Multigenerational effects of disperse blue 79 at environmentally relevant concentrations on zebrafish (Danio rerio) fecundity: An integrated approach.

The brominated azo dye (BAD) Disperse Blue (DB79) is a widespread environmental pollutant. The long-term toxicological effects of DB79 and the mechanisms thereof must be understood to allow assessment of the risks of DB79 pollution. A dual-omics approach employing in silico analysis, bioinformatics, and in vitro bioassays was used to investigate the transgenerational (F0-F2) toxicity of DB79 in zebrafish at environmentally relevant concentrations and identify molecular initiating events and key events associated with DB79-induced fertility disorders. Exposure to 500 µg/L DB79 decreased fecundity in the F0 and F1 generations by > 30 % and increased the condition factor of the F1 generation 1.24-fold. PPARα/RXR and PXR ligand binding activation were found to be critical molecular initiating events associated with the decrease in fecundity. Several key events (changes in fatty acid oxidation and uptake, lipoprotein metabolism, and xenobiotic metabolism and transport) involved in lipid dysregulation and xenobiotic disposition were found to be induced by DB79 through bioinformatic annotation using dual-omics data. The biomolecular underpinnings of decreased transgenerational fertility in zebrafish attributable to BAD exposure were elucidated and novel biomolecular targets in the adverse outcome pathway framework were identified. These results will inform future studies and facilitate the development of mitigation strategies.

Five years of change in adult twins: longitudinal changes of genetic and environmental influence on epigenetic clocks.

BACKGROUND: Epigenetic clocks were known as promising biomarkers of aging, including original clocks trained by individual CpG sites and principal component (PC) clocks trained by PCs of CpG sites. The effects of genetic and environmental factors on epigenetic clocks are still unclear, especially for PC clocks. METHODS: We constructed univariate twin models in 477 same-sex twin pairs from the Chinese National Twin Registry (CNTR) to estimate the heritability of five epigenetic clocks (GrimAge, PhenoAge, DunedinPACE, PCGrimAge, and PCPhenoAge). Besides, we investigated the longitudinal changes of genetic and environmental influences on epigenetic clocks across 5 years in 134 same-sex twin pairs. RESULTS: Heritability of epigenetic clocks ranged from 0.45 to 0.70, and those for PC clocks were higher than those for original clocks. For five epigenetic clocks, the longitudinal stability was moderate to high and was largely due to genetic effects. The genetic correlations between baseline and follow-up epigenetic clocks were moderate to high. Special unique environmental factors emerged both at baseline and at follow-up. PC clocks showed higher longitudinal stability and unique environmental correlations than original clocks. CONCLUSIONS: For five epigenetic clocks, they have the potential to identify aging interventions. High longitudinal stability is mainly due to genetic factors, and changes of epigenetic clocks over time are primarily due to changes in unique environmental factors. Given the disparities in genetic and environmental factors as well as longitudinal stability between PC and original clocks, the results of studies with original clocks need to be further verified with PC clocks.

Characteristics and Controlling Factors of Methane Adsorption of the Longmaxi Shale in Northeastern Chongqing: Implications for Shale Gas Occurrence in Complex Structural Areas.

Accurately determining the adsorption capacity of Longmaxi shale in complex structural areas is crucial for evaluating the shale gas resources in northeastern Chongqing. However, studies on the pore characteristics and methane adsorption capacity of these Longmaxi shales are currently limited. In this paper, we collected core samples from the YDB-1 well in northeastern Chongqing and determined the pore structure and adsorption capacity of the Longmaxi shale using low-pressure gas adsorption and high-temperature, high-pressure methane adsorption experiments, respectively. The results indicate that the adsorption capacity of shale in complex structural areas is significantly positively correlated with the organic matter (OM) content, weakly positively correlated with the quartz content, and weakly negatively correlated with clay minerals. Meanwhile, gas-in-place content is simultaneously controlled by the pressure and temperature of the reservoir, and with increasing depth, the adsorbed gas rapidly increases to a maximum value (at 0.8 km) and then slowly decreases, whereas the free gas continuously increases. Compared with the shale in the stable structural areas, the Longmaxi shale in complex structural areas usually develops OM-hosted pores and intergranular pores of OM and minerals and contains more micropores due to tectonic compression, resulting in a relatively larger specific surface area and adsorption capacity. This is the reason shale in complex structural areas has high development potential. The final result can provide an important basis for the evaluation of the gas content and the optimization of dessert areas in the Lower Paleozoic shale gas in southern China.

Historical biogeography and evolutionary diversification of Lilium (Liliaceae): New insights from plastome phylogenomics.

Here, we infer the historical biogeography and evolutionary diversification of the genus Lilium. For this purpose, we used the complete plastomes of 64 currently accepted species in the genus Lilium (14 plastomes were newly sequenced) to recover the phylogenetic backbone of the genus and a time-calibrated phylogenetic framework to estimate biogeographical history scenarios and evolutionary diversification rates of Lilium. Our results suggest that ancient climatic changes and geological tectonic activities jointly shaped the distribution range and drove evolutionary radiation of Lilium, including the Middle Miocene Climate Optimum (MMCO), the late Miocene global cooling, as well as the successive uplift of the Qinghai-Tibet Plateau (QTP) and the strengthening of the monsoon climate in East Asia during the late Miocene and the Pliocene. This case study suggests that the unique geological and climatic events in the Neogene of East Asia, in particular the uplift of QTP and the enhancement of monsoonal climate, may have played an essential role in formation of uneven distribution of plant diversity in the Northern Hemisphere.

Plastid phylogenomics and fossil evidence provide new insights into the evolutionary complexity of the 'woody clade' in Saxifragales.

BACKGROUND: The "woody clade" in Saxifragales (WCS), encompassing four woody families (Altingiaceae, Cercidiphyllaceae, Daphniphyllaceae, and Hamamelidaceae), is a phylogenetically recalcitrant node in the angiosperm tree of life, as the interfamilial relationships of the WCS remain contentious. Based on a comprehensive sampling of WCS genera, this study aims to recover a robust maternal backbone phylogeny of the WCS by analyzing plastid genome (plastome) sequence data using Bayesian inference (BI), maximum likelihood (ML), and maximum parsimony (MP) methods, and to explore the possible causes of the phylogenetic recalcitrance with respect to deep relationships within the WCS, in combination with molecular and fossil evidence. RESULTS: Although the four WCS families were identically resolved as monophyletic, the MP analysis recovered different tree topologies for the relationships among Altingiaceae, Cercidiphyllaceae, and Daphniphyllaceae from the ML and BI phylogenies. The fossil-calibrated plastome phylogeny showed that the WCS underwent a rapid divergence of crown groups in the early Cretaceous (between 104.79 and 100.23 Ma), leading to the origin of the stem lineage ancestors of Altingiaceae, Cercidiphyllaceae, Daphniphyllaceae, and Hamamelidaceae within a very short time span (∼4.56 Ma). Compared with the tree topology recovered in a previous study based on nuclear genome data, cytonuclear discordance regarding the interfamilial relationships of the WCS was detected. CONCLUSIONS: Molecular and fossil evidence imply that the early divergence of the WCS might have experienced radiative diversification of crown groups, extensive extinctions at the genus and species levels around the Cretaceous/Paleocene boundary, and ancient hybridization. Such evolutionarily complex events may introduce biases in topological estimations within the WCS due to incomplete lineage sorting, cytonuclear discordance, and long-branch attraction, potentially impacting the accurate reconstruction of deep relationships.

Association between epigenetic age and type 2 diabetes mellitus or glycemic traits: A longitudinal twin study.

Epigenetic clocks based on DNA methylation have been known as biomarkers of aging, including principal component (PC) clocks representing the degree of aging and DunedinPACE representing the pace of aging. Prior studies have shown the associations between epigenetic aging and T2DM, but the results vary by epigenetic age metrics and people. This study explored the associations between epigenetic age metrics and T2DM or glycemic traits, based on 1070 twins (535 twin pairs) from the Chinese National Twin Registry. It also explored the temporal relationships of epigenetic age metrics and glycemic traits in 314 twins (157 twin pairs) who participated in baseline and follow-up visits after a mean of 4.6 years. DNA methylation data were used to calculate epigenetic age metrics, including PCGrimAge acceleration (PCGrimAA), PCPhenoAge acceleration (PCPhenoAA), DunedinPACE, and the longitudinal change rate of PCGrimAge/PCPhenoAge. Mixed-effects and cross-lagged modelling assessed the cross-sectional and temporal relationships between epigenetic age metrics and T2DM or glycemic traits, respectively. In the cross-sectional analysis, positive associations were identified between DunedinPACE and glycemic traits, as well as between PCPhenoAA and fasting plasma glucose, which may be not confounded by shared genetic factors. Cross-lagged models revealed that glycemic traits (fasting plasma glucose, HbA1c, and TyG index) preceded DunedinPACE increases, and TyG index preceded PCGrimAA increases. Glycemic traits are positively associated with epigenetic age metrics, especially DunedinPACE. Glycemic traits preceded the increases in DunedinPACE and PCGrimAA. Lowering the levels of glycemic traits may reduce DunedinPACE and PCGrimAA, thereby mitigating age-related comorbidities.

Effects of zhuhong ointment on MMPs activities and production by HSF / 中国中药杂志

HuaFu Shengji is the primary traditional Chinese medicine (TCM) therapy for treating chronic skin ulcer. The high activities of the protein enzyme in the wound fluids is one of the main cause of healing delay. In order to investigate the effect of TCM Zhuhong ointment for promoting wound healing. This research focused on its influence on matrix metalloproteinase (MMP) activities in wound fluids with TCM Yang syndromes, directly on the activated MMP-1,2 activities in vitro and on MMP-1,-2,-9 production by HSF. 8 wound fluid samples were collected, which were diagnosed Yang Syndromes in TCM. Wound fluid activities of MMP-2 and MMP-9 were measured by gelatin zymogram assay. MMP-1 and MMP-2 activities in vitro were measured by substrate cleavage. CCK-8 was used to observe the toxicity of Zhuhong ointment on HSF. MMP-1,-2,-9 production by HSF were detected by confocal microscope. Zhuhong ointment from 1 to 25 g x L(-1) obviously inhibited MMP-2 activity in wound fluid. When Zhuhong ointment was over 5 g x L(-1), it showed significantly inhibitory effect on wound fluid MMP-9 activity. In vitro study, when the mercury concentration was 320 mg x L(-1), Zhuhong ointment solution directly inhibited both MMP-1 activity and MMP-2. But mercury concentration from 0.51-2.56 mg x L(-1), it could activate MMP-1 activity, and from 0.51-64 mg x L(-1), activate MMP-2 activity instead. The mercury concentration when Zhuhong ointment saturated in DMEM was 39.6 mg x L(-1). When the mercury concentration was over 1.23 mg x L(-1), Zhuhong ointment showed toxicity to HSF. At 1.23, 0.62, 0.31 mg x L(-1) of mercury concentration, it increased MMP-1 expression by HSF, and at 1.23, 0.62 mg x L(-1), decreased MMP-2 expression. However, at 1.23, 0.62, 0.31 mg x L(-1), it decreased MMP-9 expression. At higher concentration, Zhuhong ointment can inhibit MMP-2, MMP-9 activities in wound fluid with dose-dependent way and show a direct inhibitory effect on activated MMP-1 and MMP-2 in vitro. But at a lower concentration, it showed two-way adjustment, with increased MMP-1, MMP-2 activities and its expression by HSF and decreased MMP-9 activity.

Arsenic trioxide regulates the production and activities of matrix metalloproteinases-1, -2, and -9 in fibroblasts and THP-1 / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>The elevated matrix metalloproteinase (MMP) activity is an important cause of chronic wound healing failure. Arsenolite, whose main component is arsenic trioxide (As2O3), is a common traditional Chinese medicine wildly used in treating chronic wounds; it can remove necrotic tissue and promote tissue regeneration. This research was designed to evaluate the effects of As2O3 on production and activities of MMP-1, MMP-2 and MMP-9, and on regulation of its signal transduction pathway in human skin fibroblasts (HSFb) and human monocyte line (THP-1 cells) that were in an inflammatory state.</p><p><b>METHODS</b>We established three cell models; HSFb activated by TNF-α, THP-1 cells activated by phorbol 12-myristate 13-acetate (PMA) and an HSFb-THP-1 co-culture system. Three cell models was cultured with As2O3 for 24 hours. The levels of MMP-1, MMP-2, MMP-9, TNF-α and IL-1β in the cell culture supernatants were assayed by ELISA. The mRNA expressions of MMP-1, MMP-2 and MMP-9 were determined by RT-PCR. The activities of MMP-2 and MMP-9 were tested by Gelatin zymography assays. The phosphorylation levels of ERK1/2 and p38MAPK were assayed by Western blotting.</p><p><b>RESULTS</b>As2O3 inhibited the expression of MMP-1, MMP-2 and MMP-9 mRNA, the secretion and activity of MMP-1, MMP-2 and MMP-9 in HSFb and THP-1 cells in the inflammatory state (P < 0.05 and P < 0.01 respectively). It also inhibited the secretion of TNF-α and IL-1β in THP-1 cells and in the co-culture system (P < 0.05 and P < 0.01, respectively). It also decreased the phosphorylation of ERK1/2 and p38 MAPK in HSFb and THP-1 cells (P < 0.05 and P < 0.01, respectively).</p><p><b>CONCLUSIONS</b>As2O3, as a main component of arsenolite, can inhibit the production of MMPs by HSFb and THP-1 cells in an inflammatory state through inhibiting the release of inflammatory factors and the activation of the MAPK cascade pathway. This may be a possible mechanism for arsenolite healing chronic wounds.</p>