Attenuation by Time-Restricted Feeding of High-Fat and High-Fructose Diet-Induced NASH in Mice Is Related to Per2 and Ferroptosis.

Nonalcoholic steatohepatitis (NASH) is a chronic and progressive disease whose treatment strategies are limited. Although time-restricted feeding (TRF) is beneficial for metabolic diseases without influencing caloric intake, the underlying mechanisms of TRF action in NASH and its efficacy have not yet been demonstrated. We herein showed that TRF effectively alleviated NASH, producing a reduction in liver enzymes and improvements in liver pathology. Regarding the mechanisms by which TRF mitigates NASH, we ascertained that TRF inhibited ferroptosis and the expression of the circadian gene Per2. By adopting a hepatocyte-specific Per2-knockout (Per2△hep) mice model, we clarified the critical role of Per2 in exacerbating NASH. According to the results of our RNA-Seq analysis, the knockout of Per2 ameliorated NASH by inhibiting the onset of ferroptosis; this was manifested by diminished lipid peroxidation levels, decreased mRNA and protein levels for ferroptosis-related genes, and alleviated morphologic changes in mitochondria. Furthermore, using a ferroptosis inhibitor, we showed that ferroptosis significantly aggravated NASH and noted that this was likely achieved by regulation of the expression of peroxisome proliferator activated receptor (PPAR)α. Finally, we discerned that TRF and hepatocyte-specific knockout of Per2 promoted the expression of PPARα. Our results revealed a potential for TRF to effectively alleviate high-fat and high-fructose diet-induced NASH via the inhibition of Per2 and depicted the participation of Per2 in the progression of NASH by promoting ferroptosis, which was ultimately related to the expression of PPARα.

Mechanisms of ductular reaction in non-alcoholic steatohepatitis.

Non-alcoholic fatty liver disease (NAFLD) is a disease spectrum caused in part by insulin resistance and genetic predisposition. This disease is primarily characterized by excessive lipid accumulation in hepatocytes in the absence of alcohol abuse and other causes of liver damage. Histologically, NAFLD is divided into several periods: simple steatosis, non-alcoholic steatohepatitis (NASH), hepatic fibrosis, cirrhosis, and hepatocellular carcinoma. With the increasing prevalence of obesity and hyperlipidemia, NAFLD has become the main cause of chronic liver disease worldwide. As a result, the pathogenesis of this disease is drawing increasing attention. Ductular reaction (DR) is a reactive bile duct hyperplasia caused by liver injury that involves hepatocytes, cholangiocytes, and hepatic progenitor cells. Recently, DR is shown to play a pivotal role in simple steatosis progression to NASH or liver fibrosis, providing new research and treatment options. This study reviews several DR signaling pathways, including Notch, Hippo/YAP-TAZ, Wnt/ß-catenin, Hedgehog, HGF/c-Met, and TWEAK/Fn14, and their role in the occurrence and development of NASH.

Effectiveness of Tenofovir Alafenamide in Chronic Hepatitis B Patients with Normal Alanine Aminotransferase and Positive Hepatitis B Virus DNA.

BACKGROUND AND AIMS: With an increasing understanding of hepatitis B, the antiviral indications have been broadening gradually. To evaluate the effectiveness of tenofovir alafenamide (TAF) in chronic hepatitis B (CHB) patients with normal alanine aminotransferase (ALT) and detectable hepatitis B virus (HBV) DNA, those who are ineligible for broader antiviral criteria from the Chinese CHB prevention guide (2019). METHODS: A total of 117 patients were recruited and their data were collected from paper or electronic medical records. HBV DNA and liver function were measured at baseline and throughout the 24-week follow-up. The effectiveness endpoint was complete virological response. The safety endpoint was the first occurrence of any clinical adverse event during the treatment. RESULTS: Among the 117 patients, 45 had normal ALT as well as detectable HBV DNA and they were not recommended for antiviral therapy according to Chinese Guidelines (2019). After TAF antiviral therapy, the rates of patients who achieved HBV DNA <20 IU/mL at 4, 12 and 24 weeks were 77.1%, 96.7% and 96.8% respectively. Among them, the undetectable rates of HBV DNA in patients with low baseline viral load at 4, 12 and 24 weeks were 92.3%, 100% and 100%, while the rates of those with high baseline viral load were 68.2%, 94.1% and 94.4%. Compared with 71.4%, 94.4% and 94.7% in the high baseline group, the undetectable rates of HBV DNA at 4, 12 and 24 weeks in the low baseline liver stiffness group were 85.7%, 100% and 100%. There was no statistical significance among the above groups. CONCLUSIONS: CHB patients who had normal ALT and detectable HBV DNA and did not meet "CHB prevention guide (2019)", could achieve complete virological response in 24 weeks after antiviral treatment by TAF.

[Characteristics of Water-soluble Inorganic Ions in PM2.5 in Beijing During 2017-2018].

To explore the characteristics of water-soluble inorganic ions (WSIIs) in PM2.5 during the process of continuous improvement of air quality in Beijing in recent years, a continuous collection of PM2.5 sample campaign was conducted in Beijing from 2017 to 2018. The PM2.5 mass concentration and WSIIs were then determined. The results showed that the average concentration of PM2.5 in Beijing was (77.1±52.1) µg ·m-3, with the highest and lowest values during spring [(102.9±69.1) µg ·m-3]and summer [(54.7±19.9) µg ·m-3], respectively. The average concentration of WSIIs was (31.7±30.1) µg ·m-3, accounting for 41.1% of the PM2.5 mass, and the seasonal contributions were: autumn (45.9%) > summer (41.9%) > spring (39.9%) ≥ winter (39.2%). SNA was an important component of the WSIIs that accounted for 86.0%, 89.5%, 74.6%, and 73.0% of the total WSIIs during spring, summer, autumn, and winter, respectively. With an increase in temperature, the concentration of NO3- increased initially and then decreased, while the concentration of SO42- increased. When the relative humidity was less than 90%, the concentrations of both NO3- and SO42- increased with an increase in relative humidity. With the aggravation of pollution, the overall contribution of WSIIs in PM2.5 increased significantly, and the evolution characteristics of different ions were different. Among them, the concentration and contribution of NO3- continued to increase, while the contributions of SO42- and the ions from dust (Mg2+, Ca2+, and Na+) decreased. During the observation period, the primary sources of WSIIs were secondary conversion, combustion source, and dust. The control of coal combustion and motor vehicles is critical to reduce the emission of WSIIs. The backward trajectory analysis showed that the air masses from the south and west of Beijing corresponded to the high PM2.5 concentration and proportion of WSIIs, and the contribution of secondary ions was significant. However, the concentrations and proportions of the air masses from the northwest and north were relatively low, but the contribution of Ca2+ was high.

[Characteristics of Carbonaceous Species in PM2.5 in Southern Beijing].

To investigate the characteristics of carbonaceous species in PM2.5 in Beijing after the implementation of the Action Plan for the Prevention and Control of Air Pollution, PM2.5 was continuously sampled in the heavily polluted southern urban area of Beijing from December 2017 to December 2018. The characteristics of organic carbon (OC) and element carbon (EC) were then determined. The results showed that the annual concentrations of PM2.5, OC, and EC in Beijing varied in wide ranges of 4.2-366.3, 0.9-74.5, and 0.0-5.5 µg ·m-3, respectively, and the average mass concentration were (77.1±52.1), (11.2±7.8), and (1.2±0.8) µg ·m-3. Overall, the carbonaceous species (OC and EC) accounted for 16.1% of the PM2.5 mass. The seasonal characteristics of the OC mass concentrations were: winter [(13.8±8.7) µg ·m-3] > spring [(12.7±9.6) µg ·m-3] > autumn [(11.8±6.2) µg ·m-3] > summer [(6.5±2.1) µg ·m-3]. The concentration of the EC during the four seasons was low, ranging from 0.8 to 1.5 µg ·m-3. The annual average mass concentration and contribution of secondary organic carbon (SOC) were (5.4±5.8) µg ·m-3 and 48.2%, respectively, highlighting the significant contribution of the secondary process. With the aggravation of pollution, although the contribution proportion of OC and EC decreased, their mass concentrations during "heavily polluted" days were 6.3 and 3.2 times that of "excellent" days, respectively. Compare to non-heating period, the mass concentrations of PM2.5, OC, and SOC increased by 14.4%, 47.9%, and 72.1% in heating period, respectively, which emphasized the importance of carbonaceous species during heating periods. Potential source contribution function (PSCF) analysis showed that the southwest areas of Beijing (such as Shanxi and Henan province) were the main potential source areas of PM2.5 and OC. The high value area of the PSCF of EC was less and the main potential source area was in the south of Beijing (such as Shandong and Henan province).

[Concentrations and Size Distributions of Water-soluble Inorganic Ions in Aerosol Particles in Taiyuan, Shanxi].

Size-resolved filter samples were collected in Taiyuan every other week from June 2012 to May 2014. The mass concentrations of water-soluble ions (Na+, NH4+, K+, Mg2+, Ca2+, F-, Cl-, NO3- and SO42-) were measured by ion chromatography. The results showed that the total concentrations of measured water-soluble ions were (15.39±9.91), (21.10±15.49) and (36.34±18.51) µg·m-3 in PM1.1, PM2.1 and PM9, respectively. In PM1.1 and PM2.1, secondary water-soluble ions (SO42-, NO3- and NH4+) comprised 87.59% and 86.30% of all water-soluble ions, respectively, while in PM9, SO42- and Ca2+ comprised 32.78% and 28.54% of all water-soluble ions, respectively. SO42- and NH4+ had higher concentrations in winter and summer, and lower in spring and autumn. NO3-, K+and Cl- presented similar seasonal variation with a descending order of winter >autumn >spring >summer, and Ca2+ and Mg2+ followed the sequence of spring >winter >autumn >summer. SO42- and NH4+ showed a unimodal size distribution and the peak in the fine mode shifted from 0.43-0.65 µm in spring and autumn to 0.65-1.1 µm in summer. NO3- showed a bimodal size distribution. NO3- and NH4+ were dominated by the fine mode peaking at 0.43-2.1 µm in winter, and NO3- was dominated by the coarse mode peaking at 4.7-5.8 µm in summer. K+, Na+and Cl- also showed a bimodal size distribution with the fine mode at 0.43-1.1 µm and the coarse mode at 4.7-5.8 µm. Ca2+, Mg2+ and F- were unimodal with the peak in the coarse mode of 4.7-5.8 µm. On heavily polluted days, the mass concentrations of secondary water-soluble ions and Cl- accumulated, and secondary water-soluble ions were unimodal with the peak in the fine mode of 1.1-2.1 µm. However, on clear days, secondary water-soluble ions showed a bimodal size distribution with the fine mode at 0.43-0.65 µm and the coarse mode at 4.7-5.8 µm. The peak of secondary water-soluble ions in the fine mode shifted. PCA analysis showed that the sources of water-soluble ions were dominated by the secondary formation, coal combustion, industrial emission, biomass burning, and soil particles or falling dust.

[Comparative Analysis and Inspiration of Air Quality Index Between China and America].

Research on the differences of air quality index (AQI) especially AQI of particulate matters between China and America and analysis of hourly monitored readings from April to December in 2013 released by Environmental Monitoring Station of China indicated that: (1) Although China lagged behind America in formulating and publishing of AQI standards, the AQI standards published in 2012 in China covered more pollutant indexes than before and could objectively reflect the characteristics of air pollution in China, and were more close to the residens's feeling about air quality. (2) The methods adopted for calculation of particulate matter hourly AQI were different in China and America, and the comparison revealed that the calculation method adopted by China using the 24 h average concentration breakpoint of particulate matters to replace the 1 h average concentration breakpoint would enhance the severity of the pollution level. (3) The breakpoint of PM2.5 -24 h in China was less rigorous than that in America when AQI < 200, which led to the inconsistence between the ratio of PM2.5/PM10 and the real situation in China. (4) Analysis on the monitoring readings from station of Beijing Olympic Sports Center showed that when AQI < 50, the ratio of PM2.5/PM10 was less than 0.5 and increased with.the increasing of AQI. Correction and adjustment of particulate matter real-time calculation method and breakpoints of PM2.5 and PM10 were suggested in China.

[Comparative Analysis on the Improvement of Air Quality in Beijing During APEC].

In order to evaluate the effects of the implementation of emission reduction measures and the revolution of air quality of Beijing during APEC, the evolution characteristics of air quality was analyzed based on the hourly monitored readings of Olympic Sports Center from 1 to 15 November 2014 released by Environmental Monitoring Station of China, and compared with that in 2013. The results showed that: (1) PM2.5 was the main pollutant in Beijing. The air quality was good during the period of APEC with three obvious pollution events, and it was better than that in the same period in 2013, indicating that the implementation of emission reduction measures had made significant contribution to the improvement of air quality. (2) During the period of APEC, the concentrations of PM2.5 of 5 days were below the World Health Organization (WHO) standard (25 µg · m⁻³), and the concentration of SO2 met the WHO standard during this time. (3) During the period of APEC, the ratio of PM2.5, and PM10 was less than 0.5 when the air quality was good, and gradually increased with the increasing pollution level. The ratio reached 0.9 when the air was seriously polluted. (4) Compared with the same time in 2013, although the implementation of emission reduction measures made contribution to the reduction of the concentration of PM2.5, its contributions to the reduction of SO2 and CO concentration were much more obvious than that of PM2.5, and it had little impact on the reduction of NO2 concentration, and the reduction order of pollutants emission was SO2 > CO > PM > NO2, indicating that the sources, effects and emission reduction of PM2.5 were complex, and further studies are required.

[Analysis on Regional Characteristics of Air Quality Index and Weather Situation in Beijing and Its Surrounding Cities During the APEC].

Analysis on the revolution and regional characteristics of air quality by hourly monitored readings from 1 to 15 November 2014 released by Environmental Monitoring Station of China and research of the impacts of weather situation and meteorological elements released by China Meteorological Administration towards air quality of Beijing and its surrounding cities during the Asia-Pacific Economic Cooperation (APEC) indicated that: (1) The air quality was good because of the implementation of mitigation measures, while the Air Quality Index (AQI) increased along with the termination of mitigation measures. Thus it can be seen that mitigation measures made a great contribution to the improvement of air quality of Beijing and its surrounding cities. (2) Affected by thermal inversion layer, AQI of Beijing and its surrounding cities increased quickly during the initial of the implemental of reducing measures which proved that pollutants would accumulate in the context of unfavourable weather, hence the influence of weather situation towards air quality could not be ignored. (3) Although affected by thermal inversion layer, the concentration of pollutants of Beijing was not accumulated to a high degree at the end period of reducing measures, while Tianjin, Tangshan, Baoding and Xingtai suffered from moderate and severe pollution at the same time which further illustrated that the implementation of mitigation measures have made a great contribution to the improvement of air quality in Beijing during APEC.