DGAT1 inhibitors protect pancreatic ß-cells from palmitic acid-induced apoptosis.

Previous studies demonstrated that prolonged exposure to elevated levels of free fatty acids (FFA), especially saturated fatty acids, could lead to pancreatic ß-cell apoptosis, which plays an important role in the progression of type 2 diabetes (T2D). Diacylglycerol acyltransferase 1 (DGAT1), an enzyme that catalyzes the final step of triglyceride (TG) synthesis, has been reported as a novel target for the treatment of multiple metabolic diseases. In this study we evaluated the potential beneficial effects of DGAT1 inhibitors on pancreatic ß-cells, and further verified their antidiabetic effects in db/db mice. We showed that DGAT1 inhibitors (4a and LCQ908) at the concentration of 1 µM significantly ameliorated palmitic acid (PA)-induced apoptosis in MIN6 pancreatic ß-cells and primary cultured mouse islets; oral administration of a DGAT1 inhibitor (4a) (100 mg/kg) for 4 weeks significantly reduced the apoptosis of pancreatic islets in db/db mice. Meanwhile, 4a administration significantly decreased fasting blood glucose and TG levels, and improved glucose tolerance and insulin tolerance in db/db mice. Furthermore, we revealed that pretreatment with 4a (1 µM) significantly alleviated PA-induced intracellular lipid accumulation, endoplasmic reticulum (ER) stress, and proinflammatory responses in MIN6 cells, which might contribute to the protective effects of DGAT1 inhibitors on pancreatic ß-cells. These findings provided a better understanding of the antidiabetic effects of DGAT1 inhibitors.

Yhhu4488, a novel GPR40 agonist, promotes GLP-1 secretion and exerts anti-diabetic effect in rodent models.

G protein-coupled receptor 40 (GPR40) is predominantly expressed in pancreatic ß-cells and activated by long-chain fatty acids. GPR40 has drawn considerable interest as a potential therapeutic target for type 2 diabetes mellitus (T2DM) due to its important role in enhancing glucose-stimulated insulin secretion (GSIS). Encouragingly, GPR40 is also proven to be highly expressed in glucagon-like peptide-1 (GLP-1)-producing enteroendocrine cells afterwards, which opens a potential role of GPR40 in enhancing GLP-1 secretion to exert additional anti-diabetic efficacy. In the present study, we discovered a novel GPR40 agonist, yhhu4488, which is structurally different from other reported GPR40 agonists. Yhhu4488 showed potent agonist activity with EC50 of 49.96 nM, 70.83 nM and 58.68 nM in HEK293 cells stably expressing human, rat and mouse GPR40, respectively. Yhhu4488 stimulated GLP-1 secretion from fetal rat intestinal cells (FRIC) via triggering endogenous calcium store mobilization and extracellular calcium influx. The effect of yhhu4488 on GLP-1 secretion was further confirmed in type 2 diabetic db/db mice. Yhhu4488 exhibited satisfactory potency in in vivo studies. Single administration of yhhu4488 improved glucose tolerance in SD rats. Chronic administration of yhhu4488 effectively decreased fasting blood glucose level, improved ß-cell function and lipid homeostasis in type 2 diabetic ob/ob mice. Taken together, yhhu4488 is a novel GPR40 agonist that enhances GLP-1 secretion, improves metabolic control and ß-cell function, suggesting its promising potential for the treatment of type 2 diabetes.

Yhhu981, a novel compound, stimulates fatty acid oxidation via the activation of AMPK and ameliorates lipid metabolism disorder in ob/ob mice.

AIM: Defects in fatty acid metabolism contribute to the pathogenesis of insulin resistance and obesity. In this study, we investigated the effects of a novel compound yhhu981 on fatty acid metabolism in vitro and in vivo. METHODS: The capacity to stimulate fatty acid oxidation was assessed in C2C12 myotubes. The fatty acid synthesis was studied in HepG2 cells using isotope tracing. The phosphorylation of AMPK and acetyl-CoA carboxylase (ACC) was examined with Western blot analysis. For in vivo experiments, ob/ob mice were orally treated with yhhu981 acutely (300 mg/kg) or chronically (150 or 300 mg·kg(-1)·d(-1) for 22 d). On the last day of treatment, serum and tissue samples were collected for analysis. RESULTS: Yhhu981 (12.5-25 µmol/L) significantly increased fatty acid oxidation and the expression of related genes (Sirt1, Pgc1α and Mcad) in C2C12 myotubes, and inhibited fatty acid synthesis in HepG2 cells. Furthermore, yhhu981 dose-dependently increased the phosphorylation of AMPK and ACC in both C2C12 myotubes and HepG2 cells. Compound C, an AMPK inhibitor, blocked fatty acid oxidation in yhhu981-treated C2C12 myotubes and fatty acid synthesis decrease in yhhu981-treated HepG2 cells. Acute administration of yhhu981 decreased the respiratory exchange ratio in ob/ob mice, whereas chronic treatment with yhhu981 ameliorated the lipid abnormalities and ectopic lipid deposition in skeletal muscle and liver of ob/ob mice. CONCLUSION: Yhhu981 is a potent compound that stimulates fatty acid oxidation, and exerts pleiotropic effects on lipid metabolism by activating AMPK.

[Characteristics of PM2.5 Pollution in Beijing During the Historical Period of the 2022 Olympic Winter Games].

Based on the dataset derived from January to March between 2015 and 2021 in Beijing, the PM2.5 pollution characteristics and its potential source regions during the historical period of the Beijing 2022 Olympic Winter Games and Paralympic Winter Games were investigated. From 2015 to 2018, both the number of severely polluted days (daily average ρ(PM2.5)>75 µg·m-3) and the average PM2.5 concentrations during severe pollution episodes decreased significantly in the period of January to March. While, neither variable has changed obviously since 2018. On average, severely polluted days occurred 23 times in each year between 2018 and 2021 during the period of January to March, and the average of ρ(PM2.5) was approximately 120.0 µg·m-3 during such polluted days. From January to March in 2015-2021, the severely polluted event with more than 5 consecutive polluted days occurred 2-3 times in each year, and the severest one lasted 8 d. During the historical period of the Beijing 2022 Olympic Winter Games, severely polluted days took place 2-9 d every year. The large quantities of fireworks during the Spring Festival maybe one of important primary sources of the PM2.5. The number of severely polluted days during the historical period of the Paralympic Winter Games ranged from 1 to 5 d, except for 2021 with 9 d owing to the frequent stagnant weather condition. The PM2.5 chemical composition was dominated by secondary species on severely polluted days during the historical period of the Beijing 2022 Olympic Winter Games and Paralympic Winter Games. Nitrate accounted for 46% of the measurable chemical components of PM2.5 during severe pollution events in 2020, which was remarkably higher than that during clean days in the same year (11%). The mass fraction of SO42- ranged from 12% to 19% in 2018-2020, indicating that the contribution of sulfate was much less, but cannot be ignored. The main potential source regions of PM2.5 in Beijing during the period concerned in this study were central and western Inner Mongolia, Hebei Province, Tianjin City, Shanxi Province, Shaanxi Province, central and western Shandong Province, and northern Henan Province.

A novel low systemic diacylglycerol acyltransferase 1 inhibitor, Yhhu2407, improves lipid metabolism.

Diacylglycerol acyltransferase 1 (DGAT1) plays a pivotal role in lipid metabolism by catalyzing the committed step in triglyceride (TG) synthesis and has been considered as a potential therapeutic target of multiple metabolic diseases, including dyslipidemia, obesity and type 2 diabetes. Here we report a novel DGAT1 inhibitor, Yhhu2407, which showed a stronger DGAT1 inhibitory activity (IC50 = 18.24 ± 4.72 nM) than LCQ908 (IC50 = 78.24 ± 8.16 nM) in an enzymatic assay and led to a significant reduction in plasma TG after an acute lipid challenge in mice. Pharmacokinetic studies illustrated that Yhhu2407 displayed a low systemic, liver- and intestine-targeted distribution pattern, which is consistent with the preferential tissue expression pattern of DGAT1 and therefore might help to maximize the beneficial pharmacological effects and prevent the occurrence of side effects. Cell-based investigations demonstrated that Yhhu2407 inhibited free fatty acid (FFA)-induced TG accumulation and apolipoprotein B (ApoB)-100 secretion in HepG2 cells. In vivo study also disclosed that Yhhu2407 exerted a beneficial effect on regulating plasma TG and lipoprotein levels in rats, and effectively ameliorated high-fat diet (HFD)-induced dyslipidemia in hamsters. In conclusion, we identified Yhhu2407 as a novel DGAT1 inhibitor with potent efficacy on improving lipid metabolism in rats and HFD-fed hamsters without causing obvious adverse effects.

Source profiles of particulate organic matters emitted from cereal straw burnings.

Cereal straw is one of the most abundant biomass burned in China but its contribution to fine particulates is not adequately understood. In this study, three main kinds of cereal straws were collected from five grain producing areas in China. Fine particulate matters (PM2.5) from the cereal straws subjected to control burnings, both under smoldering and flaming status, were sampled by using a custom made dilution chamber and sampling system in the laboratory. Element carbon (EC) and organic carbon (OC) was analyzed. 141 compounds of organic matters were measured by gas chromatography-mass spectrum (GC-MS). Source profiles of particulate organic matters emitted from cereal straw burnings were obtained. The results indicated that organic matters contribute a large fraction in fine particulate matters. Levoglucosan had the highest contributions with averagely 4.5% in mass of fine particulates and can be considered as the tracer of biomass burnings. Methyloxylated phenols from lignin degradation also had high concentrations in PM2.5, and contained approximately equal amounts of guaiacyl and syringyl compounds. beta-Sitostrol also made up relatively a large fraction of PM2.5 compared with the other sterols (0.18%-0.63% of the total fine particle mass). Normal alkanes, PAHs, fatty acids, as well as normal alkanols had relatively lower concentrations compared with the compounds mentioned above. Carbon preference index (CPI) of normal alkanes and alkanoic acids showed characteristics of biogenic fuel burnings. Burning status significantly influenced the formations of EC and PAHs. The differences between the emission profiles of straw and wood combustions were displayed by the fingerprint compounds, which may be used to identify the contributions between wood and straw burnings in source apportionment researches.

Quantitative relationship between visibility and mass concentration of PM2.5 in Beijing.

The pollution of particulate matter less than 2.5 microm (PM2.5) is a serious environmental problem in Beijing. The annual average concentration of PM2.5 in 2001 from seasonal monitor results was more than 6 times that of the U.S. national ambient air quality standards proposed by U.S. EPA. The major contributors to mass of PM2.5 were organics, crustal elements and sulfate. The chemical composition of PM2.5 varied largely with season, but was similar at different monitor stations in the same season. The fine particles (PM2.5) cause atmospheric visibility deterioration through light extinction. The mass concentrations of PM2.5 were anti-correlated to the visibility, the best fits between atmospheric visibility and the mass concentrations of PM2.5 were somehow different: power in spring, exponential in summer, logarithmic in autumn, power or exponential in winter. As in each season the meteorological parameters such as air temperature and relative humidity change from day to day, probably the reason of above correlations between PM2.5 and visibility obtained at different seasons come from the differences in chemical compositions of PM2.5.

[Transformation Mechanism and Sources of Secondary Inorganic Components in PM2.5 at an Agriculture Site (Quzhou) in the North China Plain in Summer].

Simultaneously on-line measurements of major water-soluble inorganic ions and gaseous pollutants were performed from June 9 to July 11, 2014 at Quzhou, an agriculture site in the North China Plain using a gas-aerosol collector (GAC) and ion chromatograph (IC), aiming to track the diurnal variation rule of secondary inorganic components and gas-phase precursors as well as their interactions. The transformation mechanism and sources of fine particles (PM2.5) were also discussed. The results showed that these water-soluble ions in PM2.5 and their gas-phase precursors varied regularly. As the dominant ionic components of PM2.5 (accounting for 76.23%), the average concentrations of SO4(2-), NH4(+), NO3(-) were 26.28 µg x m(-3), 18.08 µg x m(-3) and 16.36 µg m(-3) respectively. Among the precursor gases, the NH3, generated from the discharges of local agricultural activities, displayed a significantly higher concentration at an average value of 44.85 µg x m(-3). The average fine sulfate and nitrate oxidation ratios (SOR and NOR) were SOR = 0.60, NOR = 0.30, revealing the remarkable characteristics of secondary pollution. As could be found from the relevant analysis, the NH4(+) of Quzhou showed well relations with NO3(-) and SO4(2-), and the environment here was rich of ammonia. The NH4(+) existed in the form of (NH4)2SO4 and the generation of NO3(-) was limited by the HNO3. From the analysis for the equilibrium of NH4NO3, we observed that the atmospheric environment of Quzhou was adverse to the generation and maintenance of NH4NO3 during the daytime,in contrast with the night. Integrated with the study, the results displayed that the secondary transformation was the main source of fine particles in Quzhou, and the NH3 from field and compost was the significant factor leading to the high value of S-N-A.

Chemical composition and quantitative relationship between meteorological condition and fine particles in Beijing.

The recent year's monitor results of Beijing indicated that the pollution level of fine particles PM2.5 showed an increasing trend. To understand pollution characteristics of PM2.5 and its relationship with the meteorological conditions in Beijing, a one-year monitoring of PM2.5 mass concentration and correspondent meteorological parameters was performed in Beijing in 2001. The PM2.5 levels in Beijing were very high, the annual average PM2.5 concentration in 2001 was 7 times of the National Ambient Air Quality Standards proposed by US EPA. The major chemical compositions were organics, sulfate, crustals and nitrate. It was found that the mass concentrations of PM2.5 were influenced by meteorological conditions. The correlation between the mass concentrations of PM2.5 and the relative humidity was found. And the correlation became closer at higher relative humidity. And the mass concentrations of PM2.5 were negtive-correlated to wind speeds, but the correlation between the mass concentration of PM2.5 and wind speed was not good at stronger wind.

[Improvement and application of the method for determination of OCEC split].

Aerosol samples were collected in Beijing (BD) and Atlanta (GT) from July to August in 2011 using a Micro-Orifice Uniform Deposit Impactor (MOUDI) (0.18-18 microm, eight-stage) for organic carbon (OC) and elemental carbon (EC) measurement (Sunset Laboratory Inc, USA). The laser intensity of blank filters decreased with temperature in the process of OC & EC analysis because the structure of quartz filters was changed when burned which largely affected the determination of low concentration samples' splits. It would increase the accuracy of OC & EC split to determine it manually after the change of blank filter's laser intensity was recouped. The concentrations and size distributions of OC & EC using the improved method were different from taking the moment when oxygen was introduced as the split. The split may appear before oxygen addition, when the sample was rich in metal or substances that can be decomposed after heated. The concentrations of carbonaceous components were higher at BD than those at GT. The size distributions of OC showed a bimodal pattern with peaks appeared in the particles with size of (0.56-1.0) microm and (3.2-5.6) microm. The peak concentrations of OC were (2.82 +/- 1.59) microg x m(-3) and (1.95 +/- 0.76) microg x m(-3) at BD, and (1.28 +/- 0.41) microg x m(-3) and (0.64 +/- 0.19) microg x m(-3) at GT. EC showed a bimodal pattern at BD with peaks in particles with size of (0.56-1.0) microm and (3.2-5.6) microm, while showed a trimodal pattern at GT. The peak concentrations at BD were (0.32 +/- 0.24) microg x m(-3) and (0.26 +/- 0.19) microg x m(-3). EC at GT was preferably enriched in particles with size of (0.18-0.56) microm, the mass concentrations of EC in this size accounted for 44.6%. The OC and EC were more concentrated in accumulation mode at GT than those at BD, the reason may be that the main pollution source of GT is motor vehicle emission, while there are more industrial gas emissions at BD.

Discovery and optimization of 2,4-diaminoquinazoline derivatives as a new class of potent dengue virus inhibitors.

The results of a high-throughput screening assay using the DENV-2 replicon showed that the 2,4-diaminoquinazoline derivative 4a has a high dengue virus inhibitory activity (EC(50) = 0.15 µM). A series of 2,4-diaminoquinazoline derivatives based on 4a as a lead compound were synthesized and subjected to structure-antidengue activity relationship studies. Among the series of 2,4-diaminoquinazoline derivative probed, 4o was observed to display both the highest antiviral potency (EC(50) = 2.8 nM, SI > 1000) and an excellent pharmacokinetic profile.

Fast quantitative analysis of boric acid by gas chromatography-mass spectrometry coupled with a simple and selective derivatization reaction using triethanolamine.

A fast, selective, and sensitive GC-MS method has been developed and validated for the determination of boric acid in the drinking water by derivatization with triethanolamine. This analytic strategy successfully converts the inorganic, nonvolatile boric acid B(OH)(3) present in the drinking water to a volatile triethanolamine borate B(OCH(2)CH(2))(3)N in a quantitative manner, which facilitates the GC measurement. The SIM mode was applied in the analysis and showed high accuracy, specificity, and reproducibility, as well as reducing the matrix effect effectively. The calibration curve was obtained from 0.01 microg/mL to 10.0 microg/mL with a satisfactory correlation coefficient of 0.9988. The limit of detection for boric acid was 0.04 microg/L. Then the method was applied for detection of the amount of boric acid in bottled drinking water and the results are in accordance with the reported concentration value of boric acid. This study offers a perspective into the utility of GC-MS as an alternate quantitative tool for detection of B(OH)(3), even for detection of boron in various other samples by digesting the boron compounds to boric acid.

[Comparison of EC/OC in PM2.5 between filter sampling off-line analysis and in situ on-line measurement].

Elemental carbon (EC) and organic carbon (OC) in PM2.5 were measured simultaneously at the campus of Peking University from January 2006 to April 2007 by two common used methodologies. One is quartz filter sampling followed by off-line SUNSET Lab EC/OC analyzer and the other is SUNSET in-situ on-line EC/OC analyzer. The comparison shows significant differences on OC measurements between the two methods. The results by filter sampling off-line analysis were as twice high as those by in-situ on-line method. The volatile organic carbons (VOCs) adsorbed by quartz filter led to considerable positive error of OC. The use of parallel plate organic denuder can eliminate such error but cause the evaporation of semi-volatile organic carbon on the filter which induces another negative error of OC, about 10%. The improved method of filter sampling off-line analysis using both parallel plate organic denuder and backup filter has a good agreement with in-situ online measurement.