Origins of black carbon from anthropogenic emissions and open biomass burning transported to Xishuangbanna, Southwest China.

Black carbon (BC) has importance regarding aerosol composition, radiative balance, and human exposure. This study adopted a backward-trajectory approach to quantify the origins of BC from anthropogenic emissions (BCAn) and open biomass burning (BCBB) transported to Xishuangbanna in 2017. Haze months, between haze and clean months, and clean months in Xishuangbanna were defined according to daily PM2.5 concentrations of >75, 35-75, and <35 µg/m3, respectively. Results showed that the transport efficiency density (TED) of BC transported to Xishuangbanna was controlled by the prevailing winds in different seasons. The yearly contributions to the effective emission intensity of BCAn and BCBB transported to Xishuangbanna were 52% and 48%, respectively. However, when haze occurred in Xishuangbanna, the average BCAn and BCBB contributions were 23% and 77%, respectively. This suggests that open biomass burning (BB) becomes the dominant source in haze months. Myanmar, India, and Laos were the dominant source regions of BC transported to Xishuangbanna during haze months, accounting for 59%, 18%, and 13% of the total, respectively. Furthermore, India was identified as the most important source regions of BCAn transported to Xishuangbanna in haze months, accounting for 14%. The two countries making the greatest contributions to BCBB transported to Xishuangbanna were Myanmar and Laos in haze months, accounting for 55% and 13%, respectively. BC emissions from Xishuangbanna had minimal effects on the results of the present study. It is suggested that open BB in Myanmar and Laos, and anthropogenic emissions in India were responsible for poor air quality in Xishuangbanna.

PP2A regulates metastasis and vasculogenic mimicry formation via PI3K/AKT/ZEB1 axis in non-small cell lung cancers.

Studies have shown that inhibition of PI3K/AKT signaling is a key strategy for the treatment of tyrosine kinase inhibitor resistance in non-small cell lung cancer (NSCLC). Vasculogenic mimicry (VM) not only accelerates tumor progression but also increases drug-induced resistance. As a tumor suppressor, protein phosphatase 2A (PP2A) is a ubiquitous conserved serine/threonine phosphatase. While its effects and mechanisms on VM formation and invasion in NSCLC remain unclear. The present study aimed to investigate the role of PP2A in VM formation and elucidate the underlying mechanisms. Results showed that PP2A could significantly inhibit VM formation and VM-dependent behavior, including invasion and migration both in vitro and in vivo. Activation of PP2A with FTY720 or Ad-PP2A reduced phosphorylated AKT and inhibited ZEB1 transcription, thereby further downregulating the expression of MMP-2, VE-cadherin, and VEGFR-2, whereas inhibition of PP2A with okadaic acid (OA) or Ad-dn-PP2A exerted the opposite effect. Furthermore, PP2A inhibited tumor growth and VM formation in the xenograft tumor model. PI3K inhibitor BENC-511 could potentiate activation of PP2A, leading to inhibition of p-AKT/ZEB1 and VM formation in vitro and in vivo. This study indicated that PP2A could regulate VM formation in NSCLC through the PI3K/AKT/ZEB1 axis. PP2A reactivation or combination with PI3K inhibitor might be a more effective treatment against advanced NSCLC by inhibiting VM formation.

Network pharmacology analysis on mechanism of Jian Pi Qing Gan Yin decoction ameliorating high fat diet-induced non-alcoholic fatty liver disease and validated in vivo.

ETHNOPHARMACOLOGICAL RELEVANCE: Jian Pi Qing Gan Yin (JPQGY) has been used clinically to relieve non-alcoholic fatty liver disease (NAFLD) in China for decades; however, the underlying mechanisms of JPQGY remain unclear. AIM OF THE STUDY: We evaluated the effects and mechanisms of JPQGY and hepatic steatosis caused by the middle stage of 13-week-high-fat-diet-induced NAFLD in mice. MATERIALS AND METHODS: Different dosages of JPQGY (5.5, 11, and 22 g/kg/day) were administered to NAFLD mice simultaneously. Body weight, body mass index (BMI), and liver lipid- and inflammation-related serum indicators were measured enzymatically. Liver samples were stained with Oil Red O and hematoxylin and eosin (H&E). Next, we performed a network pharmacology analysis and verified eight target genes mapping to NAFLD-related lipid metabolism pathways. The mRNA/protein expression was analyzed by real-time polymerase chain reaction (PCR) and western blotting. RESULTS: JPQGY significantly relieved histological damage (steatosis-inflammation-fibrosis), prevented the downregulation of AMPK and Pparα, and upregulated LXRα, Srebp-1c, F4/80, Nf-κb, and Cyp2e1 in the HFD-induced NAFLD mouse model. CONCLUSIONS: The present results suggest that chronic treatment with JPQGY ameliorated HFD-induced NAFLD in mice by targeting the first and second phases of hepatic steatosis by stimulating the AMPK/PPARα pathway and inhibiting the LXRα/Srebp1/Nf-κb pathway. Our findings provide evidence that supports the clinical use of this formula for high-fat diet-induced fatty liver disease.

The basic functions of phosphoglycerate kinase 1 and its roles in cancer and other diseases.

Phosphoglycerate kinase 1 (PGK1) is an essential enzyme that catalyzes adenosine 5'-triphosphate (ATP) production in aerobic glycolysis. In addition to regulating cell metabolism, PGK1 is involved in multiple biological activities, including angiogenesis, mediated autophagy starting, binding of plasminogen, the DNA replication and repair, the proliferation and metastasis of tumor cells, cell invasion (a part of the flagellar axoneme and viral replication and it occurs mainly in protists), and is also associated with resistance to chemotherapy and prognosis of cancer patients. In this review, we focus on the basic functions of PGK1 and the relationship between PGK1 and different diseases, indicating that PGK1 has a broad application prospect to find a potential biomarker for tumor prognosis and an effective inhibitor.

Lactate shuttle: from substance exchange to regulatory mechanism.

Lactate, as the product of glycolytic metabolism and the substrate of energy metabolism, is an intermediate link between cancer cell and tumor microenvironment metabolism. The exchange of lactate between the two cells via mono-carboxylate transporters (MCTs) is known as the lactate shuttle in cancer. Lactate shuttle is the core of cancer cell metabolic reprogramming between two cells such as aerobic cancer cells and hypoxic cancer cells, tumor cells and stromal cells, cancer cells and vascular endothelial cells. Cancer cells absorb lactate by mono-carboxylate transporter 1 (MCT1) and convert lactate to pyruvate via intracellular lactate dehydrogenase B (LDH-B) to maintain their growth and metabolism. Since lactate shuttle may play a critical role in energy metabolism of cancer cells, components related to lactate shuttle may be a crucial target for tumor antimetabolic therapy. In this review, we describe the lactate shuttle in terms of both substance exchange and regulatory mechanisms in cancer. Meanwhile, we summarize the difference of key proteins of lactate shuttle in common types of cancer.

The roles of IDH1 in tumor metabolism and immunity.

IDH1 is a key metabolic enzyme for cellular respiration in the tricarboxylic acid (TCA) cycle that can convert isocitrate into α-ketoglutarate (α-KG) and generate NADPH. The reduction of IDH1 may affect dioxygenase activity and damage the body's detoxification mechanism. Many studies have shown that IDH1 is closely related to the occurrence and development of tumors, and the changes in IDH1 expression levels or gene mutations have appeared in many tumor tissues and produced a series of metabolic and immunity changes at the same time. To better understand the relationship between IDH1 and tumor development, this article reviews the latest advances in IDH1 and tumor metabolism, tumor immunity, IDH1 regulatory mechanisms and IDH1 target inhibitors.

IDH1 is a key metabolic enzyme for cellular respiration. The changes in IDH1 expression or gene mutations may affect enzyme activity and damage the body's detoxification mechanism. Studies have shown that IDH1 is closely related to the occurrence and development of tumors, and the changes in IDH1 also produced a series of metabolic and immunity changes. To better understand the relationship between IDH1 and tumor development, this article reviews the latest advances in IDH1 and tumor metabolism, tumor immunity, IDH1 regulatory mechanisms and IDH1 target inhibitors.

Decomposition mechanism on different surfaces of copper azide.

Copper azide, a potential primary explosives that may replace traditional primers such as lead azide, mercury fulminate and silver azide, has received widespread attention, but its decomposition mechanism remains unclear. Here, based on first-principles calculations, (010)N3, (100)N3and (001) facets with a copper/nitrogen atom ratio of 1/6 are found to be the most stable surfaces of copper azide crystal. Through transition state (TS) calculations, we find that during the decomposition process on the surface, there is a synergy effect between two Cu-N1-N2-N3 chains, where the terminal N2-N3 bonds on two chains break simultaneously, and the dissociated N3 atom bonds with another N3' atom of adjacent chain to form a N2 molecule. Next, the Cu-N bond will rupture, and two more N2molecules (N1-N2, N1'-N2') desorb from the surface. The overall reaction releases above 4 eV energy at a barrier of 1.23 eV on (001) surface. Electronic structure calculations reveal that the TS of N2-N3 rupture is more stabilized than that of N1-N2. According to the above results, we propose a new decomposition mechanism based on simulations of N-N bond breaking on different surfaces of copper azide. The results underscore the surface effect in decomposition of energetic materials.

Effects of PP2A/Nrf2 on experimental diabetes mellitus-related cardiomyopathy by regulation of autophagy and apoptosis through ROS dependent pathway.

Diabetes mellitus-related cardiomyopathy (DMCMP) has been defined as ventricular dysfunction that occurs in diabetic patients independent of a recognized cause such as coronary artery disease or hypertension. Mechanisms underlying DMCMP have not been fully elucidated. In this study, the roles of protein phosphatase 2A/nuclear factor NF-E2-related factor 2 (PP2A/Nrf2) in experimental DMCMP induced by high glucose were studied in vitro and in vivo. The results showed that high glucose could induce experimental DMCMP and increase ROS generation, increase the expression and nuclear translocation of Nrf2, down-regulate the expression of PI3K/Akt/mTOR and up-regulate the expression of ERK, and activate the autophagy of cardiomyocytes. The activity or expression of PP2A in DMCMP increased. PP2A could up-regulate the expression of Nrf2 and promote cardiomyocytes autophagy and apoptosis. Inhibition of PP2A could reduce the expression of Nrf2 and inhibit the autophagy and apoptosis of cardiomyocytes. The results suggested that hyperglycemic-induced experimental DMCMP may be related to up-regulating the expression of Nrf2 through PP2A/Nrf2 pathway. These results will be helpful to elucidate the pathogenesis and mechanism of DMCMP and find targets for the development of new drugs to prevent or treat DMCMP.

Effects of BENC-511, a novel PI3K inhibitor, on the proliferation and apoptosis of A549 human lung adenocarcinoma cells.

The small chemical compound 8-ethoxy-2-(4-fluorophenyl)-3-nitro-2H-chromene (S14161) was recently identified as an inhibitor of phosphoinositide 3-kinase (PI3K) and reported to inhibit tumor growth. However, its chiral structure and poor solubility prevent its further use. Compound 6-bromo-8-ethoxy-3-nitro-2H-chromene (BENC-511) is an analogue of S14161 produced by structural optimization. A previous study indicated that BENC-511 acted on multiple myeloma and that it had a toxicity by inhibiting the PI3K/protein kinase B (Akt) pathway. However, the effects of BENC-511 on the proliferation and apoptosis of A549 human lung adenocarcinoma cells have not been reported. The current study investigated the effects of BENC-511 on the proliferation and apoptosis of A549 cells in vitro. Results indicated that the compound BENC-511 inhibited the viability of A549 cells in a concentration- and time- dependent manner. BENC-511 suppressed proliferation and colony formation via S phase arrest. BENC-511 decreased the expression of cyclin A, proliferating cell nuclear antigen (PCNA), B-cell lymphoma-2 (Bcl-2), phospho-mammalian target of rapamycin (p-mTOR), and phospho-Akt (p-Akt) and it increased the expression of p21WAF1CIP1(p21), Caspase-3 and Caspase-9. In conclusion, BENC-511 inhibited the proliferation of A549 human lung adenocarcinoma cells via S phase arrest as a result of up-regulation of p21 and reduction of Cyclin A/cyclin-dependent kinase 2 (CDK2)/PCNA complex and it induced apoptosis by reducing the mitochondrial membrane potential via the Akt/Bcl-2/Caspase-9 mitochondrial pathway of apoptosis.

The roles and signaling pathways of prolyl-4-hydroxylase 2 in the tumor microenvironment.

Tumor hypoxia is a well-known microenvironmental factor that causes cancer progression and resistance to cancer treatment. Proline hydroxylases (PHDs), a small protein family, belong to an evolutionarily conserved superfamily of dioxygenases, considered the central regulator of the molecular hypoxia response. Prolyl-4-hydroxylase 2 (PHD2), one member of PHDs family, regulates the stability of the hypoxia-inducible factor-1 alpha (HIF-1α) in response to oxygen availability. During hypoxia, the inhibition of PHD2 permits the accumulation of HIF-1α, allowing the cellular adaptation to oxygen limitation, causing activation of numerous genes, which enhances the angiogenesis, metastasis and invasiveness. Accurate regulation of oxygen homeostasis is essential, and which implies PHD2 may have a regulatory role in the pathogenesis of cancer. Although ample evidence exists for a positive correlation between HIFs and tumor formation, metastasis and poor prognosis, the function of the PHD2 in carcinogenesis is less well understood. Despite their original role as the oxygen sensors of the cell and many of the its functions are clearly conveyed through the HIF system, PHD2 is currently known to display HIF-independent and hydroxylase-independent functions in cancer cells and stroma in the control of different cellular pathways. In this review, we summarize the recent advances in the structure, regulation and functions of PHD2 in cancer microenvironment.

The roles of ZEB1 in tumorigenic progression and epigenetic modifications.

Highly expressed Zinc-finger E-box binding protein 1 (ZEB1) is significantly associated with the malignancy of various cancers. Signal transduction and activation of ZEB1 play important roles in cancer transformation and epithelial-mesenchymal transition (EMT). Emerging evidence suggests that ZEB1 drives the induction of EMT with activation of stem cell traits, immune evasion and epigenetic reprogramming. As an ideal target for EMT research, ZEB1 has been extensively studied for decades. However, the link between ZEB1 and epigenetic regulation of EMT has only recently been discovered. ZEB1 facilitates the epigenetic silencing of E-cadherin by recruiting multiple chromatin enzymes of E-cadherin promoter, such as histone deacetylases (HDACs), DNA methyltransferase (DNMT) and ubiquitin ligase. Destruction of the connection between ZEB1 and these chromatin-modifying enzymes may represent an efficient for treating cancer. In this review, we outlined the biological function of ZEB1 in tumorigenic progression and epigenetic modifications and elucidate its transcriptional network, which is a suitable potential target for the design of novel anticancer drugs.

BENC-511, a novel PI3K inhibitor, suppresses metastasis of non-small cell lung cancer cells by modulating ß-catenin/ZEB1 regulatory loop.

Non-small cell lung cancer (NSCLC) is known as highly metastatic disease because it is difficult to diagnose at early stage. More than 60% of NSCLC patients' overexpress receptor tyrosine kinase (RTK) such as EGFR that has been proved to display resistance to receptor tyrosine kinase inhibitor (TKI) through PI3K signaling, while single PI3K inhibitors increase RTK expression as feedback. So, to select the proper targeted agent or target an assortment of molecular subsets, such as EGFR mutations for different subgroups of patients with NSCLC is urgent. Compound BENC-511, a potent PI3K inhibitor, had effects on inhibiting cancer cell survival and delaying tumor growth, but the effects and mechanisms on cancer metastasis are not clear. Methods of Scratch assay, Transwell system, experimental metastasis mice models, plasmid transfection, quantitative real-time PCR and Western blot were used. Results showed that BENC-511 could significantly inhibit lung cancer cells invasion and metastasis both in vitro and in vivo. And it not only inhibited PI3K/Akt signal pathway, but also directly suppressed phosphorylation of EGFR and nuclear translocation of ß-catenin. Moreover, our study firstly reported BENC-511 seemed more sensitive to NSCLC cells that highly expressed Zinc-finger E-box binding protein 1 (ZEB1), one of the epithelial-mesenchymal transition (EMT) inducer, and knockdown of ZEB1 could improve the effects of this compound. These findings suggested that BENC-511 should be a promising lead molecule for anti-metastasis therapy by targeting ß-catenin/ZEB1 regulatory loop and serve as a therapeutic agent to inhibit metastasis of NSCLC.

Anti-neovascularization effects of DMBT in age-related macular degeneration by inhibition of VEGF secretion through ROS-dependent signaling pathway.

Choroidal neovascularization (CNV) is the hallmark of late-staged wet age-related macular degeneration (AMD). Vascular endothelial growth factor (VEGF) is a key component in the development and progression of wet AMD. DMBT, 6,6'-bis(2,3-dimethoxybenzoyl)-α,α-D-trehalose, had been proved that it could suppress tumor angiogenesis and metastasis by inhibiting production of VEGF. But the effects of DMBT on CNV were not known. This study was to investigate effects and mechanisms of DMBT on CNV in vitro and in vivo. Results showed that DMBT could inhibit migration and tube formation of RF/6A cells under ARPE-19 hypoxia conditioned medium. DMBT could reduce lesion area in laser-induced CNV model mice. ELISA and Western blotting assay showed that DMBT markedly inhibited secretion of VEGF in vitro and in vivo. Furthermore, DMBT restrained ROS level under hypoxia via suppressing Nrf2/HO-1 pathway. DMBT effectively suppressed hypoxia-induced the up-regulation of p-Akt, p-NF-κB, and HIF-1α. These results suggest that DMBT can inhibit CNV by down-regulation of VEGF in retina through Akt/NF-κB/HIF-1α and ERK/Nrf2/HO-1/HIF-1α pathway. DMBT might be a promising lead molecule for anti-CNV and serve as a therapeutic agent to inhibit CNV.

Inhibitory effects of compound DMBT on hypoxia-induced vasculogenic mimicry in human breast cancer.

Breast cancer is one of the most serious malignant tumors that harm to women's health. Vasculogenic mimicry (VM) is an alternative type of blood supplement independent of endothelial vessels, which refers to the formation of tumor cell-lined vessels and is associated with tumor invasion, metastasis and poor cancer patient prognosis. Prior antiangiogenic therapy just focused on vascular endothelial cells and did not significantly affect VM. DMBT, 6, 6'-bis (2, 3-dimethoxybenzoyl)-a, a-D-trehalose, has shown to have multiple anti-tumor invasion and metastasis activities; however the exact mechanism is not thoroughly elucidated. In this study, we examined key molecular mechanisms underlying VM by using breast cancer cells MDA-MB-231 and MCF-7. We found that following the hypoxia treatment, the cells were easily to form VM networks and DMBT could inhibit VM formation of both MDA-MB-231 and MCF-7 cells in hypoxic condition. When tumor cells exposed to hypoxia environment, the expression of VM related proteins such as HIF-1α, VE-cadherin, MMP-9, Cdc42, and EGFR, p-Akt, p-mTOR were increased but decreased when exposed to hypoxia medium with DMBT. In MDA-MB-231 cells, DMBT inhibit hypoxia-induced VM by suppress HIF-1α/VE-cadherin/MMPs signaling pathway and in MCF-7 cells, DMBT had little effect on HIF-1α or VE-cadherin but could inhibit cell autophagy to suppress VM formation. These results suggested that DMBT could serve as a therapeutic agent to inhibit VM formation in human breast cancer.

Protective effects of luteolin-7-O-glucoside against starvation-induced injury through upregulation of autophagy in H9c2 Cells.

Cardiomyocyte nutrient deprivation is a common clinical event that mediates various cardiac ischemic processes and is associated with autophagy activation and cell survival or death. Luteolin-7-O-glucoside (LUTG) was one of the flavonoid glycosides isolated from Dracocephalum tanguticum. Previous research had showed that LUTG pretreatment had significant protective effects against doxorubicin-induced cardiotoxicity. However, whether LUTG could protect cardiomyocytes from starvation-induced injury was not clear. In this study, cardioprotection and mechanisms of LUTG against starvation-induced injury were investigated in vitro. 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2-tetrazolium bromide (MTT) assay showed starvation-induced autophagy is a homeostatic and protective response for H9c2 cell survival. LUTG could protect against injury induced by starvation in H9c2 cells. Acridine orange (AO) staining showed that pretreatment with LUTG enhanced lysosomal autophagy. Western blotting indicated that LUTG enhanced autophagy by down-regulating the expression of phospho-extracellular signal regulated kinase1/2 (p-ERK), phospho-protein kinase B (p-Akt) and phospho-mammalian target of rapamycin (p-mTOR). These results suggest that LUTG might act as a promising therapeutic agent for preventing starvation-induced cardiotoxicity by upregulation of autophagy through the Akt/mTOR and ERK signal pathway.

The role of autophagy in angiotensin II-induced pathological cardiac hypertrophy.

Pathological cardiac hypertrophy is associated with nearly all forms of heart failure. It develops in response to disorders such as coronary artery disease, hypertension and myocardial infarction. Angiotensin II (Ang II) has direct effects on the myocardium and promotes hypertension. Chronic elevation of Ang II can lead to pathological cardiac hypertrophy and cardiac failure. Autophagy is an important process in the pathogenesis of cardiovascular diseases. Under physiological conditions, autophagy is an essential homeostatic mechanism to maintain the global cardiac structure function by ridding damaged cells or unwanted macromolecules and organelles. Dysregulation of autophagy may play an important role in Ang II-induced cardiac hypertrophy although conflicting reports on the effects of Ang II on autophagy and cardiac hypertrophy exist. Some studies showed that autophagy activation attenuated Ang II-induced cardiac dysfunction. Others suggested that inhibition of the Ang II induced autophagy should be protective. The discrepancies may be due to different model systems and different signaling pathway involved. Ang II-induced cardiac hypertrophy may be alleviated through regulation of autophagy. This review focuses on Ang II to highlight the molecular targets and pathways identified in the prevention and treatment of Ang II-induced pathological cardiac hypertrophy by regulating autophagy.

The hypoxia-related signaling pathways of vasculogenic mimicry in tumor treatment.

Tumors require a blood supply for survival, growth, and metastasis. It is widely accepted that the development of the tumor microcirculation compartment need the production of new blood vessels (angiogenesis). Vasculogenic mimicry (VM) is an alternative type of blood supplement independent of endothelial vessels which refers to the formation of tumor cell-lined vessels and is associated with tumor invasion, metastasis and poor cancer patient prognosis. Although a variety of proteins and microenvironmental factors are known to contribute to VM, the mechanisms underlying its formation remain unclear. The induction of VM seems to be related to hypoxia, which may promote the plastic, transendothelial phenotype of tumor cells capable of VM. Here, with regard to the above aspects, we review the advanced research on VM including molecular mechanisms and its clinical significance; and explore the development of VM-related strategies which are being utilized for anticancer treatment.

Protection of Luteolin-7-O-Glucoside Against Doxorubicin-Induced Injury Through PTEN/Akt and ERK Pathway in H9c2 Cells.

Luteolin-7-O-glucoside (LUTG) was isolated from the plants of Dracocephalum tanguticum Maxim. Previous research has showed that LUTG pretreatment had a significant protective effect against doxorubicin (DOX)-induced cardiotoxicity by reducing intracellular calcium overload and leakage of creatine kinase and lactate dehydrogenase. But the underlying mechanisms have not been completely elucidated. In the present study, we investigated the effects of LUTG on H9c2 cell morphology, viability, apoptosis, reactive oxygen species generation, and the mitochondrial transmembrane potentials. The expression of p-PTEN, p-Akt, p-ERK, p-mTOR, and p-GSK-3ß were detected by Western blotting. Compared with DOX alone treatment group, the morphological injury and apoptosis of the cells in groups treated by DOX plus LUTG were alleviated, cell viability was increased, ROS generation was lowered remarkably, and mitochondrial depolarization was mitigated. In DOX group, the expression of p-PTEN was lower than normal group and the expression of p-Akt and p-ERK was higher than normal group. In the groups treated with LUTG (20 µM), the expression of p-PTEN was upregulated and the expression of p-Akt, p-ERK, p-mTOR, and p-GSK-3ß was downregulated. These results indicated that the protective effects of LUTG against DOX-induced cardiotoxicity may be related to anti-apoptosis through PTEN/Akt and ERK pathway.

Downregulation of the CXCR4/CXCL12 axis blocks the activation of the Wnt/ß-catenin pathway in human colon cancer cells.

Chemokine CXCL12 is an extracellular chemokine, which binds to its cell surface receptor CXCR4. High expressions of CXCR4 and CXCL12 are associated with biological malignant potential in colon cancers. We aimed to investigate the roles of the CXCR4/CXCL12 axis in activation of the Wnt/ß-catenin pathway in the development of colon cancers. Using colon cancer cell line, we performed the RNA interference assay to downregulate the expression of CXCR4. Cells were exposed to CXCL12 and their growth and metastatic activity were examined. Matrix metalloproteinases (MMPs) activity were analyzed by the gelatin zymography assay. Cell migration ability was estimated by assays of scratch wound and transwell chamber. The expression of CXCR4 and molecules relevant to the Wnt/ß-catenin pathway were analyzed by the western blotting and real-time PCR assays. Human colon cancer HT-29 cells identified high expression of CXCR4. HT-29 cells highly responded to CXCL12 stimulation, showing the increase of cell proliferation, invasion and migration through the Matrigeal. The secretion and activity of MMP-2 and MMP-9 were also stimulated in HT-29 cells exposure to CXCL12. However, the CXCR4 knockdown HT-29 cells did not response to CXCL12 stimulation. We suggested that the activation of the CXCR4/CXCL12 axis be blocked in the CXCR4 knockdown cells. This study indicated that one key to the role of the CXCR4/CXCL12 axis is activation of the Wnt/ß-catenin pathway. Downregulation of the CXCR4/CXCL12 axis thus reduces cancer growth and metastasis. Targeted therapy utilizing the CXCR4/CXCL12 axis could be an effective strategy for treatment of colon cancers.

Synthesis and evaluation of trehalose-based compounds as novel inhibitors of cancer cell migration and invasion.

As a continuous research for the discovery of trehalose-based anti-invasive agents, we developed a convenient synthetic approach for the preparation of 6,6'-dideoxy-6,6'-bis(acylamino)-α,α-D-trehaloses. A series of trehalose-based amides were prepared through the trityl protection of the two primary hydroxyls of α,α-D-trehalose, benzoylation, the removal of the trityl protective group, mesylation, azidation, catalytic hydrogenation in the presence of hydrochloride, coupling reaction with a variety of acids, and subsequent debenzoylation and deacetylation in some cases. Compound 8b, 6,6'-dideoxy-6,6'-bis(2-hydroxybenzamide)-α,α-D-trehalose, was just as potent as the natural brartemicin against the invasion of murine colon 26-L5 cells. It exhibited no cytotoxicity on human breast adenocarcinoma MDA-MB-231 and murine colon 26-L5 cells. It can significantly inhibit the migration and invasion of the MDA-MB-231 cells. The anti-invasive effect of 8b was possibly related to its inhibitory activity on MMP-9, its suppression on the expression of MMP-9 and VEGF, and its deactivation of Akt.