PTTG1 Reprograms Asparagine Metabolism to Promote Hepatocellular Carcinoma Progression.

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and has a poor prognosis. Pituitary tumor transforming gene 1 (PTTG1) is highly expressed in HCC, suggesting it could play an important role in hepatocellular carcinogenesis. Here, we evaluated the impact of PTTG1 deficiency on HCC development using a diethylnitrosamine (DEN)-induced HCC mouse model and a hepatitis B virus (HBV) regulatory X protein (HBx)-induced spontaneous HCC mouse model. PTTG1 deficiency significantly suppressed DEN- and HBx-induced hepatocellular carcinogenesis. Mechanistically, PTTG1 promoted asparagine synthetase (ASNS) transcription by binding to its promoter, and asparagine (Asn) levels were correspondingly increased. The elevated levels of Asn subsequently activated the mTOR pathway to facilitate HCC progression. In addition, asparaginase treatment reversed the proliferation induced by PTTG1 overexpression. Furthermore, HBx promoted ASNS and Asn metabolism by upregulating PTTG1 expression. Overall, PTTG1 is involved in the reprogramming of Asn metabolism to promote HCC progression and may serve as a therapeutic and diagnostic target for HCC. SIGNIFICANCE: PTTG1 is upregulated in hepatocellular carcinoma and increases asparagine production to stimulate mTOR activity and promote tumor progression.

Transcriptomic Analysis of Yunwu Tribute Tea Leaves under Cold Stress.

Background: Cold stress usually occurs in winter and is one of the most significant environmental factors restricting the growth of the tea plant as well as its geographical distribution. Objective: It is necessary to identify the physiological and molecular mechanisms of plants under cold stress so that cold-tolerant crop varieties can be cultivated to limit production losses. At the same time, this would allow the crop planting area to be expanded, hence improving the economic benefits. Methods: In this study, the transcriptome data of Yunwu Tribute Tea under cold conditions were obtained using the Illumina HiSeq platform. By analyzing changes in transcriptome data associated with the antioxidant enzyme system, plant hormone signal transduction, proline and tyrosine metabolism pathways, and transcription factors, the molecular mechanisms involved in Yunwu Tribute Tea under cold stress were investigated. Results: In this study, Illumina HiSeq technology was applied to investigate the cold-tolerance mechanism. For this purpose, cDNA libraries were obtained from two groups of samples, namely the cold-treated group (DW) and the control group (CK). A total of 185,973 unigenes were produced from 511,987 assembled transcripts; among these, 16,020 differentially expressed genes (DEGs) (corrected p-value < 0.01, |log2(fold change)| >3), including 9606 up-regulated and 6414 down-regulated genes, were obtained. Moreover, the antioxidant enzyme system, plant hormone signal transduction, proline and tyrosine metabolism pathways, and transcription factors were analyzed; based on these results, a series of candidate genes related to cold stress were screened out and discussed. The physiological indexes related to the low-temperature response were tested, along with five DEGs which were validated by quantitative real-time PCR. Conclusions: Differential gene expression analysis has confirmed that substantial cold-responsive genes are related to the antioxidant enzyme system, plant hormone signal transduction, proline metabolism pathway, tyrosine metabolism pathway, and transcription factors.

Hepatocyte-derived MASP1-enriched small extracellular vesicles activate HSCs to promote liver fibrosis.

BACKGROUND AND AIMS: Liver fibrosis is a chronic disease characterized by different etiological agents; dysregulated interactions between hepatocytes and HSCs contribute to this disease. ß-arrestin 1 (ARRB1) plays an important role in liver fibrosis; however, the effect of ARRB1 on the crosstalk between hepatocytes and HSCs in liver fibrosis is unknown. The aim of this study is to investigate how ARRB1 modulates hepatocyte and HSC activation during liver fibrosis. APPROACH AND RESULTS: Normal and fibrotic human liver and serum samples were obtained. CCl 4 -induced liver fibrosis and methionine-choline deficiency-induced NASH models were constructed. Primary hepatocytes and HSCs were isolated, and human hepatic LO2 and stellate LX2 cells were used. Small extracellular vesicles (EVs) were purified, and key proteins were identified. ARRB1 was up-regulated in hepatocytes and associated with autophagic blockage in liver fibrosis. ARRB1 increased the release of hepatocyte-derived small EVs by inhibiting multivesicular body lysosomal degradation and activating Rab27A, thereby activating HSCs. Proteomic analyses showed that mannan-binding lectin serine protease 1 (MASP1) was enriched in hepatocyte-derived small EVs and activated HSCs via p38 mitogen-activated protein kinase (MAPK)/activating transcription factor 2 (ATF2) signaling. ARRB1 up-regulated MASP1 expression in hepatocytes. MASP1 promoted liver fibrosis in mice. Clinically, MASP1 expression was increased in the serum and liver tissue of patients with liver fibrosis. CONCLUSIONS: ARRB1 up-regulates the release of hepatocyte-derived MASP1-enriched small EVs by regulating the autophagic-lysosomal/multivesicular body pathway and Rab27A. Hepatocyte-derived MASP1 activates HSCs to promote liver fibrogenesis through p38 MAPK/ATF2 signaling. Thus, MASP1 is a pivotal therapeutic target in liver fibrosis.

Bilevel positive airway pressure for gastroscopy with sedation in patients at risk of hypoxemia: A prospective randomized controlled study.

STUDY OBJECTIVE: Hypoxemia is one of the most frequent adverse events during sedated gastroscopy, and there is still no effective means to prevent and cure it. Therefore, we conducted this randomized trial to confirm our hypothesis that, compared with the nasal cannula group, bilevel positive airway pressure (BPAP) would decrease the incidence of hypoxemia in patients with obstructive sleep apnea (OSA) or overweight status undergoing gastroscopy. DESIGN: In a single-center, prospective, randomized controlled clinical trial, 80 patients aged 18-65 years and with OSA or overweight status who underwent gastroscopy with sedation were randomly assigned to two groups: the nasal cannula and BPAP groups. The primary outcome was the incidence of hypoxemia (75% < peripheral oxygen saturation [SpO2] < 90% for >5 sand <60 s). MAIN RESULTS: Compared to the nasal cannula group, BPAP therapy significantly decreased the incidence of hypoxemia from 40.0% to 2.5% (absolute risk difference [ARD], 37.5% [95% confidence interval (CI), 21.6 to 53.4], p < 0.001), decreased subclinical respiratory depression from 52.5% to 22.5% (ARD, 30.0% [95% CI, 9.8 to 50.2], p = 0.006), and decreased severe hypoxemia from 17.5% to 0% (ARD, 17.5% [95% CI, 5.7 to 29.3], p = 0.006). The BPAP intervention also decreased the total propofol dosage and operation time and improved anesthesiologist's satisfaction. CONCLUSION: BPAP therapy significantly decreased the incidence of hypoxemia in patients with OSA or overweight status who underwent gastroscopy.

Acute hemorrhagic necrotizing enteritis: a case report and review of the literature.

Acute hemorrhagic necrotizing enteritis (AHNE) is a potentially fatal infection, triggered by beta toxin produced by Clostridium perfringens type C and characterized by extensive hemorrhagic, inflammatory, or ischemic necrosis that mainly affects the small bowel, clinically presenting as diarrhea, hematochezia, abdominal pain and hypotensive shock. AHNE is rarely reported in humans nowadays, we present a case of AHNE in a 51-year-old man presenting as watery diarrhea, hematochezia and abdominal pain along with shortness of breath who unfortunately died of the disease despite active medical treatment and multiple surgical interventions. We aim to improve awareness of clinicians on this fulminant disease, associated with high mortality rates. This is the first case report that attempts to summarize the pathogenesis, clinical characteristics, diagnostic methods, treatment and prognosis of AHNE based on the current English literature. AHNE, which is exceedingly rare in clinical practice, has been associated with poorly specific clinical manifestations, high rates of misdiagnosis in its early stages and mortality rates in severe cases. In patients with a history of ingesting contaminated food and presenting with sudden progressively worsening abdominal pain, diarrhea, hematochezia, accompanied by hypotensive shock or ileus, AHNE should be highly suspected. In order to reduce the mortality of this disease, emphasis should be laid on early recognition and timely surgical intervention in AHNE. In severe cases, death cannot be avoided despite adopting active supportive treatment and timely surgical intervention.

Lnc-TCL6 is a potential biomarker for early diagnosis and grade in liver-cirrhosis patients.

BACKGROUND: Long non-coding RNAs (lncRNAs) have been applied as biomarkers in many diseases. However, scarce biomarkers are available in single lncRNA differential expression associated with different clinical stages of liver cirrhosis (LC). The aim of the study is to identify some lncRNAs that can serve as non-invasive sensitive biomarkers for early diagnosis and grade of LC. METHODS: Blood lncRNA expression was evaluated in three independent cohorts with 305 participants including healthy controls, hepatitis B virus (HBV) carriers, and patients with chronic hepatitis B (CHB) or LC. First, candidate lncRNAs were screened by CapitalBiotech microarray to diagnose cirrhosis. Quantitative reverse-transcriptase polymerase chain reaction was then used to investigate the expression of selected lncRNAs in the whole group of cirrhosis and different Child-Pugh classes. Ultimately, the diagnostic accuracy of the promising biomarker was examined and validated via Mann-Whitney test and receiver-operating characteristics analysis. RESULTS: Lnc-TCL6 was identified as a sensitive biomarker for early diagnosis of LC (Child-Pugh A) compared with healthy controls (area under the ROC curve [AUC] = 0.636), HBV carriers (AUC = 0.671), and CHB patients (AUC = 0.672). Furthermore, lnc-TCL6 showed a favourable capacity in discriminating among different Child-Pugh classes (AUC: 0.711-0.837). Compared with healthy controls, HBV carriers, and CHB patients, the expression of lnc-TCL6 was obviously up-regulated in Child-Pugh A patients and, conversely, significantly down-regulated in Child-Pugh C patients. CONCLUSIONS: Lnc-TCL6 is a novel potential biomarker for early diagnosis of LC and is a possible predictor of disease progression.

Lnc-PCDH9-13:1 Is a Hypersensitive and Specific Biomarker for Early Hepatocellular Carcinoma.

BACKGROUND: Long non-coding RNAs (lncRNAs) show great potential as diagnostic tools in many diseases. We aimed to develop sensitive and noninvasive biomarkers in saliva for detecting early hepatocellular carcinoma (HCC). METHODS: Candidate lncRNA biomarkers identified by Agilent microarray were subjected to validation using qPCR for the quantification of their expression levels in independent tissue, plasma and saliva sample sets, including healthy controls, HBsAg carriers, patients with chronic Hepatitis B, liver cirrhosis, early HCC, and advanced HCC. Levels of candidate biomarkers were also measured in totally 108 saliva samples from patients with any one of other nine leading causes of cancer death in men and women. FINDINGS: Lnc-PCDH9-13:1 was significantly elevated in HCC tissues, plasma and saliva of HCC patients compared with healthy controls and groups of several benign liver diseases and other leading cancers. Its level was significantly reduced after curative hepatectomy but significantly elevated again if HCC recurrence occurred. Salivary lnc-PCDH9-13:1 showed reasonable specificities and sensitivities for detecting HCC compared with several control groups. Furthermore, the overexpression of lnc-PCDH9-13:1 promotes cell proliferation and migration in vitro. INTERPRETATION: Salivary lnc-PCDH9-13:1 is a desirable biomarker for early HCC. It may help warrant prospective validation with larger sample sizes in multi-centers.

ß-Arrestin-1 protects against endoplasmic reticulum stress/p53-upregulated modulator of apoptosis-mediated apoptosis via repressing p-p65/inducible nitric oxide synthase in portal hypertensive gastropathy.

Portal hypertensive gastropathy (PHG) is a serious cause of bleeding in patients, and is associated with portal hypertension. ß-Arrestins (ß-arrestin-1 and ß-arrestin-2) are well-established mediators of endocytosis of G-protein-coupled receptors (GPCRs), ubiquitination, and G-protein-independent signaling. The role of ß-arrestin-1 (ß-arr1) in mucosal apoptosis in PHG remains unclear. The aim of this study was to investigate the involvement of ß-arr1 in PHG via its regulation of endoplasmic reticulum (ER) stress/p53-upregulated modulator of apoptosis (PUMA) apoptotic signaling. Gastric mucosal injury and apoptosis were studied in PHG patients and in PHG mouse models. The induction of ß-arr1 and the ER stress/PUMA signaling pathway were investigated, and the mechanisms of ß-arr1-regulated gastric mucosal apoptosis were analyzed in vivo and in vitro experiments. ß-arr1 and ER stress/PUMA signaling elements were markedly induced in the gastric mucosa of PHG patients and mouse models. Blockage of ER stress demonstrably attenuated the mucosal apoptosis of PHG, while targeted deletion of ß-arr1 significantly aggravated the injury and ER stress/PUMA-mediated apoptosis. ß-arr1 limited the activation of p65 to repress TNF-α-induced inducible nitric oxide synthase (iNOS) expression and NO release, which could regulate ER stress/PUMA-mediated mucosal apoptosis in PHG. In vivo and in vitro experiments further demonstrated that ß-arr1 protected against mucosal apoptosis by repressing TNF-α-induced iNOS expression via inhibiting the activation of p65. These results indicated that ß-arr1 regulated ER stress/PUMA-induced mucosal epithelial apoptosis through suppression of the TNF-α/p65/iNOS signaling pathway activation and that ß-arr1 is a potential therapeutic target for PHG.

Frequent down-regulation of hABH2 in gastric cancer and its involvement in growth of cancer cells.

BACKGROUND AND AIM: Methyl or 1, N(6) -ethenoadenine base lesions are frequent and highly-mutagenic or -carcinogenic events in mammalian DNA. Human AlkB homologue-2 (hABH2), a homologue of the Escherichia coli AlkB protein, has been found to be the principal dioxygenase for the repair of these lesions. Mounting evidence indicates that impaired DNA repair contributes to gastric cancer induction and progression. Whether hABH2 is involved in this malignancy is unknown. The present study was aimed to investigate the expression profile of hABH2 in gastric cancer and the effect of hABH2 on cancer cell growth. METHODS: The expression of hABH2 in 35 pair-matched gastric neoplastic and adjacent non-neoplastic tissues, and in five gastric cancer cell lines, was examined by real-time polymerase chain reaction (PCR), immunohistochemistry, or Western blot. The cell growth was determined using cell-counting kit-8 assay. The apoptosis or cell-cycle analysis was determined using flow cytometry. RESULTS: The hABH2 expression was downregulated in 68% (24/35) of primary gastric cancers, as determined by real-time PCR; the hABH2 expression was also substantially decreased in gastric cancer cell lines. Immunohistochemical or Western blot analysis further confirmed the downregulation of hABH2 expression in gastric cancers. The overexpression of hABH2 significantly inhibited the proliferation of gastric cancer cells, and induced G(1) arrest of the cell cycle, while hABH2 knockdown promoted cell growth and cell-cycle progression of gastric cancer cells. CONCLUSIONS: These results suggest that hABH2 is downregulated in a subset of gastric cancers, and might be involved in the molecular mechanism of gastric cancer through inhibiting the proliferation of gastric cancer cells.