Daphnoretin Arrests the Cell Cycle and Induces Apoptosis in Human Breast Cancer Cells.

Emerging evidence has shown that daphnoretin, one of the main active ingredients of Daphne giraldii Nitsche, processes antitumor activities in several tumor cells (e.g., colon cancer, lung cancer, cervical cancer, and osteosarcoma). However, the antitumor effect and its mechanism in breast cancer are unexplored. In this study, our data indicated that daphnoretin obviously suppressed the proliferation of breast cancer MCF-7 and MDA-MB-231 cells. Further studies showed that daphnoretin remarkably increased the p21 level, decreased cyclin E and CDK2 levels, and then arrested the cell cycle at the S phase. Moreover, daphnoretin obviously lowered the BCL-2 level and raised the levels of BAX and cleaved caspase-9 and -3, leading to cell apoptosis. Furthermore, daphnoretin remarkably decreased the ratio of p-PI3K/PI3K and p-AKT/AKT in breast cancer cells. Collectively, these findings demonstrated that daphnoretin could suppress breast cancer cell proliferation through cell cycle arrest and inducing apoptosis, which is related to the PI3K/AKT pathway.

Activation of the CaR-CSE/H2S pathway confers cardioprotection against ischemia-reperfusion injury.

Ischemia-reperfusion (I/R) injury is a multifactorial process triggered when an organ is subjected to transiently reduced blood supply. The result is a cascade of pathological complications and organ damage due to the production of reactive oxygen species following reperfusion. The present study aims to evaluate the role of activated calcium-sensing receptor (CaR)-cystathionine γ-lyase (CSE)/hydrogen sulfide (H2S) pathway in I/R injury. Firstly, an I/R rat model with CSE knockout was constructed. Transthoracic echocardiography, TTC and HE staining were performed to determine the cardiac function of rats following I/R Injury, followed by TUNEL staining observation on apoptosis. Besides, with the attempt to better elucidate how CaR-CSE/H2S affects I/R, in-vitro culture of human coronary artery endothelial cells (HCAECs) was conducted with gadolinium chloride (GdCl3, a CaR agonist), H2O2, siRNA against CSE (siCSE), or W7 (a CaM inhibitor). The interaction between CSE and CaM was subsequently detected. Plasma oxidative stress indexes, H2S and CSE, and apoptosis-related proteins were all analyzed following cell apoptosis. We found that H2S elevation led to the improvement whereas CSE knockdown decreased cardiac function in rats with I/R injury. Moreover, oxidative stress injury in I/R rats with CSE knockout was aggravated, while the increased expression of H2S and CSE in the aortic tissues resulted in alleviated the oxidative stress injury. Moreover, increased H2S and CSE levels were found to inhibit cell apoptotic ability in the aortic tissues after I/R injury, thus attenuating oxidative stress injury, accompanied by inhibited expression of apoptosis-related proteins. In HCAECs following oxidative stress treatment, siCSE and CaM inhibitor were observed to reverse the protection of CaR agonist. Coimmunoprecipitation assay revealed the interaction between CSE and CaM. Taken together, all above-mentioned data provides evidence that activation of the CaR-CSE/H2S pathway may confer a potent protective effect in cardiac I/R injury.

Micromechanical Landscape of Three-Dimensional Disordered Graphene Networks.

Disordered carbons can be considered under the modeling framework of disordered graphene networks (DGNs) due to the continuous three-dimensional connectivity and high graphitization. Correlating microstructures and mechanical behaviors of DGNs to their topology is pivotal to revealing more intrinsic features hidden by disorder. Herein, starting from basic deformations and topology, we investigate DGNs with various densities to explore their micromechanical landscape. Both the tension and shear of DGNs exhibit prolonged plastic platforms through local tearing of microstructures. However, compression displays special plastic damages of forming kinklike puckers and sp3-bonded carbon, resulting in a tension-compression asymmetry of DGNs. Out-of-plane topological defects contribute to the main negative-curvature topology in deformed DGNs. Moreover, there are novel scaling laws where both the Young's modulus and strength (logarithms) follow an inversely proportional scaling with respect to average angular defects. Ashby charts demonstrate that the mechanical properties of DGNs can reach the theoretical limit region, surpassing those of most conventional materials.

Upregulation of acid sensing ion channel 1a (ASIC1a) by hydrogen peroxide through the JNK pathway.

Oxidative stress is intimately tied to neurodegenerative diseases, including Parkinson's disease and amyotrophic lateral sclerosis, and acute injuries, such as ischemic stroke and traumatic brain injury. Acid sensing ion channel 1a (ASIC1a), a proton-gated ion channel, has been shown to be involved in the pathogenesis of these diseases. However, whether oxidative stress affects the expression of ASIC1a remains elusive. In the current study, we examined the effect of hydrogen peroxide (H2O2), a major reactive oxygen species (ROS), on ASIC1a protein expression and channel function in NS20Y cells and primary cultured mouse cortical neurons. We found that treatment of the cells with H2O2 (20 µM) for 6 h or longer increased ASIC1a protein expression and ASIC currents without causing significant cell injury. H2O2 incubation activated mitogen-activated protein kinases (MAPKs) pathways, including the extracellular signal-regulated kinase1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), and p38 pathways. We found that neither inhibition of the MEK/ERK pathway by U0126 nor inhibition of the p38 pathway by SB203580 affected H2O2-induced ASIC1a expression, whereas inhibition of the JNK pathway by SP600125 potently decreased ASIC1a expression and abolished the H2O2-mediated increase in ASIC1a expression and ASIC currents. Furthermore, we found that H2O2 pretreatment increased the sensitivity of ASIC currents to the ASIC1a inhibitor PcTx1, providing additional evidence that H2O2 increases the expression of functional ASIC1a channels. Together, our data demonstrate that H2O2 increases ASIC1a expression/activation through the JNK signaling pathway, which may provide insight into the pathogenesis of neurological disorders that involve both ROS and activation of ASIC1a.

Removable retropubic uterine compression suture for controlling postpartum hemorrhage.

OBJECTIVE: To minimize the adverse events of uterine compression suture in controlling postpartum hemorrhage (PPH) and to search for a prophylactic approach to potential PPH. METHODS: A retrospective analysis was performed in 39 women with removable retropubic uterine compression suture (RRUCS) to stop PPH due to uterine atony during cesarean section (CS). The procedure was to suspend and compress the uterus to the retropubic abdominal wall using an absorbable suture. RESULTS: The technique was sufficient to stanch bleeding immediately in 36 patients (92.31%, 36/39). No morbidity or abnormalities occurred in women who underwent RRUCS. Subsequent pregnancies occurred in 10 cases, but the others lacked the desire for future pregnancy. CONCLUSION: RRUCS is a simple, safe, and effective technique in controlling atonic PPH; it is also used as a prophylactic application in patients with potential PPH after CS.

Shock-induced ejecta transport and breakup in reactive gas.

The transport process of micro-ejecta in reactive gases has recently attracted research attention and interest. Here, we investigate the interaction between shock-induced ejecta of Al and oxygen using a reactive molecular dynamics simulation. The results reveal that metal fragments ejected into reactive gases will quickly increase the temperature of the mixing zone, followed by the deceleration of spikes and a greater shock intensity in the compressed gases, compared with the ejection in inert gases. Moreover, we find that, in vacuum, only a small number of atoms fall out when spherical ejecta particles are finally formed. In the presence of inert gases, several small particles break away from the initial fragments during the transformation of the initially formed strip-shaped fragments into spherical particles, accompanying the detachment of a large number of atoms. When ejecta are transported in reactive gases, the chemical interactions cause more atoms to separate from particles, thus forming smaller fragments and more atomic particles. The research findings show that chemical reactions play an important role in ejecta transport and breakup, which should be considered in future ejecta-transport models for better predictions.

Speech Emotion Recognition Based on Selective Interpolation Synthetic Minority Over-Sampling Technique in Small Sample Environment.

Speech emotion recognition often encounters the problems of data imbalance and redundant features in different application scenarios. Researchers usually design different recognition models for different sample conditions. In this study, a speech emotion recognition model for a small sample environment is proposed. A data imbalance processing method based on selective interpolation synthetic minority over-sampling technique (SISMOTE) is proposed to reduce the impact of sample imbalance on emotion recognition results. In addition, feature selection method based on variance analysis and gradient boosting decision tree (GBDT) is introduced, which can exclude the redundant features that possess poor emotional representation. Results of experiments of speech emotion recognition on three databases (i.e., CASIA, Emo-DB, SAVEE) show that our method obtains average recognition accuracy of 90.28% (CASIA), 75.00% (SAVEE) and 85.82% (Emo-DB) for speaker-dependent speech emotion recognition which is superior to some state-of-the-arts works.

KRT1 gene silencing ameliorates myocardial ischemia-reperfusion injury via the activation of the Notch signaling pathway in mouse models.

Myocardial ischemia and reperfusion injury (MIRI) includes major drawbacks, such as excessive formation of free radicals and also overload of calcium, which lead to cell death, tissue scarring, and remodeling. The current study aims to explore whether KRT1 silencing may ameliorate MIRI via the Notch signaling pathway in mouse models. Myocardial tissues were used for the determination of the positive rate of KRT1 protein expression, apoptosis of myocardial cells, creatine kinase (CK) and lactate dehydrogenase (LDH) expression, expression of related biomarkers as well as myocardial infarction area. The transfected myocardial cells were treated with KRT1-siRNA, Jagged1, and DAPT (inhibitor of Notch-1 signaling pathway). The expression of KRT1, NICD, Hes1, Bcl-2, and Bax protein was detected. The MTT assay was applied for cell proliferation and flow cytometry was used for cell apoptosis. Mice with MIRI had a higher positive rate of KRT1 protein expression, apoptosis of myocardial cells, CK and LDH expression, myocardial infarction area, increased expression of MDA, NO, SDH, IL-1, IL-6, TNF-α, CRP, KRT1, Bax protein, CK, and LDH, and decreased expression of SOD, NICD, Hes1, and Bcl-2. The downregulation of KRT1 led to decreased expression of KRT1 and Bax protein, increased expression of NICD, Hes1, and Bcl-2, decreased cell apoptosis, and improved cell proliferation. The inhibition of the Notch signaling pathway leads to reduced expression of Bax, increased expression of NICD, Hes1, and Bcl 2, and also decreased cell apoptosis and increased cell proliferation. Our data conclude that KRT1 silencing is able to make MIRI better by activating the Notch signaling pathway in mice.

Highly Polarizable Hg2+ Induced a Strong Second Harmonic Generation Signal and Large Birefringence in LiHgPO4.

A new ultraviolet nonlinear optical material, namely LiHgPO4, was synthesized using the mild hydrothermal method. The structure of LiHgPO4 features novel double layers constructed by severely distorted HgO6 octahedra and PO4 tetrahedra, which are further interconnected by LiO4 tetrahedra to form a three-dimensional structure. LiHgPO4 exhibits a very strong second harmonic generation (SHG) response of 11.0 times that of KH2PO4 and a relatively large birefringence (0.068 at 1064 nm) among the reported SHG-active phosphates. Theoretical calculations revealed that the introduction of the Hg2+ in a highly distorted HgO6 octahedral geometry is crucial to produce the strong SHG response and large birefringence.

Cordycepin improves behavioral-LTP and dendritic structure in hippocampal CA1 area of rats.

Cordycepin, an adenosine analog, has been reported to improve cognitive function, but which seems to be inconsistent with the reports showing that cordycepin inhibited long-term potentiation (LTP). Behavioral-LTP is usually used to study long-term synaptic plasticity induced by learning tasks in freely moving animals. In order to investigate simultaneously the effects of cordycepin on LTP and behavior in rats, we applied the model of behavioral-LTP induced by Y-maze learning task through recording population spikes in hippocampal CA1 region. Golgi staining and Sholl analysis were employed to assess the morphological structure of dendrites in pyramidal cells of hippocampal CA1 area, and western blotting was used to examine the level of adenosine A1 receptors and A2A receptors (A2AR). We found that cordycepin significantly improved behavioral-LTP magnitude, accompanied by increases in the total length of dendrites, the number of intersections and spine density but did not affect Y-maze learning task. Furthermore, cordycepin obviously reduced A2AR level without altering adenosine A1 receptors level; and the agonist of A2AR (CGS 21680) rather than antagonist (SCH 58261) could reverse the potentiation of behavioral-LTP induced by cordycepin. These results suggested that cordycepin improved behavioral-LTP and morphological structure of dendrite in hippocampal CA1 but did not contribute to the improvement of learning and memory. And cordycepin improved behavioral-LTP may be through reducing the level of A2AR in hippocampus. Collectively, the effects of cordycepin on cognitive function and LTP were complex and involved multiple mechanisms.

Comparison of Laparoscopic and Open Approach in Treating Gallbladder Cancer.

BACKGROUND: Preliminary study on the feasibility and efficacy of laparoscopic cholecystectomy and radical cholecystectomy in stage Tis-T3 gallbladder cancer (GBC). METHODS: Retrospective analysis of the clinical data of 102 patients with GBC from August 2008 to August 2017 in the Department of Hepatopancreatobiliary Surgery at the Third Affiliated Hospital of Soochow University. The clinical and pathological data of laparoscopic surgery and open surgery were compared. RESULTS: Of 102 patients with GBC, 41 underwent laparoscopic treatment, 12 of whom underwent laparoscopic cholecystectomy, and the others underwent laparoscopic radical cholecystectomy/extended radical cholecystectomy. Sixty-one patients underwent radical cholecystectomy/extended radical cholecystectomy. Based on the individual patient's condition, excision of the extrahepatic biliary tract and cholangioenterostomy were performed. There were no perioperative deaths. There was no significant difference in the operative blood loss (P = 0.732), operative time (P = 0.058), postoperative complications (P = 0.933), R0 margins (P = 0.679), and tumor-related death (P = 0.396) between the laparoscopic group and the laparotomy group. The postoperative activity time (P < 0.001), postoperative eating time (P < 0.001), drainage tube removal time (P < 0.001), and postoperative hospital discharge time (P < 0.001) in the laparoscopic group were all earlier than those in the laparotomy group, and the difference was statistically significant. The number of lymph nodes resected in the laparoscopic group and the laparotomy group was 1-17, average (5 ± 3) and 1-13 average (5 ± 3), respectively, with no statistically significant difference (P = 0.973). The 1-, 3-, and 5-y survival rates in the laparoscopic group were 97.1%, 69.4%, and 51.9%, respectively, and those in the laparotomy group were 94.7%, 64.9%, and 55.7%, respectively; there were no significant difference between the two groups (P = 0.453). In terms of different pathologic T stages, the 5-y survival rates of patients with stage Tis (9 cases), T1a (2 cases), T1b (8 cases), T2 (14 cases), and T3 (8 cases) disease in the laparoscopic group were 100%, 100%, 75%, 48.1%, and 12.5%, respectively, and the 5-y survival rates in patients with stage Tis (4 cases), T1b (9 cases), T2 (32 cases), and T3 (16 cases) disease in the laparotomy group were 100%, 87.5%, 64.7%, and 16%, respectively; there were no significant differences between the two groups. CONCLUSIONS: Laparoscopic treatment of stage Tis-T3 GBC is feasible. Laparoscopic treatment of GBC does not increase the incision metastasis rate on the basis of the intact gallbladder wall. The same survival rates can be achieved with laparoscopic treatment as with open treatment of GBC. In terms of postoperative rehabilitation, laparoscopic treatment has more advantages.

HBa2.5(IO3)6(I2O5) and HBa(IO3)(I4O11): Explorations of Second-Order Nonlinear Optical Materials in the Alkali-Earth Polyiodate System.

Two new barium polyiodate compounds in the alkali-earth system, namely, HBa2.5(IO3)6(I2O5) ( Fdd2) and HBa(IO3)(I4O11) ( P1̅) have been obtained through hydrothermal reaction. Interestingly, the structures of both compounds feature different polyiodate groups, i.e., I2O5 and I4O11 groups. HBa2.5(IO3)6(I2O5) can be depicted as an alternative stacking of two-dimensional (2D) [Ba4(IO3)8(I2O5)2] and [Ba(IO3)4(I2O5)2]2- layers with the I2O5 and IO3 group serving as linkers. HBa(IO3)(I4O11) can be depicted as a 3D network with 2D [Ba(I4O11)] layers being interconnected by IO3 groups. The 0D I4O11 polyiodate group can be seen also viewed as formed by an I3O8 group further corner-sharing with an IO3 group or an I2O5 group further corner-sharing with two IO3 groups. Powder second harmonic generation (SHG) measurements show that HBa2.5(IO3)6(I2O5) crystals display a moderate SHG efficiency of ∼1.6 times that of KH2PO4 (KDP) and are phase-matchable. Optical properties measurements, thermal analyses, and laser damage threshold (LDT) measurements have been performed. Results of theoretical calculation show that the formation of I4O112- is thermodynamically much easier than I3O8- and I2O5, because of the lower reaction energy. Our studies shed light on exploring alkali-earth polyiodates as potential NLO materials.

pH and Thermo Dual-Responsive Fluorescent Hydrogel Actuator.

As one of the most important smart materials, fluorescent hydrogel actuators can produce both color and shape changes under external stimuli. In the present work, an effective approach to develop a novel fluorescent hydrogel actuator with pH and thermo dual responsiveness is proposed. Through incorporating pH-responsive perylene tetracarboxylic acid (PTCA), which is a typical fluorescent moiety with aggregation-caused quenching (ACQ) effect, into an anisotropic poly(N-isopropylacrylamide)-polyacrylamide (PNIPAm-PAAm) structure, the obtained hydrogel exhibits stable thermoresponsive shape deformation and switchable fluorescence performance upon a pH trigger. Therefore, fluorescence-quenching-based and actuation-based information can be revealed when exposed to UV light and immersed into warm water, respectively. Moreover, the thermoresponsive actuating behavior can be applied to further hide the fluorescence-quenching-based images. The present work may provide new insights into the design and preparation of novel stimuli-responsive hydrogel actuators.

The preoperative fibrosis score 4 predicts posthepatectomy liver failure in patients with hepatocellular carcinoma.

INTRODUCTION AND OBJECTIVES: The fibrosis score 4 (FIB-4) has been identified as a biochemical surrogate for histological fibrogenesis and fibrosis in cirrhosis. This study investigates the impact of preoperative FIB-4 on postoperative liver failure of patients with hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Data from 205 patients who underwent curative resection for HCC were retrospectively analyzed. The receiver operating characteristic (ROC) curve analysis was performed to determine the cutoff value of the FIB-4. Univariate analysis and multivariate analysis were performed to identify risk factors for postoperative liver failure. The clinical outcomes were compared between patients with high FIB-4 and low FIB-4. RESULTS: The optimal cutoff value of the FIB-4 was set at 5.92 for postoperative liver failure according to ROC curve. By univariate and multivariate analysis, the number of resected segments, FIB-4, and model for end-stage liver disease score were identified as independent risk factors for postoperative liver failure. Patients with preoperative FIB-4>5.92 had poorer liver function and higher occurrence of postoperative liver failure. CONCLUSIONS: Preoperative FIB-4 was associated with postoperative liver failure. Patients with preoperative FIB-4>5.92 carry a high risk of postoperative liver failure.

Progress in diagnosis and surgical treatment of perihilar cholangiocarcinoma.

Cholangiocarcinomas are heterogeneous biliary tract tumors that cause devastating disease. Perihilar cholangiocarcinoma (PHC) is the most common type of biliary tract cancer and are associated with a high mortality. Diagnoses of PHC depend on the results of its clinical presentation, serum biomarkers and imaging techniques. Pre-operative managements including pre-operative biliary drainage (PBD) and portal vein embolization (PVE) could reduce mortality. The best chance of long-term survival and potential cure is surgical resection with negative surgical margin. Lymph node metastasis over N2 nodes precludes long-term survival. The benefit of concomitant vascular resection remains uncertain. Liver transplantation combined with neoadjuvant chemotherapy with radiotherapy is a promising option in highly selected patients with unresectable tumors. Herein, an overview is provided of developments in diagnosis, peri-operative management and surgical treatment among patients with PHCs.

[Identification and single-cell sequencing analysis of rare tumor cells in malignant pleural effusion of lung cancer patients].

Tumor heterogeneity refers to distinct genomic or phenotypic characteristics of tumor cells. Under the environmental or drug stress, tumor cells exhibit different responses, corresponding to different properties of cell proliferation, invasion, metastasis and drug resistance. In particular, a small fraction of tumor cells are capable of detaching from primary tumor sites and initiating distant metastases. Thus, tumor heterogeneity sets the basis for tumor resistance and metastasis. Traditional methods in studying tumor heterogeneity are mainly based on bulk cells from different locations in primary tumors, lacking analysis at the single-cell level and of metastatic tumor cells. This study establishes a single-cell method to study metastatic tumor cells in malignant pleural effusions of lung cancer patients. Metabolically active tumor cells in malignant pleural effusions are firstly identified with a metabolic marker 2-NBDG, a fluorescent glucose analog. These metabolically active tumor cells are confirmed to harbor the same driver oncogenic mutations by Sanger sequencing, followed by high-throughput sequencing to analyze copy number variation profiles. Our results show metastatic tumor cells in pleural effusion have the same driver mutations but different features in copy number variation patterns. The study provides new insights to understand the mechanism of tumor metastasis.

Cs2 Bi2 O(Ge2 O7 ) (CBGO): A Larger SHG Effect Induced by Synergistic Polarizations of BiO5 Polyhedra and GeO4 Tetrahedra.

A cesium bismuth germanate, Cs2 Bi2 O(Ge2 O7 ) (CBGO), was synthesized by a traditional high-temperature solid-state reaction. Its structure features a 3D network composed of a 1D chains composed of Bi2 O8 dimers that are further bridged by Ge2 O7 dimers, forming tunnels of seven member rings (MRs) that are filled by the Cs+ cations. CBGO exhibits extraordinary larger second harmonic generation (SHG) response of about 13.7 times that of KDP (KH2 PO4 ) under 1064 nm laser radiation and 1.1 times that of KTP (KTiOPO4 ) under 2.05 µm laser radiation, which is the highest among all of the metal germanates reported so far. CBGO possesses a moderate birefringence (0.073 at 1064 nm) and is phase matchable. Furthermore, CBGO melts congruently and exhibits high thermal stability.

The role of microRNA-1 targeting of MAPK3 in myocardial ischemia-reperfusion injury in rats undergoing sevoflurane preconditioning via the PI3K/Akt pathway.

Recent studies have uncovered the vital roles played by microRNAs in regulating cardiac injury. Among them, the cardiac enriched microRNA-1 (miR-1) has been extensively studied and proven to be detrimental to cardiac myocytes. Hence, the current study aimed to explore whether miR-1 affects myocardial ischemia-reperfusion injury (MIRI) in rats undergoing sevoflurane preconditioning and the underlying mechanism. After successful model establishment, rats with MIRI were transfected with mimics or inhibitors of miR-1, or siRNA against MAPK3, and then were injected with sevoflurane. A luciferase reporter gene assay was conducted to evaluate the targeting relationship between miR-1 and MAPK3. Reverse transcription quantitative polymerase chain reaction and Western blot analysis were employed to evaluate the expressions of miR-1, MAPK3, phosphatidylinositol 3-kinase (PI3K), and Akt. Additionally, the concentration of lactate dehydrogenase (LDH) was determined. Cell apoptosis and viability were assessed using TUNEL and cell counting kit-8 assays, and the ischemic area at risk and infarct size were detected using Evans blue and triphenyltetrazolium chloride staining. MAPK3 was found to be the target gene of miR-1. miR-1 expressed at a high level whereas MAPK3 expressed at a low level in MIRI rats. Overexpressing miR-1 or silencing MAPK3 blocked the PI3K/Akt pathway to increase cell apoptosis, ischemic area at risk, and infarct area but decreased cell viability and increased LDH concentration. In contrast, miR-1 downregulation abrogated the effects induced by miR-1 mimics or siRNA against MAPK3. These findings indicate that inhibition of miR-1 promotes MAPK3 to protect against MIRI in rats undergoing sevoflurane preconditioning through activation of the PI3K/Akt pathway.

Hotair facilitates hepatic stellate cells activation and fibrogenesis in the liver.

Long non-coding RNAs (lncRNAs) are increasingly recognized as major players in regulating various biological processes. LncRNA HOX transcript antisense RNA (Hotair) has been extensively studied in cancer. However, the role of Hotair in liver fibrosis remains unknown. Here we observed that Hotair expression was significantly increased in CCl4-induced mouse liver fibrosis models, human fibrotic livers and activated hepatic stellate cells (HSCs) by TGF-ß1 stimulation. Enforced expression of Hotair in LX-2 cells promoted cell proliferation and activation while inhibition of its expression had an opposite effect. Furthermore, we found that Hotair may act as an endogenous 'sponge' of miR-148b, which regulates expression of the DNMT1/MEG3/p53 pathways in HSCs. Intriguingly, Hotair enhanced polycomb repressive complex 2 (PRC2) occupancy and histone H3K27me3 repressive marks, specifically at the MEG3 promoter region. Finally, we found that Hotair forms an RNA/DNA hybrid and recruits PRC2 to MEG3 promoter. These data suggest that Hotair inhibition may represent a promising therapeutic option for suppressing liver fibrosis.

A microbial model of mammalian metabolism: biotransformation of 4,5-dimethoxyl-canthin-6-one using Cunninghamella blakesleeana CGMCC 3.970.

1. A filamentous fungus, Cunninghamella blakesleeana CGMCC 3.970, was applied as a microbial system to mimic mammalian metabolism of 4,5-dimethoxyl-canthin-6-one (1). Compound 1 belongs to canthin-6-one type alkaloids, which is a major bioactive constituent of a traditional Chinese medicine (the stems of Picrasma quassioides). 2. After 72 h of incubation in potato dextrose broth, 1 was metabolized to seven metabolites as follows: 4-methoxyl-5-hydroxyl-canthin-6-one (M1), 4-hydroxyl-5-methoxyl-canthin-6-one (M2), canthin-6-one (M3), canthin-6-one N-oxide (M4), 10-hydroxyl-4,5-dimethoxyl-canthin-6-one (M5), 1-methoxycarbonl-ß-carboline (M6), and 4-methoxyl-5-O-ß-D-glucopyranosyl-canthin-6-one (M7). 3. The structures of metabolites were determined using spectroscopic analyses, chemical methods, and comparison of NMR data with those of known compounds. Among them, M7 was a new compound. 4. The metabolic pathways of 1 were proposed, and the metabolic processes involved phase I (O-demethylation, dehydroxylation, demethoxylation, N-oxidation, hydroxylation, and oxidative ring cleavage) and phase II (glycosylation) reactions. 5. This was the first research on microbial transformation of canthin-6-one alkaloid, which could be a useful microbial model for producing the mammalian phase I and phase II metabolites of canthin-6-one alkaloids. 6. 1, M1-M5, and M7 are canthin-6-one alkaloids, whereas M6 belongs to ß-carboline type alkaloids. The strain of Cunninghamella blakesleeana can supply an approach to transform canthin-6-one type alkaloids into ß-carboline type alkaloids.