The association between S100A13 and HMGA1 in the modulation of thyroid cancer proliferation and invasion.

BACKGROUND: S100A13 and high mobility group A (HMGA1) are known to play essential roles in the carcinogenesis and progression of cancer. However, the correlation between S100A13 and HMGA1 during cancer progression is not yet well understood. In this study, we determined the effects of S100A13 on HMGA1 expression in thyroid cancer cells and examined the role of HMGA1 in thyroid cancer progression. METHODS: Stable ectopic S100A13 expression TT cellular proliferation was evaluated by nude mice xenografts assays. The effect of lentivirus-mediated S100A13 knockdown on thyroid cancer cellular oncogenic properties were evaluated by MTT, colony formation assays and transwell assays in TPC1 and SW579 cells. The effect of siRNA-mediated HMGA1 knockdown on thyroid cancer cellular proliferation and invasion were evaluated by MTT, colony formation assays and transwell assays. The tissue microarray was performed to investigate the correlation between S100A13 and HMGA1 expression in tumor tissues. RESULTS: The ectopic expression of S100A13 could increase tumor growth in a TT cell xenograft mouse model. Moreover, lentivirus-mediated S100A13 knockdown led to the inhibition of cellular oncogenic properties in thyroid cancer cells, and HMGA1 was found to be involved in the effect of S100A13 on thyroid cancer growth and invasion. Furthermore, siRNA-mediated HMGA1 knockdown was proved to inhibit the growth of TPC1 cells and invasive abilities of SW579 cells. Clinically, it was revealed that both S100A13 and HMGA1 showed a higher expression levels in thyroid cancer cases compared with those in matched normal thyroid cases (P = 0.007 and P = 0.000); S100A13 and HMGA1 expressions were identified to be positively correlated (P = 0.004, R = 0.316) when analyzed regardless of thyroid cancer types. CONCLUSIONS: This is the first report for the association between HMGA1 and S100A13 expression in the modulation of thyroid cancer growth and invasion. Those results would provide an essential insight into the effect of S100A13 on carcinogenesis of thyroid tumor, rending S100A13 to be potential biological marker for the diagnosis of thyroid cancer.

Cellular models for mitochondrial DNA-based diseases: lymphoblastoid cell lines and transmitochondrial cybrids.

Mitochondrial DNA (mtDNA) mutations cause a variety of mitochondrial DNA-based diseases which have been studied using Lymphoblastoid cell lines (LCLs) and transmitochondrial cybrids. Individual genetic information is preserved permanently in LCLs while the development of transmitochondrial cybrids provide ex-vivo cellular platform to study molecular mechanism of mitochondrial DNA-based diseases. The cytoplasmic donor cells for previous transmitochondrial cybrids come from patient's tissue or platelet directly. Here, we depicted in details the principle, methods and techniques to establish LCLs from frozen peripheral bloods harboring mitochondrial 4401G > A mutation by infection of Epstein Barr virus, and then to generate cybrids using ρ0 206 and LCLs. The process of establishing these two cellular models was summarized into four steps as follows: (1) Generation of LCLs; (2) Transformation; (3) Selection; (4) Verification. To faithfully represent the function of mtDNA mutation, we analyzed and identified the sites of mtDNA mutations and copy numbers of each cellular models as well as the karyotype of transmitochondrial cybrids. Those clones with consistent parameters were selected for preservation and future analysis of the function of point mutations of mtDNA. Although these two cellular models play important roles in understanding molecular mechanism of mitochondrial DNA-based diseases on the cellular level, their limitations should be considered when elucidating the character of tissue specificity of mitochondrial DNA-based diseases.

[Evaluation and cumulative characteristics of heavy metals in soil-Uncaria rhynchophylla system of different functional areas].

Soil and Uncaria rhynchophylla in different functional areas were selected for the study,the content of heavy metals such as As, Cd, Cu, Cr, Pb, and Hg in soil and U. rhynchophylla was discussed, the characteristics of their accumulation in the U.rhynchophylla was analyzed, the contamination levels of heavy metals in soil in different functional areas was evaluated. The results showed that content of Cu, As, Pb and Cr in soil was being cropland>woodland>wasteland, content of Cd was being woodland>cropland>wasteland, content of Hg was being cropland>woodland>wasteland. According to quality standard of soil environment, soil Cd in woodland, cropland and wasteland all exceeded the state-level standards, soil Cd in woodland exceeded the secondary standard, soil Hg in cropland and wasteland all exceeded the state-level standards. According to technical conditions of green food producing area, soil Cd in woodland exceeded the limit value of standard. According to Green Trade Standards of Importing Exporting Medicinal Plants Preparations,the content of heavy metals of U.rhynchophylla in cropland,woodland and wasteland were correspond to the specification. From the single factor pollution index, the soil in woodland was polluted by Cd. From the comprehensive pollution index, the soils in different functional areas were not contaminated by heavy metals. The enrichment coefficient of heavy metals such as As, Cu, Cr, and Pb in hook of U.rhynchophylla was being wasteland>woodland>cropland, the enrichment coefficient of Cu in hook of U. rhynchophylla in wasteland was more than 1. Except Cu, the enrichment coefficient of other heavy metals was low.

Oxidized low-density lipoprotein attenuated desmoglein 1 and desmocollin 2 expression via LOX-1/Ca(2+)/PKC-ß signal in human umbilical vein endothelial cells.

Numerous studies have reported the presence of oxidized LDL (ox-LDL) and expression of its lectin-like receptor, LOX-1, have been shown in atherosclerotic regions. The present study aims to investigate the effects of ox-LDL on expression of desmoglein 1 (DSG1) and desmocollin 2 (DSC2) in endothelial cells, and to explore the role of LOX-1 mediated signal in the permeability injury associated with DSG1 and DSC2 disruption induced by oxidized lipoprotein. RT-PCR and Western blotting were applied to determine the mRNA and protein expression levels of DSG1 and DSC2 in human umbilical vein endothelial cells (HUVECs) respectively. Immunoreactivities of DSG1 and DSC2 were detected by laser scanning confocal microscope (LSCM). HUVEC monolayers permeability was evaluated by FITC-labeled LDL in transwell assay system. The possible signal was assessed using in vitro blocking LOX-1 or Ca(2+) channel or PKC. The DSG1 and DSC2 expression were decreased by ox-LDL in concentration- and time-dependent manner. The effects of ox-LDL were mediated by its endothelial receptor, LOX-1. In parallel experiments, ox-LDL increased the influx of extracellular calcium, activation of protein kinase C (PKC) and permeability to LDL, which was inhibited by the LOX-1blocking antibody (10 µg/ml), Ca(2+) channel blocker (Diltiazem, 50 µmol/L) and PKC-ß inhibitor (hispidin, 4 µmol/L). These results suggested that ox-LDL-induced decrease in DSG1 and DSC2 expression and monolayer barrier injury via calcium uptake and PKC-ß activation following up-regulation of LOX-1 is one of the mechanisms of inducing greater permeability in HUVECs.

[Determination of Six Ingredients in Gardenia jaminoides Fruits with Quantitative Analysis of Muti-components by Single Marker].

OBJECTIVE: To establish a method of quantitative analysis of multi-components, by single marker(QAMS)for simultaneously determining six ingredients in Gardenia jasminoides fruits. METHODS: A multi-wavelength segmentation detection method was used. A methodological mode was found to analysis six ingredients in Gardenia jasminoides fruits by quantitative analysis of QAMS. Taken geniposide as reference to create RCF with gardenia acid, chlorogenic acid, crocin I, crocin II and crocin III. RESULTS: The good reproducibility and acceptable durability of method was validated between two HPLC systems and three columns. 20 batches of Gardenia jaminoides fruits was analysis, and the results showed good linear correlation compared to external standard method (r > 0. 999). CONCLUSION: QAMS can be used as quality evaluation method of multi-component Gardenia jaminoides fruits.

Veno-arterial extracorporeal membrane oxygenation for the treatment of obstructive shock caused by venous air embolism: A case report.

BACKGROUND: Venous air embolism (VAE) is a potentially lethal condition, with a reported incidence rate of about 0.13%, and the true incidence may be higher since many VAE are asymptomatic. The current treatments for VAE include Durant's maneuver, aspiration and removal of air through venous catheters, and hyperbaric oxygen therapy. For critically ill patients, use of cardiotonic drugs and chest compressions remain useful strategies. The wider availability of extracorporeal membrane oxygenation (ECMO) has brought a new option for VAE patients. CASE SUMMARY: A 53-year-old female patient with VAE presented to the emergency clinic due to abdominal pain with fever for 1 d and unconsciousness for 2 h. One day ago, the patient suffered from abdominal pain, fever, and diarrhea. She suddenly became unconscious after going to the toilet during the intravenous infusion of ciprofloxacin 2 h ago, accompanied by nausea and vomiting, during which a small amount of gastric contents were discharged. She was immediately sent to a local hospital, where cranial and chest computed tomography showed bilateral pneumonia as well as accumulated air visible in the right ventricle and pulmonary artery. The condition deteriorated despite endotracheal intubation, rehydration, and other treatments, and the patient was then transferred to our hospital. Veno-arterial ECMO was applied in our hospital, and the patient's condition gradually improved. The patient was successfully weaned from ECMO and extubated after two days. CONCLUSION: ECMO may be an important treatment for patients with VAE in critical condition.

An involvement of SR-B1 mediated PI3K-Akt-eNOS signaling in HDL-induced cyclooxygenase 2 expression and prostacyclin production in endothelial cells.

It is well-known that sphingosine-1-phosphate (S1P), the phospholipid content of HDL, binding to S1P receptors can raise COX-2 expression and PGI(2) release through p38MAPK/CREB pathway. In the present study we assess the action of SR-B1 initiated PI3K-Akt-eNOS signaling in the regulation of COX-2 expression and PGI(2) production in response to HDL. We found that apoA1 could increase PGI(2) release and COX-2 expression in ECV 304 endothelial cells. Furthermore, SR-B1 was found to be involved in HDL induced up-regulation of COX-2 and PGI(2). Over-expressed SR-B1 did not significantly increase the expression of COX-2 and the PGI(2) levels, but knock-down of SR-B1 by siRNA could significantly attenuate COX-2 expression and PGI(2) release together with p38MAPK and CREB phosphorylation. Consistently, the declines of p-p38MAPK, p-CREB, COX-2 and PGI(2) were also observed after incubation with LY294002 (25µmol/L; PI3K special inhibitor) or L-NAME (50µmol/L; eNOS special inhibitor). In addition, we demonstrated the increases of PGI(2) release, COX-2 expression and p38MAPK phosphorylation, when nitric oxide level was raised through the incubation of L-arginine (10 or 20nmol/L) in endothelial cells. Taking together, our data support that SR-B1 mediated PI3K-Akt-eNOS signaling was involved in HDL-induced COX-2 expression and PGI(2) release in endothelial cells.

Regulation of metabolism and transport of sphingosine-1-phosphate in mammalian cells.

Sphingosine-1-phosphate (S1P), which is generated from the sphingosine kinase-catalyzed phosphorylation of sphingosine, is now recognized as a critical regulator of many kinds of physiological and pathological processes, including cancer, cardiovascular function, and diabetes. It can also trigger a wide variety of biological effect, such as cell movement, differentiation, survival, inflammation, immunity, calcium homeostasis, and angiogenesis. As we know, a number of the biological effects of S1P are mediated by its binding to five specific G protein-coupled receptors located on the cell surface or intracellular targets. However, the synthesis and the secretion of S1P are regulated by various endogenetic or ectogenous stimuli and involve many kinds of enzymes and transporters. In this review, we discuss the regulation of S1P synthesis by many kinds of enzymes and mainly introduce the process of ceramide to S1P. Moreover, S1P deterioration is important balance in physiologic adjustment. We also describe the role of verified or potential transporters in S1P release in detail.

Knowledge of stroke warning signs and risk factors among patients with previous stroke or TIA in China.

AIMS AND OBJECTIVES: The purpose of this study was to describe knowledge about stroke warning signs and risk factors in patients with previous stroke or transient ischaemic attacks in China and to investigate the relationship between socio-demographic characteristics & health status and patients' knowledge about stroke. BACKGROUND: Stroke is the leading cause of death and functional impairment in China. Survivors are at high risk of new vascular events. Secondary prevention after stroke or transient ischaemic attacks is not satisfactory. Previous research suggests that awareness of stroke plays an important role in facilitating secondary prevention. However, little is known about knowledge of stroke warning signs and risk factors among patients with previous stroke/transient ischaemic attacks. DESIGN: A cross-sectional questionnaire study. METHODS: This study was conducted in Hunan Province, China, between July and December in 2010. Subjects were recruited using a cluster sampling method. A questionnaire was administered to 1600 patients with stroke/transient ischaemic attacks diagnose from eight hospitals, and 1200 patients (75%) responded. Patients' knowledge about stroke warning signs and risk factors were collected and analysed. Results. Patients' knowledge about stroke warning signs was very poor (only 3.3% identified all warning signs and 28.3% identified three). Patients' knowledge about important risk factors (e.g. atrial fibrillation, diabetes, metabolic syndrome, etc.) was also very poor (<30%). Patients' action in emergency was extremely poor (only 9.2% reported to call emergency service). The age, education, stroke-related diagnoses and family history of cardiovascular disease were significantly associated with patients' knowledge about stroke. CONCLUSIONS: Knowledge about stroke warning signs and risk factors was very poor in patients with previous stroke or transient ischaemic attacks in China. RELEVANCE TO CLINICAL PRACTICE: Dissemination of stroke knowledge should be a core responsibility for Chinese clinical nurse. Future clinical education to improve patient's knowledge about stroke and further intervention to manage cardiovascular risk factors are indicated.

Physarum polycephalum macroplasmodium exhibits countermeasures against TiO2 nanoparticle toxicity: A physiological, biochemical, transcriptional, and metabolic perspective.

Concerns about the environmental and human health implications of TiO2 nanoparticles (nTiO2) are growing with their increased use in consumer and industrial products. Investigations of the underlying molecular mechanisms of nTiO2 tolerance in organisms will assist in countering nTiO2 toxicity. In this study, the countermeasures exhibited by the slime mold Physarum polycephalum macroplasmodium against nTiO2 toxicity were investigated from a physiological, transcriptional, and metabolic perspective. The results suggested that the countermeasures against nTiO2 exposure include gene-associated metabolic rearrangements in cellular pathways involved in amino acid, carbohydrate, and nucleic acid metabolism. Gene-associated nonmetabolic rearrangements involve processes such as DNA repair, DNA replication, and the cell cycle, and occur mainly when macroplasmodia are exposed to inhibitory doses of nTiO2. Interestingly, the growth of macroplasmodia and mammal cells was significantly restored by supplementation with a combination of responsive metabolites identified by metabolome analysis. Taken together, we report a novel model organism for the study of nTiO2 tolerance and provide insights into countermeasures taken by macroplasmodia in response to nTiO2 toxicity. Furthermore, we also present an approach to mitigate the effects of nTiO2 toxicity in cells by metabolic intervention.

MicroRNA-24 aggravates atherosclerosis by inhibiting selective lipid uptake from HDL cholesterol via the post-transcriptional repression of scavenger receptor class B type I.

BACKGROUND AND AIMS: Liver scavenger receptor class B type I (SR-BI) exerts atheroprotective effects through selective lipid uptake (SLU) from high-density lipoprotein cholesterol (HDL-C). Low hepatic SR-BI expression leads to high HDL-C levels in the circulation and an increased risk of atherosclerosis. Furthermore, macrophage SR-BI mediates bidirectional cholesterol flux and may protect against atherogenesis. Previous studies have revealed that miR-24 is closely related to cardiovascular disease (CVD) progression. We aimed to investigate the molecular mechanisms by which miR-24 participates in SR-BI-mediated selective HDL cholesteryl ester (HDL-CE) uptake and further atherogenesis in apoE-/- mice. METHODS: Bioinformatic predictions and luciferase reporter assays were utilized to detect the association between miR-24 and the SR-BI 3' untranslated region (3' UTR), and RT-PCR and western blotting were used to evaluate SR-BI mRNA and protein expression, respectively. The effects of miR-24 on Dil-HDL uptake were determined by flow cytometry assay. Double-radiolabeled HDL (125I-TC-/[3H] CEt-HDL) was utilized to measure the effects of miR-24 on HDL and CE binding and SLU in HepG2 and PMA-treated THP-1 cells. In addition, total cholesterol (TC) levels in HepG2 cells were analyzed using enzymatic methods, and macrophage lipid content was evaluated by high-performance liquid chromatography (HPLC) assay. Small interfering RNA (siRNA) and pcDNA3.1(-)-hSR-BI plasmid transfection procedures were utilized to confirm the role of SR-BI in the effects of miR-24 on Dil-HDL uptake, SLU and cholesterol levels in both cell types. Hepatic SR-BI level in apoE-/- mice was measured by western blotting. Liver TC, FC and CE levels and plasma triglycerides (TG), TC and HDL-C levels were evaluated enzymatically using commercial test kits. Atherosclerotic lesion sizes were measured using Oil Red O and hematoxylin-eosin staining. RESULTS: miR-24 directly repressed SR-BI expression by targeting its 3'UTR. In addition, miR-24 decreased Dil-HDL uptake and SLU in HepG2 and THP-1 macrophages. In the presence of HDL, miR-24 decreased TC levels in HepG2 cells and TC, free cholesterol (FC) and CE levels in macrophages. Overexpression and down-regulation assays showed that SR-BI mediated the effects of miR-24 on Dil-HDL uptake, SLU and cholesterol levels. Lastly, miR-24 administration decreased hepatic SR-BI expression and promoted atheromatous plaque formation in apoE-/- mice, findings in line with those of our in vitro studies. CONCLUSIONS: These findings indicate that miR-24 accelerates atherogenesis by repressing SR-BI-mediated SLU from HDL-C.

PRMT2ß, a C-terminal splice variant of PRMT2, inhibits the growth of breast cancer cells.

Our previous study reported several alternative splicing variants of arginine N-methyltransferase 2 (PRMT2), which lose different exons in the C-terminals of the wild-type PRMT2 gene. Particularly, due to frame-shifting, PRMT2ß encodes a novel amino acid sequence at the C-terminus of the protein, the function of which is not understood. In the present study, we determined the role of PRMT2ß in breast cancer cell proliferation, apoptosis and its effect on the Akt signaling pathway. Stable breast cancer MCF7 cell line with lentivirus-mediated PRMT2ß overexpression was obtained after selection by puromycin for 2 weeks. The effect of lentivirus-mediated PRMT2ß overexpression on breast cancer cellular oncogenic properties was evaluated by MTT, colony formation, cell cycle analysis and apoptosis assays in MCF7 cells. Luciferase activity assay and western blot analysis were performed to characterize the effects of PRMT2ß on cyclin D1 promoter activities and the Akt signaling pathway. Tissue microarray was performed to investigate the association of PRMT2ß with breast cancer progression. Lentivirus-mediated PRMT2ß overexpression suppressed the cell proliferation and colony formation of breast cancer MCF7 cells. PRMT2ß overexpression induced cell cycle arrest and apoptosis of MCF7 cells. Furthermore, PRMT2ß was revealed to suppress the transcription activity of the cyclin D1 promoter, and PRMT2ß was also found to inhibit cyclin D1 expression via the suppression of Akt/GSK-3ß signaling in breast cancer cells. Clinically, it was revealed that PRMT2ß expression was negatively correlated with human epidermal growth factor receptor 2 (HER2) (p=0.033) in breast tumors. Our results revealed that PRMT2ß, a novel splice variant of PRMT2, plays potential antitumor effect by suppressing cyclin D1 expression and inhibiting Akt signaling activity. This also opens a new avenue for treating breast cancer.

ApoA-I/SR-BI modulates S1P/S1PR2-mediated inflammation through the PI3K/Akt signaling pathway in HUVECs.

Endothelial dysfunction plays a vital role during the initial stage of atherosclerosis. Oxidized low-density lipoprotein (ox-LDL) induces vascular endothelial injury and vessel wall inflammation. Sphingosine-1-phosphate (S1P) exerts numerous vasoprotective effects by binding to diverse S1P receptors (S1PRs; S1PR1-5). A number of studies have shown that in endothelial cells (ECs), S1PR2 acts as a pro-atherosclerotic mediator by stimulating vessel wall inflammation through the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. Scavenger receptor class B member I (SR-BI), a high-affinity receptor for apolipoprotein A-I (apoA-I)/high-density lipoprotein (HDL), inhibits nuclear factor-κB (NF-κB) translocation and decreases the plasma levels of inflammatory mediators via the PI3K/Akt pathway. We hypothesized that the inflammatory effects of S1P/S1PR2 on ECs may be regulated by apoA-I/SR-BI. The results showed that ox-LDL, a pro-inflammatory factor, augmented the S1PR2 level in human umbilical vein endothelial cells (HUVECs) in a dose- and time-dependent manner. In addition, S1P/S1PR2 signaling influenced the levels of inflammatory factors, including tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and IL-10, aggravating inflammation in HUVECs. Moreover, the pro-inflammatory effects induced by S1P/S1PR2 were attenuated by SR-BI overexpression and enhanced by an SR-BI inhibitor, BLT-1. Further experiments showed that the PI3K/Akt signaling pathway was involved in this process. Taken together, these results demonstrate that apoA-I/SR-BI negatively regulates S1P/S1PR2-mediated inflammation in HUVECs by activating the PI3K/Akt signaling pathway.

TGF-ß1 induces HMGA1 expression: The role of HMGA1 in thyroid cancer proliferation and invasion.

The role of transforming growth factor-ß1 (TGF-ß1) is complicated and plays a different role in the development of cancer. High mobility group A (HMGA1) participates in multiple cellular biology processes, and exerts important roles in the epithelial-mesenchymal transition (EMT). However, the correlation of TGF-ß1 and HMGA1 in cancer cells is not yet fully understood. In this study, we determined the effects of TGF-ß1 on HMGA1 expression in thyroid cancer cells and examined the role of HMGA1 in thyroid cancer progression. With real-time PCR and immunofluorescence staining, our study demonstrated that TGF-ß1 induced the expression of HMGA1 through phosphoinositide 3-kinase (PI3K) and the extracellular signal-related kinase (ERK) signaling in thyroid cancer cells. With luciferase reported assay, the HMGA1 promoter activity was activated by TGF-ß1 in the SW579 cells. Furthermore, lentivirus-mediated HMGA1 knockdown inhibits cellular oncogenic properties of thyroid cancer cells. Clinically, tissue microarray revealed that HMGA1 was expressed in thyroid carcinoma more than that in normal thyroid tissues (P<0.001); expression of HMGA1 and MMP-2 was identified to be positively correlated (P=0.017). The present study established the first link between HMGA1 and TGF-ß1 in the regulation of thyroid cancer proliferation and invasion, and provided evidence for the pivotal role of HMGA1 in the progression of thyroid cancer, indicating HMGA1 to be potential biological marker for the diagnosis of thyroid cancer.

TGF-ß Down-regulates Apolipoprotein M Expression through the TAK-1-JNK-c-Jun Pathway in HepG2 Cells.

Apolipoprotein M (apoM) is a relatively novel apolipoprotein that plays pivotal roles in many dyslipidemia-associated diseases; however, its regulatory mechanisms are poorly understood. Many cytokines have been identified that down-regulate apoM expression in HepG2 cells, among which transforming growth factor-ß (TGF-ß) exerts the most potent effects. In addition, c-Jun, a member of the activated protein 1 (AP-1) family whose activity is modulated by c-Jun N-terminal kinase (JNK), decreases apoM expression at the transcriptional level by binding to the regulatory element in the proximal apoM promoter. In this study, we investigated the molecular mechanisms through which TGF-ß decreases the apoM level in HepG2 cells. The results revealed that TGF-ß inhibited apoM expression at both the mRNA and protein levels in a dose- and time-dependent manner and that it suppressed apoM secretion. These effects were attenuated by treatment of cells with either SP600125 (JNK inhibitor) or c-Jun siRNA. 5Z-7-oxozeaenol [(a TGF-ß-activated kinase 1 (TAK-1) inhibitor)] also attenuated the TGF-ß-mediated inhibition of apoM expression and suppressed the activation of JNK and c-Jun. These results have demonstrated that TGF-ß suppresses apoM expression through the TAK-1-JNK-c-Jun pathway in HepG2 cells.

ApoA-I induces S1P release from endothelial cells through ABCA1 and SR-BI in a positive feedback manner.

Sphingosine-1-phosphate (S1P), which has emerged as a pivotal signaling mediator that participates in the regulation of multiple cellular processes, is derived from various cells, including vascular endothelial cells. S1P accumulates in lipoproteins, especially HDL, and the majority of free plasma S1P is bound to HDL. We hypothesized that HDL-associated S1P is released through mechanisms associated with the HDL maturation process. ApoA-I, a major HDL apolipoprotein, is a critical factor for nascent HDL formation and lipid trafficking via ABCA1. Moreover, apoA-I is capable of promoting bidirectional lipid movement through SR-BI. In the present study, we confirmed that apoA-I can facilitate the production and release of S1P by HUVECs. Furthermore, we demonstrated that ERK1/2 and SphK activation induced by apoA-I is involved in the release of S1P from HUVECs. Inhibitor and siRNA experiments showed that ABCA1 and SR-BI are required for S1P release and ERK1/2 phosphorylation induced by apoA-I. However, the effects triggered by apoA-I were not suppressed by inhibiting ABCA1/JAK2 or the SR-BI/Src pathway. S1P released due to apoA-I activation can stimulate the (ERK1/2)/SphK1 pathway through S1PR (S1P receptor) 1/3. These results indicated that apoA-I not only promotes S1P release through ABCA1 and SR-BI but also indirectly activates the (ERK1/2)/SphK1 pathway by releasing S1P to trigger their receptors. In conclusion, we suggest that release of S1P induced by apoA-I from endothelial cells through ABCA1 and SR-BI is a self-positive-feedback process: apoA-I-(ABCA1 and SR-BI)-(S1P release)-S1PR-ERK1/2-SphK1-(S1P production)-(more S1P release induced by apoA-I).

Involvement of the IRE1α-XBP1 pathway and XBP1s-dependent transcriptional reprogramming in metabolic diseases.

The X-box binding protein 1 (XBP1) is not only an important component of the unfolded protein response (UPR), but also an important nuclear transcription factor. Upon endoplasmic reticulum stress, XBP1 is spliced by inositol-requiring enzyme 1 (IRE1), thereby generating functional spliced XBP1 (XBP1s). XBP1s functions by translocating into the nucleus to initiate transcriptional programs that regulate a subset of UPR- and non-UPR-associated genes involved in the pathophysiological processes of various diseases. Recent reports have implicated XBP1 in metabolic diseases. This review summarizes the effects of XBP1-mediated regulation on lipid metabolism, glucose metabolism, obesity, and atherosclerosis. Additionally, for the first time, we present XBP1s-dependent transcriptional reprogramming in metabolic diseases under different conditions, including pathology and physiology. Understanding the function of XBP1 in metabolic diseases may provide a basic knowledge for the development of novel therapeutic targets for ameliorating these diseases.

HDL drug carriers for targeted therapy.

Plasma concentrations of high-density lipoprotein cholesterol (HDL-C) are strongly and inversely associated with cardiovascular risk. HDL is not a simple lipid transporter, but possesses multiple anti-atherosclerosis activities because it contains special proteins, signaling lipid, and microRNAs. Natural or recombinant HDLs have emerged as potential carriers for delivering a drug to a specified target. However, HDL function also depends on enzymes that alter its structure and composition, as well as cellular receptors and membrane micro-domains that facilitate interactions with the microenvironment. In this review, four mechanisms predicted to enhance functions or targeted therapy of HDL in vivo are discussed. The first involves caveolae-mediated recruitment of HDL signal to bind their receptors. The second involves scavenger receptor class B type I (SR-BI) mediating anchoring and fluidity for signal-lipid of HDL. The third involves lecithin-cholesterol acyltransferase (LCAT) concentrating the signaling lipid at the surface of the HDL particle. The fourth involves microRNAs (miRNAs) being delivered in the blood to special targets by HDL. Exploitation of these four mechanisms will promote HDL to carry targeted drugs and increase HDL's clinical value.

[Accumulation, distribution and pollution assessment of heavy metals in surface sediment of Caohai plateau wetland, Guizhou province].

The objective of this paper is to investigate the concentrations and distribution characteristics of heavy metals in surface sediments of different areas in the Caohai plateau wetland. 16 samples of surface sediments were collected and 7 heavy metals were analyzed. Heavy metal pollution in surface sediments of different areas in the Caohai plateau wetland was estimated by the Tomlinson Pollution Load Index (PLI) method. The analyzed results indicated that the average contents of Cd, Hg, As, Pb, Cr, Cu, Zn were 0.985, 0.345, 15.8, 38.9, 38.6, 22.8 and 384 mg x kg(-1), respectively. The heavy metal distributions varied with regional environment changes, the order of average contents of Cd and Hg in different regions was E (the eastern region) > S (the southern region) > N (the northern region), the order of the average content of Pb was N > E > S, and that of Zn was S > E > N. The results also suggested a medium heavy metal pollution level in the surface sediment of the Caohai plateau wetland with the PLI(zone) reaching 1.17. The order of pollution level in surface sediments of different regions was E > S > N. The results showed medium pollution levels in E and Hg which reached the extreme intensity pollution level were also the major polluted elements in surface sediments of the Caohai plateau wetland. And also, results showed medium pollution levels of Cd and Pb in surface sediments of Caohai plateau wetland. Cluster analysis results showed similar pollution sources of Cd, Zn, Pb and Hg, which should be attached great importance in terms of the prevention of the Caohai plateau wetland.

Drosophila miR-5 suppresses Hedgehog signaling by directly targeting Smoothened.

Hedgehog (Hh) signaling plays many important roles in developmental processes and cancers. Smoothened (Smo) is an important signal transducer in the Hh pathway, and its expression is tightly regulated by several different post-transcriptional mechanisms. However, whether microRNAs (miRNAs) are involved in Smo regulation is still unclear. Here, we found that miR-5 acts as a suppressor of the Hh pathway by targeting Smo. Through in vivo sensor assay and in vitro luciferase assay, we found that miR-5 downregulates Smo through directly binding to its 3'UTR. Moreover, our data indicated Costal-2 (Cos2) and Fused (Fu) do not play a role in the reduction of Smo mediated by miR-5. Furthermore, we determined that miR-5 not involved in Notch or Dpp signaling pathways by detecting target gene expression. Together, our results indicate that miR-5 can specifically suppress Hh signaling by directly targeting Smo in Drosophila.