Gastrodin (GAS), the main phenolic glycoside extracted from
Blume, exhibited potential neuroprotective properties. Here we examined the protective effects of GAS against lead(Pb)-induced nerve injury ...in mice, and explores its underlying mechanisms. Our research findings revealed that GAS improved behavioral deficits in Pb-exposed mice. GAS reduced the accumulation of p-tau and amyloid-beta (Aβ). GAS inhibited Pb-induced inflammation in the brain, as indicated by the decreased levels of pro-inflammatory cytokines, including tumor necrosis factor-a (TNF-α), cyclooxygenase-2 (COX-2). GAS increased the expression levels of NR2A and neurotrophin brain-derived neurotrophic factor (BDNF). GAS inhibited Pb-induced apoptosis of neurons in hippocampus tissue, as indicated by the decreased levels of pro-apoptotic proteins Bax and cleaved caspase-3. Furthermore, the neuroprotective effects of GAS were associated with inhibiting oxidative stress by modulating nuclear factor-erythroid 2-related factor 2 (Nrf2)-mediated antioxidant signaling. GAS supplement activated the Wnt/β-catenin signaling pathway and reduced the expression of Wnt inhibitor Dickkopf-1 (Dkk-1). Collectively, this study clarified that GAS exhibited neuroprotective property by anti-oxidant, anti-inflammatory and anti-apoptosis effects and its ability to regulate the Wnt/Nrf2 pathway.
We propose a new compact alternating direction implicit (ADI) finite difference scheme on uniform meshes for a weakly singular integro-differential equation in three space dimensions. Compared with ...the compact non-ADI scheme, the proposed compact ADI scheme is easy to implement and significantly reduces the computational cost of solving the resulting linear system, while maintaining the same order of the local truncation error. We prove that the new compact ADI scheme is unconditionally stable, and has second-order convergence in time and fourth-order convergence in space for weakly singular solutions. Numerical results are given to confirm the theoretical analysis result and demonstrate the computational efficiency of the proposed compact ADI scheme.
Human cancers induce a chaotic, dysfunctional vasculature that promotes tumor growth and blunts most current therapies; however, the mechanisms underlying the induction of a dysfunctional vasculature ...have been unclear. Here, we show that split end (SPEN), a transcription repressor, coordinates rRNA synthesis in endothelial cells (ECs) and is required for physiological and tumor angiogenesis. SPEN deficiency attenuated EC proliferation and blunted retinal angiogenesis, which was attributed to p53 activation. Furthermore, SPEN knockdown activated p53 by upregulating noncoding promoter RNA (pRNA), which represses rRNA transcription and triggers p53-mediated nucleolar stress. In human cancer biopsies, a low endothelial SPEN level correlated with extended overall survival. In mice, endothelial SPEN deficiency compromised rRNA expression and repressed tumor growth and metastasis by normalizing tumor vessels, and this was abrogated by p53 haploinsufficiency. rRNA gene transcription is driven by RNA polymerase I (RNPI). We found that CX-5461, an RNPI inhibitor, recapitulated the effect of Spen ablation on tumor vessel normalization and combining CX-5461 with cisplatin substantially improved the efficacy of treating tumors in mice. Together, these results demonstrate that SPEN is required for angiogenesis by repressing pRNA to enable rRNA gene transcription and ribosomal biogenesis and that RNPI represents a target for tumor vessel normalization therapy of cancer.
G-quadruplex (GQ) structures are implicated in important physiological and pathological processes. Millions of GQ-forming motifs are enriched near transcription start sites (TSSs) of animal genes. ...Transcription can induce the formation of GQs, which in turn regulate transcription. The kinetics of the formation and persistence of GQs in transcription is crucial for the role they play but has not yet been explored. We established a method based on the fluorescence resonance energy transfer (FRET) technique to monitor in real-time the cotranscriptional formation and post-transcriptional persistence of GQs in DNA. Using a T7 transcription model, we demonstrate that a representative intramolecular DNA GQ and DNA:RNA hybrid GQ promptly form in proportion to transcription activity and, once formed, are maintained for hours or longer at physiological temperature even after transcription is stopped. Both their formation and persistence strongly depend on R-loop, a DNA:RNA hybrid duplex formed during transcription. Enzymatic removal of R-loop dramatically slows their formation and accelerates their unfolding. These results suggest that a transcription event is promptly read-out by GQ-forming motifs and the GQ formed can either perform regulation in fast response to transcription and/or memorized in DNA to mediate time-delayed regulation under the control of RNA metabolism and GQ-resolving activity. Alternatively, GQs need to be timely resolved to warrant success of translocating activities such as replication. The kinetic characteristics of GQs and its connection with the R-loop may have implications in transcription regulation, signal transduction, G-quadruplex processing, and genome stability.
Diterpenoids are considered the major active compounds in
in virtue of their special structures and activities. Herein, an analytical method was developed for rapid screening and identification of ...diterpenoids in
using high-performmance liquid chromatography coupled with linear ion trap-Orbitrap mass spectrometry (HPLC-LTQ-Orbitrap) in negative ion mode. Two diterpenoid reference standards were first analyzed to obtain their characteristic ESI-MS/MS fragmentation patterns. Then, based on the extracted ion chromatogram (EIC) data-mining method and characteristic fragmentation pathways analysis, diterpenoids in
were rapidly screened and identified. After that, an important parameter, Clog
, was adopted to discriminate between the isomers of diterpenoids. As a result, 63 diterpenoids were characterized from the extract of
, including 10 diterpenoids and 53 diterpenoid glycosides. Among them, 15 compounds were tentatively identified as new compounds. Finally, target isolation of one diterpenoid glycoside named tinosineside A was performed based on the obtained results, which further confirmed the deduced fragmentation patterns and identified diterpenoid profile in
. The results demonstrated that the established method could be a rapid, effective analytical tool for screening and characterization of diterpenoids in the complex systems of natural medicines.
G‐quadruplexes are implicated in important cellular processes. Previous studies mostly focused on intramolecular G‐quadruplexes of three or more G‐quartets. Those composed of two G‐quartets were only ...shown to form in single‐stranded oligonucleotides. On the basis of electrophoresis, DMS footprinting, fluorescence labeling, and photo‐cross‐linking, we detected the formation of DNA:RNA hybrid G‐quadruplexes (HQs) of two G‐quartets during the transcription of DNA duplexes. These HQs have a lifetime on the minute scale and are stabilized by a stabilizing ligand. They are far shorter‐lived than the HQs of three G‐quartets, which last for hours. The occurrence of putative formation motifs of such HQs shows a transcription‐dependent strand‐biased selection, thus supporting their formation and function in genomes. They are present in almost all human genes in large amounts. We speculate that the two‐G‐quartet HQs may be a distinct type of G‐quadruplexes that may play a role in timely responsive processes and for purposes of fine‐tuning.
Quartets unite to call the tune: The transcription of G‐rich DNA produces G‐rich RNA transcripts. G‐tracts from DNA and RNA were found to form hybrid G‐quadruplexes (HQs) of two or more G‐quartets (see picture) with a possible role in transcription regulation. DNA:RNA HQs composed of two G‐quartets were less stable and more flexible than HQs composed of three G‐quartets, and their folding and unfolding were more responsive to transcription activity.
Tinospora sinensis, a kind of Chinese folk medicine, has functions of harmonizing qi and blood, dredging the channels and collaterals, calming and soothing the nerves. In the present study, a method ...based on high-performance liquid chromatography coupled with linear ion trap-Orbitrap mass spectrometry (HPLC-LTQ-Orbitrap) was developed for the systematical characterization of the non-diterpenoid constituents which possessed remarkable biological activities in T. sinensis, like anti-tumor, anti-inflammatory, hypoglycemic activity and immunomodulatory activity. Based on the accurate mass measurement (<5 ppm), retention times and MS fragmentation ions, 60 non-diterpenoid constituents were unambiguously or tentatively characterized from T. sinensis extract, including 27 alkaloids, 23 phenylpropanoids, seven sesquiterpenoids and three other constituents. Among them, 13 compounds were tentatively identified as new compounds. Finally, three of the non-diterpenoid constituents were purified and identified, which further confirmed the validity of the results. This study demonstrated that the HPLC-LTQ-Orbitrap MSn platform was a useful and efficient analytical tool to screen and identify constituents in natural medicine.
Volatile organic compounds (VOCs) have been identified as the most crucial precursors of tropospheric photochemical O_3 formation and secondary organic aerosols. In this study, field measurement was ...conducted to develop VOCs emission factors and source profiles of the wood furniture coating industry in China. An activity-based database was established, involving coat consumption-based, coating area-based, furniture production-based, and output value-based VOCs emission factors. Combining the results of field tests and literature surveys, emission factors were calculated by enterprise scale, coating type, spraying technology, and emission control device. The uncertainties were quantified by using Monte Carlo simulations. VOCs emission factors were estimated: 0.22 (0.10-0.34, 95% CI) kg kg^(-1) for coat consumption-based; 21.97 (10.10-29.38) g m^(-2) for coating area-based; 0.69 (0.34-1.00) kg piece^(-1) for furniture production-based; and 6.95 (3.42–10.21) kg 10^(-4) yuan for output value-based calculation, respectively. Aromatics and oxygenated VOCs (OVOCs) were predominant species of solvent borne paint emission, with the proportion of 71.1% and 22.9% of totals, respectively. VOCs emissions from the wood furniture coating industry were estimated at 179.76 × 10^3 (88.58 × 10^3 - 260.52 × 10^3, 95% CI) t in 2016. Due to the huge production output and intensive distribution of enterprises, VOCs emissions mainly concentrated in Guangdong, Zhejiang, Shandong, Fujian, Jiangxi, and Sichuan province, with the combined contribution of 43.8% of the national totals.
Land use and cover change (LUCC) has a non-negligible impact on both carbon emissions and carbon sinks. Based on the analysis of land use dynamics in Shandong Province, this study simulates land use ...changes in Shandong Province in 2030 under the Natural Development Scenario (NDS) and Sustainable Development Scenario (SDS), classifies the risk level of carbon emissions in Shandong Province using the Land Use Carbon Emission (LUCE) risk indexes, and compares the differences between the risk level regions under NDS and SDS. This study shows that under the influence of LUCC, the carbon emissions in Shandong province increased significantly, from 90.5591 million tons in 2000 to 493.538 million tons in 2020, with urban land being the main source of carbon emissions, which increased from 90.0757 million tons in 2000 to 490.139 million tons in 2020. The main source of the increase in urban land was cropland. The LUCE was positively correlated with urban land area. The LUCE of SDS was 7.2423 million tons less than that of NDS. From 2000 to 2020, the risk areas of LUCE in Shandong province were mainly no-risk and mild-risk areas. The number of moderate-risk areas and high-risk areas of SDS was less than that of NDS. The rational organization of land use is important for Shandong Province to achieve low-carbon development.
Chlorogenic acid (5-CQA), neochlorogenic acid (3-CQA), and cryptochlorogenic acid (4-CQA), usually simultaneously exist in many traditional Chinese medicines (TCMs). However, insufficient attentions ...have been paid to the comparative metabolism study on these three isomeric constituents with similar effects on anti-inflammation until now. In this study, a novel strategy was established to perform comparative analysis of their metabolic fates in rats and elucidate the pharmacological mechanism of anti-inflammation. Firstly, diagnostic product ions (DPIs) deduced from the representative reference standards were adopted to rapidly screen and characterize the metabolites in rat plasma, urine and faeces using UHPLC-Q-TOF MS. Subsequently, Network pharmacology was utilized to elucidate their anti-inflammatory mechanism. Consequently, a total of 73 metabolites were detected and characterized, including 50, 47 and 43 metabolites for 5-CQA, 4-CQA and 3-CQA, orderly. Moreover, the network pharmacology study indicated that these three isomeric constituents and their major metabolites with similar in vivo metabolic pathways exerted anti-inflammatory effects through co-owned 20 biological processes, which involved 10 major signal pathways and 159 potential targets. Our study shed light on the similarities and differences of the metabolic profiling and anti-inflammatory activity among these three isomeric constituents and set an example for the further researches on the active mechanism of isomeric constituents existing in TCMs based on comparative metabolism study.
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