EGCG suppressed activation of hepatic stellate cells by regulating the PLCE1/IP3/Ca2+ pathway.

(-)-Epigallocatechin-3-O-gallate (EGCG), one of the green tea catechins, exhibits significant antioxidant properties that play an essential role in various diseases. However, the functional role and underlying mechanism of EGCG in stimulating of hepatic stellate cells (HSCs) remain unexplored in transcriptomics sequencing studies. The present study suggests that oral administration of EGCG at a dosage of 200 mg/kg/day for a duration of four weeks exhibits significant therapeutic potential in a murine model of liver fibrosis induced by CCl4. The activation of HSCs in vitro was dose-dependently inhibited by EGCG. The sequencing analysis data reveled that EGCG exerted a regulatory effect on the calcium signal in mouse HSCs, resulting in a decrease in calcium ion concentration. Further analysis revealed that EGCG inhibited the expression of phospholipase C epsilon-1 (PLCE1) and inositol 1, 4, 5-trisphosphate (IP3) in activated mouse HSCs. Additionally, EGCG contributes to the reduction the concentration of calcium ions by regulating PLCE1. After the knockdown of PLCE1, free calcium ion concentrations decreased, resulting in the inhibition of both cell proliferation and migration. Interestingly, the expression of PLCE1 and cytosolic calcium levels were regulated by reactive oxygen species(ROS). Furthermore, our findings suggest that ROS might inhibit the expression of PLCE1 by inhibiting TFEB, a transcription activator involved in the nuclear translocation process. Our study provided novel evidence regarding the regulatory effects of EGCG on activated HSCs (aHSCs) in mice by the calcium signaling pathway, emphasizing the crucial role of PLCE1 within the calcium signaling network of HSCs. The proposition was also made that PLCE1 holds promise as a novel therapeutic target for murine liver fibrosis.

Multifunctional chitosan-based hydrogels loaded with iridium nanoenzymes for skin wound repair.

Hemostasis, infection, oxidative stress, and inflammation still severely impede the wound repair process. It is significant to develop multifunctional wound dressings that can function as needed in various stages of wound healing. In this study, iridium nanoparticles (IrNPs) with multi-enzyme mimetic activity were complexed with chitosan (CS) and fucoidan (FD) for the first time to make a multifunctional CS/FD/IrNPs hydrogel with excellent antioxidant effect. The hydrogel has excellent physicochemical properties. In particular, the incorporation of IrNPs imparts excellent antioxidant properties to the hydrogel, which could scavenge reactive oxygen species (ROS). In addition, the hydrogel shows excellent hemostatic and antibacterial properties. The CS/FD/IrNPs hydrogel performs fast and efficient hemostasis in 21 s. Moreover, the blood loss of the CS/FD/IrNPs hydrogel group was approximately 10% of that in the control group and the antibacterial rate of CS/FD/IrNPs hydrogel against E. coli and S. aureus was up to 95 %. In vivo results demonstrate that CS/FD/IrNPs hydrogel promotes wound healing by attenuating ROS levels, reducing oxidative damage, mitigating inflammation, and accelerating angiogenesis. To summarize, the CS/FD/IrNPs hydrogel system, with hemostatic, antibacterial, antioxidant, anti-inflammatory and pro-healing activities, can be a promising and effective strategy for the treatment of clinically difficult-to-heal wounds.

ß-hydroxybutyrate restrains colitis-associated tumorigenesis by inhibiting HIF-1α-mediated angiogenesis.

Decreased levels of ß-hydroxybutyrate (BHB), a lipid metabolic intermediate known to slow the progression of colorectal cancer (CRC), have been observed in the colon mucosa of patients with inflammatory bowel diseases (IBD). In particular, patients with recurrent IBD present an increased risk of developing colitis-associated colorectal cancer (CAC). The role and molecular mechanism of BHB in the inflammatory and carcinogenic process of CAC remains unclear. Here, the anti-tumor effect of BHB was investigated in the Azoxymethane (AOM)/Dextran Sulfate Sodium (DSS)-induced CAC model and tumor organoids derivatives. The underlying mechanisms were studied using transcriptome and non-target metabolomic assay and further validated in colon tumor cell lineage CT26 in vitro. The tumor tissues and the nearby non-malignant tissues from colon cancer patients were collected to measure the expression levels of ketogenic enzymes. The exogenous BHB supplement lightened tumor burden and angiogenesis in the CAC model. Notably, transcriptome analysis revealed that BHB effectively decreased the expression of VEGFA in the CAC tumor mucosa. In vitro, BHB directly reduced VEGFA expression in hypoxic-treated CT26 cells by targeting transcriptional factor HIF-1α. Conversely, the deletion of HIF-1α largely reversed the inhibitory effect of BHB on CAC tumorigenesis. Additionally, decreased expression of ketogenesis-related enzymes in tumor tissues were associated with poor survival outcomes in patients with colon cancer. In summary, BHB carries out anti-angiogenic activity in CAC by regulating HIF-1α/VEGFA signaling. These findings emphasize the role of BHB in CAC and may provide novel perspectives for the prevention and treatment of colonic tumors.

Autophagic degradation of MVBs in LSECs promotes Aldosterone induced-HSCs activation.

BACKGROUND AND AIMS: The important role of extracellular vesicles (EVs) in liver fibrosis has been confirmed. However, EVs derived from liver sinusoidal endothelial cells (LSECs) in the activation of hepatic stellate cells (HSCs) and liver fibrosis is still unclear. Our previous work demonstrated that Aldosterone (Aldo) may have the potential to regulate EVs from LSECs via autophagy pathway. Thus, we aim to investigate the role of Aldo in the regulation of EVs derived from LSECs. APPROACH AND RESULTS: Using an Aldo-continuous pumping rat model, we observed that Aldo-induced liver fibrosis and capillarization of LSECs. In vitro, transmission electron microscopy (TEM) revealed that stimulation of Aldo led to the upregulation of autophagy and degradation of multivesicular bodies (MVBs) in LSECs. Mechanistically, Aldo upregulated ATP6V0A2, which promoted lysosomal acidification and subsequent autophagy in LSECs. Inhibiting autophagy with si-ATG5 adeno-associated virus (AAV) in LSECs effectively mitigated Aldo-induced liver fibrosis in rats. RNA sequencing and nanoparticle tracking (NTA) analyses of EVs derived from LSECs indicated that Aldo result in a decrease in both the quantity and quality of EVs. We also observed a reduction in the protective miRNA-342-5P in EVs derived from Aldo-treated LSECs, which may play a critical role in HSCs activation. Target knockdown of EV secretion with si-RAB27a AAV in LSECs led to the development of liver fibrosis and HSC activation in rats. CONCLUSION: Aldo-induced Autophagic degradation of MVBs in LSECs promotes a decrease in the quantity and quality of EVs derived from LSECs, resulting in the activation of HSCs and liver fibrosis under hyperaldosteronism. Modulating the autophagy level of LSECs and their EV secretion may represent a promising therapeutic approach for treating liver fibrosis.

Molten salt electrolytic synthesis of porous carbon from SiC and its application in supercapacitors.

Nanoscale porous carbide-derived carbon (CDC) microspheres were successfully synthesized via the electrolysis etching of nano-SiC microsphere powder precursors with a particle diameter of 200 to 500 nm in molten CaCl2. Electrolysis was conducted at 900 °C for 14 h in argon at an applied constant voltage of 3.2 V. The results show that the obtained product is SiC-CDC, which is a mixture of amorphous carbon and a small quantity of ordered graphite with a low degree of graphitization. Similar to the SiC microspheres, the obtained product retained its original shape. The specific surface area was 734.68 m2 g-1. The specific capacitance of the SiC-CDC was 169 F g-1, and it exhibited excellent cycling stability (98.01% retention of the initial capacitance after 5000 cycles) at a current density of 1000 mA g-1.

Caveolin-1 depletion attenuates hepatic fibrosis via promoting SQSTM1-mediated PFKL degradation in HSCs.

The key glycolytic enzyme phosphofructokinase (PFK) is responsible for maintaining glycolytic stability and an important energy source for activating hepatic stellate cells (HSCs). However, its regulation in activated HSCs remains unclear. Caveolin-1 (Cav1), a major constituent of caveolae, has emerged as a key target for triggering glycolysis. However, the relationship between Cav1 and glycolysis during HSC activation is not well established. In this study, Cav1 was upregulated in mouse and human fibrotic liver tissues. We concluded that HSC-specific Cav1 knockdown markedly alleviates liver injury and fibrosis. Mechanistically, Cav1 was elevated during primary mouse HSC activation, competing with SQSTM1 for the regulatory subunit of PFK liver type and inhibiting the SQSTM1-mediated autophagy-independent lysosomal degradation pathway to sustain HSC activation. We also identified the heptapeptide alamandine as a promising therapeutic agent that downregulates Cav1 protein levels via proteasomal degradation and may impair glycolysis. Our study provides evidence of the crucial role and mechanism of Cav1 in the glucose metabolic network in HSCs and highlights Cav1 as a critical therapeutic target for the treatment of liver fibrosis.

Sacubitril/valsartan alleviates sepsis-induced acute lung injury via inhibiting GSDMD-dependent macrophage pyroptosis in mice.

Sepsis-induced acute lung injury (ALI) is a life-threatening disorder with intricate pathogenesis. Macrophage pyroptosis reportedly plays a vital role in ALI. Although it has been established that angiotensin receptor blockers (ARBs) can reduce sepsis-induced organ injury, the efficacy of sacubitril/valsartan (SV) for sepsis has been largely understudied. Here, we aimed to investigate the role of SV in sepsis-induced ALI. Caecal ligation and puncture (CLP) were used to induce polymicrobial sepsis and related ALI. The therapeutic effects of SV in CLP mice were subsequently assessed. Gasdermin D (GSDMD)-/- mice were used to validate the signalling pathways affected by SV. In vitro, mouse bone marrow-derived macrophages (BMDMs) and Raw264.7 cells were treated with SV following exposure to lipopolysaccharide and adenosine triphosphate. Finally, the serum obtained from 42 septic patients was used for biochemical analysis. Compared to the other ARBs, SV yielded more pronounced anti-inflammatory effects on macrophages. In vivo, SV decreased mortality rates, significantly reduced lung damage and prevented the inflammatory response in CLP mice. In addition, SV suppressed GSDMD-mediated macrophage pyroptosis in mice. In BMDMs and Raw264.7 cells, the anti-inflammatory and anti-pyroptosis properties of SV were verified. SV treatment effectively inhibited NLRP3 inflammasome activation and prevented macrophage pyroptosis in a GSDMD-dependent manner. Furthermore, we found that septic individuals had considerably higher serum angiotensin II levels. Overall, we found that SV might prevent ALI in CLP mice by inhibiting GSDMD-mediated pyroptosis of macrophages. Thus, SV might be a viable drug for sepsis-induced ALI.

The regionalized ecological, economic and social benefit of China's sloping cropland erosion control during the 12th five-year plan (2011-2015).

With Kriging interpolation, analytic hierarchy process and grey relational analysis, this paper evaluates the regionalized benefit of China's sloping cropland erosion control (SCEC) during 2011-2015, including the ecological, economic, social benefit and the comprehensive benefit. The results show that, in the ecological benefits, the distribution of soil erosion control degree presents patchy characteristics. The reduction of runoff modulus gradually decreases from southeast to northwest. The reduction of soil erosion modulus is the largest in the Northwest Loess Plateau and the smallest in the Northeast Black Soil Zone. In the economic benefits, the increase in the annual output value per unit land area is characterized by "high in the south and low in the north", but there are patchy high-value areas in central Loess Plateau and the Northern Earthy-Rocky Mountain Zone. The increase in the agricultural population's per capita income is higher in the western area than that in the eastern area. In the social benefits, the per capita grain increase in most of the northern China is larger than that in the south, while the characteristic agricultural development in the south is more advantageous than that in the north. The comprehensive benefit is "high in the south and low in the north; highest in the southwest and lowest in the northeast". The spatial heterogeneity implies the necessity to specify the influencing factors for the SCEC benefit in different areas and take pointed measures to improve the benefit.

Association between ambient temperature and hypertensive disorders in pregnancy in China.

Hypertensive disorders in pregnancy (HDPs) are leading perinatal diseases. Using a national cohort of 2,043,182 pregnant women in China, we evaluated the association between ambient temperatures and HDP subgroups, including preeclampsia or eclampsia, gestational hypertension, and superimposed preeclampsia. Under extreme temperatures, very cold exposure during preconception (12 weeks) increases odds of preeclampsia or eclampsia and gestational hypertension. Compared to preconception, in the first half of pregnancy, the impact of temperature on preeclampsia or eclampsia and gestational hypertension is opposite. Cold exposure decreases the odds, whereas hot exposure increases the odds. Under average temperatures, a temperature increase during preconception decreases the risk of preeclampsia or eclampsia and gestational hypertension. However, in the first half of pregnancy, temperature is positively associated with a higher risk. No significant association is observed between temperature and superimposed preeclampsia. Here we report a close relationship exists between ambient temperature and preeclampsia or eclampsia and gestational hypertension.

Spatiotemporal distributions of ambient SO2 across China based on satellite retrievals and ground observations: Substantial decrease in human exposure during 2013-2016.

Multiyear spatiotemporal distributions of daily ambient sulfur dioxide (SO2) are essential for evaluating management effectiveness and assessing human health risk. In this study, we estimate the daily SO2 levels across China on 0.1o grid from 2013 to 2016 by assimilating satellite- and ground-based SO2 observations using the random-forest spatiotemporal kriging (RF-STK) model. The cross-validation R2 is 0.64 and 0.81 for predicting the daily and multiyear averages, respectively. The multiyear population-weighted average of SO2 for China is 28.1 ±â€¯14.0 µg/m3, and the severest SO2 pollution occurs in the northern China (45.1 ±â€¯14.7 µg/m3). The SO2 concentration shows a strong seasonality, i.e., highest in winter (41.6 ±â€¯26.4 µg/m3) and lowest in summer (19.6 ±â€¯8.3 µg/m3). During 2013-2016, the annual SO2 decreases from 34.4 ±â€¯18.2 to 22.7 ±â€¯11.1 µg/m3, and the population% exposed for more than 100 nonattainment days (SO2 > 20 µg/m3) drops from 86% to 48%. While the seasonality of SO2 is mainly determined by the meteorological variation, the substantial decrease attributes to the reduced emissions such as from coal consumption. The effectiveness of SO2 emission reduction varies widely in different prefectures of China. In Shandong province, the SO2 concentration decreases by -45% while the coal consumption increases by 9%. In Shanxi province, the SO2 concentration decreases by -15% while the coal consumption decreases by -3%. The contrasting effectiveness between these two provinces is associated with the much fewer waste gas disposal facilities in Shanxi than Shandong. Stricter regulation is required to further lower the SO2 concentration in order to protect the public health, especially in the northern China.

Assessing Susceptibility of Debris Flow in Southwest China Using Gradient Boosting Machine.

A gradient boosting machine (GBM) was developed to model the susceptibility of debris flow in Sichuan, Southwest China for risk management. A total of 3839 events of debris flow during 1949-2017 were compiled from the Sichuan Geo-Environment Monitoring program, field surveys, and satellite imagery interpretation. In the cross-validation, the GBM showed better performance, with the prediction accuracy of 82.0% and area under curve of 0.88, than the benchmark models, including the Logistic Regression, the K-Nearest Neighbor, the Support Vector Machine, and the Artificial Neural Network. The elevation range, precipitation, and aridity index played the most important role in determining the susceptibility. In addition, the water erosion intensity, road construction, channel gradient, and human settlement sites also largely contributed to the formation of debris flow. The susceptibility map produced by the GBM shows that the spatial distributions of high-susceptibility watersheds were highly coupled with the locations of the topographical extreme belt, fault zone, seismic belt, and dry valleys. This study provides critical information for risk mitigating and prevention of debris flow.