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•ATE promoted the charcoal transit, reduced the amount of remnant fecal and increased fecal water content.•ATE alleviated colonic pathological damage.•ATE inhibited the binding of Ach ...to the muscarinic receptor and Ca2+ influx.•ATE attenuated constipation both through inhibiting intestinal abnormal contractions and relieving intestinal inflammation.
The dried root and rhizome of Aster tataricus (RA), is a traditional Chinese medicine has been used for more than 2000 years with the function of antitussive, expectorant and antiasthmatic. Ancient books and modern pharmacological researches demonstrated that RA may have the function of moistening intestines and relieving constipation, but there was a lack of systematic evidence. The aim of this study was to comprehensively evaluate the efficacy and possible mechanisms of ethanol extract of Aster tataricus (ATE) in treating constipation from in vivo to in vitro.
In vivo, the ATE was studied in loperamide-induced constipation of mice. In vitro, different concentrations of ATE was tested separately or cumulatively on spontaneous and agonists-induced contractions of isolated rat duodenum strips.
In vivo, at doses of 0.16, 0.8 g/mL, ATE showed significantly promotion of the small intestinal charcoal transit, decrease of the amount of remnant fecal, and increase of the content of fecal water in colon. In addition, ATE could effectively relieve colonic pathological damage caused by loperamide as well. In vitro, with the cumulative concentration increase of ATE from 0.8 to 6.4 mg/mL, it could significantly decrease the contraction caused by KCl or Ach, and gradually restore to near base tension value.Meanwhile, it could also partially but significantly inhibit the contractions induced by Ach and CaCl2 on rat duodenum in a concentration related manner.
Taking all these findings together, it could be speculated that ATE may attenuate constipation mainly through antagonizing the binding of acetylcholine to muscarinic receptor, inhibiting Ca2+ influx and anti-inflammation.
We develop PIRCh-seq, a method which enables a comprehensive survey of chromatin-associated RNAs in a histone modification-specific manner. We identify hundreds of chromatin-associated RNAs in ...several cell types with substantially less contamination by nascent transcripts. Non-coding RNAs are found enriched on chromatin and are classified into functional groups based on the patterns of their association with specific histone modifications. We find single-stranded RNA bases are more chromatin-associated, and we discover hundreds of allele-specific RNA-chromatin interactions. These results provide a unique resource to globally study the functions of chromatin-associated lncRNAs and elucidate the basic mechanisms of chromatin-RNA interactions.
. (PMT), a commonly used Chinese herbal medicine for treating diseases such as poisoning and white hair, has attracted constant attention due to the frequent occurrence of liver injury incidents. To ...date, its hepatotoxic equivalent markers (HEMs) and potential hepatotoxic mechanisms are still unclear. In order to clarify the HEMs of PMT and further explore the potential mechanisms of hepatotoxicity, firstly, the chemical constituents in PMT extract were globally characterized, and the fingerprints of PMT extracts were established along with the detection of their hepatotoxicity in vivo. Then, the correlations between hepatotoxic features and component contents were modeled by chemometrics to screen HEMs of PMT, which were then further evaluated. Finally, the hepatotoxic mechanisms of PMT were investigated using liver metabolomics and molecular docking. The results show that the chemical combination of 2,3,5,4-tetrahydroxystilbene-2-O-β-D-glucoside (TSG) and emodin-8-O-glucoside (EG) was discovered as the HEMs of PMT through pre-screening and verifying process. Liver metabolomics revealed that PMT caused liver injury by interfering with purine metabolism, which might be related to mitochondrial function disorder and oxidative injury via the up-regulations of xanthosine and xanthine, and the down-regulation of 5' nucleotidase (NT5E) and adenylate kinase 2 (AK2). This study not only found that the HEMs of PMT were TSG and EG, but also clarified that PMT might affect purine metabolism to induce liver injury, which contributed to our understanding of the underlying mechanisms of PMT hepatotoxicity.
•A sensitive IC-HRMS approach for HAA analysis with direct injection and no postcolumn infusion of solvent•Using potassium hydroxide as the mobile phase for IC-HRMS provided better sensitivity than a ...carbonate/bicarbonate mobile phase•An analytical performance comparison of the three quantitative modes (full MS/dd-MS2, t-SIM/dd-MS2 and PRM) of HRMS for HAA determinations•In addition to highly sensitive HAA quantification, retrospective data mining was applied for the detection of non-targeted analytes, particularly for halogenated compounds
A highly selective, sensitive, and simple analytical method for identification and quantification of nine haloacetic acids, bromate, and dalapon has been developed. This method uses ion chromatography (IC) coupled with electrospray ionization-high-resolution mass spectrometry (IC-ESI-HRMS) to directly analyze water samples on a high capacity anion-exchange column, eliminating the need for sample pretreatment/derivatization. Our study compared the following three types of targeted quantitation experiments using a quadrupole–orbitrap hybrid mass spectrometer, full-scan MS with data-dependent tandem mass spectrometry (full MS/dd-MS2 with inclusion list), targeted selected ion monitoring (SIM) with data-dependent tandem mass spectrometry (t-SIM/dd-MS2), and parallel reaction monitoring (PRM). Sensitivity, linearity, accuracy, and precision were validated following the guidelines of U.S. EPA Method 557. Single laboratory lowest concentration minimum reporting levels (LCMRLs) for the analytes using three different acquisition modes ranged from 0.0011 to 0.18 μg/L. All three quantitation modes showed good linearity for the eleven analytes with coefficients of determination of 0.9981- 0.9993. This IC-ESI-HRMS method was successfully applied to the analysis of commercial bottled water, tap water from San Francisco Bay Area, and the same tap water that has been through a filtered drinking water faucet. Both t-SIM/dd-MS2 and PRM modes were sensitive to confirm the trace-level presence of all nine HAAs, bromate, and dalapon in the tap water sample. Full-scan HRMS data acquisition provided the benefits of simultaneous data collection for both targeted and non-targeted components, and thus, suitability for simultaneous quantification of an unlimited number of compounds. Data-dependent MS/MS (dd-MS2) product-ion spectra were used for confirmation. All three modes showed good quantitative performance and obtained similar values. Single laboratory precision and accuracy data are presented for three water matrices: reagent water, laboratory synthetic sample matrix (LSSM), and tap water. Single laboratory precision was 0.078- 8.04%, and accuracy was in the range 70–130% for the three MS modes.
To explore the possible mechanisms of cholestasis induced by Polygoni Multiflori Radix (PM).
Low and high doses of water extract of PM were given to mice by gavage for 8 weeks. The serum biochemical ...indexes of aspartate aminotransferase (AST), alanine aminotransferase (ALT), glutamyltransferase (GGT) alkaline phosphatase (ALP) and so on were detected in the second, fourth, sixth, and eighth weeks after administration. At the end of the eighth week of administration, the bile acid metabolic profiles of liver and bile were screened by high-performance liquid chromatography tandem triple quadrupole mass spectrometry (HPLC-QQQ-MS/MS). Liver pathological changes were observed by hematoxylin and eosin staining. Real-time quantitative polymerase chain reaction (RT-qPCR) was used to detect the mRNA transcription of the target genes and Western blotting (WB) was used to the detect target protein expression.
Biochemical tests results showed the values of ALP and GGT were two and three times greater than the normal values respectively, and the value of R was less than 2. Histopathology also showed that PM caused lymphocyte infiltration, a small amount of hepatocyte necrosis and nuclear fragmentation in mouse liver. The proliferation of bile duct epithelial cells was observed in the high group. These results indicated that PM may lead to cholestatic liver injury. HPLC-QQQ-MS/MS analysis with the multivariate statistical analysis revealed significant alterations of individual bile acids in liver and gallbladder as compared to those of the control group. RT-qPCR showed that the transcription of
,
,
,
,
, and
were downregulated and that of
,
, and
was significantly upregulated in the treatment group. WB demonstrated that PM also markedly downregulated the protein expression of FXR, BSEP, and MDR2, and upregulated CYP7A1.
PM inhibited the expression of FXR, which reduced the expression of MDR2 and BSEP, leading to the obstruction of bile acids outflow, and increased the expression of CYP7A1, resulting in an increase of intrahepatic bile acid synthesis, which can lead to cholestasis.
Accurate prediction of drug response is a crucial step in personalized medicine. Recently, deep learning techniques have been witnessed with significant breakthroughs in a variety of areas including ...biomedical research and chemogenomic applications. This motivated us to develop a novel deep learning platform to accurately and reliably predict the response of cancer cells to different drug treatments. In the present work, we describe a Java-based implementation of deep neural network method, termed JavaDL, to predict cancer responses to drugs solely based on their chemical features. To this end, we devised a novel cost function and added a regularization term which suppresses overfitting. We also adopted an early stopping strategy to further reduce overfit and improve the accuracy and robustness of our models. To evaluate our method, we compared with several popular machine learning and deep neural network programs and observed that JavaDL either outperformed those methods in model building or obtained comparable predictions. Finally, JavaDL was employed to predict drug responses of several aggressive breast cancer cell lines, and the results showed robust and accurate predictions with
as high as 0.81.
Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease that involves a variety of cell types. However, how the epigenetic dysregulations of peripheral immune cells contribute to the ...pathogenesis of RA still remains largely unclear.
Here, we analysed the genome-wide active DNA regulatory elements of four major immune cells, namely monocytes, B cells, CD4
T cells and CD8
T cells, in peripheral blood of RA patients, osteoarthritis (OA) patients and healthy donors using Assay of Transposase Accessible Chromatin with sequencing (ATAC-seq). We found a strong RA-associated chromatin dysregulation signature in monocytes, but no other examined cell types. Moreover, we found that serum C-reactive protein (CRP) can induce the RA-associated chromatin dysregulation in monocytes via in vitro experiments. And the extent of this dysregulation was regulated through the transcription factor FRA2.
Together, our study revealed a CRP-induced pathogenic chromatin dysregulation signature in monocytes from RA patients and predicted the responsible signalling pathway as potential therapeutic targets for the disease.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A novel tyrosine aminotransferase gene (designated as SmTAT) involved in rosmarinic acid biosynthesis pathway is cloned from Salvia miltiorrhiza Bung. The full-length cDNA of SmTAT is 1,603 bp long ...with an open reading frame (ORF) of 1,233 bp encoding a polypeptide of 411 amino acid residues. The deduced amino acid sequence of the SmTAT gene shared high homology with other known TATs. Analysis of SmTAT genomic DNA reveals that it contains 6 exons, 5 introns. The analysis of SmTAT promoter region and terminator region was also presented. Semi-quantitative RT-PCR analysis reveals that the constitutive expression of SmTAT in stem is much higher than that in root, leaf. Further expression analysis reveals that the signaling components of defense/stress pathways, such as methyl jasmonate (MeJA), abscisic acid (ABA), salicylic acid (SA) and ultraviolet-B radiation (UV-B), up-regulate the SmTAT transcript levels over the control. This study provides useful information for further studying this gene and its function in rosmarinic acid biosynthetic pathway in S. miltiorrhiza, the roots of which so-called ''Danshen'' possess many pharmaceutical properties for human health.
In recent months, the novel coronavirus disease 2019 (COVID-19) pandemic has become a major public health crisis with takeover more than 1 million lives worldwide. The long-lasting existence of ...severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has not yet been reported. Herein, we report a case of SARS-CoV-2 infection with intermittent viral polymerase chain reaction (PCR)-positive for >4 months after clinical rehabilitation. A 35-year-old male was diagnosed with COVID-19 pneumonia with fever but without other specific symptoms. The treatment with lopinavir-ritonavir, oxygen inhalation, and other symptomatic supportive treatment facilitated recovery, and the patient was discharged. However, his viral PCR test was continually positive in oropharyngeal swabs for >4 months after that. At the end of June 2020, he was still under quarantine and observation. The contribution of current antivirus therapy might be limited. The prognosis of COVID-19 patients might be irrelevant to the virus status. Thus, further investigation to evaluate the contagiousness of convalescent patients and the mechanism underlying the persistent existence of SARS-CoV-2 after recovery is essential. A new strategy of disease control, especially extending the follow-up period for recovered COVID-19 patients, is necessary to adapt to the current situation of pandemic.
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