Also published as: A Li, A. Li, AA Li, AF Li, Albert M Li, B Li, B. Li, Bao-jun Li, Baojun Li, Baosheng Li, Beilei Li, C Li, C. Li, C.-F. Li, C.F. Li, C.H. Li, CP Li, Cai, Li, Cai-Rong Li, Changfeng Li, Chao Li, Chen-Yang Li, Chengcheng Li, Chengjun Li, Cuifeng Li, D Li, D. F. Li, D. H. Li, D. Li, DD Li, E Li, F Li, F. F. Li, F. Li, FJ Li, G Li, G. Li, GM Li, Guang Ming Li, Guanwei Li, Guanying Li, Guo-Bi Li, Guo-dong Li, Guodong Li, H Li, H. Li, H. S. Li, Haihang Li, Hanying Li, Hao Li, Haoju Li, Haoran Li, Hao‐Ming Li, Hengyuan Li, Hong Li, Hongmei Li, Hui Li, Huifang-Jie Li, J Li, J. D. Li, J. J. Li, J. Li, J.G. Li, J.H. Li, J.J. Li, J.L. Li, JB Li, Jia Li, Jia-Jun Li, Jiao Li, Jiaqi Li, Jiarui Li, Jiaxiang Li, Jie-Ying Li, Jieshou Li, Juan Li, JuanJuan Li, Junbai Li, K Li, K. Li, K. Y. Li, L Li, L. Li, L.B. Li, Li Li, Lian Li, Liang, Li, Lihua Li, Lin Li, Linchuan Li, Liping Li, M Li, M. Li, M.-C. Li, M.C. Li, MO Li, MT Li, Ma, Li, Mei-Jin Li, Meng Li, Mengshan Li, Mengwei Li, N Li, Nai Li, O Li, O. Li, P Li, PA Li, Peiyuan Li, Q Li, Q. Li, QY Li, Qian Li, Qiao Yun Li, Qin Li, Qiuyi Li, R Li, R. Li, RS Li, Ren, Li, Rong-Tao Li, Ru-Qian Li, S Li, S. Li, S. W. Li, S.D. Li, S.F. Li, S.N. Li, S.Z. Li, SH Li, SY Li, Sam Fong Yau Li, Shawn S-C Li, Shumin Li, Shuo Li, Siqi Li, Song-Yan Li, Songhan Li, T Li, T. Li, T. T. W. Li, TE Li, TS Li, Tao Li, Tingxuan Li, Veronica L Li, W Li, W. F. Li, W. H. Li, W. Li, W.-M. Li, W.M. Li, WM Li, WT Li, Wanchun Li, Wei Li, Wu-Guo Li, X Li, X. Li, X.-L. Li, X.H. Li, X.N. Li, X.Z. Li, XA Li, XF Li, XJ Li, XN Li, Xian-Chuan Li, Xiang Li, Xiangchi Li, Xiaokun Li, Xiaoli Li, Xin Li, Xin-Yan Li, Xingye Li, Xuan Li, Y Li, Y. J. Li, Y. Li, Y. Y. Li, Y.J. Li, Y.Z. Li, Y.‐L. Li, YC Li, YY Li, Ya Li, Yalin Li, Yanchun Li, Yane Li, Yang Li, Yangqiu Li, Yaxu Li, Yi Li, Yichen Li, Yixuan Li, Yong Li, Yong-Xing Li, Yu-Xuan Li, Yumei Li, Yumeng Li, Yupeng Li, Z Li, Z. Li, ZL Li, ZW Li, Zan Li, Zesong Li, Zhao, Li, Zheng-Zheng Li, Zheng‐Zheng Li, Zhi-Ling Li, Zhi-Yuan Li, Zhihong Li, Zhipeng Li, Zhuang, Li, Zhuyin Li
Disruption of the mucosal barrier following intestinal ischemia reperfusion (I/R) is life threatening in clinical practice. Mitochondrial dysfunction and oxidative stress significantly contribute to t Show more
Disruption of the mucosal barrier following intestinal ischemia reperfusion (I/R) is life threatening in clinical practice. Mitochondrial dysfunction and oxidative stress significantly contribute to the early phase of I/R injury and amplify the inflammatory response. MitoQ is a mitochondrially targeted antioxidant that exerts protective effects following I/R injury. In the present study, we aimed to determine whether and how MitoQ protects intestinal epithelial cells (IECs) from I/R injury. In both in vivo and in vitro studies, we found that MitoQ pretreatment downregulated I/R-induced oxidative stress and stabilized the intestinal barrier, as evidenced by MitoQ-treated I/R mice exhibiting attenuated intestinal hyperpermeability, inflammatory response, epithelial apoptosis, and tight junction damage compared to controls. Mechanistically, I/R elevated mitochondrial 8-hydroxyguanine content, reduced mitochondrial DNA (mtDNA) copy number and mRNA transcription levels, and induced mitochondrial disruption in IECs. However, MitoQ pretreatment dramatically inhibited these deleterious effects. mtDNA depletion alone was sufficient to induce apoptosis and mitochondrial dysfunction of IECs. Mitochondrial transcription factor A (TFAM), a key activator of mitochondrial transcription, was significantly reduced during I/R injury, a phenomenon that was prevented by MitoQ treatment. Furthermore, we observed that thee protective properties of MitoQ were affected by upregulation of cellular antioxidant genes, including HO-1, NQO-1, and γ-GCLC. Transfection with Nrf2 siRNA in IECs exposed to hypoxia/reperfusion conditions partially blocked the effects of MitoQ on mtDNA damage and mitochondrial oxidative stress. In conclusion, our data suggest that MitoQ exerts protective effect on I/R-induced intestinal barrier dysfunction. Show less
A novel high-nitrogen compound, 1,2-bis(3-nitro-1-(1H-tetrazol-5-yl)-1H-1,2,4-triazol-5-yl)diazene, was designed and synthesized. The corresponding hydrazine energetic salts were prepared thro Show more
A novel high-nitrogen compound, 1,2-bis(3-nitro-1-(1H-tetrazol-5-yl)-1H-1,2,4-triazol-5-yl)diazene, was designed and synthesized. The corresponding hydrazine energetic salts were prepared through spontaneous reductive conversion by structurally varied amino salts. All energetic salts showed good thermal stabilities with decomposition temperatures ranging from 212 to 259 °C, and high positive heats of formation in the range of 411.1 to 1554.7 kJ mol−1. Furthermore, hydroxyammonium salt featured a promising integrated energetic performance (vD = 9038 m s−1, IS = 8 J, and FS = 360 N), which is superior to that of RDX (vD = 8890 m s−1, IS = 7.4 J, FS = 120 N), showing promising properties for new high-nitrogen high-energy-density materials.
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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
RuII compounds have been universally investigated due to their unique physical and chemical properties. In this paper, a new RuII compound based on 2,2′‐bipy and Hpmtz [2,2′‐bipy = 2,2′‐bipyridine, Hp Show more
RuII compounds have been universally investigated due to their unique physical and chemical properties. In this paper, a new RuII compound based on 2,2′‐bipy and Hpmtz [2,2′‐bipy = 2,2′‐bipyridine, Hpmtz = 5‐(2‐pyrimidyl)‐1H‐tetrazole], namely [Ru(2,2′‐bipy)2(pmtz)][PF6]·0.5H2O was prepared and characterized by elemental analysis, IR and single‐crystal X‐ray diffraction. [Ru(2,2′‐bipy)2(pmtz)][PF6]·0.5H2O shows a mononuclear structure and forms a three‐dimensional network by non‐classic hydrogen bonds. The ability of generation of ROS (reactive oxygen species) makes it has a low phototoxicity IC50 (half‐maximal inhibitory concentration) after Xenon lamp irradiation on Hela cells in vitro. The results demonstrate that [Ru(2,2′‐bipy)2(pmtz)][PF6]·0.5H2O with high light toxicity and low dark toxicity may be a potential candidate for photodynamic therapy. Show less
Mitochondrial calcium uptake plays critical roles in regulating ATP
production, intracellular calcium signaling, and cell death. This uptake is
mediated by a highly selective calcium channel called th Show more
Mitochondrial calcium uptake plays critical roles in regulating ATP
production, intracellular calcium signaling, and cell death. This uptake is
mediated by a highly selective calcium channel called the mitochondrial calcium
uniporter. Here, we determined the structures of the pore-forming MCU proteins
by X-ray crystallography and single-particle cryo-electron microscopy. The
stoichiometry, overall architecture, and individual subunit structure differed
markedly from those in the recent nuclear magnetic resonance structure of the
Caenorhabditis elegans MCU. In our studies, we observed a dimer-of-dimer
architecture across species and chemical environments, which was corroborated by
biochemical experiments. Structural analyses and functional characterizations
uncovered the roles of critical residues in the pore. These results reveal a new
ion channel architecture, provide insights into calcium coordination,
selectivity, and conduction, and establish a structural framework for
understanding the mechanism of mitochondrial calcium uniporter function. Show less
Although cisplatin and its analogues have been widely utilized as anticancer metallodrugs in clinics, their serious side effects and damage to normal tissues cannot be avoided because cisplati Show more
Although cisplatin and its analogues have been widely utilized as anticancer metallodrugs in clinics, their serious side effects and damage to normal tissues cannot be avoided because cisplatin kills cancer cells by attacking genomic DNA. Thus the design of metallodrugs possessing different actions of anti-cancer mechanism is promising. G-quadruplex nucleic acid, which is formed by self-assembly of guanine-rich nucleic acid sequences, has recently been considered as an attractive target for anticancer drug design. The basic unit of a G-quadruplex is a G-quartet, a planar motif generated from four guanine residues pairing together through Hoogsteen like hydrogen bonds. DNA G-quadruplex (G4) structures exist in the chromosomal telomeric sequences and the promoter regions of numerous genes, including oncogenetic promoters. Formation of G4 structures within the 3′-overhang of telomeric DNA can inhibit the telomerase activity, which is silent in normal cells but up-regulated in most cancer cells, thus significantly shortening telomeres and preventing cancer cell proliferation and immortalization. Intramolecular G4 structures formed within the oncogene promoter regions can effectively inhibit oncogenen transcription and expression. Thus rational design of small molecular ligands to selectively interact, stabilize or cleave G4 structures is a promising strategy for developing potent anti-cancer drugs with selective toxicity towards cancer cells over normal ones. This review will highlight the recent development of G4-interacting metal complexes, termed G4-ligands, discussing their binding modes with G-quadruplex DNA and their potential to serve as anticancer drugs in the medical field.
Introduction to the international collaboration
The collaboration between Prof. Zong-Wan Mao from Sun Yat-Sen University, P. R. China and Prof. Roland K. O. Sigel from the University of Zurich, Switzerland officially began in January, 2014. The international collaborative research project titled “Chemical Biology Research of New Metallodrugs for Cancer Therapy” is supported by the Science and Technology Program of Guangdong Provincial Government [20130501c]. With the rapid development of tumor molecular pharmacology, molecular targeted anti-tumor drugs have become a hot spot in the research of cancer therapy. This international collaborative research project combines the computer simulation and in vitro drug screening platform to design a series of metallodrugs that are systematic and have structural diversity, which can target specific nucleic acid structures (e.g. G-quadruplexes), key proteins (DNA topoisomerase, telomerase, CDK kinase) associated with the occurrence and development of tumor. With the advantages of both laboratories, the structural–functional relationship, interaction modes, co-crystallization, and mechanisms of action of these newly designed metallodrugs are intensively studied, and their in vitro and in vivo anti-tumor activities are comprehensively evaluated.
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Highly ordered interactions between immune and metabolic responses are evolutionarily conserved and paramount for tissue and organismal health. Disruption of these interactions underlies the emergence Show more
Highly ordered interactions between immune and metabolic responses are evolutionarily conserved and paramount for tissue and organismal health. Disruption of these interactions underlies the emergence of many pathologies, particularly chronic non-communicable diseases such as obesity and diabetes. Here, we examine decades of research identifying the complex immunometabolic signaling networks and the cellular and molecular events that occur in the setting of altered nutrient and energy exposures and offer a historical perspective. Furthermore, we describe recent advances such as the discovery that a broad complement of immune cells play a role in immunometabolism and the emerging evidence that nutrients and metabolites modulate inflammatory pathways. Lastly, we discuss how this work may eventually lead to tangible therapeutic advancements to promote health. Show less
Mitochondrial Ca 2+ uptake plays a pivotal role both in cell energy balance and in cell fate determination. Studies on the role of mitochondrial Ca 2+ signaling in pathophysiology have been favored Show more
Mitochondrial Ca 2+ uptake plays a pivotal role both in cell energy balance and in cell fate determination. Studies on the role of mitochondrial Ca 2+ signaling in pathophysiology have been favored by the identification of the genes encoding the mitochondrial calcium uniporter (MCU) and its regulatory subunits. Thus, research carried on in the last years on one hand has determined the structure of the MCU complex and its regulation, on the other has uncovered the consequences of dysregulated mitochondrial Ca 2+ signaling in cell and tissue homeostasis. Whether mitochondrial Ca 2+ uptake can be exploited as a weapon to counteract cancer progression is debated. In this review, we summarize recent research on the molecular structure of the MCU, the regulatory mechanisms that control its activity and its relevance in pathophysiology, focusing in particular on its role in cancer progression. Show less