Abstract
Pharmacotranscriptomics has become a powerful approach for evaluating the therapeutic efficacy of drugs and discovering new drug targets. Recently, studies of traditional Chinese medicine ...(TCM) have increasingly turned to high-throughput transcriptomic screens for molecular effects of herbs/ingredients. And numerous studies have examined gene targets for herbs/ingredients, and link herbs/ingredients to various modern diseases. However, there is currently no systematic database organizing these data for TCM. Therefore, we built HERB, a high-throughput experiment- and reference-guided database of TCM, with its Chinese name as BenCaoZuJian. We re-analyzed 6164 gene expression profiles from 1037 high-throughput experiments evaluating TCM herbs/ingredients, and generated connections between TCM herbs/ingredients and 2837 modern drugs by mapping the comprehensive pharmacotranscriptomics dataset in HERB to CMap, the largest such dataset for modern drugs. Moreover, we manually curated 1241 gene targets and 494 modern diseases for 473 herbs/ingredients from 1966 references published recently, and cross-referenced this novel information to databases containing such data for drugs. Together with database mining and statistical inference, we linked 12 933 targets and 28 212 diseases to 7263 herbs and 49 258 ingredients and provided six pairwise relationships among them in HERB. In summary, HERB will intensively support the modernization of TCM and guide rational modern drug discovery efforts. And it is accessible through http://herb.ac.cn/.
Ten-eleven translocation (TET) enzymes oxidize 5-methylcytosine, facilitating DNA demethylation and generating new epigenetic marks. Here we show that concomitant loss of Tet2 and Tet3 in mice at ...early B cell stage blocked the pro- to pre-B cell transition in the bone marrow, decreased Irf4 expression and impaired the germline transcription and rearrangement of the Igκ locus. Tet2/3-deficient pro-B cells showed increased CpG methylation at the Igκ 3' and distal enhancers that was mimicked by depletion of E2A or PU.1, as well as a global decrease in chromatin accessibility at enhancers. Importantly, re-expression of the Tet2 catalytic domain in Tet2/3-deficient B cells resulted in demethylation of the Igκ enhancers and restored their chromatin accessibility. Our data suggest that TET proteins and lineage-specific transcription factors cooperate to influence chromatin accessibility and Igκ enhancer function by modulating the modification status of DNA.
Pregnancy loss occurs in about 15% of clinically recognized pregnancies, and defective maternal-fetal immune tolerance contributes to more than 50% of these events. We found that signaling by the ...type I membrane protein T cell immunoglobulin and mucin-containing protein 3 (Tim-3) in natural killer (NK) cells had an essential protective role during early pregnancy. Tim-3 on peripheral NK (pNK) cells was transiently increased in abundance during the first trimester of pregnancy, which depended on interleukin-4 (IL-4)-signal transducer and activator of transcription 6 (STAT6) and progesterone signaling. Tim-3
pNK cells displayed immunosuppressive activities, including the production of anti-inflammatory cytokines and the induction of regulatory T cells (T
) in a transforming growth factor-β1 (TGF-β1)-dependent manner. Tim-3 on pNK cells was stimulated by its ligand galectin-9 (Gal-9), leading to signaling by the kinases c-Jun N-terminal kinase (JNK) and AKT. In recurrent miscarriage (RM) patients, Tim-3 abundance on pNK cells was reduced and the immunosuppressive activity of Tim-3
pNK cells was impaired. Compared to Tim-3
pNK cells from donors with normal pregnancies, RM patient Tim-3
pNK cells exhibited changes in DNA accessibility in certain genetic loci, which were reversed by inhibiting accessible chromatin reader proteins. Furthermore, Tim-3
pNK cells, but not Tim-3
pNK cells, reduced fetal loss in abortion-prone and NK cell-deficient mice. Together, our findings reveal a critical role for Tim-3-Gal-9 signaling-mediated immunoregulation by pNK cells in maternal-fetal immune tolerance and suggest that Tim-3 abundance on pNK cells is a potential biomarker for RM diagnosis.
Cadmium (Cd) is a toxic heavy metal in soil that seriously threatens crop production, food security, and human health. Syntaxins, a prototype family of Soluble N-ethyl-maleimide-associated protein ...receptors (SNAREs) involved in vesicle trafficking, are implicated in resistance to abiotic stresses, including Cd stress, but the molecular mechanisms underlying the involvement of syntaxins in Cd tolerance in plants are unclear. In this study, we isolated and functionally characterized the syntaxin gene RtSYP121 from Reaumuria trigyna to evaluate its potential for phytoremediation. RtSYP121 resides in the plasma membrane. The transcriptional level of RtSYP121 was strongly increased by salt, drought, and Cd stress. Overexpression of RtSYP121 significantly enhanced the Cd tolerance of transgenic Arabidopsis. The Cd tolerance of transgenic plants mainly depended on elevated vesicle trafficking, which increased the content of K+ and Ca2+ and thus decreased the accumulation of Cd2+ by regulating the delivery or activity of ion transporters, channels, and pumps. Moreover, overexpression of RtSYP121 in Arabidopsis ameliorated Cd stress–induced phytotoxic effects, including growth inhibition, ROS burst, photosynthetic impairment, and cell death. Therefore, we suggest that RtSYP121 plays multiple roles in the plant response to Cd stress by promoting vesicle trafficking, maintaining ion homeostasis, and alleviating photosynthetic inhibition.
●Overexpression of RtSYP121 showed strong tolerance to Cd toxicity in Arabidopsis by enhancing vesicle trafficking.●Overexpression of RtSYP121 in Arabidopsis increased K+ and Ca2+ content and decreased Cd2+ accumulation under Cd stress.●RtSYP121 overexpression alleviated Cd-mediated photosynthetic impairment, ROS burst, and growth inhibition in transgenic Arabidopsis.
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in most parts of the world. Although there is no first-line drug approved for the treatment of NAFLD, polyene ...phosphatidylcholine (PPC) is used by clinicians to treat NAFLD patients. This study aimed to evaluate the efficacy of PPC on a mice model of NAFLD, and to study the PPC's mechanism of action. The mice were fed a choline-deficient, L-amino acid-defined (CDAA) diet to induce NAFLD and were subsequently treated with PPC. The treatment effects were evaluated by the liver index, histopathological examination, and routine blood chemistry analyses. Lipidomics and metabolomics analyses of 54 samples were carried out using ultraperformance liquid chromatography (UPLC) coupled to a mass spectrometer to select for changes in metabolites associated with CDAA diet-induced NAFLD and the effects of PPC treatment. The intestinal flora of mice were extracted for gene sequencing to find differences before and after the induction of NAFLD and PPC treatment. PPC significantly improved the CDAA diet-induced NAFLD condition in mice. A total of 19 metabolites including 5 polar metabolites and 14 lipids showed marked changes. In addition, significant differences in the abundance of
were associated with NAFLD. We inferred that the protective therapeutic effect of PPC on the liver was related to the supplement of phosphatidylcholine, lysophosphatidylcholine, and sphingomyelin (PC, LPC, and SM, resectively) and acylcarnitine metabolism. This study developed a methodology for exploring the pathogenesis of NAFLD and can be extended to other therapeutic agents for treating NAFLD.
Increasing evidence have demonstrated the N6-methyladenosine (m
A) plays critical roles in osteoarthritis (OA) progression, but the role of m
A in OA has not been completely illuminated. Herein, we ...investigated the function and underlying mechanism of m
A demethylase fat mass and obesity-associated protein (FTO) in OA progression.
The FTO expression was detected in mice OA cartilage tissues and lipopolysaccharide (LPS)-stimulated chondrocytes. Gain-of-function assays was used to evaluate the role of FTO in OA cartilage injury in vitro and in vivo. The miRNA-sequencing, RNA-binding protein immunoprecipitation (RIP), luciferase reporter assay, and in vitro pri-miRNA processing assays were conducted to confirm that FTO modulated the pri-miR-3591 process in an m6A-dependent manner and then the binding sites of miR-3591-5p with PRKAA2.
FTO was outstandingly downregulated in LPS-stimulated chondrocytes and OA cartilage tissues. FTO overexpression enhanced the proliferation, suppressed apoptosis, and decreased degradation of extracellular matrix in LPS-induced chondrocytes, whereas FTO knockdown contributed to the opposite effects. In vivo animal experiments showed that FTO overexpression markedly alleviated OA mice cartilage injury. Mechanically, FTO-mediated m6A demethylation of pri-miR-3591 leaded to a maturation block of miR-3591-5p, which relieved the inhibitory effect of miR-3591-5p on PRKAA2 and then promoted the increase of PRKAA2, thereby alleviating OA cartilage damage.
Our results attested that FTO alleviated the OA cartilage damage by mediating FTO/miR-3591-5p/PRKAA2 axis, which provided fresh insights into the therapeutic strategies for OA.
BACKGROUND:Chemotherapy (CT) is an important adjuvant treatment that has been widely used for breast cancer (BC) patients. However, no research has focused on trends in emotions and quality of life ...(QOL) during intermittent periods between CT sessions that are critical for recovery.
OBJECTIVE:The aim of this study was to investigate longitudinal trends in anxiety, depression, and QOL during the different intermittent periods between adjuvant CT for BC.
METHODS:A longitudinal study design was adopted. Eighty-eight women undergoing CT for BC were selected using a purposive sampling method, and they completed the Self-rating Anxiety Scale (SAS), Self-rating Depression Scale (SDS), and Functional Assessment of Cancer Therapy–Breast (FACT-B) at 5 points. A repeated-measures analysis-of-variance model was used to compare anxiety, depression, and QOL at different time points.
RESULTS:The results showed a significant difference in SAS (F = 187.78, P < .00), SDS (F = 263.07, P < .00), and FACT-B (F = 140.82, P < .00) scores at the 5 time points. The SAS and SDS scores were highest at T3, whereas the FACT-B score was lowest at T3.
CONCLUSIONS:The BC patients had psychological distress during intermittent periods between adjuvant CT, as evidenced by anxiety and depression, which were highest in the third cycle. Meanwhile, QOL was lowest at the third CT cycle and highest at the first CT cycle.
IMPLICATIONS FOR PRACTICE:Clinical staff should focus on critical time periods during CT, particularly during the third cycle, and provide additional support to patients to ensure that CT is delivered in an optimal fashion.
Many animals actively change their own characteristics, such as color and texture, through camouflage, a natural defense mechanism, making them difficult to be detected in the natural environment, ...which makes the task of camouflaged object detection extremely challenging. Biological research shows that the eyes of animals have three-dimensional perception ability, and the obtained depth information can provide useful object positioning clues for finding camouflaged objects. However, almost all the current studies for camouflaged object detection do not combine depth maps with RGB images. Therefore, combining depth maps with traditional unimodal RGB images is of great research significance to improve the accuracy of camouflaged object detection. In this paper, we propose a depth alignment interaction network for camouflaged object detection in which the depth maps used are generated from existing monocular depth estimation networks. To address the problem that the quality of the generated depth maps varies, we propose a depth alignment index method to evaluate the quality of the depth maps. The method dynamically assigns the proportion of depth maps in the fusion process to depth maps of different quality according to their alignment with RGB images. Then, to fully extract the fused artifact features, we design an expanded pyramid interaction module, which first expands the receptive field of the features in each layer. Then, the features at the higher levels interacted with the features at the lower levels by connecting them step-by-step to further refine the predicted camouflaged area. Extensive experiments on 4 camouflaged object detection datasets demonstrate the effectiveness of our solution for camouflaged object detection.
The ending effect describes the phenomenon that at the end of a series of repeated risky decision-making tasks, participants become more likely to engage in risk-taking behavior. Past research has ...suggested that the ending effect might be caused by a motivational shift induced by changes in time perception. Previous studies mainly tested this phenomenon in a binary decision-making setting (e.g., a decision-making task usually includes two alternatives). However, none of these prior studies included safe options and risky options that differed in risk levels. To address this knowledge gap, the present study replicated the ending effect in a repeated decision-making task that included both a safe option and risky options that differed in risk levels (
N
= 104). We found that at the end of the decision-making task, participants became more likely to engage in risk-taking and to favor the option with the highest risk. Further, we found that the investment likelihood and investment amount of high-risk options both increased significantly at the ending. In addition, a shift in favoring the safe option emerged in the noninformed condition at the end. We also found that the emotional motivation in the last round could predict the increased preference for high-risk at the ending. This study extended previous findings on the ending effect by adopting a more complex decision-making scenario and, more broadly, helped further our understanding of the psychological consequences of perceived endings.
Apigenin, a natural plant flavone, has been shown to possess a variety of biological properties.
In this report, a highly selective and sensitive LC-MS/MS method was developed and validated for the ...determination of apigenin in rat plasma.
Analysts were separated on the HSS T3 column (1.8 μm 2.1×100 mm) using acetonitrile and 0.1% formic acid in 2mM ammonium acetate buffer at a supply rate of 0.200 mL/min as eluent in gradient model.
Plasma samples were treated by protein precipitation using acetonitrile for the recovery ranging from 86.5% to 90.1% for apigenin. The calibration curves followed linearity in the concentration range of 0.50-500ng/mL. The inter-day and intra-day precisions at different QC levels within 13.1% and the accuracies ranged from -10.6% to 8.6%.
The assay has been successfully applied to the pharmacokinetic study of apigenin in rats.
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