Six-Transmembrane Epithelial Antigen of the Prostate 3 Deficiency in Hepatocytes Protects the Liver Against Ischemia-Reperfusion Injury by Suppressing Transforming Growth Factor-ß-Activated Kinase 1.

BACKGROUND AND AIMS: Hepatic ischemia-reperfusion (I/R) injury remains a major challenge affecting the morbidity and mortality of liver transplantation. Effective strategies to improve liver function after hepatic I/R injury are limited. Six-transmembrane epithelial antigen of the prostate 3 (Steap3), a key regulator of iron uptake, was reported to be involved in immunity and apoptotic processes in various cell types. However, the role of Steap3 in hepatic I/R-induced liver damage remains largely unclear. APPROACH AND RESULTS: In the present study, we found that Steap3 expression was significantly up-regulated in liver tissue from mice subjected to hepatic I/R surgery and primary hepatocytes challenged with hypoxia/reoxygenation insult. Subsequently, global Steap3 knockout (Steap3-KO) mice, hepatocyte-specific Steap3 transgenic (Steap3-HTG) mice, and their corresponding controls were subjected to partial hepatic warm I/R injury. Hepatic histology, the inflammatory response, and apoptosis were monitored to assess liver damage. The molecular mechanisms of Steap3 function were explored in vivo and in vitro. The results demonstrated that, compared with control mice, Steap3-KO mice exhibited alleviated liver damage after hepatic I/R injury, as shown by smaller necrotic areas, lower serum transaminase levels, decreased apoptosis rates, and reduced inflammatory cell infiltration, whereas Steap3-HTG mice had the opposite phenotype. Further molecular experiments showed that Steap3 deficiency could inhibit transforming growth factor-ß-activated kinase 1 (TAK1) activation and downstream c-Jun N-terminal kinase (JNK) and p38 signaling during hepatic I/R injury. CONCLUSIONS: Steap3 is a mediator of hepatic I/R injury that functions by regulating inflammatory responses as well as apoptosis through TAK1-dependent activation of the JNK/p38 pathways. Targeting hepatocytes, Steap3 may be a promising approach to protect the liver against I/R injury.

Prognostic factors of recurrent intrahepatic cholangiocarcinoma after hepatectomy: A retrospective study.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is a highly malignant tumour. Hepatectomy is an effective treatment for early ICC, but postoperative recurrence greatly affects patient survival. Studies on recurrent ICC after hepatectomy are lacking. AIM: To investigate the clinical characteristics of patients with recurrent ICC after hepatectomy, analyse prognostic factors and explore diagnosis and treatment strategies. METHODS: A retrospective analysis was performed on all ICC patients undergoing hepatectomy from January 2013 to August 2021. Patients with postoperative recurrence were selected according to the inclusion and exclusion criteria. Cumulative overall survival was plotted by the Kaplan-Meier method, and differences were assessed by univariate survival analysis using the log-rank test. Multivariate analysis of cumulative survival was performed using the Cox proportional risk model. RESULTS: During the 8-year study period, 103 patients underwent ICC-related hepatectomy, and 54 exhibited postoperative recurrence. The median disease-free survival (DFS) was 6 mo, the median overall survival (OS) was 9 mo, and the cumulative OS rates at 1, 2 and 3 years after the operation were 40.7%, 14.8% and 7.4%, respectively. The median OS after recurrence was 4 mo, and the cumulative OS rates at 1, 2 and 3 years after recurrence were 16.1%, 6.7% and 3.4%, respectively. Multivariate analysis showed that alcohol consumption [hazard ratio (HR) = 4.64, 95% confidence interval (CI): 1.53-14.04, P = 0.007] and DFS < 6 mo (HR = 3.47, 95%CI: 1.59-7.60, P = 0.002) were independent risk factors for the cumulative survival of patients with recurrence, while treatment after recurrence (HR = 0.21, 95%CI: 0.08-0.55, P = 0.001) was an independent protective factor. The median OS time of patients receiving multimodality therapy after recurrence of ICC was 7 mo, which was significantly higher than that of patients receiving only local therapy (3 mo), patients receiving systematic therapy (4 mo) and patients receiving the best supportive therapy (1 mo). Patients with recurrent ICC who received multimodality therapy had a significantly better long-term survival after recurrence than those who did not (P = 0.026). CONCLUSION: The prognosis of patients with recurrence after ICC-related hepatectomy is poor. Alcohol consumption and DFS < 6 mo are independent risk factors in terms of the cumulative survival of patients with recurrence, while treatment after recurrence is an independent protective factor. Multimodality therapy can effectively improve the prognosis of patients.

[Variety of the Composition and Sources of VOCs During the Spring Festival and Epidemic Prevention in the Pearl River Delta].

Volatile organic compounds (VOCs) are the key precursors of the ozone (O3) formation processes in the troposphere and are important control objects for the coordinated governance of O3 and PM2.5. The Spring Festival of 2020 was affected by the novel coronavirus (COVID-19) pneumonia epidemic:companies stopped work and production, and traffic was restricted, providing scientific experimentation opportunities for pollutant emission reduction research. This study analyzed the variety of the composition, chemical reaction activity, and sources of VOCs in the Pearl River Delta during the Spring Festival and the epidemic control period, using real-time online monitoring data of VOCs obtained at four sites(Guangzhou, Dongguan, Zhongshan, and Duanfen)in the Pearl River Delta from January 1, 2020 to February 29, 2020. The results showed that during the Spring Festival and the epidemic control period, the average of φ (VOCs) in the Pearl River Delta was 15.89×10-9, and the maximum hourly average concentration was 45.43×10-9, values that were 44% and 60% lower, respectively, than those before the Spring Festival holiday. Among the VOCs component concentration decreases, the aromatic hydrocarbon component decreased the most, and the decrease in the urban area of the Pearl River Delta (74%) was significantly greater than that in the suburban area (56%). As a result, the contribution rate of aromatic hydrocarbons to the total VOCs was reduced to less than 10%. The analysis of the·OH reaction activity of VOCs(L·OH)and ozone formation potential(OFP)showed that the L·OH and OFP of VOCs decreased significantly in the Pearl River Delta during the Spring Festival and the epidemic control period. Compared with those before the Spring Festival holiday, the total L·OH and total OFP decreased by an average of 60% and 63% in the urban area of the Pearl River Delta, respectively. Additionally, the atmospheric oxidation had also been significantly reduced, which showed a 28% decrease in ρ(Ox). The ratio of toluene/benzene showed that the influence of industrial sources had almost disappeared during the Spring Festival and the epidemic control period, and the total points of the representative components of industrial-related solvent-use sources such as toluene, ethylbenzene, and m/p-xylene dropped by 72% to 91%. The results of this study suggest that solvent-use sources and vehicle exhaust emission sources are the current sources of VOCs that need to be paid attention to in the prevention and control of O3 pollution in the Pearl River Delta region, and the impact of petrochemical sources cannot be ignored in the work of further reducing the background concentration of O3.

Natural constituents of St. John's Wort inhibit the proteolytic activity of human thrombin.

Thrombin, a multifunctional serine protease responsible for the proteolytic hydrolysis of soluble fibrinogen, plays a pivotal role in the blood coagulation cascade. Currently, thrombin inhibitor therapy has been recognized as an effective therapeutic strategy for the prevention and treatment of thrombotic diseases. In this study, the inhibitory effects of natural constituents in St. John's Wort against human thrombin are carefully investigated by a fluorescence-based biochemical assay. The results clearly demonstrate that most of naphthodianthrones, flavonoids and biflavones exhibit strong to moderate inhibition on human thrombin. Among all tested compounds, hypericin shows the most potent inhibitory capability against thrombin, with the IC50 value of 3.00 µM. Further investigation on inhibition kinetics demonstrates that hypericin is a potent and reversible inhibitor against thrombin-mediated Z-GGRAMC acetate hydrolysis, with the Ki value of 2.58 µM. Inhibition kinetic analyses demonstrate that hypericin inhibits thrombin-mediated Z-GGRAMC acetate hydrolysis in a mixed manner, which agrees well with the results from docking simulations that hypericin can bind on both catalytic cavity and anion binding exosites. All these findings suggest that hypericin is a natural thrombin inhibitor with a unique dianthrone skeleton, which can be used as a good candidate to develop novel thrombin inhibitors with improved properties.

[Effects and mechanism of bFGF on rat myoblast oxidative injury induced by hydrogen peroxide].

OBJECTIVE: To explore the protective role of basic fibroblast growth factor (bFGF) on attenuating hydrogen peroxide-induced injury in cultured rat myoblasts. METHODS: Cultured rat myoblasts at growth phase were randomly divided into four groups (n=6):control group (control), bFGF group (bFGF), model group(H2O2) and the treatment group (bFGF + H2O2). Model group was treated with 100 µmol/L hydrogen peroxide for 4h. B-cell lymphoma-2 (Bcl-2) positive particles were detected by immunohistochemistry; Reactive oxygen species (ROS) and expression for Bcl-2 associated X protein (Bax), Bcl-2 and Cytochrome C (Cyt. C) fluorescence were observed under the invented microscope; Cyt. C and Poly ADP-ribose polymerase(PARP)protein were assessed by Western blot. RESULTS: Compared with control group, the myoblats in the model group showed low expression of Bcl-2 positive particles, accompanied by high expression of ROS level and Cyt. C fuorescence (P < 0.05); Compared with model group, bFGF enhanced Bcl-2 activity of the myoblasts, and significantly downregulated Cyt. C and PARP expression (P < 0.05). CONCLUSIONS: bFGF could attenuate oxidative injury of rat myoblasts induced by hydrogen peroxide, which mechanism might be related to enhanced Bcl-2 and reduced ROS, Cyt. C levels.

Protective effects of salubrinal on liver injury in rat models of brain death.

BACKGROUND: Previous studies have indicated that endoplasmic reticulum stress participates in and mediates liver injury and apoptosis in brain-dead (BD) rats. In this study, we observed the effect of salubrinal (Sal, Sigma, USA) on liver cells in BD rats and explored its relevant mechanisms. METHODS: Thirty Sprague-Dawley rats were equally randomized into three groups: BD group, Sal group, and DMSO group. The BD models were established by increasing intracranial pressure in a modified, slow, and intermittent way. In the drug groups, Sal was administered 1 h before the induction of BD. After modeling was completed, the blood and liver samples were harvested. CHOP and Caspase-12 mRNA expression was detected using quantitative polymerase chain reaction. PKR-like ER kinase (PERK), P-eukaryotic translation initiation factor 2α (eIF2α), eIF2α, CHOP and caspase-12 expression was detected using western blotting (WB). CHOP and caspase-12 distribution and expression in liver tissues were determined using immunohistochemistry (IHC). Alanine aminotransferase and aspartate aminotransferase level were detected using an automatic biochemical analyzer. Hepatic cell apoptosis was detected using TUNEL. The results were analyzed using Quantity-one v4.62 software (Bio-Rad, USA). RESULTS: CHOP and caspase-12 expression and PERK, eIF2α, and P-eIF2α protein expression showed no significant difference between BD group and DMSO group. Compared with BD group, Sal group had a significantly higher P-eIF2C level and a lower P-PERK level 2 h and 6 h after BD (P < 0.05). However, eIF2α expression showed no significant difference (P > 0.05). After the Sal treatment, CHOP and caspase-12 mRNA expression significantly decreased 4 h after BD (P < 0.05). WB and IHC indicated that CHOP and caspase-12 expression also significantly decreased after Sal treatment. Sal was associated with improved liver function and decreased hepatic cell apoptosis. CONCLUSIONS: Sal can significantly reduce apoptosis in hepatic cells of BD rats. This protective effect may be achieved via the PERK-eIF2α signaling pathway.

HDAC3 augments the autoregulation of neuroD gene in P19 cells.

NeuroD, a basic helix-loop-helix transcription factor, is capable of converting embryonic epidermal cells into neuronal cells. However, whether histone deacetylases (HDACs) are involved in the autoregulation of neuroD or not is unclear. In this study, neuroD expression was found to be significantly increased in the all-trans retinoid acid-treated P19 cells. Meanwhile, neuroD could itself enhance its promoter activity and mRNA expression. By using specific inhibitors to histone modification enzymes, HDAC3 was identified to specifically augment the autoactivation of neuroD in P19 cells. The data suggest that the elevation of HDAC3 and neuroD in all-trans retinoid acid-treated cells exponentially increases the neuroD expression and mediates an early commitment of P19 cells for neuronal differentiation.