Caffeic-Acid-Functionalized MWCNTs and PEDOT:PSS Formed Composite Flexible Films with "Reinforced Concrete" Structure for Electrical Heating and EMI Shielding.

Nowadays, flexible multifunctional composites are attracting much attention and are practically being used in various emerging electronic devices. However, most composites suffer from the disadvantages of high loadings of conductive fillers, complicated preparation processes, and low energy conversion efficiency. In this article, Caffeic acid-modified multiwalled carbon nanotubes (C-MWCNTs)/poly(3,4-ethylene dioxythiophene):polystyrene sulfonic acid (PEDOT:PSS)/polyimide (PI) composite films (CPFs) were prepared using a simple layer-by-layer deposition method. The "reinforced concrete" structure of the C-MWCNTs/PEDOT:PSS layer ensures high electrical conductivity of the film, while the PI layer provides excellent mechanical properties (72.69 MPa). The composite film exhibits excellent electrothermal response and thermal stability up to approximately 125 °C at 5 V. In addition, the good conductivity of the film provides its electromagnetic shielding effectiveness (32.69 dB). With these advantages, we expect that flexible CPFs will be widely utilized in wearable devices, electromagnetic interference (EMI) shielding applications, and thermal management of personal or electronic devices.

Aggregation-Induced Emission Luminogens: A New Possibility for Efficient Visualization of RNA in Plants.

RNAs play important roles in regulating biological growth and development. Advancements in RNA-imaging techniques are expanding our understanding of their function. Several common RNA-labeling methods in plants have pros and cons. Simultaneously, plants' spontaneously fluorescent substances interfere with the effectiveness of RNA bioimaging. New technologies need to be introduced into plant RNA luminescence. Aggregation-induced emission luminogens (AIEgens), due to their luminescent properties, tunable molecular size, high fluorescence intensity, good photostability, and low cell toxicity, have been widely applied in the animal and medical fields. The application of this technology in plants is still at an early stage. The development of AIEgens provides more options for RNA labeling. Click chemistry provides ideas for modifying AIEgens into RNA molecules. The CRISPR/Cas13a-mediated targeting system provides a guarantee of precise RNA modification. The liquid-liquid phase separation in plant cells creates conditions for the enrichment and luminescence of AIEgens. The only thing that needs to be looked for is a specific enzyme that uses AIEgens as a substrate and modifies AIEgens onto target RNA via a click chemical reaction. With the development and progress of artificial intelligence and synthetic biology, it may soon be possible to artificially synthesize or discover such an enzyme.

MXene and AgNW based flexible transparent conductive films with sandwich structure for high-performance EMI shielding and electrical heaters.

With the popularization of 5G technology and the development of science and technology, flexible and transparent conductive films (TCF) are increasingly used in the preparation of optoelectronic devices such as electromagnetic shielding devices, transparent flexible heaters, and solar cells. Silver nanowires (AgNW) are considered the best material for replacing indium tin oxide to prepare TCFs due to their excellent comprehensive properties. However, the loose overlap between AgNWs is a significant reason for the high resistance. This article investigates a sandwich structured conductive network composed of AgNW and Ti3C2Tx MXene for high-performance EMI shielding and transparent electrical heaters. Polyethylene pyrrolidone (PVP) solution was used to hydrophilic modify PET substrate, and then MXene, AgNW, and MXene were assembled layer by layer using spin coating method to form a TCF with a sandwich structure. One-dimensional AgNW is used to provide electron transfer channels and improve light penetration, while two-dimensional MXene nanosheets are used for welding AgNWs and adding additional conductive channels. The flexible TCF has excellent transmittance (85.1 % at 550 nm) and EMI shielding efficiency (27.1 dB). At the voltage of 5 V, the TCF used as a heater can reach 85.6 °C. This work offers an innovative approach to creating TCFs for the future generation.

High-Throughput, Quantitative Screening of Quorum-Sensing Inhibitors Based on a Bacterial Biosensor.

Quorum sensing (QS) is a cell-cell communication mechanism by which bacteria synchronize social behaviors such as biofilm formation and virulence factor secretion by producing and sensing small molecular signals. Quorum quenching (QQ) by degrading signals or blocking signal transmissions has become a promising strategy for disrupting QS and preventing bacterial infection and biofilm formation. However, studies of high-throughput screening and identification approaches for quorum-sensing inhibitors (QSIs) are still inadequate. In this work, we developed a sensitive, high-throughput approach for screening QSIs based on the bacterial biosensor strain Agrobacterium tumefaciens N5 (pBA7P), which contains a traG gene promoter induced by QS signals fused with a promoterless ß-lactamase gene reporter. Using this approach, we identified 31 QQ bacteria from ∼2000 soil bacterial isolates, some belonging to the genera Bosea, Cupriavidus, and Flavobacterium that have not been reported previously as QQ bacteria. We also identified four QS inhibitory compounds and one QS signal analogue from ∼5000 small-molecule compounds, which profoundly affected the expression of QS-regulated genes and phenotypes of the pathogenic bacteria. This high-throughput screening system is effective and sensitive for screening of both QQ microbes and small molecules, enabling the discovery of a wide variety of biocompatible compounds.

Layer-Structured Multitransition-Metal Oxide Cathode Materials for Potassium-Ion Batteries with Long Cycling Lifespan and Superior Rate Capability.

Manganese (Mn)-based layer-structured transition metal oxides are considered as excellent cathode materials for potassium ion batteries (KIBs) owing to their low theoretical cost and high voltage plateau. The energy density and cycling lifetime, however, cannot simultaneously satisfy the basic requirements of the market for energy storage systems. One of the primary causes results from the complex structural transformation and transition metal migration during the ion intercalation and deintercalation process. The orbital and electronic structure of the octahedral center metal element plays an important role for maintaining the octahedral structural integrity and improving the K+ diffusivity by the introduced heterogeneous [Me-O] chemical bonding. A multitransition metal oxide, P3-type K0.5Mn0.85Co0.05Fe0.05Al0.05O2 (KMCFAO), was synthesized and employed as a cathode material for KIBs. Beneficial from the larger layer spacing for K+ to better accommodate and effectively preventing the irreversible structural transformation in the insertion/extraction process, it can reach a superior capacity retention up to 96.8% after 300 cycles at a current density of 500 mA g-1. The full cell of KMCFAO//hard carbon exhibits an encouraging promising energy density of 113.8 W h kg-1 at 100 mA g-1 and a capacity retention of 72.6% for 500 cycles.

Clinical Evaluation of Cystic Renal Masses With Bosniak Classification by Contrast-Enhanced Ultrasound and Contrast-Enhanced Computer Tomography.

OBJECTIVES: The study aims to compare retrospectively three clinically applied methods for the diagnostic performance of cystic renal masses (CRMs) by contrast-enhanced ultrasound (CEUS) and contrast-enhanced computer tomography (CECT) with Bosniak classification system. METHODS: A total of 52 cases of Bosniak II-IV CRMs in 49 consecutive patients were diagnosed from January 2013 to July 2022 and their data were analyzed. All patients had been subjected to CEUS and CECT simultaneously. Pathological diagnoses and masses stability were used as standard references to determine whether lesions were malignant or benign. Then 49 CRMs only with pathologic results were classified into group 1 and 2. RESULTS: A total of 52 CRMs in 49 enrolled patients were classified into 8 category II, 16 category IIF, 15 category III, and 13 category IV by CEUS (EFSUMB 2020), 10 category II, 13 category IIF, 16 category III, and 13 category IV by CEUS (V2019), while 15 category II, 9 category IIF, 13 category III, and 15 category IV by CECT (V2019). Pathological results and masses stability longer than 5 years follow-up performed substantially for CEUS (EFSUMB 2020), CEUS (V2019), and CECT (V2019) (kappa values were 0.696, 0.735, and 0.696, respectively). Among 49 pathologic approving CRMs, wall/septation thickness ≥4 mm, wall/septation thickness, presence of enhancing nodule and the diameter were found to be statistically significant for malignancy. Twenty-two malignant masses were correctly diagnosed by CEUS (V2019), while 21 malignant masses were both correctly diagnosed by CEUS (EFSUMB 2020) and CECT (V2019), and 1 mass was misdiagnosed. CONCLUSIONS: Bosniak classification of EFSUMB 2020 version might be as accurate as version 2019 CEUS and version 2019 CECT in diagnosing CRMs, and CEUS is found to have an excellent safety profile in dealing with clinical works.

Characteristics and risk assessment of sewage sludge from urban wastewater treatment plants in Shaanxi Province, China.

In this study, an investigation of important properties, including moisture content, pH, plant nutrients, organic matter, mineral oil, and the contents of heavy metals (HMs) in sewage sludge (SS) collected from 32 urban treatment plants in Shaanxi Province, China, was carried out. The test results showed that the pH and the moisture, organic matter, total nitrogen (TN), total phosphorus (TP), and mineral oil contents of the SS varied over different rainfall periods, and most of the indicators met the standard criteria for SS agricultural reuse in China. Principal component analysis (PCA) and correlation analysis indicated that the pollutant characteristics of the SS depended on time span and geographical distribution. The mean contents of Pb, Cd, Cu, Zn, Ni, Cr, Hg, and As in SS were 3.95, 16.38, 5.43, 7.70, 1.31, 1.53, 32.77, and 1.40 times higher than the soil background values, respectively. Speciation analysis showed that the forms of HMs in the SS were significantly different. Assessments based on the geoaccumulation index (Igeo), Nemerow integrated pollution index (NIPI), and potential ecological risk index (RI) suggested that HM pollution risk levels were either uncontaminated or moderately contaminated in some regions and that SS recycled for agricultural applications carried a low risk. In conclusion, certain potential ecological risks exist for SS agricultural utilization in Shaanxi Province, and it is necessary to reduce the HM content before SS resource utilization for land application.

Effectiveness of Traditional Chinese Medicine on coronavirus disease 2019 in 92 patients: a retrospective study.

OBJECTIVE: To investigate the antipyretic effect of early treatment with Traditional Chinese Medicine (TCM) on coronavirus disease 2019 (COVID-19) patients. METHODS: We retrospectively analyzed 369 patients from January 26th, 2020 to April 15th, 2020, who had been diagnosed with COVID-19. Among 92 eligible cases, 45 cases were identified as treatment group Ⅰ ( 45) and 47 cases were identified as treatment group Ⅱ. Patients in the treatment group Ⅰ were treated with TCM herbal decoction within 5 d after admission. Patients in the treatment group Ⅱ were treated with TCM herbal decoction after the 6th admission day. The onset time of antipyretic effect, the antipyretic time, the time of negative oropharyngeal swab nucleic acid conversion, and the changes of cell count in blood routine test were compared. RESULTS: The treatment group I showed shorter average antipyretic duration (4 7 d; <0.05), and shorter average time for polymerase chain reaction (PCR) nucleic acid test results to turn negative (7 11 d; <0.05) than the treatment group II. For patients ( 54) with body temperature>38 ℃, patients in the treatment group I had shorter median onset time of antipyretic effect than those in the treatment group II (3 4 d; <0.05). The absolute lymphocyte (LYMPH) count and absolute eosinophil (EOS) count on the 3rd day after admission and the neutrophil/lymphocyte ratio on the 6th day after admission of patients in the treatment group I were notably different from those in the treatment group II at the same time point (0.05). Based on Spearman's rank correlation analysis, the change of body temperature on the 3rd day after admission was positively correlated with the increase of EOS count and the increase of EOS count and LYMPH counts on the 6th day after admission (0.01). CONCLUSIONS: Early TCM intervention within 5 d after hospital admission shortened the onset time of antipyretic effect and fever duration of COVID-19 patients, reduced the time required for PCR test results to turn negative. Moreover, early TCM intervention also improved the results of inflammatory markers for COVID-19 patients. LYMPH and EOS counts can be used as indicators of TCM antipyretic effect.

Liver metabolomic characteristics in three different rat models of deficiency based on ultra-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry.

OBJECTIVE: To investigate the mechanism of deficiency syndrome (YDS) by analyzing the liver metabolomic characteristics of three different deficiency rat models METHODS: Following the TCM etiology, for clinical features and pathological manifestations of modern medicine, three kinds of animal models of deficiency were induced and replicated. Totally 48 Sprague-Dawley (SD) male rats were randomly divided into blank group, irritation induced model group, Fuzi-Ganjiang induced model group, and thyroxine-reserpine induced model group. After successful development of model, the ultra-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry was carried out to detect metabolites in each group. The metabolites of rat liver were analyzed for the characteristics of their biomarkers. The pathway enrichment analysis and metabolic network construction were performed through various online databases including Metabolite Biology Role, Human Metabolome Database, MetaboAnalyst, and Kyoto Encyclopedia of Genes and Genomes. RESULTS: The SD rats in the experimental group showed symptoms like less weight gain, reduced diet and water intake, high body temperature, increased liver and kidney indexes, and abnormal liver and kidney tissue morphology. Moreover, the rats showed high increased levels of serum cyclic adenosine monophosphate, estradiol, alanine transaminase, and aspartate aminotransferase and decreased levels of cyclic guanosinc monophosphate and testosterone. We found four key interrelated metabolic pathways in the liver tissue metabolomics, including the biosynthesis of pantothenic acid and coenzyme A, and metabolism of alpha-linolenic acid metabolism, glycerophospholipid metabolism, and sphingolipid. CONCLUSION: The liver and kidney YDS is closely related to the biosynthesis of pantothenic acid and CoA and abnormal metabolism of α-linolenic acid, glycerophospholipid, and sphingolipid in SD rats.

Label-free target discovery technology of small molecule drug and its application in traditional Chinese medicines / 药学学报

The discovery of drug targets plays a crucial role in drug research. Accurate information of small molecule drug-protein interaction can be provided by label-free target discovery technology without any structural modification at the small molecule. So, the label-free drug target discovery technology had become the powerful tool to discover the targets of drugs. Due to the “multi-component and multi-target” characteristics of traditional Chinese medicines (TCMs), the research on its targets and mechanism had been restricted. Based on potential of the label-free target discovery technology in the research of TCMs, this paper summarized the label-free target discovery technology and its application in TCMs research. It will provide a reference for the discovery of targets of TCMs and a new view for promoting the modernization of TCMs.

Yangyin Huayu Jiedu Preseription Regulates Autophagy and Apoptosis of Colon Cancer Cells in Hypoxic Environment Through PI3K/Akt Signaling Pathway / 中国实验方剂学杂志

ObjectiveTo investigate the effect of different oxygen concentration on the proliferation and autophagy of colon cancer cells and to explore the effect of Yangyin Huayu Jiedu Preseription （YHJP） on autophagy and apoptosis of colon cancer cells under hypoxia based on phosphatidylinositol 3-kinase/protein kinase B （PI3K/Akt） signaling pathway. MethodHCT-116 cells were divided into normoxia group， 1% O2 group， and 5% O2 group. Cell viability was detected by cell proliferation assay （MTS）， and autophagy was observed based on monodansylcadaverine （MDC） staining. HCT-116 cells were treated with YHJP in 5% O2 microenvironment. The cells were divided into normal group， blank serum group， and low-， medium-， high-dose YHJP groups （5%， 15%， 25% serum containing YHJP）. Cell inhibition rate in each group was calculated by MTS， and changes in the rate of autophagy were detected based on MDC staining. Annexin V-fluorescein isothiocyanate （FITC）/propidium iodide （PI） was employed to detect the apoptosis rate of each group. Western blotting was applied to measure the expression of autophagy proteins microtubule-associated protein 1 light chain 3 （LC3Ⅱ/Ⅰ）， yeast Atg6 homolog （Beclin-1）， ubiquitin-binding scaffold protein p62 （p62）， apoptosis-related proteins B-cell lymphoma-2 （Bcl-2）， Bcl-2/adenovirus E1B interacting protein 3 （BNIP-3）， and Bcl-2 associated X protein （Bax）， cleaved cysteine-aspartic acid protease-3 （Caspase-3）， hypoxia-inducible factor-1α （HIF-1α） and pathway proteins PI3K， phosphorylated （p）-PI3K， Akt， and p-Akt. ResultCell survival rates of the 1% O2 and 5% O2 groups were increased compared with that in the normoxia group， particularly the 5% O2 group （P<0.01）. The fluorescence intensity for autophagy in 1% O2 and 5% O2 groups was significantly increased compared with that in the normoxia group， especially the 5% O2 group. In the presence of 5% O2， compared with the blank serum group， medium-dose and high-dose YHJP groups showed high cell inhibition rate， low autophagy rate， high apoptosis rate （P<0.01）， and low expression of Beclin-1 protein （P<0.05）. Compared with low-dose YHJP group， high-dose YHJP group demonstrated low expression of Beclin-1 protein （P<0.05）. Compared with the blank serum group， the three YHJP groups had low expression of LC3Ⅱ/Ⅰ protein （P<0.05， P<0.01）. Compared with the blank serum group， medium-dose and high-dose YHJP groups showed high expression of p62 protein （P<0.01）. Compared with low-dose YHJP group， high-dose YHJP group showed high expression of p62 protein （P<0.05）. Compared with the blank serum group， high-dose YHJP increased the expression of BNIP-3 and Bax and decreased the expression of Bcl-2 （P<0.01）. The expression of Bax protein in the high-dose YHJP group was increased compared with that in the low-dose YHJP group （P<0.05）. The expression of HIF-1α in the medium-dose and high-dose YHJP groups was decreased （P<0.01） and the expression of p-PI3K/PI3K and p-Akt/Akt in the high-dose YHJP group was increased （P<0.05， P<0.01） compared with that in the blank serum group. The expression of p-Akt/Akt was higher in the high-dose YHJP group than in the medium-dose YHJP （P<0.05）. ConclusionHypoxic microenvironment can significantly promote autophagy and proliferation of colon cancer cells. YHJP can significantly inhibit autophagy and proliferation and promote apoptosis of colon cancer cells in 5% O2 environment by up-regulating the PI3K/Akt signaling pathway.

Comparison of prediction ability of two extended Cox models in nonlinear survival data analysis / 南方医科大学学报

OBJECTIVE@#To compare the predictive ability of two extended Cox models in nonlinear survival data analysis.@*METHODS@#Through Monte Carlo simulation and empirical study and with the conventional Cox Proportional Hazards model and Random Survival Forests as the reference models, we compared restricted cubic spline Cox model (Cox_RCS) and DeepSurv neural network Cox model (Cox_DNN) for their prediction ability in nonlinear survival data analysis. Concordance index was used to evaluate the differentiation of the prediction results (a larger concordance index indicates a better prediction ability of the model). Integrated Brier Score was used to evaluate the calibration degree of the prediction (a smaller index indicates a better prediction ability).@*RESULTS@#For data that met requirement of the proportion risk, the Cox_RCS model had the best prediction ability regardless of the sample size or deletion rate. For data that failed to meet the proportion risk, the prediction ability of Cox_DNN was optimal for a large sample size (≥500) with a low deletion (< 40%); the prediction ability of Cox_RCS was superior to those of other models in all other scenarios. For example data, the Cox_RCS model showed the best performance.@*CONCLUSION@#In analysis of nonlinear low maintenance data, Cox_RCS and Cox_DNN have their respective advantages and disadvantages in prediction. The conventional survival analysis methods are not inferior to machine learning or deep learning methods under certain conditions.

Mechanism of Yanghe Decoction against subcutaneous tumor in pulmonary metastasis from breast cancer through HIF-1α signaling pathway regulating glycolysis:based on network pharmacology and animal experiment / 中国中药杂志

This study aims to explore the mechanism of Yanghe Decoction(YHD) against subcutaneous tumor in pulmonary metastasis from breast cancer, which is expected to lay a basis for the treatment of breast carcinoma with YHD. The chemical components of medicinals in YHD, and the targets of the components were retrieved from Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP) and SwissTargetPrediction. The disease-related targets were searched from GeneCards and Online Mendelian Inheritance in Man(OMIM). Excel was employed to screen the common targets and plot the Venn diagram. The protein-protein interaction network was constructed. R language was used for Gene Ontology(GO) term enrichment and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment. A total of 53 female SPF Bablc/6 mice were randomized into normal group(same volume of normal saline, ig), model group(same volume of normal saline, ig), and low-dose and high-dose YHD groups(YHD, ig, 30 days), with 8 mice in normal group and 15 mice in each of the other groups. Body weight and tumor size was measured every day. Curves for body weight variation and growth of tumor in situ were plotted. In the end, the subcutaneous tumor sample was collected and observed based on hematoxylin and eosin(HE) staining. The mRNA and protein levels of hypoxia inducible factor-1α(HIF-1α), pyruvate kinase M2(PKM2), lactate dehydrogenase A(LDHA), and glucose transporter type 1(GLUT1) were detected by PCR and Western blot. A total of 213 active components of YHD and 185 targets against the disease were screened out. The hypothesis that YHD may regulate glycolysis through HIF-1α signaling pathway to intervene in breast cancer was proposed. Animal experiment confirmed that the mRNA and protein levels of HIF-1α, PKM2, LDHA, and GLUT1 in the high-and low-dose YHD groups were lower than those in the model group. YHD has certain inhibitory effect on subcutaneous tumor in pulmonary metastasis from breast cancer in the early stage, which may intervene pulmonary metastasis from breast cancer by regulating glycolysis through HIF-1α signaling pathway.

Mechanism of melatonin regulation of PI3K/Akt/mTOR signaling in hypothalamus delaying the initiation of puberty in female mice / 解剖学报

Objective To explore the effect of melatonin ( MLT) on the initiation of puberty in female mice and on the expression level of phosphatidylinositol-3-kinases ( PI3K)/protein kinase B ( Akt)/mammalian target of rapamycin (mTOR) signaling pathway in the frypothalamus. Methods Seventy-eight 20-day-old female KM mice were randomly divided into melatonin (MLT) group and normal saline (NS) group, with 39 mice in each group. Starting at 22 days of age, the MLT group was given a subcutaneous injection of 1 mg/kg melatonin and the NS group was given an equal volume of saline. Thirty-two days of age were selected as the sampling point before puberty initiation and 13 mice were executed in each of the two groups, while 37 and 42 days of age were selected as the sampling point after puberty initiation and 13 mice were executed in each of the two groups. Observation of vaginal opening time in mice, weighing of ovaries and uterus to calculate organ indices. HE staining to observe the number of ovarian corpora lutea. The levels of serum luteinizing hormone (LH)were determined by ELISA. The mRNA and protein expression levels of PI3K/Akt/mTOR pathway in frypothalamus were detected by Real-time PCR and Western blotting. Results Compared with the normal saline group, mice in the melatonin group had significantly delayed vaginal opening time ( P < 0. 05 ) , decreased significantly ovarian and uterine volume and index (P<0. 05) , decreased significantly serum LH levels (P<0. 05) , and decreased significantly mRNA and protein expression levels of the frypothalamic PI3K/Akt/mTOR pathway (P<0. 05). Conclusion Melatonin delays puberty initiation in mice by a mechanism that ma)' be related to inhibition of the hypothalamic PI3K/Akt/mTOR signalling pathway.

Role and mechanism of glucagon-like peptide-1 in depression / 中国药理学通报

Glucagon-like peptide-1 (GLP-1) is a major hormone of incretin hormone and gut-brain axis, which is related to the control of energy homeostasis and the occurrence of obesity. In addition to suppressing appetite, GLP-1 has neuroprotective effects by acting on areas of the brain involved in stress response and mood regulation. Depression is a common mental disease, and GLP-1 is closely related to depression. This article reviews the role and mechanism of GLP-1 in depression.

Yiqi Huayu decoction alleviates bleomycin-induced pulmonary fibrosis in rats by inhibiting senescence.

Overview: In treating pulmonary fibrosis (PF), traditional Chinese medicine (TCM) has received much attention, but its mechanism is unclear. The pharmacological mechanisms of TCM can be explored through network pharmacology. However, due to its virtual screening properties, it still needs to be verified by in vitro or in vivo experiments. Therefore, we investigated the anti-PF mechanism of Yiqi Huayu Decoction (YHD) by combining network pharmacology with in vivo experiments. Methods: Firstly, we used classical bleomycin (BLM)-induced rat model of PF and administrated fibrotic rats with YHD (low-, medium-, and high-dose). We comprehensively assessed the treatment effect of YHD according to body weight, lung coefficient, lung function, and histopathologic examination. Second, we predict the potential targets by ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) combined with network pharmacology. In brief, we obtained the chemical ingredients of YHD based on the UHPLC-MS/MS and TCMSP database. We collected drug targets from TCMSP, HERB, and Swiss target prediction databases based on active ingredients. Disease targets were acquired from drug libraries, Genecards, HERB, and TTD databases. The intersecting targets of drugs and disease were screened out. The STRING database can obtain protein-protein interaction (PPI) networks and hub target proteins. Molecular Complex Detection (MCODE) clustering analysis combined with enrichment analysis can explore the possible biological mechanisms of YHD. Enrichment analyses were conducted through the R package and the David database, including the Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO), and Reactome. Then, we further validated the target genes and target proteins predicted by network pharmacology. Protein and gene expression detection by immunohistochemistry, Western blot (WB), and real-time quantitative PCR (rt-qPCR). Results: The results showed that high-dose YHD effectively attenuated BLM-induced lung injury and fibrosis in rats, as evidenced by improved lung function, relief of inflammatory response, and reduced collagen deposition. We screened nine core targets and cellular senescence pathways by UHPLC-MS/MS analysis and network pharmacology. We subsequently validated key targets of cellular senescence signaling pathways. WB and rt-qPCR indicated that high-dose YHD decreased protein and gene expression of senescence-related markers, including p53 (TP53), p21 (CDKN1A), and p16 (CDKN2A). Increased reactive oxygen species (ROS) are upstream triggers of the senescence program. The senescence-associated secretory phenotypes (SASPs), containing interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-α), and transforming growth factor-ß1 (TGF-ß1), can further exacerbate the progression of senescence. High-dose YHD inhibited ROS production in lung tissue and consistently reduced the SASPs expression in serum. Conclusion: Our study suggests that YHD improves lung pathological injury and lung function in PF rats. This protective effect may be related to the ability of YHD to inhibit cellular senescence.

Network analysis for the identification of hub genes and related molecules as potential biomarkers associated with the differentiation of bone marrow-derived stem cells into hepatocytes.

The incidence of liver diseases has been increasing steadily. However, it has some shortcomings, such as high cost and organ donor scarcity. The application of stem cell research has brought new ideas for the treatment of liver diseases. Therefore, it is particularly important to clarify the molecular and regulatory mechanisms of differentiation of bone marrow-derived stem cells (BMSCs) into liver cells. Herein, we screened differentially expressed genes between hepatocytes and untreated BMSCs to identify the genes responsible for the differentiation of BMSCs into hepatocytes. GSE30419 gene microarray data of BMSCs and GSE72088 gene microarray data of primary hepatocytes were obtained from the Gene Expression Omnibus database. Transcriptome Analysis Console software showed that 1896 genes were upregulated and 2506 were downregulated in hepatocytes as compared with BMSCs. Hub genes were analyzed using the STRING and Cytoscape v 3.8.2, revealing that twenty-four hub genes, play a pivotal role in the differentiation of BMSCs into hepatocytes. The expression of the hub genes in the BMSCs and hepatocytes was verified by reverse transcription-quantitative PCR (RT-qPCR). Next, the target miRNAs of hub genes were predicted, and then the lncRNAs regulating miRNAs was discovered, thus forming the lncRNA-miRNA-mRNA interaction chain. The results indicate that the lncRNA-miRNA-mRNA interaction chain may play an important role in the differentiation of BMSCs into hepatocytes, which provides a new therapeutic target for liver disease treatment.

Inhibitory Effects of Rhein on Renal Interstitial Fibrosis via the SHH-Gli1 Signal Pathway.

Background: Rhein is the main extract of Rheum palmatum L., which has been proved to improve the renal function of chronic kidney disease, but its mechanism is not clear. Therefore, this experiment explored the potential pharmacological effect of rhein on renal interstitial fibrosis rats. Methods: This study explores the potential pharmacological action of rhein. In this work, we investigate the potential pharmacological action of rhein in unilateral urethral obstruction (UUO) rats. Thirty Sprague Dawley rats were randomly divided into three groups: sham, UUO, and rhein (rhein-treated UUO rats) groups. The left ureters of the UUO group rats were exposed and bluntly dissected. The rhein group rats were administered an intragastric gavage of rhein (2 mg·kg-1·d-1) for 14 d. Kidney function-related indicators were monitored in these rats, while indexes of pathologic aspects were determined histologically. The expression of α-SMA, TGF-ß1, SHH, Gli1, and Snail was quantified using real-time polymerase chain reaction and western blotting. The NRK-49F cells were incubated with and without SHH (100 ng·ml-1) for 48 hours. The SHH-activated NRK-49F cells were incubated with cyclopamine (CNP, 20 umol L-1) or rhein (1 ng·ml-1). The Gli1 and Snail mRNA and protein level were detected. Results: In the in vivo experiment, the results exhibited that UUO caused renal pathological damages. However, these changes could be significantly reversed by the administration of rhein. Compared with the untreated UUO group, the rhein group showed reduced kidney tubular atrophy and necrosis, interstitial fibrosis, hyperplasia, and abnormal deposition of extracellular matrix. Rhein reduced the RNA and protein expression of SHH, Gli1, and Snail of the UUO rats. In the in vitro experiment, CNP or rhein treatment decreased the expression of Gli1 and Snail on mRNA and protein levels in SHH-induced NRK-49F cells, suggesting that CNP or rhein suppresses SHH-induced NRK-49F activation. Taken together, these results demonstrated that rhein suppresses SHH-Gli1-Snail signal pathway activation, with potential implications for the treatment of renal fibrosis. Conclusions: Treatment with rhein remarkably ameliorated renal interstitial fibrosis in UUO rats by regulating the SHH-Gli1-Snail signal pathway.

Discovery of potent immune-modulating molecule taccaoside A against cancers from structures-active relationships of natural steroidal saponins.

BACKGROUND: In recent years, the T-cell therapy and immune checkpoint inhibitors toward CTLA-4 and PD-1/PD-L1 axis antibody therapy have acquired encouraging success. However, most of patients were still not benefited with lots of troubles, such as low penetration of tissues/cells, strong immunogenicity and cytokine release syndrome, and long manufacturing process and expensive costs. By contrast, the immune-modulating small molecules possessed natural advantages to overcome these obstacles and might achieve greater success. PURPOSE: Exploring the potent immune-modulating natural small molecules and revealing what kinds of molecules or structures with the immunomodulatory activity against cancers. METHODS: A novel non-cytotoxic T-cell immunomodulating screening model was used to identify the cytotoxic/selective/immunomodulatory bioactivity for 148 natural steroidal saponins. The structure-activity relationships (SARs) research was used to reveal the key groups for immunomodulation/cytotoxicity/selectivity. The negative selection was used to isolate and purify the T-cell. The cell viability assay was used to measure the anti-cancer effect in vitro. The ELISA assay was used to detect the cytokines for IL-1ß, IL-6, TNF-α, IFN-γ, IL-12, perforin and granzyme B (GZMB). The western blotting assay was used to research the immunomodulatory mechanism. The siRNA knockdown was used to generate the IFN-γ resistant melanoma cells. The NOG immune-deficient mice were used to evaluate the anti-tumor efficacy in vivo. The peripheral blood samples from 10 cancer patients were used to detect the broad population anti-tumor efficacy. RESULTS: It was reported that the correlation among structures and immunomodulation/ cytotoxicity/selectivity, in which opening ring-F with 26-O-glucopyranosyl, disaccharide and trisaccharide chains at C-3, steric hindrance and polarity of C-22 were key immunomodulatory groups. Moreover, taccaoside A was identified as the most potent candidate against cancer cells, including non-small cell lung cancer, triple negative breast cancer, and the IFN-γ resistant melanoma, partly through enhancing T lymphocyte mTORC1-Blimp-1 signal to secrete GZMB. Besides, 10 patients derived T-cell also would be modulated against cancer cells in vitro. Moreover, the overall survival was great extended (>140 days vs 93 days) with nearly 100% tumor burden disappearance (0 mm3vs 1006 ± 79.5 mm3) in mice. CONCLUSION: This work demonstrated one possibility for this concerned purpose, and identified a potent immune-modulating natural molecule taccaoside A, which might contribute to cancer immunotherapy in future.

Network Pharmacology and In Vivo Analysis of Dahuang-Huangqi Decoction Effectiveness in Alleviating Renal Interstitial Fibrosis.

Dahuang and Huangqi are the most frequently prescribed treatment methods for chronic kidney disease in China. Our study aimed to clarify the pharmacological mechanism of action of Dahuang-Huangqi decoction (DHHQD) in renal interstitial fibrosis (RIF). The intersection of genes targeted by DHHQD active ingredients and RIF target genes was searched using network pharmacology to build a chemical ingredient and disease target network. For in vivo analysis, Sprague-Dawley rats with unilateral urethral obstruction (UUO) were administered DHHQD, and their kidney function-related indicators and pathological indices were determined. The expression of core targets was quantified using real-time polymerase chain reaction and western blotting. A total of 139 common targets for DHHQD and RIF in chronic kidney disease were detected. Compared with the untreated UUO rats, the DHHQD-treated rats showed reductions in the following: blood urea nitrogen and serum creatinine levels, kidney tubular atrophy and necrosis, interstitial fibrosis, hyperplasia and abnormal deposition of extracellular matrix, and microstructural changes in the mesangial matrix and glomerular basement membrane. DHHQD treatment significantly regulated the levels of renal core proteins, such as eNOS, IL-6, EGFR, and VEGF and reduced the mRNA and protein expression of the core targets involved in inflammation pathways, such as PI3K/AKT and TLR4/NF-κB. DHHQD treatment ameliorated the severity of RIF by potentially regulating the AKT/PI3K and TLR4/NF-κB signaling pathways. Our study findings provide insights into the mechanisms associated with DHHQD action and essential data for future research.