Formation of Guanine-6-sulfonate from 6‑Thioguanine and Singlet Oxygen: A Combined Theoretical and Experimental Study

As an end metabolism product of the widely used thiopurine drugs, 6-thioguanine (6-TG) absorbs UVA and produces ¹O₂ by photosensitization. This unusual photochemical property triggers a variety of DNA damage, among which the oxidation of 6-TG itself by ¹O₂ to the promutagenic product guanine-6-sulfonate (G^SO3) represents one of the major forms. It has been suspected that there exists an initial intermediate, G^SO, prior to its further oxidation to G^SO2 and G^SO3, but G^SO has never been observed. Using density functional theory, we have explored the energetics and intermediates of 6-TG and ¹O₂. A new mechanism via G^SOOH → G^SO2 → G^SO4 → G^SO3 has been discovered to be the most feasible energetically, whereas the anticipated G^SO mechanism is found to encounter an inaccessibly high barrier and thus is prevented. The mechanism through the G^SOOH and G^SO4 intermediates can be validated further by joint experimental measurements, where the fast rate constant of 4.9 × 10⁹ M^–1 s^–1 and the reaction stoichiometry of 0.58 supports this low-barrier new mechanism. In addition to the dominant pathway of G^SOOH → G^SO2 → G^SO4 → G^SO3, a side pathway with higher barrier, G^SOOH → G, has also been located, providing a rationalization for the observed product distributions of G^SO2 and G^SO3 as major products and G as minor product. From mechanistic and kinetics points of view, the present findings provide new chemical insights to understand the high phototoxicity of 6-TG in DNA and point to methods of using 6-TG as a sensitive fluorescence probe for the quantitative detection of ¹O₂, which holds particular promise for detecting ¹O₂ in DNA-related biological surroundings

Fluorescence Products from Terrylenediimide with Singlet Oxygen: Red, Green, and Near-Infrared Emission

The rich photo-oxidation pathways and products of terrylenediimide (TDI) with singlet oxygen (¹O₂) have been examined by powerful computational approaches. Potential energy profiles and product fluorescence properties are characterized. A variety of new products are unraveled and predicted to emit fluorescence at both visible and near-infrared ranges, which could open the possibility for interesting applications of using TDI as a fluorescence probe for the single-molecule detection of ¹O₂ and designing multicolor photoconvertible fluorophores based on ¹O₂ oxidation

A new abietane mono-norditerpenoid from <i>Podocarpus nagi</i>

A new abietane mono-norditerpenoid, nagiol A (1), along with three known diterpenoids were isolated from the leaves of Podocarpus nagi. Their structures were elucidated by means of extensive spectroscopic analysis. This is the first report of abietane mono-norditerpenoid separated from plant of the genus Podocarpus. Compound 1 was assessed for its cytotoxicity against five human tumour lines (HL-60, SMMC-7721, A-549, MCF-7 and SW-480), and the result showed that it had no activity.</p

Isolation of a new carboline alkaloid from <i>Trigonostemon lii</i>

<div><p>A new carboline alkaloid, 1-(7-methoxy-quinolinyl-4′-yl)-3,4-dihydro-β-carboline (<b>1</b>), was isolated from the leaves and twigs of <i>Trigonostemon lii</i> Y.T. Chang, together with three known ones, trigonostemonines C and D (<b>2</b> and <b>3</b>), and trigonoliimine A (<b>4</b>). Their structures were elucidated by spectroscopic analyses, including 2D-NMR techniques.</p></div

Mechanism of the Deamination Reaction of Isoguanine: A Theoretical Investigation

Mechanisms of the deamination reactions of isoguanine with H₂O, OH^–, and OH^–/H₂O and of protonated isoguanine (isoGH⁺) with H₂O have been investigated by theoretical calculations. Eight pathways, paths A–H, have been explored and the thermodynamic properties (Δ<i>E</i>, Δ<i>H</i>, and Δ<i>G</i>), activation energies, enthalpies, and Gibbs energies of activation were calculated for each reaction investigated. Compared with the deamination reaction of isoguanine or protonated isoguanine (isoGH⁺) with water, the deamination reaction of isoguanine with OH^– shows a lower Gibbs energy of activation at the rate-determining step, indicating that the deamination reaction of isoguanine is favorably to take place for the deprotonated form isoG^– with water. With the assistance of an extra water, the reaction of isoguanine with OH^–/H₂O, pathways F and H, are found to be the most feasible pathways in aqueous solution due to their lowest Gibbs energy of activation of 174.7 and 172.6 kJ mol^–1, respectively, at the B3LYP/6-311++G­(d,p) level of theory

Image6_Multi-Omics Reveals Inhibitory Effect of Baicalein on Non-Alcoholic Fatty Liver Disease in Mice.TIF

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, whose etiology is poorly understood. Accumulating evidence indicates that gut microbiota plays an important role in the occurrence and progression of various human diseases, including NAFLD. In this study, NAFLD mouse models were established by feeding a high-fat diet (HFD). Baicalein, a natural flavonoid with multiple biological activities, was administered by gavage, and its protective effect on NAFLD was analyzed by histopathological and blood factor analysis. Gut microbiota analysis demonstrated that baicalein could remodel the overall structure of the gut microbiota from NAFLD model mice, especially Anaerotruncus, Lachnoclostridium, and Mucispirillum. Transcriptomic analysis showed baicalein restored the expressions of numerous genes that were upregulated in hepatocytes of NAFLD mice, such as Apoa4, Pla2g12a, Elovl7, Slc27a4, Hilpda, Fabp4, Vldlr, Gpld1, and Apom. Metabolomics analysis proved that baicalein mainly regulated the processes associated with lipid metabolism, such as alpha-Linolenic acid, 2-Oxocarboxylic acid, Pantothenate and CoA biosynthesis, and bile secretion. Multi-omics analysis revealed that numerous genes regulated by baicalein were significantly correlated with pathways related to lipid metabolism and biosynthesis and secrection of bile acid, and baicalein might affect lipid metabolism in liver via regulating the ecological structure of gut microbiota in NAFLD mice. Our results elucidated the correlated network among diet, gut microbiota, metabolomic, and transcriptional profiling in the liver. This knowledge may help explore novel therapeutic approaches against NAFLD.</p

Image1_Multi-Omics Reveals Inhibitory Effect of Baicalein on Non-Alcoholic Fatty Liver Disease in Mice.TIF

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, whose etiology is poorly understood. Accumulating evidence indicates that gut microbiota plays an important role in the occurrence and progression of various human diseases, including NAFLD. In this study, NAFLD mouse models were established by feeding a high-fat diet (HFD). Baicalein, a natural flavonoid with multiple biological activities, was administered by gavage, and its protective effect on NAFLD was analyzed by histopathological and blood factor analysis. Gut microbiota analysis demonstrated that baicalein could remodel the overall structure of the gut microbiota from NAFLD model mice, especially Anaerotruncus, Lachnoclostridium, and Mucispirillum. Transcriptomic analysis showed baicalein restored the expressions of numerous genes that were upregulated in hepatocytes of NAFLD mice, such as Apoa4, Pla2g12a, Elovl7, Slc27a4, Hilpda, Fabp4, Vldlr, Gpld1, and Apom. Metabolomics analysis proved that baicalein mainly regulated the processes associated with lipid metabolism, such as alpha-Linolenic acid, 2-Oxocarboxylic acid, Pantothenate and CoA biosynthesis, and bile secretion. Multi-omics analysis revealed that numerous genes regulated by baicalein were significantly correlated with pathways related to lipid metabolism and biosynthesis and secrection of bile acid, and baicalein might affect lipid metabolism in liver via regulating the ecological structure of gut microbiota in NAFLD mice. Our results elucidated the correlated network among diet, gut microbiota, metabolomic, and transcriptional profiling in the liver. This knowledge may help explore novel therapeutic approaches against NAFLD.</p

Image8_Multi-Omics Reveals Inhibitory Effect of Baicalein on Non-Alcoholic Fatty Liver Disease in Mice.TIF

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, whose etiology is poorly understood. Accumulating evidence indicates that gut microbiota plays an important role in the occurrence and progression of various human diseases, including NAFLD. In this study, NAFLD mouse models were established by feeding a high-fat diet (HFD). Baicalein, a natural flavonoid with multiple biological activities, was administered by gavage, and its protective effect on NAFLD was analyzed by histopathological and blood factor analysis. Gut microbiota analysis demonstrated that baicalein could remodel the overall structure of the gut microbiota from NAFLD model mice, especially Anaerotruncus, Lachnoclostridium, and Mucispirillum. Transcriptomic analysis showed baicalein restored the expressions of numerous genes that were upregulated in hepatocytes of NAFLD mice, such as Apoa4, Pla2g12a, Elovl7, Slc27a4, Hilpda, Fabp4, Vldlr, Gpld1, and Apom. Metabolomics analysis proved that baicalein mainly regulated the processes associated with lipid metabolism, such as alpha-Linolenic acid, 2-Oxocarboxylic acid, Pantothenate and CoA biosynthesis, and bile secretion. Multi-omics analysis revealed that numerous genes regulated by baicalein were significantly correlated with pathways related to lipid metabolism and biosynthesis and secrection of bile acid, and baicalein might affect lipid metabolism in liver via regulating the ecological structure of gut microbiota in NAFLD mice. Our results elucidated the correlated network among diet, gut microbiota, metabolomic, and transcriptional profiling in the liver. This knowledge may help explore novel therapeutic approaches against NAFLD.</p

Image4_Multi-Omics Reveals Inhibitory Effect of Baicalein on Non-Alcoholic Fatty Liver Disease in Mice.TIF

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, whose etiology is poorly understood. Accumulating evidence indicates that gut microbiota plays an important role in the occurrence and progression of various human diseases, including NAFLD. In this study, NAFLD mouse models were established by feeding a high-fat diet (HFD). Baicalein, a natural flavonoid with multiple biological activities, was administered by gavage, and its protective effect on NAFLD was analyzed by histopathological and blood factor analysis. Gut microbiota analysis demonstrated that baicalein could remodel the overall structure of the gut microbiota from NAFLD model mice, especially Anaerotruncus, Lachnoclostridium, and Mucispirillum. Transcriptomic analysis showed baicalein restored the expressions of numerous genes that were upregulated in hepatocytes of NAFLD mice, such as Apoa4, Pla2g12a, Elovl7, Slc27a4, Hilpda, Fabp4, Vldlr, Gpld1, and Apom. Metabolomics analysis proved that baicalein mainly regulated the processes associated with lipid metabolism, such as alpha-Linolenic acid, 2-Oxocarboxylic acid, Pantothenate and CoA biosynthesis, and bile secretion. Multi-omics analysis revealed that numerous genes regulated by baicalein were significantly correlated with pathways related to lipid metabolism and biosynthesis and secrection of bile acid, and baicalein might affect lipid metabolism in liver via regulating the ecological structure of gut microbiota in NAFLD mice. Our results elucidated the correlated network among diet, gut microbiota, metabolomic, and transcriptional profiling in the liver. This knowledge may help explore novel therapeutic approaches against NAFLD.</p

Image3_Multi-Omics Reveals Inhibitory Effect of Baicalein on Non-Alcoholic Fatty Liver Disease in Mice.TIF

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, whose etiology is poorly understood. Accumulating evidence indicates that gut microbiota plays an important role in the occurrence and progression of various human diseases, including NAFLD. In this study, NAFLD mouse models were established by feeding a high-fat diet (HFD). Baicalein, a natural flavonoid with multiple biological activities, was administered by gavage, and its protective effect on NAFLD was analyzed by histopathological and blood factor analysis. Gut microbiota analysis demonstrated that baicalein could remodel the overall structure of the gut microbiota from NAFLD model mice, especially Anaerotruncus, Lachnoclostridium, and Mucispirillum. Transcriptomic analysis showed baicalein restored the expressions of numerous genes that were upregulated in hepatocytes of NAFLD mice, such as Apoa4, Pla2g12a, Elovl7, Slc27a4, Hilpda, Fabp4, Vldlr, Gpld1, and Apom. Metabolomics analysis proved that baicalein mainly regulated the processes associated with lipid metabolism, such as alpha-Linolenic acid, 2-Oxocarboxylic acid, Pantothenate and CoA biosynthesis, and bile secretion. Multi-omics analysis revealed that numerous genes regulated by baicalein were significantly correlated with pathways related to lipid metabolism and biosynthesis and secrection of bile acid, and baicalein might affect lipid metabolism in liver via regulating the ecological structure of gut microbiota in NAFLD mice. Our results elucidated the correlated network among diet, gut microbiota, metabolomic, and transcriptional profiling in the liver. This knowledge may help explore novel therapeutic approaches against NAFLD.</p