TREM2 protects against inflammation by regulating the release of mito-DAMPs from hepatocytes during liver fibrosis.

BACKGROUND: Liver fibrosis typically develops as a result of chronic liver injury, which involves inflammatory and regenerative processes. The triggering receptor expressed on myeloid cells 2 (TREM2), predominantly expressing in hepatic non-parenchymal cells, plays a crucial role in regulating the function of macrophages. However, its mechanism in liver fibrosis remains poorly defined. METHODS: Experimental liver fibrosis models in wild type and TREM2-/- mice, and in vitro studies with AML-12 cells and Raw264.7 cells were conducted. The expression of TREM2 and related molecular mechanism were evaluated by using samples from patients with liver fibrosis. RESULTS: We demonstrated that TREM2 was upregulated in murine model with liver fibrosis. Mice lacking TREM2 exhibited reduced phagocytosis activity in macrophages following carbon tetrachloride (CCl4) intoxication. As a result, there was an increased accumulation of necrotic apoptotic hepatocytes. Additionally, TREM2 knockout aggravated the release of mitochondrial damage-associated molecular patterns (mito-DAMPs) from dead hepatocytes during CCl4 exposure, and further promoted the occurrence of macrophage-mediated M1 polarization. Then, TREM2-/- mice showed more serious fibrosis pathological changes. In vitro, the necrotic apoptosis inhibitor GSK872 effectively alleviated the release of mito-DAMPs in AML-12 cells after CCl4 intoxication, which confirmed that mito-DAMPs originated from dead liver cells. Moreover, direct stimulation of Raw264.7 cells by mito-DAMPs from liver tissue can induce intracellular inflammatory response. More importantly, TREM2 was elevated and inflammatory factors were markedly accumulated surrounding dead cells in the livers of human patients with liver fibrosis. CONCLUSION: Our study highlights that TREM2 serves as a negative regulator of liver fibrosis, suggesting its potential as a novel therapeutic target.

Multi-objective winter wheat irrigation strategies optimization based on coupling AquaCrop-OSPy and NSGA-III: A case study in Yangling, China.

The contradiction between crop water requirements and water supplies in Guanzhong Plain of Northwest China restricts the production of local winter wheat. The optimization of irrigation strategies considering multiple-objectives is of great significance to alleviate water crisis and sustainability of winter wheat production. This paper considered three typical hydrological years (dry year, normal year, and wet year), and a simulation optimization model coupling AquaCrop and NSGA-III was developed using Python language. The multi-objective optimization problem considered four objectives: (1) maximize crop yield (Y), (2) minimize irrigation water (IW), (3) maximize irrigation water productivity (IWP), and (4) maximize water use efficiency (WUE). The TOPSIS-Entropy method was then adopted for decision-making based on the Pareto fronts which were generated by multi-objective optimization, thus facilitating the optimization of the irrigation strategies. The results show that AquaCrop model could accurately simulate the growth process of winter wheat in the study area, the relative error is acceptable. The R2 of canopy cover (CC) is 0.75 and 0.61, and above ground biomass production (B) is 0.94 and 0.93, respectively. In the Pareto fronts, the difference between the maximum and minimum yield of winter wheat is 9.48 %, reflecting the diversity of multi-objective optimization results. According to the analysis results of this paper, the performance of different irrigation scenarios in each typical year varies greatly. The performance of the optimization in dry years is significantly better than that in normal years and wet years. The optimization of irrigation strategies and comparison of different scenarios play a positive role in improving the local water use efficiency, the winter wheat yield, as well as the sustainable development level of water resources.

Activation of p62-keap1-Nrf2 antioxidant pathway in the early stage of acetaminophen-induced acute liver injury in mice.

Acetaminophen (APAP) overdose can cause severe liver failure even death. Nearly half of drug-induced liver injury is attributed to APAP in the US and many European countries. Oxidative stress has been validated as a critical event involved in APAP-induced liver failure. p62/SQSTM1, a selective autophagy adaptor protein, is reported to regulate Nrf2-ARE antioxidant pathway in response to oxidative stress. However, the exact role of p62-keap1-Nrf2 antioxidant pathway in APAP-induced hepatotoxicity remains unknown. In the present study, the dose-response and time-course model in C57/BL6 mice were established by intraperitoneal injection of APAP. The results of serum alanine/aspartate aminotransferases (ALT/AST) and histological examination demonstrated that APAP overdose resulted in the severe liver injury. In the meantime, the levels of p62, phospho-p62 and nuclear Nrf2 were significantly increased by APAP in mice liver, suggesting an activation of p62-keap1-Nrf2 pathway. In addition, the expression of GSTA1 mRNA was increased in a dose-dependent manner, while the mRNA levels of HO-1 and GCLC were decreased with the increase of APAP dose. Our further investigation found that expression of HO-1 and GCLC peaked at 3 h∼6 h, and then were decreased gradually. Taken together, these results indicated that p62-keap1-Nrf2 antioxidant pathway was primarily activated in the early stage of APAP hepatotoxicity, which might play a protective role in the process of APAP-induced acute liver injury.

p53ß: a new prognostic marker for patients with clear-cell renal cell carcinoma from 5.3 years of median follow-up.

We previously reported six different p53 isoforms in renal cell carcinoma (RCC). In the present study, influences of p53ß on recurrence-free survival (RFS) and overall survival (OS) were evaluated. Patients diagnosed with RCC in our center were into this study. mRNA expressions of p53 isoforms (p53α, p53ß, p53γ) in tumors were determined by RT-PCR and real-time PCR. Functional yeast-based assay was performed to analyze p53 mutational status. p53ß transfected 786-O and CAKi-1 cells were cultured to examine expressions of B-cell lymphoma 2-associated X protein (bax) and caspase-3, and ratios of apoptosis. After surgeries, all patients were followed up at programmed intervals. 266 patients were analyzed in this study. Median follow-up time was 5.3 years. RT-PCR (r = -0.72, P = 0.016) and real-time PCR (r = -0.65, P = 0.033) both showed only p53ß expressed higher level in lower tumor stage versus higher stage. p53 wild-type and p53 mutation had comparable RFS (P = 0.361) and OS (P = 0.218), respectively. Kaplan-Meier analysis showed high p53ß expression was associated with significantly improved RFS and OS, regardless of p53 mutational status. High p53ß expression indicated better RFS [hazard ratio (HR) 2.599, 95% confidence interval (CI) 1.472-4.551, P = 0.038] and OS (HR 2.604, 95% CI 1.453-4.824, P = 0.031). p53ß transfected 786-O and CAKi-1 cells expressed significantly higher level of bax and caspase-3, and had higher ratios of apoptosis than untransfected cells. Taken together, higher level of p53ß predict better prognosis in patients with RCC through enhancing apoptosis in tumors.

FOXP3 expression in esophageal cancer cells is associated with poor prognosis in esophageal cancer.

BACKGROUND/AIMS: The aim of this study was to determine FOXP3 expression in human esophageal cancer cells and to examine the relationship between the FOXP3 expression levels and the prognosis of esophageal cancer in patients. METHODOLOGY: We evaluated FOXP3 in esophageal cancer tissue obtained from 60 patients by immunohistochemistry. The data were analyzed by SPSS16.0 software with χ² test, Kaplan-Meier survival curves, log-rank test and Cox regression analysis. Data was expressed as mean ±SD. A two-tailed p-value of 0.05 was considered significant. RESULTS: Twenty nine (48.33%) were found to have FOXP3 over-expression in esophageal cancer cells, while normal esophageal mucosal cells are negative. The FOXP3 over-expression had a significant correlation between tumor staging and lymph node metastasis. The FOXP3 negative group showed significantly better overall survival than the over-expression group (32.3% vs. 13.8%, log-rank test, χ²=11.801, p=0.001). Cox regression analysis showed that T stage, N stage and FOXP3 protein expression were independent prognostic risk factors. The FOXP3 protein expression increased in a subset of esophageal cancers and the over-expression is associated with poor prognosis in patients with esophageal cancer. CONCLUSIONS: Our study suggests that blocking FOXP3 expression in cancer cells may lead to a novel therapeutic strategy for esophageal cancer.