized through combining the functions of different BICAs, which helps overcome the limitations of monomodal imaging. In this review, the focus is on the properties, mechanisms, applications, and future directions of BICAs. Show less
Developing novel therapeutics often follows three steps: target identification, design of strategies to suppress target activity and drug development to implement the strategies. In this review, we re Show more
Developing novel therapeutics often follows three steps: target identification, design of strategies to suppress target activity and drug development to implement the strategies. In this review, we recount the evidence identifying the basic leucine zipper transcription factors ATF5, CEBPB, and CEBPD as targets for brain and other malignancies. We describe strategies that exploit the structures of the three factors to create inhibitory dominant-negative (DN) mutant forms that selectively suppress growth and survival of cancer cells. We then discuss and compare four peptides (CP-DN-ATF5, Dpep, Bpep and ST101) in which DN sequences are joined with cell-penetrating domains to create drugs that pass through tissue barriers and into cells. The peptide drugs show both efficacy and safety in suppressing growth and in the survival of brain and other cancers in vivo, and ST101 is currently in clinical trials for solid tumors, including GBM. We further consider known mechanisms by which the peptides act and how these have been exploited in rationally designed combination therapies. We additionally discuss lacunae in our knowledge about the peptides that merit further research. Finally, we suggest both short- and long-term directions for creating new generations of drugs targeting ATF5, CEBPB, CEBPD, and other transcription factors for treating brain and other malignancies. Show less
Title: Coordination of Ru(II)-Arene Fragments to Dipyridophenazine Ligands Leads to the Modulation of Their In Vitro and In Vivo Anticancer Activity.
Abstract: Despite extensive research on the antic Show more
Title: Coordination of Ru(II)-Arene Fragments to Dipyridophenazine Ligands Leads to the Modulation of Their In Vitro and In Vivo Anticancer Activity.
Abstract: Despite extensive research on the anticancer properties of Ru complexes with dipyrido[3,2-a:2',3'-c]phenazine (dppz) ligands, their in vivo efficacy is rarely investigated. Aiming to understand whether the coordination of certain half-sandwich Ru(II)-arene fragments might improve the therapeutic potential of dppz ligands, we prepared a series of Ru(II)-arene complexes with the general formula [(η6-arene)Ru(dppz-R)Cl]PF6, where the arene fragment was benzene, toluene, or p-cymene and R was -NO2, -Me, or -COOMe. All compounds were fully characterized by 1H and 13C NMR spectroscopy and high-resolution ESI mass-spectrometry, and their purity was verified by elemental analysis. The electrochemical activity was investigated using cyclic voltammetry. The anticancer activity of dppz ligands and their respective Ru complexes was assessed against several cancer cell lines, and their selectivity toward cancer cells was assessed using healthy MRC5 lung fibroblasts. The substitution of benzene with a p-cymene fragment resulted in a more than 17-fold increase of anticancer activity and selectivity of Ru complexes and significantly enhanced DNA degradation in HCT116 cells. All Ru complexes were electrochemically active in the biologically accessible redox window and were shown to markedly induce the production of ROS in mitochondria. The lead Ru-dppz complex significantly reduced tumor burden in mice with colorectal cancers without inducing liver and kidney toxicity. Show less
Metabolic theories for the origin of life posit that inorganic catalysts enabled self-organized chemical precursors to the pathways of metabolism, including those that make genetic molecules. Recently Show more
Metabolic theories for the origin of life posit that inorganic catalysts enabled self-organized chemical precursors to the pathways of metabolism, including those that make genetic molecules. Recently, experiments showing nonenzymatic versions of a number of core metabolic pathways have started to support this idea. However, experimental demonstrations of nonenzymatic reaction sequences along the de novo ribonucleotide biosynthesis pathways are limited. Here we show that all three reactions of pyrimidine nucleobase biosynthesis that convert aspartate to orotate proceed at 60 °C without photochemistry under aqueous conditions in the presence of metals such as Cu2+ and Mn4+ . Combining reactions into one-pot variants is also possible. Life may not have invented pyrimidine nucleobase biosynthesis from scratch, but simply refined existing nonenzymatic reaction channels. This work is a first step towards uniting metabolic theories of life's origin with those centered around genetic molecules. Show less
In the analysis of gene expression data, network approaches take a system perspective and have played an irreplaceably important role. Gaussian graphical models (GGMs) have been popular in the network Show more
In the analysis of gene expression data, network approaches take a system perspective and have played an irreplaceably important role. Gaussian graphical models (GGMs) have been popular in the network analysis of gene expression data. They investigate the conditional dependence between genes and "transform" the problem of estimating network structures into a sparse estimation of precision matrices. When there is a moderate to large number of genes, the number of parameters to be estimated may overwhelm the limited sample size, leading to unreliable estimation and selection. In this article, we propose incorporating information from previous studies (for example, those deposited at PubMed) to assist estimating the network structure in the present data. It is recognized that such information can be partial, biased, or even wrong. A penalization-based estimation approach is developed, shown to have consistency properties, and realized using an effective computational algorithm. Simulation demonstrates its competitive performance under various information accuracy scenarios. The analysis of TCGA lung cancer prognostic genes leads to network structures different from the alternatives. Show less
Z-DNA, a noncanonical helical structure of double-stranded DNA (dsDNA), plays pivotal roles in various biological processes, including transcription regulation. Mechanical stresses on dsDNA, such as t Show more
Z-DNA, a noncanonical helical structure of double-stranded DNA (dsDNA), plays pivotal roles in various biological processes, including transcription regulation. Mechanical stresses on dsDNA, such as twisting and stretching, help to form Z-DNA. However, the effect of DNA bending, one of the most common dsDNA deformations, on Z-DNA formation is utterly unknown. Here, we show that DNA bending induces the formation of Z-DNA, that is, more Z-DNA is formed as the bending force becomes stronger. We regulated the bending force on dsDNA by using D-shaped DNA nanostructures. The B-Z transition was observed by single-molecule fluorescence resonance energy transfer. We found that as the bending force became stronger, Z-DNA was formed at lower Mg2+ concentrations. When dsDNA contained cytosine methylations, the B-Z transition occurred at 78 mM Mg2+ (midpoint) in the absence of the bending force. However, the B-Z transition occurred at a 28-fold lower Mg2+ concentration (2.8 mM) in the presence of the bending force. Monte Carlo simulation suggested that the B-Z transition stabilizes the bent form via the formation of the B-Z junction with base extrusion, which effectively releases the bending stress on DNA. Our results clearly show that the bending force facilitates the B-Z transition under physiological salt conditions. Show less
Abstract TFIIH is a 10‐subunit complex that regulates RNA polymerase II (pol II) transcription but also serves other important biological roles. Although much remains unknown about TFIIH function in Show more
Abstract TFIIH is a 10‐subunit complex that regulates RNA polymerase II (pol II) transcription but also serves other important biological roles. Although much remains unknown about TFIIH function in eukaryotic cells, much progress has been made even in just the past few years, due in part to technological advances (e.g. cryoEM and single molecule methods) and the development of chemical inhibitors of TFIIH enzymes. This review focuses on the major cellular roles for TFIIH, with an emphasis on TFIIH function as a regulator of pol II transcription. We describe the structure of TFIIH and its roles in pol II initiation, promoter‐proximal pausing, elongation, and termination. We also discuss cellular roles for TFIIH beyond transcription (e.g. DNA repair, cell cycle regulation) and summarize small molecule inhibitors of TFIIH and diseases associated with defects in TFIIH structure and function. Show less
Abstract Significance: Mitochondria are the energetic, metabolic, redox, and information signaling centers of the cell. Substrate pressure, mitochondrial network dynamics, and cristae morphology Show more
Abstract Significance: Mitochondria are the energetic, metabolic, redox, and information signaling centers of the cell. Substrate pressure, mitochondrial network dynamics, and cristae morphology state are integrated by the protonmotive force Δ p or its potential component, Δ Ψ , which are attenuated by proton backflux into the matrix, termed uncoupling. The mitochondrial uncoupling proteins (UCP1–5) play an eminent role in the regulation of each of the mentioned aspects, being involved in numerous physiological events including redox signaling. Recent Advances: UCP2 structure, including purine nucleotide and fatty acid (FA) binding sites, strongly support the FA cycling mechanism: UCP2 expels FA anions, whereas uncoupling is achieved by the membrane backflux of protonated FA. Nascent FAs, cleaved by phospholipases, are preferential. The resulting Δ p dissipation decreases superoxide formation dependent on Δ p . UCP-mediated antioxidant protection and its impairment are expected to play a major role in cell physiology and pathology. Moreover, UCP2-mediated aspartate, oxaloacetate, and malate antiport with phosphate is expected to alter metabolism of cancer cells. Critical Issues: A wide range of UCP antioxidant effects and participations in redox signaling have been reported; however, mechanisms of UCP activation are still debated. Switching off/on the UCP2 protonophoretic function might serve as redox signaling either by employing/releasing the extra capacity of cell antioxidant systems or by directly increasing/decreasing mitochondrial superoxide sources. Rapid UCP2 degradation, FA levels, elevation of purine nucleotides, decreased Mg 2+ , or increased pyruvate accumulation may initiate UCP-mediated redox signaling. Future Directions: Issues such as UCP2 participation in glucose sensing, neuronal (synaptic) function, and immune cell activation should be elucidated. Antioxid. Redox Signal. 29, 667–714. Show less