[Spatio-temporal dynamics of gross primary productivity in China from 1982 to 2017 based on different datasets]. / 不同数据集的1982­2017年中国总初级生产力的时空动态.

Understanding the spatio-temporal variations of gross primary productivity (GPP) of terrestrial ecosystem and its relationship with climatic factors can provide important basis for vegetation restoration and protection. Based on meteorological data and three public GPP datasets (EC-LUE GPP, GLASS GPP, and NIRv GPP), we syste-matically analyzed the spatial-temporal variations of GPP and its response to climate change in China during 1982-2017. All the results based on the three GPP datasets showed that the annual and seasonal GPP in China increased annually from 1982 to 2017, with that in 1998 and 2002 significantly being higher than the average level during the study period, and that in 1989 and 1992 significantly being lower than the average annual GPP. From 1982 to 2017, GPP showed a significant upward trend in most regions of China, with the regions with significant increases accounting for 75.7%, 73.0%, and 69.6% of the whole study area, respectively. There was a significant positive correlation between annual GPP and precipitation and temperature, but spatial heterogeneity was strong. Among them, the regions with positive correlation between GPP and temperature were mainly distributed in Northwest and Central China, while the regions with positive correlation between GPP and precipitation were mainly distributed in North China. There was obvious spatial-temporal heterogeneity in regions that GPP being affected by temperature and precipitation in different seasons. Temperature was the limiting factor of GPP in spring, autumn and winter, while summer GPP was mainly affected by precipitation.

[Variation in fractional vegetation cover and its attribution analysis of different regions of Beijing-Tianjin Sand Source Region, China]. / äº¬æ´¥é£Žæ²™æºåŒºä¸åŒåˆ†åŒºæ¤è¢«è¦†ç›–åº¦å˜åŒ–åŠå½’å› åˆ†æž.

Based on the MODIS NDVI data from 2000 to 2018, we estimated the fractional vegetation cover (FVC) using the dimidiate pixel model and analyzed the spatiotemporal characteristics of FVC in the Beijing-Tianjin sand source region (BTSSR). The geographical detector model was used to estimate the impacts of natural and human factors on FVC spatial distribution at the regional scale. The results showed that the FVC of the BBTSR showed an increasing trend from 2000 to 2018, with an annual growth rate of 0.013·(10 a)-1 and a vegetation increase rate of 8.2%. The area with high FVC was concentrated in the Yanshan Mountain water source protection area, followed by the pastoral transitional zone desertified land control area and the Otindag sandy land area. The area with poor FVC was concentrated in the northern arid grassland area. The explanatory power of driving factors to FVC varied across different regions. Among the natural factors, annual precipitation was the main driving factor for the spatial distribution of FVC in the northern arid grassland area, the Otindag sandy land area and the Yanshan Mountain water source protection area. Slope was the main driving factor for the spatial distribution of FVC in the pastoral transitional zone desertified land control area. Among different human activities, the number of large livestock at the year-end was the main driving factor controlling the spatial distribution of FVC in the northern arid grassland area and the pastoral transitional zone desertified land control area, while population density was the main driving factor controlling the spatial distribution of FVC in the Otindag sandy land area and the Yanshan Mountain water source protection area. There were regional differences in the influen-ce of other factors on FVC spatial distribution. The results of the interaction detector showed that the two-factor interactions were mainly the double-synergy and nonlinear synergy. The interaction of human activities with annual precipitation and slope could more fully explain the spatial variations of FVC. The range of suitable vegetation growth identified by the risk detector was the area with annual precipitation of 316.4-486.0 mm, average relative humidity of 48.4%-57.6%, and average annual temperature of 2.5-7.9 ℃, while other driving factors were different in different zones.

[Quantitative analysis of the effects of human activities on vegetation in the Beijing-Tianjin sandstorm source region under the climate change].

It is of great practical significance for regional ecological management to understand the quantitative impacts of human activities on vegetation under climate change. Based on GIMMS NDVI3g data, meteorological data (temperature, precipitation) and standardized precipitation evapotranspiration index (SPEI), we used correlation analysis and trend analysis to examine the spatio-temporal variation of vegetation and its driving factors in different periods from 1982 to 2014 in the Beijing-Tianjin sandstorm source region. Regression analysis and residual analysis were used to quantify the impacts of human activities on vegetation changes in different sub-regions. The results showed that from 1982 to 2014, the degradation status in 77.1% of degraded vegetation was significantly improved and 64.1% of vegetation had an increasing trend in the study area, with mean annual NDVI decreasing from southeast to northwest. Vegetation coverage increased in 74.5% of the areas after the implementation of the Beijing-Tianjin sandstorm source control project, with mountains in northern Shanxi showing the most obvious increases. Among all the climate factors, rainfall had the strongest correlation with vegetation change. Human activities, such as ecological engineering, played an active role in most areas, especially in mountains of northern Shanxi, where the contribution of human activities reached 94.9%.

Leflunomide increased the renal exposure of acyclovir by inhibiting OAT1/3 and MRP2.

Rheumatoid arthritis patients can be prescribed a combination of immunosuppressive drug leflunomide (LEF) and the antiviral drug acyclovir to reduce the high risk of infection. Acyclovir is a substrate of organic anion transporter (OAT) 1/3 and multidrug resistance-associated protein (MRP) 2. Considering the extraordinarily long half-life of LEF's active metabolite teriflunomide (TER) and the kidney injury risk of acyclovir, it is necessary to elucidate the potential impact of LEF on the disposition of acyclovir. Here we used a specific MRP inhibitor MK571 and probenecid (OAT1/3 and MRP2 inhibitor) to assess the effects of MRP2 and OAT1/3 on the pharmacokinetics and tissue distribution of acyclovir in rats. We showed that LEF and probenecid, but not MK571 significantly increased the plasma concentration of acyclovir. However, kidney and liver exposures of acyclovir were increased when coadministered with LEF, probenecid or MK571. The kidney/plasma ratio of acyclovir was increased to approximately 2-fold by LEF or probenecid, whereas it was increased to as much as 14.5-fold by MK571. Consistently, these drugs markedly decreased the urinary excretion of acyclovir. TER (0.5-100 µmol/L) dose-dependently increased the accumulation of acyclovir in MRP2-MDCK cells with an IC50 value of 4.91 µmol/L. TER (5 µmol/L) significantly inhibited the uptake of acyclovir in hOAT1/3-HEK293 cells. These results suggest that LEF/TER increased the kidney accumulation of acyclovir by inhibiting the efflux transporter MRP2, which increased its kidney/plasma ratio and renal injury risk. However, the inhibitory effects of LEF/TER on OAT1/3 reduced the tubular cells' uptake of acyclovir and increased the plasma concentration.

[Responses of vegetation growth to temperature during 1982-2015 in Xinjiang, China.] / 1982­2015年新疆地区植被生长对气温的响应.

Combined with the normalized difference vegetation index (NDVI) dataset, vegetation type data, and meteorological data, we revealed the variation of vegetation growth responses to air temperature in the growing-season during 1982-2015 in Xinjiang, using the moving-windows based partial correlation analysis, the unitary linear regression analysis and GIS spatial analysis. Results showed that, in the whole growing-seasons of study period, there was a significant downturn trend in the responses of vegetation growth to temperature. At the seasonal scale, the downturn trend was obvious especially in summer and autumn, while it was in adverse in spring. During the whole gro-wing season, the responses of different vegetation types to air temperature change showed a decreasing trend. Seasonally, the responses of grassland and forest to temperature change showed a significant increase, while that of shrubland and desert were exactly the opposite in spring. The responses of all natural vegetation (grassland, shrubland, desert and forest) to temperature change showed a significant decreasing trend in summer, whereas their responses in autumn had no significant statistical characteristics. Spatially, the decreasing influence of temperature on the vegetation growth during the growing season in Xinjiang was universal, which might be due to the change in precipitation and solar radiation.

Optimized Hepatocyte-Like Cells with Functional Drug Transporters Directly-Reprogrammed from Mouse Fibroblasts and their Potential in Drug Disposition and Toxicology.

BACKGROUND/AIMS: To develop a suitable hepatocyte-like cell model that could be a substitute for primary hepatocytes with essential transporter expression and functions. Induced hepatocyte-like (iHep) cells directly reprogrammed from mice fibroblast cells were fully characterized. METHODS: Naïve iHep cells were transfected with nuclear hepatocyte factor 4 alpha (Hnf4α) and treated with selected small molecules. Sandwich cultured configuration was applied. The mRNA and protein expression of transporters were determined by Real Time PCR and confocal. The functional transporters were estimated by drug biliary excretion measurement. The inhibition of bile acid efflux transporters by cholestatic drugs were assessed. RESULTS: The expression and function of p-glycoprotein (P-gp), bile salt efflux pump (Bsep), multidrug resistance-associated protein 2 (Mrp2), Na+-dependent taurocholate cotransporting polypeptide (Ntcp), and organic anion transporter polypedtides (Oatps) in iHep cells were significantly improved after transfection of hepatocyte nuclear factor 4 alpha (Hnf4α) and treatment with selected inducers. In vitro intrinsic biliary clearances (CLb,int) of optimized iHep cells for rosuvastatin, methotrexate, d8-TCA (deuterium-labeled sodium taurocholate acid) and DPDPE ([D-Pen2,5] enkephalin hydrate) correlated well with that of sandwich-cultured primary mouse hepatocytes (SCMHs) (r2 = 0.984). Cholestatic drugs were evaluated and the results were compared well with primary mice hepatocytes. CONCLUSION: The optimized iHep cells expressed functional drug transporters and were comparable to primary mice hepatocytes. This study suggested direct reprogramming could provide a potential alternative to primary hepatocytes for drug candidate hepatobiliary disposition and hepatotoxicity screening.

Inhibition of hepatic cytochrome P450 enzymes and sodium/bile acid cotransporter exacerbates leflunomide-induced hepatotoxicity.

AIM: Leflunomide is an immunosuppressive agent marketed as a disease-modifying antirheumatic drug. But it causes severe side effects, including fatal hepatitis and liver failure. In this study we investigated the contributions of hepatic metabolism and transport of leflunomide and its major metabolite teriflunomide to leflunomide induced hepatotoxicity in vitro and in vivo. METHODS: The metabolism and toxicity of leflunomide and teriflunomide were evaluated in primary rat hepatocytes in vitro. Hepatic cytochrome P450 reductase null (HRN) mice were used to examine the PK profiling and hepatotoxicity of leflunomide in vivo. The expression and function of sodium/bile acid cotransporter (NTCP) were assessed in rat and human hepatocytes and NTCP-transfected HEK293 cells. After Male Sprague-Dawley (SD) rats were administered teriflunomide (1,6, 12 mg · kg(-1) · d(-1), ig) for 4 weeks, their blood samples were analyzed. RESULTS: A nonspecific CYPs inhibitor aminobenzotriazole (ABT, 1 mmol/L) decreased the IC50 value of leflunomide in rat hepatocytes from 409 to 216 µmol/L, whereas another nonspecific CYPs inhibitor proadifen (SKF, 30 µmol/L) increased the cellular accumulation of leflunomide to 3.68-fold at 4 h. After oral dosing (15 mg/kg), the plasma exposure (AUC0-t) of leflunomide increased to 3-fold in HRN mice compared with wild type mice. Administration of leflunomide (25 mg·kg(-1) · d(-1)) for 7 d significantly increased serum ALT and AST levels in HRN mice; when the dose was increased to 50 mg·kg(-1) · d(-1), all HRN mice died on d 6. Teriflunomide significantly decreased the expression of NTCP in human hepatocytes, as well as the function of NTCP in rat hepatocytes and NTCP-transfected HEK293 cells. Four-week administration of teriflunomide significantly increased serum total bilirubin and direct bilirubin levels in female rats, but not in male rats. CONCLUSION: Hepatic CYPs play a critical role in detoxification process of leflunomide, whereas the major metabolite teriflunomide suppresses the expression and function of NTCP, leading to potential cholestasis.

[Advances in studies on chemical compositions of Atractylodes lancea and their biological activities].

This article mainly summarises the results of the chemical compositions and its pharmacological activities of Atractylodes Radix. The chemistry components isolated from Atractylodes Radix are mainly sesquiterpenoids, enediynes, triterpenoids, aromatic glycosides, and etc. Pharmacological results showed that Atractylodes Radix has inhibition of gastric acid secretion, promoting gastrointestinal movement and gastric emptying, hpyerglycemic, antibacterial, anti-inflammatory, cardiovascular protection and nervous system activity, etc. This article hopefully to provide a reference for further research, development and utilization of Atractylodes Radix.

Organic anion-transporting polypeptides contribute to the hepatic uptake of berberine.

1. The purpose of this study was to investigate the mechanism of hepatic uptake of berberine. Berberine accumulation in hepatocytes was found to be highly dependent on active uptake, which could not be explained by liver organic cation transporter (OCT) alone. 2. Our studies indicated that berberine uptake was significantly suppressed by rifampicin, cyclosporine A and glycyrrhizic acid, which act as specific inhibitors of different Oatp isoforms (Oatp1a1, Oatp1a4 and Oatp1b2) in rat hepatocytes. The combination of OCT and OATP inhibitors further reduced berberine accumulation in both rat and human hepatocytes. The uptake of berberine could be increased in human HEK293-OATP1B3 but not in OATP1B1-transfected HEK 293 cells. 3. Rifampicin could reduce the berberine liver extraction ratio (ER) and double its concentration in the effluent in isolated rat livers. Further in vivo study indicated that berberine plasma exposure could be significantly increased by co-administration of the OATP inhibitor rifampicin or the substrate rosuvastatin. 4. In conclusion, this study demonstrated that both OCT and OATP contribute to the accumulation of berberine in the liver. OATPs may have important roles in berberine liver disposition and potential clinically relevant drug--drug interactions.

Timosaponin A3 induces hepatotoxicity in rats through inducing oxidative stress and down-regulating bile acid transporters.

AIM: To investigate the mechanisms underlying the hepatotoxicity of timosaponin A3 (TA3), a steroidal saponin from Anemarrhena asphodeloides, in rats. METHODS: Male SD rats were administered TA3 (100 mg·kg(-1)·d(-1), po) for 14 d, and the blood and bile samples were collected after the final administration. The viability of a sandwich configuration of cultured rat hepatocytes (SCRHs) was assessed using WST-1. Accumulation and biliary excretion index (BEI) of d8-TCA in SCRHs were determined with LC-MS/MS. RT-PCR and Western blot were used to analyze the expression of relevant genes and proteins. ROS and ATP levels, and mitochondrial membrane potential (MMP) were measured. F-actin cytoskeletal integrity was assessed under confocal microscopy. RESULTS: TA3 administration in rats significantly elevated the total bile acid in serum, and decreased bile acid (BA) component concentrations in bile. TA3 inhibited the viability of the SCRHs with an IC50 value of 15.21±1.73 µmol/L. Treatment of the SCRHs with TA3 (1-10 µmol/L) for 2 and 24 h dose-dependently decreased the accumulation and BEI of d8-TCA. The TA3 treatment dose-dependently decreased the expression of BA transporters Ntcp, Bsep and Mrp2, and BA biosynthesis related Cyp7a1 in hepatocytes. Furthermore, the TA3 treatment dose-dependently increased ROS generation and HO-1 expression, decreased the ATP level and MMP, and disrupted F-actin in the SCRHs. NAC (5 mmol/L) significantly ameliorated TA3-induced effects in the SCRHs, whereas mangiferin (10-200 µg/mL) almost blocked TA3-induced ROS generation. CONCLUSION: TA3 triggers liver injury through inducing ROS generation and suppressing the expression of BA transporters. Mangiferin, an active component in Anemarrhena, may protect hepatocytes from TA3-induced hepatotoxicity.