SERPINB1 promotes Senecavirus A replication by degrading IKBKE and regulating the IFN pathway via autophagy.

IMPORTANCE: Senecavirus A (SVA) is an emerging picornavirus associated with vesicular disease, which wide spreads around the world. It has evolved multiple strategies to evade host immune surveillance. The mechanism and pathogenesis of the virus infection remain unclear. In this study, we show that SERPINB1, a member of the SERPINB family, promotes SVA replication, and regulates both innate immunity and the autophagy pathway. SERPINB1 catalyzes K48-linked polyubiquitination of IκB kinase epsilon (IKBKE) and degrades IKBKE through the proteasome pathway. Inhibition of IKBKE expression by SERPINB1 induces autophagy to decrease type I interferon signaling, and ultimately promotes SVA proliferation. These results provide importantly the theoretical basis of SVA replication and pathogenesis. SERPINB1 could be a potential therapeutic target for the control of viral infection.

DNAJC10 maintains survival and self-renewal of leukemia stem cells through PERK branch of the unfolded protein response.

Leukemia stem cells (LSC) require frequent adaptation to maintain their self-renewal ability in the face of longer exposure to cell-intrinsic and cell-extrinsic stresses. However, the mechanisms by which LSC maintain their leukemogenic activities, and how individual LSC respond to stress, remain poorly understood. Here, we found that DNAJC10, a member of HSP40 family, was frequently up-regulated in various types of acute myeloid leukemia (AML) and in LSC-enriched cells. Deficiency of DNAJC10 leads to a dramatic increase in the apoptosis of both human leukemia cell lines and LSC-enriched populations. Although DNAJC10 is not required for normal hematopoiesis, deficiency of Dnajc10 significantly abrogated AML development and suppressed self-renewal of LSC in the MLL-AF9-induced murine leukemia model. Mechanistically, inhibition of DNAJC10 specifically induces endoplasmic reticulum stress and promotes activation of PERK-EIF2α-ATF4 branch of unfolded protein response (UPR). Blocking PERK by GSK2606414 (PERKi) or shRNA rescued the loss of function of DNAJC10 both in vitro and in vivo. Importantly, deficiency of DNAJC10 increased sensitivity of AML cells to daunorubicin (DNR) and cytarabine (Ara-C). These data revealed that DNAJC10 functions as an oncogene in MLL-AF9-induced AML via regulation of the PERK branch of the UPR. DNAJC10 may be an ideal therapeutic target for eliminating LSC, and improving the effectiveness of DNR and Ara-C.

Loureirin A Promotes Cell Differentiation and Suppresses Migration and Invasion of Melanoma Cells via WNT and AKT/mTOR Signaling Pathways.

Resina Draconis is a traditional Chinese medicine, with the in-depth research, its medicinal value in anti-tumor has been revealed. Loureirin A is extracted from Resina Draconis, however, research on the anti-tumor efficacy of Loureirin A is rare. Herein, we investigated the function of Loureirin A in melanoma. Our research demonstrated that Loureirin A inhibited the proliferation of and caused G0/G1 cell cycle arrest in melanoma cells in a concentration-dependent manner. Further study showed that the melanin content and tyrosinase activity was enhanced after Loureirin A treatment, demonstrated that Loureirin A promoted melanoma cell differentiation, which was accompanied with the reduce of WNT signaling pathway. Meanwhile, we found that Loureirin A suppressed the migration and invasion of melanoma cells through the protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway. Taken together, this study demonstrated for the first time the anti-tumor effects of Loureirin A in melanoma cells, which provided a novel therapeutic strategy against melanoma.

The circHMGCS1-miR-205-5p-ErBB3 axis mediated the Sanggenon C-induced anti-proliferation effects on human prostate cancer.

Prostate cancer (PCa) is associated with a high incidence and metastasis rate globally, resulting in an unsatisfactory prognosis and a huge economic burden due to the current deficient of therapeutic strategies. As the most abundant component of Cortex Mori, Sanggenon C (SC) is well known to possess bioactivities in tumors, but its mechanism is poorly understood. Consequently, we attempted to investigate whether SC could modulate circular RNA(s) levels and hence anti-PCa development. We found that SC dramatically promoted cell apoptosis and induced G0/G1 phase arrest in PCa cell lines via the circHMGCS1-miR-205-5p-ErBB3 axis. In brief, circHMGCS1 is highly expressed in PCa and is positively correlated with the degree of malignancy. Over-expression of circHMGCS1 is not only associated with the proliferation of PCa cells but also blocks SC-induced pro-apoptotic effects. As a verified sponge of circHMGCS1, miR-205-5p is down-regulated in PCa tumors, which negatively regulates PCa cell proliferation by modulating ErBB3 expression. After miR-205-5p mimics or inhibitors were used to transfect PCa cells, the effects of circHMGCS1 OE and SC on PCa cells were completely diminished. Similar to miR-205-5p inhibitors, siErBB3 could oppose SC-triggered pro-apoptotic effects on PCa cells. All these results were confirmed in vivo. Together, SC exerts its anti-tumor effects on PCa by inhibiting circHMGCS1 expression and results in the latter losing the ability to sponge miR-205-5p. Subsequently, unfettered miR-205-5p could mostly down-regulate ErBB3 expression by binding to the 5'UTR of ErBB3 mRNA, which eventually resulted in PCa cell cycle arrest and pro-apoptosis.

Gamabufotalin Induces Apoptosis and Cytoprotective Autophagy through the mTOR Signaling Pathway in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a malignant tumor with a high rate of recurrence and a poor prognosis. Here, we investigated the effect and the potential antitumor mechanism of Gamabufotalin (CS-6) against HCC. Our results show that CS-6 strikingly reduced cell viability, inhibited colony formation, and promoted apoptosis in Hep3B and Huh7 cells. In vivo, CS-6 inhibited HCC xenograft tumor growth with no toxicity to normal tissues. Mechanistically, we found that CS-6 could induce cytoprotective autophagy through the mTOR-ULK1 signaling pathway through downregulation of p62 and upregulation of LC3 II/LC3 I. Meanwhile, CS-6 activated caspase-3 and PARP mediated apoptosis, and the caspase inhibitor Z-VAD-FMK blocked the CS-6-induced cell death in HCC cells. Moreover, autophagy and apoptosis were found to have antagonistic effects in Hep3B and Huh7 cells. Both the autophagy inhibitor chloroquine (CQ) and the mTOR activator MHY1485 blocked autophagy and further enhanced CS-6-induced apoptosis. Taken together, we demonstrated for the first time that CS-6 promotes apoptosis and cytoprotective autophagy through the mTOR signaling pathway in HCC, which proposes a novel strategy for HCC therapy.

Distribution and risk assessment of antibiotics under water level fluctuation in the riparian zone of the Hanjiang River.

The riparian zone (RZ) is an important region connecting surface water and groundwater, and it has widely been acknowledged for its pollutant buffering capacity. However, the decontaminating effect of RZ on trace organic compounds such as antibiotics has received little attention. This study explored the distribution of 21 antibiotics and 4 sulfonamide metabolites in river water and groundwater in the lower reaches of the Hanjiang River. The diffusion and exchange of contaminants between the river and riverbanks under the influence of water conservancy projects (Xinglong Dam and the Yangtze-Hanjiang Water Diversion Project) were investigated. Macrolide antibiotics were prevalent in river water (62.5-100%) and groundwater samples (42.9-80.4%). Ofloxacin and chlortetracycline were detected with the highest concentrations in river water (12.2 ng L-1) and groundwater (9.3 ng L-1) respectively. Higher levels of antibiotics were observed in spring and winter than in other seasons. The river-groundwater interaction has a certain interception effect on antibiotics, especially near riverbanks. Redox sensitive element Fe2+ showed significantly positive correlations with some tetracycline and macrolide antibiotics (p < 0.05), and thus the migration mechanism between Fe2+ and antibiotics under the condition of redox change should be investigated further. Environmental risks posed by antibiotics were assessed for algae, daphnids, and fish in surface water and groundwater. Only clarithromycin and chlortetracycline presented a medium risk to algae (0.1 < RQ < 1), and the rest presented low risk (RQ < 0.1). Nevertheless, the risk range may be further extended by interactions between groundwater and surface water. Accurate understanding of antibiotic transport in RZ is critical for developing management strategies aimed at reducing the pollution load on the watershed.

Targeting HSP90 with picropodophyllin suppresses gastric cancer tumorigenesis by disrupting the association of HSP90 and AKT.

Gastric cancer (GC) is one of the most common malignant tumors worldwide. Thus, the development of safe and effective therapeutic compounds for GC treatment is urgently required. Here, we aimed to examine the role of picropodophyllin (PPP), a compound extracted from the rhizome of Dysosma versipellis (Hance) M. Cheng ex Ying, on the proliferation of GC cells. Our study revealed that PPP inhibits the proliferation of GC cells in a dose-dependent manner by inducing apoptosis. Moreover, our study elucidated that PPP suppresses the growth of GC tumor xenografts with no side effects of observable toxicity. Mechanistically, PPP exerts its effects by blocking the AKT/mammalian target of rapamycin (mTOR) signaling pathway; these effects are markedly abrogated by the overexpression of constitutively active AKT. Furthermore, drug affinity responsive target stability (DARTS) and liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) revealed that heat shock protein 90 (HSP90) may be a potential target of PPP. Surface plasmon resonance and immunoprecipitation assay validated that PPP directly targets HSP90 and disrupts the binding of HSP90 to AKT, thereby suppressing GC cell proliferation. Thus, our study revealed that PPP may be a promising therapeutic compound for GC treatment.

CLDN4 promotes growth of acute myeloid leukemia cells via regulating AKT and ERK1/2 signaling.

Acute myeloid leukemia (AML) is the most common acute leukemia affecting adults. The tight junction protein CLDN4 is closely related to the development of various epithelial cell carcinomas. However, whether CLDN4 contributes to AML development remains unclear. For the first time, we found that expression of CLDN4 is aberrantly up-regulated in AML cells. Knockdown of CLDN4 expression resulted in a dramatic decreased cell growth, elevated apoptosis of AML cells. Further, we revealed that knockdown of CLDN4 inhibits mRNA expression of PIK3R3 and MAP2K2, thus suppresses activation of AKT and ERK1/2. More importantly, activating AKT branch by SC79 partially compromised CLDN4 knockdown induced cell viability inhibition. In addition, we found that higher expression of CLDN4 is connected to worse survival and is an independent indicator of shorter disease free survival (DFS) in AML patients. Together, our results indicate that CLDN4 contributes to AML pathogenesis, and suggests that targeting CLDN4 is a promising option for AML treatment.

Sanggenon C Suppresses Tumorigenesis of Gastric Cancer by Blocking ERK-Drp1-Mediated Mitochondrial Fission.

Sanggenon C is a flavonoid extracted from the root bark of white mulberry, which is a traditional Chinese medicine with anti-inflammatory, antioxidative, and antitumor pharmacological effects. In this study, sanggenon C was found to inhibit human gastric cancer (GC) cell proliferation and colony formation, induce GC cell cycle arrest in the G0-G1 phase, and promote GC cell apoptosis. Moreover, sanggenon C was found to decrease the level of mitochondrial membrane potential in GC cells and inhibit mitochondrial fission. Mechanistically, RNA sequencing, bioinformatics analysis, and a series of functional analyses confirmed that sanggenon C inhibited mitochondrial fission to induce apoptosis by blocking the extracellular regulated protein kinases (ERK) signaling pathway, and constitutive activation of ERK significantly abrogated these effects. Finally, sanggenon C was found to suppress the growth of tumor xenografts in nude mice without obvious side effects to the vital organs of animals. This study reveals that sanggenon C could be a novel therapeutic strategy for GC treatment.

Picropodophyllin Inhibits the Proliferation of Human Prostate Cancer DU145 and LNCaP Cells via ROS Production and PI3K/AKT Pathway Inhibition.

The reactive oxygen species (ROS) and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway play critical roles in the pathogenesis of prostate cancer by modulating cell proliferation. Picropodophyllin (PPP), an inhibitor of the insulin-like growth factor 1 receptor (IGF-1R), exerts significant antitumor effects via the PI3K/AKT signaling pathway. However, the effects of PPP on prostate cancer via ROS production and the PI3K/AKT signaling pathway remain elusive. Herein, we focused on examining the antitumor effects of PPP on DU145 and LNCaP human prostate cancer cells to determine the possible molecular mechanism. Our data indicated that the inhibitory effect of PPP on the proliferation of DU145 and LNCaP human prostate cancer cells was mediated by apoptosis induction and cell cycle blockade. Furthermore, PPP significantly influenced the expression of apoptosis-related, cell cycle, ROS production, and PI3K/AKT signaling proteins. These findings suggest that PPP can induce cell cycle arrest and apoptosis via the production of ROS and inhibition of PI3K/AKT signaling pathway, thereby suppressing the proliferation of prostate cancer cells.

[Effect and mechanism of microRNA-155 in chronic obstructive pulmonary disease by targeting PIK3R1].

This study aimed to investigate the effect of microRNA-155 (miR-155) in chronic obstructive pulmonary disease (COPD) and cigarette smoke extract (CSE)-treated airway smooth muscle cells (ASMCs) by targeting phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1) to regulate the PTEN/PI3K/Akt signaling pathway. The COPD mouse model was induced by lipopolysaccharide (LPS) combined with passive smoking. After modeling, miR-155 mimics and miR-155 inhibitor were used for intervention treatment. The pulmonary function of each group was detected by an EMKA detector. Hematoxylin-eosin (HE) staining was used to observe the pathological changes and scores of lung tissues. The expression of TNF-α, IL-6, and IL-1ß in bronchial alveolar lavage fluid (BALF) was detected by ELISA. Primary ASMCs were isolated and cultured in adherent tissue culture. The proliferation activity was detected by CCK-8 and EdU assays. Transwell and wound healing assays were used to measure the migration of ASMCs. The targeting relationship between miR-155 and PIK3R1 was validated by a double luciferase reporter gene assay. The expression levels of miR-155 and PIK3R1 mRNA in lung tissues of mice in each group were detected by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Western blot was used to detect the expression levels of Ki67, PNCA, PTEN, p-PI3K, PI3K, p85α, p-Akt, and Akt in lung tissues and ASMCs. The results showed that lung function was significantly reduced in the miR-155 mimic group, and the levels of PIK3R1 were significantly increased; while lung function in the miR-155 inhibitor group was significantly improved. The results of HE staining showed that there was obvious inflammatory cell infiltration in the miR-155 mimics group compared to that of the model group. Lung histopathological injury was significantly reduced in the miR-155 inhibitor group, accompanied by decreased expression of Ki67, PNCA, PI3K, p-Akt, increased PTEN and p85α protein levels, and reduced levels of TNF-α, IL-6, and IL-1ß in BALF. The results of the double luciferase reporter gene assay showed that miRNA-155 could target bind to PIK3R1. Compared with those in the CSE+miR-155 NC group, the proliferation and migration of ASMCs were significantly increased in the CSE+miR-155 group. The proliferation and migration of ASMCs were significantly attenuated in the CSE+miR-155+pcDNA PIK3R1 group compared with those in the CSE+miR-155 group, accompanied by decreased expression of Ki67, PNCA, p-Akt and increased PTEN and p85α protein levels. These results suggest that miR-155 activates the PTEN/PI3K/Akt signaling pathway by targeting PIK3R1 to promote the occurrence and development of COPD, which provides new evidence for the use of miR-155 in the treatment of COPD.

Tiotropium in Early-Stage Chronic Obstructive Pulmonary Disease.

BACKGROUND: Patients with mild or moderate chronic obstructive pulmonary disease (COPD) rarely receive medications, because they have few symptoms. We hypothesized that long-term use of tiotropium would improve lung function and ameliorate the decline in lung function in patients with mild or moderate COPD. METHODS: In a multicenter, randomized, double-blind, placebo-controlled trial that was conducted in China, we randomly assigned 841 patients with COPD of Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 1 (mild) or 2 (moderate) severity to receive a once-daily inhaled dose (18 µg) of tiotropium (419 patients) or matching placebo (422) for 2 years. The primary end point was the between-group difference in the change from baseline to 24 months in the forced expiratory volume in 1 second (FEV1) before bronchodilator use. Secondary end points included the between-group difference in the change from baseline to 24 months in the FEV1 after bronchodilator use and the between-group difference in the annual decline in the FEV1 before and after bronchodilator use from day 30 to month 24. RESULTS: Of 841 patients who underwent randomization, 388 patients in the tiotropium group and 383 in the placebo group were included in the full analysis set. The FEV1 in patients who received tiotropium was higher than in those who received placebo throughout the trial (ranges of mean differences, 127 to 169 ml before bronchodilator use and 71 to 133 ml after bronchodilator use; P<0.001 for all comparisons). There was no significant amelioration of the mean (±SE) annual decline in the FEV1 before bronchodilator use: the decline was 38±6 ml per year in the tiotropium group and 53±6 ml per year in the placebo group (difference, 15 ml per year; 95% confidence interval [CI], -1 to 31; P=0.06). In contrast, the annual decline in the FEV1 after bronchodilator use was significantly less in the tiotropium group than in the placebo group (29±5 ml per year vs. 51±6 ml per year; difference, 22 ml per year [95% CI, 6 to 37]; P=0.006). The incidence of adverse events was generally similar in the two groups. CONCLUSIONS: Tiotropium resulted in a higher FEV1 than placebo at 24 months and ameliorated the annual decline in the FEV1 after bronchodilator use in patients with COPD of GOLD stage 1 or 2. (Funded by Boehringer Ingelheim and others; Tie-COPD ClinicalTrials.gov number, NCT01455129 .).

MARCH1 encourages tumour progression of hepatocellular carcinoma via regulation of PI3K-AKT-ß-catenin pathways.

Membrane-associated RING-CH-1 (MARCH1) is a membrane-anchored E3 ubiquitin ligase that is involved in a variety of cellular processes. MARCH1 was aberrantly expressed as a tumour promoter in ovarian cancer, but the signalling about the molecular mechanism has not yet been fully illuminated. Here, we first determined that MARCH1 was obviously highly expressed in human hepatocellular carcinoma samples and cells. In addition, our findings demonstrated that the proliferation, migration and invasion of hepatocellular carcinoma were suppressed, but the apoptosis was increased, as a result of MARCH1 knockdown by either siRNA targeting MARCH1 or pirarubicin treatment. Conversely, the proliferation, migration and invasion of hepatocellular carcinoma were obviously accelerated, and the apoptosis was decreased, by transfecting the MARCH1 plasmid to make MARCH1 overexpressed. Moreover, in vivo, the results exhibited a significant inhibition of the growth of hepatocellular carcinoma in nude mice, which were given an intra-tumour injection of siRNA targeting MARCH1. Furthermore, our study concluded that MARCH1 functions as a tumour promoter, and its role was up-regulated the PI3K-AKT-ß-catenin pathways both in vitro and in vivo. In summary, our work determined that MARCH1 has an important role in the development and progression of hepatocellular carcinoma and may be used as a novel potential molecular therapeutic target in the future treatment of hepatocellular carcinoma.

Underwater superoleophobic and anti-oil microlens array prepared by combing femtosecond laser wet etching and direct writing techniques.

As an important micro-optical device, microlens array (MLA) also has broad applications in aqueous environment apart from atmosphere, such as bioscience research, ocean exploration, and microfluidic systems. However, the surface of the normal MLA is easily polluted by oil contaminations when the MLA is practically applied in a water medium, leading to the loss of its optical imaging ability. Herein, we fabricated a functional MLA with underwater anti-oil and self-cleaning abilities by combining the femtosecond laser wet etching (FLWE) and the femtosecond laser direct writing (FLDW) techniques. The as-prepared close-packed MLA is composed of 10000 single microlenses with the aperture diameter of 50 µm. The surface of each microlens is further textured with micro/nanoparticles. Clear and uniform images could be captured by using the resultant MLA in water, demonstrating great underwater imaging ability. The modulation transfer function value is larger than 0.6 at 55 lp/mm. In addition, the micro/nanostructures endow the as-fabricated MLA surface with underwater superoleophobicity and oil-repellent performance. Various oils can be repelled by the resultant MLA in water. Underwater 1,2-dichloroethane oil droplet on the textured MLA has a contact angle of 158.0 ± 0.5° and a sliding angle of 2.0 ± 0.2°. The underwater superoleophobic MLA also has good mechanical durability. The anti-oil and self-cleaning functions will broaden the applications of the MLA in ocean exploration, bioscience research, microfluidic system, and many underwater MLA-based systems.

Secalonic Acid-F, a Novel Mycotoxin, Represses the Progression of Hepatocellular Carcinoma via MARCH1 Regulation of the PI3K/AKT/ß-catenin Signaling Pathway.

Liver cancer is a very common and significant health problem. Therefore, powerful molecular targeting agents are urgently needed. Previously, we demonstrated that secalonic acid-F (SAF) suppresses the growth of hepatocellular carcinoma (HCC) cells (HepG2), but the other anticancer biological functions and the underlying mechanism of SAF on HCC are unknown. In this study, we found that SAF, which was isolated from a fungal strain in our lab identified as Aspergillus aculeatus, could inhibit the progression of hepatocellular carcinoma by targeting MARCH1, which regulates the PI3K/AKT/ß-catenin and antiapoptotic Mcl-1/Bcl-2 signaling cascades. First, we confirmed that SAF reduced the proliferation and colony formation of HCC cell lines (HepG2 and Hep3B), promoted cell apoptosis, and inhibited the cell cycle in HepG2 and Hep3B cells in a dose-dependent manner. In addition, the migration and invasion of HepG2 and Hep3B cells treated with SAF were significantly suppressed. Western blot analysis showed that the level of MARCH1 was downregulated by pretreatment with SAF through the regulation of the PI3K/AKT/ß-catenin signaling pathways. Moreover, knockdown of MARCH1 by small interfering RNAs (siRNAs) targeting MARCH1 also suppressed the proliferation, colony formation, migration, and invasion as well as increased the apoptotic rate of HepG2 and Hep3B cells. These data confirmed that the downregulation of MARCH1 could inhibit the progression of hepatocellular carcinoma and that the mechanism may be via PI3K/AKT/ß-catenin inactivation as well as the downregulation of the antiapoptotic Mcl-1/Bcl-2. In vivo, the downregulation of MARCH1 by treatment with SAF markedly inhibited tumor growth, suggesting that SAF partly blocks MARCH1 and further regulates the PI3K/AKT/ß-catenin and antiapoptosis Mcl-1/Bcl-2 signaling cascade in the HCC nude mouse model. Additionally, the apparent diffusion coefficient (ADC) values, derived from magnetic resonance imaging (MRI), were increased in tumors after SAF treatment in a mouse model. Taken together, our findings suggest that MARCH1 is a potential molecular target for HCC treatment and that SAF is a promising agent targeting MARCH1 to treat liver cancer patients.

Bifunctional enzyme ATIC promotes propagation of hepatocellular carcinoma by regulating AMPK-mTOR-S6 K1 signaling.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the cancer types with poor prognosis. To effectively treat HCC, new molecular targets and therapeutic approaches must be identified. 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/inosine monophosphate (IMP) cyclohydrolase (ATIC), a bifunctional protein enzyme, catalyzes the last two steps of the de novo purine biosynthetic pathway. Whether ATIC contributes to cancer development remains unclear. METHODS: ATIC mRNA levels in different types of human HCC samples or normal tissues were determined from Gene Expression across Normal and Tumor tissue (GENT) database. The expression level of ATIC in human HCC samples or cell lines were examined by RT-PCR and western blot. Overall survival and disease-free survival of HCC patients in the ATIC low and ATIC high groups were determined by Kaplan-Meier analysis. Effects of ATIC knockdown by lentivirus infection were evaluated on cell-proliferation, cell-apoptosis, colony formation and migration. The mechanisms involved in HCC cells growth, apoptosis and migration were analyzed by western blot and Compound C (C-C) rescue assays. RESULTS: Here, we first demonstrated that expression of ATIC is aberrantly up-regulated in HCC tissues and high level of ATIC is correlated with poor survival in HCC patients. Knockdown of ATIC expression resulted in a dramatic decrease in proliferation, colony formation and migration of HCC cells. We also identified ATIC as a novel regulator of adenosine monophosphate-activated protein kinase (AMPK) and its downstream signaling mammalian target of rapamycin (mTOR). ATIC suppresses AMPK activation, thus activates mTOR-S6 K1-S6 signaling and supports growth and motility activity of HCC cells. CONCLUSION: Taken together, our results indicate that ATIC acts as an oncogenic gene that promotes survival, proliferation and migration by targeting AMPK-mTOR-S6 K1 signaling.

Functional Enzyme-Based Approach for Linking Microbial Community Functions with Biogeochemical Process Kinetics.

The kinetics of biogeochemical processes in natural and engineered environmental systems is typically described using Monod-type or modified Monod-type models. These models rely on biomass as surrogates for functional enzymes in microbial communities that catalyze biogeochemical reactions. A major challenge of applying such models is the difficulty of quantitatively measuring functional biomass for the constraining and validation of the models. However, omics-based approaches have been increasingly used to characterize microbial community structure, functions, and metabolites. Here, we propose an enzyme-based model that can incorporate omics data to link microbial community functions with biogeochemical process kinetics. The model treats enzymes as time-variable catalysts for biogeochemical reactions and applies a biogeochemical reaction network to incorporate intermediate metabolites. The sequences of genes and proteins from metagenomes, as well as those from the UniProt database, were used for targeted enzyme quantification and to provide insights into the dynamic linkage among functional genes, enzymes, and metabolites that are required in the model. The application of the model was demonstrated using denitrification, as an example, by comparing model simulations with measured functional enzymes, genes, denitrification substrates, and intermediates.

ACER3 supports development of acute myeloid leukemia.

No new therapy for acute myeloid leukemia (AML) has been approved for more than 30 years. To effectively treat AML, new molecular targets and therapeutic approaches must be identified. In silico analysis of several databases of AML patients demonstrated that the expression of alkaline ceramidase 3 (ACER3) significantly inversely correlates with the overall survival of AML patients. To determine whether ACER3 supports AML development, we employed an shRNA-encoding lentivirus system to inhibit acer3 expression in human AML cells including NB4, U937, and THP-1 cells. The ACER3 deficiency resulted in decreased cell growth and colony formation, elevated apoptosis, and lower AKT signaling of leukemia cells. Our study indicates that ACER3 contributes to AML pathogenesis, and suggests that alkaline ceramidase inhibition is an option to treat AML.

Copper-induced alteration in sucrose partitioning and its relationship to the root growth of two Elsholtzia haichowensis Sun populations.

Hydroponic culture was used to comparatively investigate the copper (Cu)-induced alteration to sucrose metabolism and biomass allocation in two Elsholtzia haichowensis Sun populations with one from a Cu-contaminated site (CS) and the other from a non-contaminated site (NCS). Experimental results revealed that biomass allocation preferred roots over shoots in CS population, and shoots over roots in NCS population under Cu exposure. The difference in biomass allocation was correlated with the difference in sucrose partitioning between the two populations. Cu treatment (45 µM) significantly decreased leaf sucrose content and increased root sucrose content in CS population as a result of the increased activities of leaf sucrose synthesis enzymes (sucrose phosphate synthetase and sucrose synthase) and root sucrose cleavage enzyme (vacuolar invertase), which led to increased sucrose transport from leaves to roots. In contrast, higher Cu treatment increased sucrose content in leaves and decreased sucrose content in roots in NCS population as a result of the decreased activities of root sucrose cleavage enzymes (vacuolar and cell wall invertases) that led to less sucrose transport from leaves to roots. These results provide important insights into carbon resource partitioning and biomass allocation strategies in metallophytes and are beneficial for the implementation of phytoremediation techniques.

Anti-inflammatory effect of resveratrol through the suppression of NF-κB and JAK/STAT signaling pathways.

Resveratrol, the most important ingredient extracted from Polygonum cuspidatum, exerts cytoprotective effects via anti-inflammatory actions in vitro. In this study, we investigated this effect of resveratrol on the lipopolysaccharide (LPS)-induced inflammatory response and its underlying molecular mechanism of action in RAW264.7 murine macrophages. Results showed that resveratrol down-regulated the expression of inducible nitric oxide synthase (iNOS) and interleukin-6 (IL-6), therefore, suppressed the production of nitric oxide and the secretion of IL-6 in LPS-stimulated RAW264.7 cells in a dose-dependent manner. Resveratrol also inhibited the translocation of high-mobility group box 1 (HMGB1) from the nucleus to the cytoplasm and of nuclear transcription factor kappa-B (NF-κB) p65 from the cytoplasm to the nucleus; it suppressed the phosphorylation of IκBα. Furthermore, these actions were mediated by suppressing the phosphorylation of signal transducer and activator of transcription (STAT)-1 and -3. In conclusion, these data indicate that resveratrol exerts anti-inflammatory effects, at least in part by reducing the release of HMGB1 and modulating the NF-κB and Janus kinase/STAT signaling pathways. Resveratrol could potentially be developed as a useful agent for the chemoprevention of inflammatory diseases.