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Cannabinoid receptor 2 (CB2R) is highly expressed in immune cells and plays an important role in regulating immune responses. In the current study, we investigated the effects of GW405833 (GW), a specific CB2R agonist, on acute liver injury induced by concanavalin A (Con A). In animal experiments, acute liver injury was induced in mice by injection of Con A (20 mg/kg, i.v.). The mice were treated with GW (20 mg/kg, i.p., 30 min after Con A injection) or GW plus the selective CB2R antagonist AM630 (2 mg/kg, i.p., 15 min after Con A injection). We found that Con A caused severe acute liver injury evidenced by significantly increased serum aminotransferase levels, massive hepatocyte apoptosis, and necrosis, as well as lymphocyte infiltration in liver tissues. Treatment with GW significantly ameliorated Con A-induced pathological injury in liver tissue, decreased serum aminotransferase levels, and decreased hepatocyte apoptosis. The therapeutic effects of GW were prevented by AM630. In cell experiments, we showed that CB2Rs were highly expressed in Jurkat T cells, but little expression in L02 liver cells. Treatment with GW (10−40 μg/mL) dose-dependently decreased the viability of Jurkat T cells and induced cell apoptosis, which was reversed by AM630. In the coculture of Jurkat T cells with L02 liver cells, GW dose-dependently protected L02 cells from apoptosis induced by Con A (5 μg/mL). The protective effect of GW was reversed by AM630 (1 μg/mL). Our results suggest that GW protects against Con A-induced acute liver injury in mice by inhibiting Jurkat T-cell proliferation through the CB2Rs.

The inflammatory responses involving infiltration and activation of liver macrophages play a vital role in acute liver failure (ALF). In the liver of ALF mice, cannabinoid receptor 2 (CB2R) is significantly upregulated on macrophages, while CB2R agonist GW405833 (GW) could protect against cell death in acute liver damage. In this study, we investigated the molecular mechanisms underlying the protective effects of GW against ALF in vivo and in vitro from a perspective of macrophage glycometabolism. Mice were pretreated with GW (10 mg/kg, i.p.), then were injected with D-GalN (750 mg/kg, i.p.) and LPS (10 mg/kg, i.p.) to induce ALF. We verified the protective effects of GW pretreatment in ALF mice. Furthermore, GW pretreatment significantly reduced liver macrophage infiltration and M1 polarization, and inhibited the release of inflammatory factors TNF-α and IL-1β in ALF mice. These protective effects were eliminated by CB2R antagonist SR144528 or in CB2R −/− ALF mice. We used LPS-stimulated RAW264.7 cells as an in vitro M1 macrophage-centered model of inflammatory response, and demonstrated that pretreatment with GW (10 μM) significantly reduced glucose metabolism by inhibiting glycolysis, which inhibited LPS-induced macrophage proliferation and inflammatory cytokines release. We verified these results in a stable CB2R −/− RAW264.7 cell line. Moreover, we found that GW significantly inhibited the expression of hypoxia inducible factor 1α (HIF-1α). Using a stable HIF-1α −/− RAW264.7 cell line, we confirmed that GW reduced the release of inflammatory cytokines from macrophages and inhibited glycolysis by downregulating HIF-1α expression. In conclusion, activation of CB2Rs inhibits the proliferation of hepatic macrophages and release of inflammatory factors in ALF mice through downregulating HIF-1α to inhibit glycolysis.

Cancer cells are known for their capacity to rewire metabolic pathways to support survival and proliferation under various stress conditions. Ketone bodies, though produced in the liver, are not consumed in normal adult liver cells. We find here that ketone catabolism or ketolysis is re-activated in hepatocellular carcinoma （HCC） cells under nutrition deprivation conditions. Mechanistically, 3-oxoacid CoA-transferase 1 （OXCT1）, a rate-limiting ketolytic enzyme whose expression is suppressed in normal adult liver tissues, is re-induced by serum starvation-triggered mTORC2- AKT-SP1 signaling in HCC cells. Moreover, we observe that enhanced ketolysis in HCC is critical for repression of AMPK activation and protects HCC cells from excessive autophagy, thereby enhancing tumor growth. Importantly, analysis of clinical HCC samples reveals that increased OXCT1 expression predicts higher patient mortality. Taken together, we uncover here a novel metabolic adaptation by which nutrition-deprived HCC cells employ ketone bodies for energy supply and cancer progression.

Background Health care workers are at the frontline in the fight against infectious disease, and as a result are at a high risk of infection. During the 2014–2015 Ebola outbreak in West Africa, many health care workers contracted Ebola, some fatally. However, no members of the Chinese Anti-Ebola medical team, deployed to provide vital medical care in Liberia were infected. This study aims to understand how this zero infection rate was achieved. Methods Data was collected through 15 in-depth interviews with participants from the People’s Liberation Army of China medical team which operated the Chinese Ebola Treatment Center from October 2014 to January 2015 in Liberia. Data were analysed using systematic framework analysis. Results This study found numerous bio-psycho-socio-behavioural risk factors that directly or indirectly threatened the health of the medical team working in the Chinese Ebola Treatment Center. These factors included social and emotional stress caused by: (1) the disruption of family and social networks; (2) adapting to a different culture; (3) and anxiety over social and political unrest in Liberia. Exposure to Ebola from patients and local co-workers, and the incorrect use of personal protective equipment due to fatigue was another major risk factor. Other risk factors identified were: (1) shortage of supplies; (2) lack of trained health personnel; (3) exposure to contaminated food and water; (4) and long working hours. Comprehensive efforts were taken throughout the mission to mitigate these factors. Every measure was taken to prevent the medical team’s exposure to the Ebola virus, and to provide the medical team with safe, comfortable working and living environments. There were many challenges in maintaining the health safety of the team, such as the limited capability of the emergency command system (the standardized approach to the command, control, and coordination of an emergency response), and the lack of comprehensive international protocols for dealing with emerging infectious disease pandemics. Conclusions The comprehensive and multidisciplinary measures employed to protect the health of the medical team proved successful even in Liberia’s resource-limited setting. The global health community can learn valuable lessons from this experience which could improve the safety of health care workers in future emergencies. These lessons include: establishing capable command systems; implementing effective coordination mechanisms; providing adequate equipment; providing training for medical teams; investing in the development of global health professionals; and improving research on ways to protect health care workers.

Arnebiae Radix (dried root of Arnebia euchroma (Royle) Johnst.) is a traditional Chinese medicine (TCM) used to treat macular eruptions, measles, sore throat, carbuncles, burns, skin ulcers, and inflammations. The Arnebiae Radix extract can exert anti-breast cancer effects through various mechanisms of action. This study aimed to rapidly screen potential estrogen receptor (estrogen receptor α and estrogen receptor β) ligands from the Arnebiae Radix extract. In this study, an analytical method based on affinity ultrafiltration coupled with UHPLC-Q-Exactive Orbitrap mass spectrometry was established for rapidly screening and identifying estrogen receptor ligands. Then, bindings of the components to the active site of estrogen receptor (estrogen receptor α and estrogen receptor β) were investigated via molecular docking. Moreover, surface plasmon resonance (SPR) experiments with six compounds were performed to verify the affinity. As a result, a total of 21 ligands were screened from Arnebiae Radix using affinity ultrafiltration. Among them, 14 and 10 compounds from Arnebiae Radix showed affinity with estrogen receptor α and estrogen receptor β, respectively. All of those ligands could have a good affinity for the multiple amino acid residues of the estrogen receptor based on molecular docking. In addition, six compounds display the great affinity by SPR. The method established in the study could be used to rapidly screen estrogen receptor ligands in Traditional Chinese medicine. The results demonstrated that the affinity ultrafiltration–UHPLC-Q-Exactive Orbitrap mass spectrometry method not only aids in the interpretation of the potential bioactive components and possible mechanisms of action of Arnebiae Radix but also provides a further effective basis for the quality control of this valuable herb medicine.

Cholangiocarcinoma (CCA) leads to poor prognosis due to high aggressiveness and common chemoresistance. Dihydromyricetin (DMY), the main bioactive compound isolated from Ampelopsis grossedentata, exhibits broad anti-tumor effects. This study aimed to investigate the inhibitory effect of DMY on CCA tumor growth and epithelial-mesenchymal transition (EMT) and its underlying mechanism in CCA. DMY treatment significantly inhibited cell proliferation and EMT in CCA cell lines. The expression of ZEB1 and vimentin were down-regulated, while the level of E-cadherin was increased after DMY treatment. By analyzing the TCGA dataset, we found that miR-455 expression was significantly downregulated, while the level of ZEB1 was up-regulated in human CCA tumor tissues compared to normal samples. Mechanistic studies showed that ZEB1 was a direct target of miR-455-3p in CCA. Moreover, DMY treatment potently increased miR-455-3p expression and inhibited ZEB1 expression. Inhibition of miR-455-3p expression abolished DMY's inhibitory effects on tumor growth and EMT in both CCA cells and cell-engrafted nude mice. Finally, DMY significantly suppressed the expressions of p-PI3K and p-AKT, while silencing miR-455-3p remarkably abrogated the inhibitory effect. In conclusion, DMY suppresses tumor growth and EMT through regulating miR-455-3p in human cholangiocarcinoma, suggesting a potential option for CCA treatment.

To develop and to validate a risk-predicted nomogram for downgrading Breast Imaging Reporting and Data System (BI-RADS) category 4a breast lesions. We enrolled 680 patients with breast lesions that were diagnosed as BI-RADS category 4a by conventional ultrasound from December 2018 to June 2019. All 4a lesions were randomly divided into development and validation groups at the ratio of 3:1. In the development group consisting of 499 cases, the multiple clinical and ultrasound predicted factors were extracted, and dual-predicted nomograms were constructed by multivariable logistic regression analysis, named clinical nomogram and ultrasound nomogram, respectively. Patients were twice classified as either \"high risk\" or \"low risk\" in the two nomograms. The performance of these dual nomograms was assessed by an independent validation group of 181 cases. Receiver Operating Characteristic (ROC) curve and diagnostic value were calculated to evaluate the applicability of the new model. After multiple logistic regression analysis, the clinical nomogram included 2 predictors: age and the first-degree family members with breast cancer. The area under the curve (AUC) value for the clinical nomogram was 0.661 and 0.712 for the development and validation groups, respectively. The ultrasound nomogram included 3 independent predictors (margins, calcification and strain ratio), and the AUC value in this nomogram was 0.782 and 0.747 in the development and validation groups, respectively. In the development group of 499 patients, approximately 50.90% (254/499) of patients were twice classified \"low risk\", with a malignancy rate of 1.18%. In the validation group of 181 patients, approximately 47.51% (86/181) of patients had been twice classified as \"low risk\", with a malignancy rate of 1.16%. A dual-predicted nomogram incorporating clinical factors and imaging characteristics is an applicable model for downgrading the low-risk lesions in BI-RADS category 4a and shows good stability and accuracy, which is useful for decreasing the rate of invasive examinations and surgery.

: To assess the performance of elastography (ES) and ultrasound (US) in predicting the malignancy of breast lesions and to compare their combined diagnostic value with that of magnetic resonance imaging (MRI). : The study prospectively enrolled 242 female patients with dense breasts treated in 35 heath care facilities in China between November 2018 and October 2019. Based on conventional US and elastography, radiologists classified the degree of suspicion of breast lesions according to the US Breast Imaging Reporting and Data System (BI-RADS) criteria. The diagnostic value was compared between US BI-RADS and MRI BI-RADS, with pathological results used as the reference standard. : The results demonstrated that irregular tumor shape, a nonparallel growth orientation, indistinct margins, angular contours, microcalcifications, color Doppler flow and ES score on US imaging were significantly related to breast cancer in dense breasts (P=0.001; P=0.001; P=0.008; P<0.001; P=0.019; P=0.008; P=0.002, respectively). The sensitivity, specificity, PPV, NPV, accuracy and AUC of US BI-RADS category were 94.7%, 90.7%, 95.8%, 88.0%, 93.4% and 0.93 (95%CI, 0.88-0.97), respectively, while those of MRI BI-RADS category were 98.2%, 57.5%, 84.3%, 83.3%, 86.0% and 0.78 (95%CI, 0.71-0.85), respectively. MRI BI-RADS showed a significantly higher sensitivity than US BI-RADS (98.2% vs 94.7%, P=0.043), whereas US BI-RADS showed significantly higher specificity (90.7% vs 57.5%, P<0.001). US BI-RADS showed better diagnostic efficiency in differentiating nodules in dense breasts than MRI BI-RADS (AUC 0.93 vs 0.78, P<0.001). : By combining the use of ES and conventional US, US BI-RADS had better diagnostic efficiency in differentiating nodules in dense breasts than MRI. For the diagnosis of malignant tumors in patients with dense breasts, MRI and US BI-RADS can be used as supplemental diagnostic tools to detect lesions, with US BI-RADS considered the preferred adjunctive resource.

Recent studies have indicated that pyroptosis may participate in the regulation of tumorigenesis and immune microenvironment. However, the role of pyroptosis-related genes (PRGs) in pancreatic adenocarcinoma (PAAD) remains unclear. Through multiple bioinformatics analysis, we constructed a prognostic gene model and competing endogenous RNA network. The correlation between PRGs and prognosis, immune infiltration, immune checkpoints, and tumor mutational burden was analyzed by Kaplan–Meier curve, univariate Cox, multivariate regression, and Spearman’s analysis in PAAD patients. The qRT-PCR, Western blotting, CCK-8, Wound healing, and Transwell assay were applied to examine the role of CASP6 in PANC-1 cell. Thirty-one PRGs were upregulated in PAAD. Functional enrichment analysis revealed that the PRGs were mainly involved in pyroptosis, NOD-like receptor signaling pathway, and response to bacteria. We established a novel 4-gene signature related to PRGs for evaluating the prognosis of PAAD patients. Patients with PAAD in the low-risk group had a better prognosis than those in the high-risk group. The nomogram suggested that the 1-, 3-, and 5-years survival probability exhibited robust predictive performance. Significant correlation was observed between prognostic PRGs and immune infiltration, immune checkpoints, and tumor mutational burden. We first identified the potential competing endogenous RNA regulatory axis in PAAD: lncRNA PVT1/hsa-miR-16-5p/CASP6/CASP8. Moreover, knockdown of CASP6 dramatically inhibited the proliferation, migration, and invasion ability of PANC-1 cell in vitro. In conclusion, CASP6 could be a potential biomarker, promoting the occurrence and progression in PAAD. The lncRNA PVT1/hsa-miR-16-5p/CASP6/CASP8 regulatory axis plays an vital role in regulating the anti-tumor immune responses for PAAD.

Objective　To evaluate the efficacy of nutrition therapy in alcoholic liver diseases (ALD). Methods　PubMed, Embase, Web of Science, The Cochrane Central Register of Controlled Trials, Chinese Journals Full-Text Database, Chinese Biomedical Database and Wan Fang Digital Journal Full-Text Database were searched for relevant articles. Statistical analysis was performed by meta-analysis using Review Manager 5.1.0. Results　Twelve randomized controlled trials including 508 cases were analyzed. Meta-analysis results were as follows: Compared with conventional therapy, nutrition therapy was more effective in reducing the serum total bilirubin (P=0.04) and alkaline phosphatase (P=0.04), and increasing serum transferrin (P＜0.00001), but there was no statistically significant difference between the two groups in other liver functions and complications associated with ALD. There was no statistically significant difference between the two groups in the incidence of infection, short-term or long-term mortality of ALD. Concl