G-quadruplexes on chromosomal DNA negatively regulates topoisomerase 1 activity.

Human DNA topoisomerase 1 (Top1) is a crucial enzyme responsible for alleviating torsional stress on DNA during transcription and replication, thereby maintaining genome stability. Previous researches had found that non-working Top1 interacted extensively with chromosomal DNA in human cells. However, the reason for its retention on chromosomal DNA remained unclear. In this study, we discovered a close association between Top1 and chromosomal DNA, specifically linked to the presence of G-quadruplex (G4) structures. G4 structures, formed during transcription, trap Top1 and hinder its ability to relax neighboring DNAs. Disruption of the Top1-G4 interaction using G4 ligand relieved the inhibitory effect of G4 on Top1 activity, resulting in a further reduction of R-loop levels in cells. Additionally, the activation of Top1 through the use of a G4 ligand enhanced the toxicity of Top1 inhibitors towards cancer cells. Our study uncovers a negative regulation mechanism of human Top1 and highlights a novel pathway for activating Top1.

Mangiferin alleviates diabetic pulmonary fibrosis in mice via inhibiting endothelial-mesenchymal transition through AMPK/FoxO3/SIRT3 axis.

Diabetes mellitus results in numerous complications. Diabetic pulmonary fibrosis (DPF), a late pulmonary complication of diabetes, has not attracted as much attention as diabetic nephropathy and cardiomyopathy. Mangiferin (MF) is a natural small molecular compound that exhibits a variety of pharmacological effects including anti-inflammatory, anti-cancer, anti-diabetes, and anti-fibrosis effects. In this study, we investigated whether long-term diabetes shock induces DPF, and explored whether MF had a protective effect against DPF. We first examined the lung tissues and sections of 20 diabetic patients obtained from discarded lung surgical resection specimens and found that pulmonary fibrosis mainly accumulated around the pulmonary vessels, accompanied by significantly enhanced endothelial-mesenchymal transition (EndMT). We established a mouse model of DPF by STZ injections. Ten days after the final STZ injection, the mice were administered MF (20, 60 mg/kg, i.g.) every 3 days for 4 weeks, and kept feeding until 16 weeks and euthanized. We showed that pulmonary fibrotic lesions were developed in the diabetic mice, which began around the pulmonary vessels, while MF administration did not affect long-term blood glucose levels, but dose-dependently alleviated diabetes-induced pulmonary fibrosis. In human umbilical vein endothelial cells (HUVECs), exposure to high glucose (33.3 mM) induced EndMT, which was dose-dependently inhibited by treatment with MF (10, 50 µM). Furthermore, MF treatment promoted SIRT3 expression in high glucose-exposed HUVECs by directly binding to AMPK to enhance the activity of FoxO3, which finally reversed diabetes-induced EndMT. We conclude that MF attenuates DPF by inhibiting EndMT through the AMPK/FoxO3/SIRT3 axis. MF could be a potential candidate for the early prevention and treatment of DPF.

Mitochondrial quality control in human health and disease.

Mitochondria, the most crucial energy-generating organelles in eukaryotic cells, play a pivotal role in regulating energy metabolism. However, their significance extends beyond this, as they are also indispensable in vital life processes such as cell proliferation, differentiation, immune responses, and redox balance. In response to various physiological signals or external stimuli, a sophisticated mitochondrial quality control (MQC) mechanism has evolved, encompassing key processes like mitochondrial biogenesis, mitochondrial dynamics, and mitophagy, which have garnered increasing attention from researchers to unveil their specific molecular mechanisms. In this review, we present a comprehensive summary of the primary mechanisms and functions of key regulators involved in major components of MQC. Furthermore, the critical physiological functions regulated by MQC and its diverse roles in the progression of various systemic diseases have been described in detail. We also discuss agonists or antagonists targeting MQC, aiming to explore potential therapeutic and research prospects by enhancing MQC to stabilize mitochondrial function.

Genome-Wide Identification, Evolution and Expression Analysis of the Glutathione S-Transferase Supergene Family in Euphorbiaceae.

Euphorbiaceae, a family of plants mainly grown in the tropics and subtropics, is also widely distributed all over the world and is well known for being rich in rubber, oil, medicinal materials, starch, wood and other economically important plant products. Glutathione S-transferases (GSTs) constitute a family of proteins encoded by a large supergene family and are widely expressed in animals, bacteria, fungi and plants, but with few reports of them in Euphorbiaceae plants. These proteins participate in and regulate the detoxification and oxidative stress response of heterogeneous organisms, resistance to stress, growth and development, signal transduction and other related processes. In this study, we identified and analyzed the whole genomes of four species of Euphorbiaceae, namely Ricinus communis, Jatropha curcas, Hevea brasiliensis, and Manihot esculenta, which have high economic and practical value. A total of 244 GST genes were identified. Based on their sequence characteristics and conserved domain types, the GST supergene family in Euphorbiaceae was classified into 10 subfamilies. The GST supergene families of Euphorbiaceae and Arabidopsis have been found to be highly conserved in evolution, and tandem repeats and translocations in these genes have made the greatest contributions to gene amplification here and have experienced strong purification selection. An evolutionary analysis showed that Euphorbiaceae GST genes have also evolved into new subtribes (GSTO, EF1BG, MAPEG), which may play a specific role in Euphorbiaceae. An analysis of expression patterns of the GST supergene family in Euphorbiaceae revealed the functions of these GSTs in different tissues, including resistance to stress and participation in herbicide detoxification. In addition, an interaction analysis was performed to determine the GST gene regulatory mechanism. The results of this study have laid a foundation for further analysis of the functions of the GST supergene family in Euphorbiaceae, especially in stress and herbicide detoxification. The results have also provided new ideas for the study of the regulatory mechanism of the GST supergene family, and have provided a reference for follow-up genetics and breeding work.

Synthesis and anti-HIV activity of [ddN]-[ddN] dimers and benzimidazole nucleoside dimers.

In an attempt to combine the HIV-inhibitory capacity of different 2',3'-dideoxynucleoside (ddN) analogs, we have designed and synthesized several dimers of [AZT]-[AZT] and [AZT]-[d4T]. In addition, we also synthesized the dimers of 1-(1H-benzimidazol-1-yl)-1-deoxy-beta-D-ribofuranose. The in vitro anti-HIV activity of these compounds on a pseudotype virus, pNL4-3.Luc.R-E-, in the 293T cells has been determined. Among these compounds, 2,2'-(propane-1,3-diyl)bis[1-(beta-D-ribofuranosyl)-1H-benzimidazole] showed the highest anti-HIV activity with similar effect as AZT.