Absolute Quantification of Dynamic Cellular Uptake of Small Extracellular Vesicles via Lanthanide Element Labeling and ICP-MS.

Small extracellular vesicles (sEVs) are increasingly reported to play important roles in numerous physiological and pathological processes. Cellular uptake of sEVs is of great significance for functional regulation in recipient cells. Although various sEV quantification, labeling, and tracking methods have been reported, it is still highly challenging to quantify the absolute amount of cellular uptake of sEVs and correlate this information with phenotypic variations in the recipient cell. Therefore, we developed a novel strategy using lanthanide element labeling and inductively coupled plasma-mass spectrometry (ICP-MS) for the absolute and sensitive quantification of sEVs. This strategy utilizes the chelation interaction between Eu3+ and the phosphate groups on the sEV membrane for specific labeling. sEVs internalized by cells can then be quantified by ICP-MS using a previously established linear relationship between the europium content and the particle numbers. High Eu labeling efficiency and stability were demonstrated by various evaluations, and no structural or functional alterations in the sEVs were discovered after Eu labeling. Application of this method revealed that 4020 ± 171 sEV particles/cell were internalized by HeLa cells at 37 °C and 61% uptake inhibition at 4 °C. Further investigation led to the quantitative differential analysis of sEV cellular uptake under the treatment of several chemical endocytosis inhibitors. A 23% strong inhibition indicated that HeLa cells uptake sEVs mainly through the macropinocytosis pathway. This facile labeling and absolute quantification strategy of sEVs with ppb-level high sensitivity is expected to become a potential tool for studying the functions of sEVs in intracellular communication and cargo transportation.

Deacylated Derivative of Hericenone C Treated by Lipase Shows Enhanced Neuroprotective Properties Compared to Its Parent Compound.

Hericium erinaceus, a mushroom species commonly known as Yamabushitake in Japan, is known to have a stimulatory effect on neurotrophic factors, such as brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF). Hericenone C, a meroterpenoid with palmitic acid as the fatty acid side chain, is reported to be one such stimulant. However, according to the structure of the compound, the fatty acid side chain seems highly susceptible to lipase decomposition, under in vivo metabolic conditions. To study this phenomenon, hericenone C from the ethanol extract of the fruiting body was subjected to lipase enzyme treatment and observed for changes in the chemical structure. The compound formed after the lipase enzyme digestion was isolated and identified using LC-QTOF-MS combined with 1H-NMR analysis. It was found to be a derivative of hericenone C without its fatty acid side chain and was named deacylhericenone. Interestingly, a comparative investigation of the neuroprotective properties of hericenone C and deacylhericenone showed that the BDNF mRNA expression in human astrocytoma cells (1321N1) and the protection against H2O2-induced oxidative stress was considerably higher in the case of deacylhericenone. These findings suggest that the stronger bioactive form of the hericenone C compound is in fact deacylhericenone.

Assessing the decision quality of artificial intelligence and oncologists of different experience in different regions in breast cancer treatment.

Background: AI-based clinical decision support system (CDSS) has important prospects in overcoming the current informational challenges that cancer diseases faced, promoting the homogeneous development of standardized treatment among different geographical regions, and reforming the medical model. However, there are still a lack of relevant indicators to comprehensively assess its decision-making quality and clinical impact, which greatly limits the development of its clinical research and clinical application. This study aims to develop and application an assessment system that can comprehensively assess the decision-making quality and clinical impacts of physicians and CDSS. Methods: Enrolled adjuvant treatment decision stage early breast cancer cases were randomly assigned to different decision-making physician panels (each panel consisted of three different seniority physicians in different grades hospitals), each physician made an independent "Initial Decision" and then reviewed the CDSS report online and made a "Final Decision". In addition, the CDSS and guideline expert groups independently review all cases and generate "CDSS Recommendations" and "Guideline Recommendations" respectively. Based on the design framework, a multi-level multi-indicator system including "Decision Concordance", "Calibrated Concordance", " Decision Concordance with High-level Physician", "Consensus Rate", "Decision Stability", "Guideline Conformity", and "Calibrated Conformity" were constructed. Results: 531 cases containing 2124 decision points were enrolled; 27 different seniority physicians from 10 different grades hospitals have generated 6372 decision opinions before and after referring to the "CDSS Recommendations" report respectively. Overall, the calibrated decision concordance was significantly higher for CDSS and provincial-senior physicians (80.9%) than other physicians. At the same time, CDSS has a higher " decision concordance with high-level physician" (76.3%-91.5%) than all physicians. The CDSS had significantly higher guideline conformity than all decision-making physicians and less internal variation, with an overall guideline conformity variance of 17.5% (97.5% vs. 80.0%), a standard deviation variance of 6.6% (1.3% vs. 7.9%), and a mean difference variance of 7.8% (1.5% vs. 9.3%). In addition, provincial-middle seniority physicians had the highest decision stability (54.5%). The overall consensus rate among physicians was 64.2%. Conclusions: There are significant internal variation in the standardization treatment level of different seniority physicians in different geographical regions in the adjuvant treatment of early breast cancer. CDSS has a higher standardization treatment level than all physicians and has the potential to provide immediate decision support to physicians and have a positive impact on standardizing physicians' treatment behaviors.

New benzaldehyde derivatives from the fruiting bodies of Hericium erinaceus with cytotoxic activity.

Four new natural compounds named hericenone O (1), hericenone P (2), hericenone Q (3), and hericenone R (4), two of them were reported synthetically (3-4), together with eleven known compounds were isolated from the fruiting bodies of Hericium erinaceus. The chemical structures of the isolated compounds were elucidated by using NMR analysis and mass spectrometry, as well as comparisons with the reported data in the literature. The bioactivity evaluation revealed that hericenone Q showed significant cytotoxic activity against Hep-G2 with IC50 values of 23.89 µM, and against HCT-116 with IC50 values of 65.64 µM.

Epigenetic regulator KDM4A activates Notch1-NICD-dependent signaling to drive tumorigenesis and metastasis in breast cancer.

BACKGROUND: Altered epigenetic reprogramming and events contribute to breast cancer (Bca) progression and metastasis. How the epigenetic histone demethylases modulate breast cancer progression remains poorly defined. We aimed to elucidate the biological roles of KDM4A in driving Notch1 activation and Bca progression. METHODS: The KDM4A expression in Bca specimens was analyzed using quantitative PCR and immunohistochemical assays. The biological roles of KDM4A were evaluated using wound-healing assays and an in vivo metastasis model. The Chromatin Immunoprecipitation (ChIP)-qPCR assay was used to determine the role of KDM4A in Notch1 regulation. RESULTS: Here, we screened that targeting KDM4A could induce notable cell growth suppression. KDM4A is required for the growth and progression of Bca cells. High KDM4A enhances tumor migration abilities and in vivo lung metastasis. Bioinformatic analysis suggested that KDM4A was highly expressed in tumors and high KDM4A correlates with poor survival outcomes. KDM4A activates Notch1 expressions via directly binding to the promoters and demethylating H3K9me3 modifications. KDM4A inhibition reduces expressions of a list of Notch1 downstream targets, and ectopic expressions of ICN1 could restore the corresponding levels. KDM4A relies on Notch1 signaling to maintain cell growth, migration and self-renewal capacities. Lastly, we divided a panel of cell lines into KDM4Ahigh and KDM4Alow groups. Targeting Notch1 using specific LY3039478 could efficiently suppress cell growth and colony formation abilities of KDM4Ahigh Bca. CONCLUSION: Taken together, KDM4A could drive Bca progression via triggering the activation of Notch1 pathway by decreasing H3K9me3 levels, highlighting a promising therapeutic target for Bca.

Long non-coding RNA RP11-283G6.5 confines breast cancer development through modulating miR-188-3p/TMED3/Wnt/ß-catenin signalling.

The contributions of long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) to breast cancer are critical areas of investigation. In this study, we identified a novel lncRNA RP11-283G6.5 which was lowly expressed in breast cancer and whose low expression was correlated with poor overall survival and disease-free survival of breast cancer patients. Functional experiments revealed that ectopic expression of RP11-283G6.5 confined breast cancer cellular growth, migration, and invasion, and promoted cellular apoptosis. Conversely, RP11-283G6.5 silencing facilitated breast cancer cellular growth, migration, and invasion, and repressed cellular apoptosis. Moreover, RP11-283G6.5 was found to confine breast cancer tumour growth and metastasis in vivo. Mechanistically, RP11-283G6.5 competitively bound to ILF3, reduced the binding of ILF3to primary miR-188 (pri-miR-188), abolished the suppressive effect of ILF3 on pri-miR-188 processing, and therefore promoted pri-miR-188 processing, leading to the reduction of pri-miR-188 and the upregulation of mature miR-188-3p. The expression of RP11-283G6.5 was significantly positively correlated with that of miR-188-3p in breast cancer tissues. Through increasing miR-188-3p, RP11-283G6.5 decreased TMED3, a target of miR-188-3p. RP11-283G6.5 further suppressed Wnt/ß-catenin signalling via decreasing TMED3. Rescue assays revealed that inhibition of miR-188-3p, overexpression of TMED3 or blocking Wnt/ß-catenin signalling all attenuated the roles of RP11-283G6.5 in breast cancer. Collectively, these findings demonstrated that RP11-283G6.5 is a tumour suppressive lncRNA in breast cancer via modulating miR-188-3p/TMED3/Wnt/ß-catenin signalling. This study indicated that RP11-283G6.5 might be a promising prognostic biomarker and therapeutic target for breast cancer.

Real-Time In Situ Navigation System With Indocyanine Green Fluorescence for Sentinel Lymph Node Biopsy in Patients With Breast Cancer.

BACKGROUND: The naked-eye invisibility of indocyanine green fluorescence limits the application of near-infrared fluorescence imaging (NIR) systems for real-time navigation during sentinel lymph node biopsy (SLNB) in patients with breast cancer undergoing surgery. This study aims to evaluate the effectiveness and safety of a novel NIR system in visualizing indocyanine green fluorescence images in the surgical field and the application value of combined methylene blue (MB) and the novel NIR system in SLNB. METHODS: Sixty patients with clinical node-negative breast cancer received indocyanine green (ICG) and MB as tracers. Two NIR system instruments, namely, lymphatic fluorescence imaging system (LFIS) designed by the University of Science and Technology of China and vascular imager by Langfang Mingde Medical Biotechnology Co., Ltd. (Langfang vascular imager), were used as navigation assistance to locate sentinel lymph nodes (SLNs). Excising the lymph nodes developed by both MB and ICG by two NIR systems or palpably suspicious as SLNs and undergoing rapid pathological examination. RESULTS: Both instruments exhibited 95% (57/60) success for real-time lymphatic fluorescent images. A total of 186 SLNs were identified, of which two were pathologically confirmed as lacking any lymph node tissue. SLN identification rate was 100% (184/184) for MB plus LFIS and 86.96% (160/184) for MB alone. The median number of SLNs identified by LFIS combined with MB was 3 (range of 1-8), which was significantly higher than that by MB alone at 2 (range 1-7) (P<0.05). CONCLUSION: LFIS effectively detects SLNs in breast cancer, projects the fluorescence signals during surgery, and provides a continuous surgical navigation system without the need for a remote monitor. The ICG method navigated by combined LFIS and MB may be a promising alternative tracer for radioisotope in SLN mapping. CLINICAL TRIAL REGISTRATION: This clinical trial was registered with the China Clinical Trial Center, registration number ChiCTR2000039542.

Prospective assessment of breast cancer risk from multimodal multiview ultrasound images via clinically applicable deep learning.

The clinical application of breast ultrasound for the assessment of cancer risk and of deep learning for the classification of breast-ultrasound images has been hindered by inter-grader variability and high false positive rates and by deep-learning models that do not follow Breast Imaging Reporting and Data System (BI-RADS) standards, lack explainability features and have not been tested prospectively. Here, we show that an explainable deep-learning system trained on 10,815 multimodal breast-ultrasound images of 721 biopsy-confirmed lesions from 634 patients across two hospitals and prospectively tested on 912 additional images of 152 lesions from 141 patients predicts BI-RADS scores for breast cancer as accurately as experienced radiologists, with areas under the receiver operating curve of 0.922 (95% confidence interval (CI) = 0.868-0.959) for bimodal images and 0.955 (95% CI = 0.909-0.982) for multimodal images. Multimodal multiview breast-ultrasound images augmented with heatmaps for malignancy risk predicted via deep learning may facilitate the adoption of ultrasound imaging in screening mammography workflows.

Clavariopsins C-I, Antifungal Cyclic Depsipeptides from the Aquatic Hyphomycete Clavariopsis aquatica.

Seven new cyclic depsipeptides, clavariopsins C-I (3-9), together with two known congeners, clavariopsins A and B (1 and 2), were isolated from the aquatic hyphomycete Clavariopsis aquatica. Their planar structures, which consist of nine amino acids and one α-hydroxy acid, were elucidated by NMR spectroscopy and HRESIMS. The absolute configurations were established by the advanced Marfey's method and chiral-phase HPLC analysis. Their antifungal and cytotoxic activities were evaluated against six plant pathogenic fungi (Botrytis cinerea, Magnaporthe oryzae, Colletotrichum orbiculare, Fusarium oxysporum, Alternaria alternata, and Aspergillus niger) and a cancer cell line (HeLa-S3), respectively. The majority of the compounds exhibited potent antifungal activity against the fungi tested (minimum inhibition dose = 0.01-10 µg/disk) and induced hyphal swelling in A. niger (minimum effective dose = 0.3-3 µg/disk), whereas the compounds exhibited no cytotoxicity toward the cancer cell line. The results suggest that the clavariopsins could be a promising class of antifungal agents.

Regioselective and oxidant-free sulfinylation of indoles and pyrroles with sulfinamides.

An unexpected time-controlled highly selective C3- or C2-sulfinylation of pyrroles with sulfinamides is reported for the first time. The sulfinylation of indoles with sulfinamides using this protocol is oxidant-free and can be performed under obviously more feasible conditions (1.2 equiv. of indoles, 10 min) in comparison with the precedent procedure (3-20 equiv. of indoles, 16-18 h, ammonium persulfate as oxidant, hv). A variety of functional groups were tolerated, and various C2-thioindoles and C2/3-thiopyrroles were obtained in moderate to excellent yields.

Lycosides, Unusual Carotenoid-Derived Terpenoid Glycosides from a Vegetable Juice, Inhibit Asexual Reproduction of the Plant Pathogen Phytophthora.

Vegetable juices, typical culture media for the plant pathogen Phytophthora, effectively induce its asexual reproduction (zoosporangia formation). However, some chromatographic fractions from a vegetable juice were found to inhibit asexual reproduction. Bioassay-guided chromatographic steps led to the isolation of four novel compounds, named lycosides A-D, 1-4, that could be metabolic products from a carotenoid. They showed 50% inhibitory activity against the asexual reproduction of P. capsici at 2.1-7.6 µM. The structure-activity relationship and the universality of the inhibitory activity within the Phytophthora genus were also investigated. In addition, the quantitative analysis of lycosides in fresh vegetables and vegetable juices revealed that tomato is the source of these active substances. These food-derived chemicals could help provide safe agents to control the outbreak of the agricultural pest Phytophthora in fields.

W1, a Novel Oral Antiplatelet Agent With Less Resistance Than Clopidogrel.

Clopidogrel (CLO) is a clinical antiplatelet agent, about which there are major concerns because its antiplatelet efficiency decreases with insufficient metabolic activation, leading to "clopidogrel resistance." We aimed to determine the antiplatelet effects of W1, a novel molecule composed of 2-O-clopidogrel and aspirin (1:1 ratio), on platelet aggregation ex vivo and thrombus formation in vivo, and its susceptibility to CLO resistance in combination with other therapies in rats. Platelets were prepared, and an arteriovenous shunt thrombosis model was established using Wistar rats to measure platelet aggregation and thrombus formation, respectively. W1 markedly inhibited adenosine 5'-diphosphate (ADP)-induced platelet aggregation and thrombus formation dose dependently (0.3, 1, and 3 mg/kg). W1 (3 mg/kg) acted rapidly at 0.5 hours and lasted for 72 hours. W1 prolonged bleeding and clotting times in mice, confirming its antithrombotic properties. Compared with CLO 10 mg/kg, the positive control, W1 3 mg/kg exerted equivalent effects on the above specifications. In addition, cyclic adenosine monophosphate levels, measured in rat platelets, increased rapidly after prostaglandin E1 (alprostadil) stimulation of the vehicle control (0.5% methyl cellulose suspension) and W1 (3 mg/kg)-treated groups. ADP (50 µm) reduced the control levels more remarkably than W1 did (P < 0.05 in 3 minutes or P < 0.001 at 5 minutes), suggesting that W1 suppressed ADP-induced cyclic adenosine monophosphate reduction. This was associated with a significant platelet reactivity inhibition measured using the vasodilator-stimulated phosphoprotein assay. CLO or W1 coadministration with or without omeprazole and amlodipine to rats to investigate the pharmacodynamic interactions revealed that W1 exhibited more stable and potent antithrombotic effects than CLO did. In conclusion, both W1 and CLO showed antiplatelet and antithrombotic effects, while the former exhibited less CLO resistance in combination with omeprazole or amlodipine, 2 drugs that inhibit CLO metabolism. Therefore, this study implies that W1 may be a promising oral antiplatelet agent for reducing CLO resistance after percutaneous coronary intervention.

Linckosides enhance proliferation and induce morphological changes in human olfactory ensheathing cells.

Linckosides are members of the steroid glycoside family isolated from the starfish Linckia laevigata. These natural compounds have notable neuritogenic activity and synergistic effects on NGF-induced neuronal differentiation of PC12 cells. Neurogenic factors or molecules that are able to mimic their activities are known to be involved in the survival, proliferation and migration of neurons and glial cells; however how glial cells respond to specific neurogenic molecules such as linckosides has not been investigated. This study aimed to examine the effect of three different linckosides (linckoside A, B and granulatoside A) on the morphological properties, proliferation and migration of human olfactory ensheathing cells (hOECs). The proliferation rate after all the treatments was higher than control as detected by MTS assay. Additionally, hOECs displayed dramatic morphological changes characterized by a higher number of processes after linckoside treatment. Interestingly changes in microtubule organization and expression levels of some early neuronal markers (GAP43 and ßIII-tubulin) were also observed. An increase in the phosphorylation of ERK 1/2 after addition of the compounds suggests that this pathway may be involved in the linckoside-mediated effects particularly those related to morphological changes. These results are the first description of the stimulating effects of linckosides on hOECs and raise the potential for this natural compound or its derivatives to be used to regulate and enhance the therapeutic properties of OECs, particularly for cell transplantation therapies.

Bioactive Maleic Anhydrides and Related Diacids from the Aquatic Hyphomycete Tricladium castaneicola.

Four maleic anhydride derivatives, tricladolides A-D (1-4), and three alkylidene succinic acid derivatives, tricladic acids A-C (5-7), were isolated from the aquatic hyphomycete Tricladium castaneicola. The structures of these compounds were determined by spectroscopic analysis, and all were found to be novel. The compounds exhibited inhibitory activity against fungi, particularly Phytophthora sp., a plant pathogen of oomycetes. The inhibitory activity of these metabolites revealed the importance of the cyclic anhydride structure and the lipophilicity of the alkyl side chain. On the other hand, the cytotoxicity of the compounds against B16 melanoma cells indicated that the cyclic anhydride structure was not essential.

Effect of Atorvastatin on Expression of Peroxisome Proliferator-activated Receptor Beta/delta in Angiotensin II-induced Hypertrophic Myocardial Cells In Vitro.

OBJECTIVE: To explore the effect of atorvastatin on cardiac hypertrophy and to determine the potential mechanism involved. METHODS: An in vitro cardiomyocyte hypertrophy from neonatal rats was induced with angiotensin II (Ang II) stimulation. Before Ang II stimulation, the cultured rat cardiac myocytes were pretreated with atorvastatin at different concentrations (0.1, 1, and 10 µmol/L). The following parameters were evaluated: the myocyte surface area, 3H-leucine incorporation into myocytes, mRNA expressions of atrial natriuretic peptide, brain natriuretic peptide, matrix metalloproteinase 9, matrix metalloproteinase 2, and interleukin-1ß, mRNA and protein expressions of the δ/ß peroxisome proliferator-activated receptor (PPAR) subtypes. RESULTS: It was shown that atorvastatin could ameliorate Ang II-induced neonatal cardiomyocyte hypertrophy in the area of cardiomyocytes, 3H-leucine incorporation, and the expression of atrial natriuretic peptide and brain natriuretic peptide markedly. Meanwhile, atorvastatin also inhibited the augmented mRNA level of several cytokines in hypertrophic myocytes. Furthermore, the down-regulated expression of PPAR- δ/ß at both the mRNA and protein levels in hypertrophic myocytes could be significantly reversed by atorvastatin treatment. CONCLUSIONS: Atorvastatin could improve Ang II-induced cardiac hypertrophy and inhibit the expression of cytokines. Such effect might be partly achieved through activation of the PPAR-δ/ß pathway.

Protective effects of kojic acid on the periphery blood and survival of beagle dogs after exposure to a lethal dose of gamma radiation.

In previous studies, it has been shown that pretreatment with kojic acid (KA) not only increased the 30 day survival rate of mice after exposed to a lethal dose of gamma radiation but also had significant radioprotective effects on the hematopoietic system, the immune system and DNA of mice exposed to a 4 Gy sublethal dose of radiation. Furthermore, pretreatment with KA has also been shown to protect Chinese hamster ovary (CHO) cells against ionizing radiation-induced damage. In this investigation, beagle dogs were used to evaluate whether KA could also be radioprotective in a large animal model. Dogs in the group pretreated with kojic acid after whole-body exposure to a lethal dose of 3 Gy gamma radiation had a 51 day survival rate of 66.7% versus the dogs in the 3 Gy irradiation only group, which all died within 16 days of postirradiation. General vital signs (body weight or temperature) of animals in the kojic acid pretreated group reduced and increased maximally at day 14 postirradiation and then reverted to normal levels gradually. The hematopoiesis studies indicated that the white blood cells/red blood cells, hemoglobin content and hematocrit of dogs pretreated with kojic acid decreased sharply at day 23/day 21 postirradiation, and then gradually elevated. In addition, the DNA content of dogs pretreated with KA were significantly increased compared with that of dogs in the irradiation group at day 4 postirradiation and the number of micronuclei in the group pretreated with kojic acid declined sharply compared with that of the irradiation only group. KA appears to possess marked protective effects from radiation-induced damage and therefore, may be a promising novel radioprotective agent.

Kojic acid protects C57BL/6 mice from gamma-irradiation induced damage.

The radioprotective effects of a single administration of kojic acid (KA) against ionizing radiation were evaluated via assessment of 30-day survival and alterations of peripheral blood parameters of adult C57BL/6 male mice. The 30-day survival rate of mice pretreated with KA (75 or 300 mg/kg body weight, KA75 or KA300) subcutaneously 27 h prior to a lethal dose (8 Gy, 153.52 cGy/min) of gamma irradiation was higher than that of mice irradiated alone (40% or 60% vs 0%). It was observed that the white blood cell (WBC) count/the red blood cell (RBC) count, haemoglobin content, haematocrit and platelet count of mice with or without KA pretreatment as exposed to a sub-lethal dose (4 Gy, 148.14 cGy/min) of gamma irradiation decreased maximally at day 4/day 8 post-irradiation. Although the initial WBC values were low in KA300 or WR-2721 (amifostine) groups, they significantly recovered to normal at day 19, whereas in the control group they did not. The results from the cytotoxicity and cell viability assays demonstrated that KA could highly protect Chinese hamster ovary (CHO) cells against ionizing radiation with low toxicity. In summary, KA provides marked radioprotective effects both in vivo and in vitro.

GRK 2 level in peripheral blood lymphocytes of elderly patients with acute myocardial infarction.

OBJECTIVE: To investigate the G protein-coupled receptor kinase 2 (GRK 2) level in peripheral blood lymphocytes with cardiac function in elderly patients with acute myocardial infarction. METHODS: This study enrolled 40 patients with acute ST-segment elevation myocardial infarction (STEMI) and 40 patients with unstable angina. All patients were 65 years or older. Cardiac function was evaluated by echocardiography, and the GRK 2 level in peripheral blood lymphocytes was measured. Patients with STEMI were followed up for 2 years. RESULTS: The GRK 2 level in peripheral blood lymphocytes was significantly higher in patients with STEMI than in patients with unstable angina, and was negatively correlated with left ventricular ejection fraction, cardiac output, stroke volume, and left ventricular fractional shortening. The GRK 2 level was significantly elevated in some patients with acute STEMI and poor cardiac function. CONCLUSIONS: Increased GRK 2 level in patients with acute STEMI may contribute to poor myocardial systolic function and myocardial remodeling. Measurement of the GRK 2 level in peripheral blood lymphocytes may assist in the evaluation of cardiac function and myocardial remodeling in elderly patients with acute STEMI.

Proton sponge-functionalized silica as high performance adsorbents for solid-phase extraction of trace perfluoroalkyl sulfonates in the environmental water samples and their direct analysis by MALDI-TOF-MS.

1,8-Bis(dimethylamino)naphthalene (DMAN), a classical 'proton sponge', was functionalized on silica particles as a novel solid-phase extraction (SPE) adsorbent (DMAN@silica) for extracting perfluoroalkyl sulfonates (PFSs). High reproducibility and excellent extraction capability for PFSs were obtained in a wide pH range (3.0~8.5). The adsorbed PFSs on DMAN@silica sorbents could be efficiently eluted by 1,8-bis(tetramethylguanidino)naphthalene (TMGN) solution which is a proton sponge with higher proton affinity than DMAN. The elution could be directly analyzed by MALDI-TOF-MS using TMGN as matrix. Clear mass spectra for the PFSs were obtained due to no matrix ions interference observed. Furthermore, a novel strategy based on the DMAN@silica-SPE enrichment, followed by MALDI-TOF-MS analysis, was proposed and applied for PFSs quantification in environmental water samples. The calibration curves of each of the target analytes showed a wide linear dynamic range of response (0.1-10 ng L(-1) for perfluorooctane sulfonate (PFOS), perfluorohexyl sulfonate (PFHxS) and perfluorobutylsulfonate (PFBS)), which were over 2 orders of magnitude. The detection limits for PFOS, PFHxS, and PFBS were 0.021, 0.016, and 0.013 ng L(-1), respectively (S/N = 3). Recoveries of PFOS, PFHxS, and PFBS are in the ranges of 92-104%, 95-102%, and 98-109% for spiked river water samples. These results indicated that the prepared DMAN@silica adsorbents could efficiently enrich PFSs and that the proposed method is reliable.

Atorvastatin may delay cardiac aging by upregulating peroxisome proliferator-activated receptors in rats.

AIMS: To investigate the effect of atorvastatin on cardiac aging in rats. MATERIALS: Ninety 20-month-old Wistar rats were administered oral atorvastatin (AVT; 10 or 1 mg·kg(-1)·day(-1)) or saline for 4 months. At the end of the experiment, age-related changes in hearts were measured. RESULTS: Compared with young rats, obvious increases were found in the aging rats in left ventricle thickness, diameter of cardiocytes, collagen deposition, the ratio of type I/type III collagen, ß-galactosidase and malondialdehyde (MDA), and obvious decreases were found in superoxide dismutase (SOD), catalase (CAT) and nitric oxide synthase (NOS). The treatment with AVT led to significant decreases in the thickness of the left ventricle, diameter of cardiocytes, collagen deposition, I/III collagen ratio, MDA, ß-galactosidase and increases in the activity of SOD, CAT and NOS. Some aging-related inflammatory cytokines like interleukin (IL)-1ß, tumour necrosis factor (TNF)-α and matrix metalloproteinase (MMP)-9 were found to be overexpressed in the aging rats. AVT treatment could inhibit the expression of IL-1ß, TNF-α and MMP-9 on both the mRNA and protein levels, and increase the expression of peroxisome proliferator-activated receptors (PPAR-α/ß/δ/γ). Pretreatment with PPAR inhibitors attenuated the inhibitory effect of AVT on the expression of inflammatory cytokines. CONCLUSION: AVT may retard the cardiac aging process by upregulating PPARs.