Overview of ferroptosis and pyroptosis in acute liver failure.

In this editorial, we comment on the article by Zhou et al published in a recent issue. We specifically focus on the crucial roles of ferroptosis and pyroptosis in acute liver failure (ALF), a disease with high mortality rates. Ferroptosis is the result of increased intracellular reactive oxygen species due to iron accumulation, glutathione (GSH) depletion, and decreased GSH peroxidase 4 activity, while pyroptosis is a procedural cell death mediated by gasdermin D which initiates a sustained inflammatory process. In this review, we describe the characteristics of ferroptosis and pyroptosis, and discuss the involvement of the two cell death modes in the onset and development of ALF. Furthermore, we summarize several interfering methods from the perspective of ferroptosis and pyroptosis for the alleviation of ALF. These observations might provide new targets and a theoretical basis for the treatment of ALF, which are also crucial for improving the prognosis of patients with ALF.

Protein succinylation, hepatic metabolism, and liver diseases.

Succinylation is a highly conserved post-translational modification that is processed via enzymatic and non-enzymatic mechanisms. Succinylation exhibits strong effects on protein stability, enzyme activity, and transcriptional regulation. Protein succinylation is extensively present in the liver, and increasing evidence has demonstrated that succinylation is closely related to hepatic metabolism. For instance, histone acetyltransferase 1 promotes liver glycolysis, and the sirtuin 5-induced desuccinylation is involved in the regulation of the hepatic urea cycle and lipid metabolism. Therefore, the effects of succinylation on hepatic glucose, amino acid, and lipid metabolism under the action of various enzymes will be discussed in this work. In addition, how succinylases regulate the progression of different liver diseases will be reviewed, including the desuccinylation activity of sirtuin 7, which is closely associated with fatty liver disease and hepatitis, and the actions of lysine acetyltransferase 2A and histone acetyltransferase 1 that act as succinyltransferases to regulate the succinylation of target genes that influence the development of hepatocellular carcinoma. In view of the diversity and significance of protein succinylation, targeting the succinylation pathway may serve as an attractive direction for the treatment of liver diseases.

MiR-195 inhibits the ubiquitination and degradation of YY1 by Smurf2, and induces EMT and cell permeability of retinal pigment epithelial cells.

The dysregulated microRNAs (miRNAs) are involved in diabetic retinopathy progression. Epithelial mesenchymal transition (EMT) and cell permeability are important events in diabetic retinopathy. However, the function and mechanism of miR-195 in EMT and cell permeability in diabetic retinopathy remain largely unclear. Diabetic retinopathy models were established using streptozotocin (STZ)-induced diabetic mice and high glucose (HG)-stimulated ARPE-19 cells. Retina injury was investigated by hematoxylin-eosin (HE) staining. EMT and cell permeability were analyzed by western blotting, immunofluorescence, wound healing, and FITC-dextran assays. MiR-195 expression was detected via qRT-PCR. YY1, VEGFA, Snail1, and Smurf2 levels were detected via western blotting. The interaction relationship was analyzed via ChIP, Co-IP, or dual-luciferase reporter assay. The retina injury, EMT, and cell permeability were induced in STZ-induced diabetic mice. HG induced EMT and cell permeability in ARPE-19 cells. MiR-195, YY1, VEGFA, and Snail1 levels were enhanced, but Smurf2 abundance was reduced in STZ-induced diabetic mice and HG-stimulated ARPE-19 cells. VEGFA knockdown decreased Snail1 expression and attenuated HG-induced EMT and cell permeability. YY1 silence reduced VEGFA and Snail1 expression, and mitigated HG-induced EMT and cell permeability. YY1 could bind with VEGFA and Snail1, and it was degraded via Smurf2-mediated ubiquitination. MiR-195 knockdown upregulated Smurf2 to decrease YY1 expression and inhibited HG-induced EMT and cell permeability. MiR-195 targeted Smurf2, increased expression of YY1, VEGFA, and Snail1, and promoted HG-induced EMT and cell permeability. MiR-195 promotes EMT and cell permeability of HG-stimulated ARPE-19 cells by increasing VEGFA/Snail1 via inhibiting the Smurf2-mediated ubiquitination of YY1.

Clinicopathological characteristics and surgical outcomes of sarcomatoid hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is the sixth most common type of cancer and the fourth leading cause of cancer-related death worldwide. Sarcomatoid HCC, which contains poorly differentiated carcinomatous and sarcomatous components, is a rare histological subtype of HCC that differs from conventional HCC. It is highly aggressive and has a poor prognosis. Its clinicopathological characteristics, surgical outcomes and underlying mechanisms of its highly aggressive nature have not been fully elucidated. AIM: To examine the clinicopathological characteristics and surgical outcomes of sarcomatoid HCC and explore the histogenesis of sarcomatoid HCC. METHODS: In total, 196 patients [41 sarcomatoid HCC and 155 high-grade (Edmondson-Steiner grade III or IV) HCC] who underwent surgical resection between 2007 and 2017 were retrospectively reviewed. The characteristics and surgical outcomes of sarcomatoid HCC were compared with those of patients with high-grade HCC. The histological composition of invasive and metastatic sarcomatoid HCCs was evaluated. RESULTS: Sarcomatoid HCC was more frequently diagnosed at an advanced stage with a larger tumor and higher rates of nonspecific symptom, adjacent organ invasion and lymph node metastasis than high-grade HCC (all P < 0.05). Compared with high-grade HCC patients, sarcomatoid HCC patients are less likely to have typical dynamic imaging features of HCC (44.4% vs 72.7%, P = 0.001) and elevated serum alpha-fetoprotein levels (> 20 ng/mL; 36.6% vs 78.7%, P < 0.001). The sarcomatoid group had a significantly shorter median recurrence-free survival (5.6 mo vs 16.4 mo, log-rank P < 0.0001) and overall survival (10.5 mo vs 48.1 mo, log-rank P < 0.0001) than the high-grade group. After controlling for confounding factors, the sarcomatoid subtype was identified as an independent predictor of poor prognosis. Pathological analyses indicated that invasive and metastatic lesions were mainly composed of carcinomatous components. CONCLUSION: Sarcomatoid HCC was associated with a more advanced stage, atypical dynamic imaging, lower serum alpha-fetoprotein levels and a worse prognosis. The highly aggressive nature of sarcomatoid HCC is perhaps mediated by carcinomatous components.

Medical expenses of urban Chinese patients with stomach cancer during 2002-2011: a hospital-based multicenter retrospective study.

BACKGROUND: In China, stomach cancer is the third most common cancer and the third leading cause of cancer death. Few studies have examined Chinese stomach cancer patients' medical expenses and their associated trends. The Cancer Screening Program in Urban China (CanSPUC) is a Major Public Health Project funded by the central government. Through this project, we have extracted patients' medical expenses from hospital billing data to examine the costs of the first course treatments (which refers to 2 months before and 10 months after the date of cancer diagnosis) in Chinese patients with stomach cancer and the associated trends. METHODS: The expense data of 14,692 urban Chinese patients with stomach cancer were collected from 40 hospitals in 13 provinces. We estimated the inflation-adjusted medical expenses per patient during 2002-2011. We described the time trends of medical expenses at the country-level, and those trends by subgroup, and analyzed the compositions of medical expenses. We constructed the Generalized Linear Mixed (GLM) regression model with Poisson distribution to examine the factors that were associated with medical expenses per patient. RESULTS: The average medical expenses of the first course treatments were about 43,249 CNY (6851 USD) in 2011, more than twice of that in 2002. The expenses increased by an average annual rate of 7.4%. Longer stay during hospitalization and an increased number of episodes of care are the two main contributors to the expense increase. The upward trend of medical expenses was observed in almost all patient subgroups. Drug expenses accounted for over half of the medical expenses. CONCLUSIONS: The average medical expenses of the first course (2 months before and 10 months after the date of cancer diagnosis) treatments per stomach cancer patient in urban China in 2011 were doubled during the previous 10 years, and about twice as high as the per capita disposable income of urban households in the same year. Such high expenses indicate that it makes economic sense to invest in cancer prevention and control in China.

ING5 is a Potential Target for Osteosarcoma Therapy.

Osteosarcoma is one of the most common primary malignant bone tumors. The inhibitor of growth family of protein 5 has been identified as a tumor suppressor in many cancers. In this study, we confirmed the downregulation of the both inhibitor of growth family of protein 5 and messenger RNA levels in cancer tissues using Western blot and real-time polymerase chain reaction. In order to find the antitumor roles of inhibitor of growth family of protein 5, osteosarcoma cells, HOS, and MG63 were transfected with the plasmid pCDNA-3.1-inhibitor of growth family of protein 5. Overexpression of Inhibitor of growth family of protein 5 could induce apoptosis and inhibit cell proliferation in osteosarcoma cells. Furthermore, Western blot analysis showed that p-Smad2, p-Smad3, and Smad4 were increased in inhibitor of growth family of protein 5-expressing osteosarcoma cells. Our results indicated that overexpression of inhibitor of growth family of protein 5 in osteosarcoma cells induces apoptosis by activating the Smad pathway, thus proposing a promising role for inhibitor of growth family of protein 5 in treatment of patients with osteosarcoma.

Targeted drugs for systemic therapy of lung cancer with brain metastases.

Brain metastases are very common in lung cancer patients. The condition of these patients is complicated and difficult to treat, and adverse reactions following treatment can affect the nervous system, which severely reduces quality of life. Lung cancers are categorized as small cell lung cancers and non-small cell lung cancers. Patients with brain metastasis of small cell lung cancers are generally treated with brain radiotherapy and systemic chemotherapy, but stage III/IV patients with brain metastasis of non-small cell lung cancers are generally not responsive to radiotherapy or chemotherapy. With the recent development of targeted drugs, tumor molecular profile detection allows the selection of appropriate targeted drugs for adjuvant pharmacological treatment of brain metastasis in lung cancer patients. In recent years, immune checkpoint inhibitors have emerged and have been approved by the Food and Drug Administration (FDA) for the treatment of certain cancers, but their efficacy in lung cancer patients with brain metastases still needs to be confirmed. This paper focuses on highlighting drugs for targeted therapy of brain metastasis in lung cancer patients and their molecular targets and mechanisms of drug resistance.

Rheinheimera marina sp. nov., isolated from a deep-sea seamount.

A bacterial strain designated TP462T, isolated from a seamount near the Yap Trench in the tropical western Pacific, was characterized using a polyphasic taxonomic approach. Strain TP462T was found to be Gram-stain-negative, aerobic, rod-shaped and motile by means of a single polar flagellum. Growth occurred at 4-37 °C (optimum, 25-30 °C) and with 0-4.0 % NaCl (optimum, 2-3 %). Phylogenetic analysis based on 16S rRNA gene sequence showed that strain TP462T was related to the genus Rheinheimera and had the highest 16S rRNA gene sequence similarity with the type strain Rheinheimera tangshanensis JA3-B52T (96.8 %). The predominant cellular fatty acids were C17 : 1ω8c, summed feature 3 (composed of iso-C15 : 0 2-OH and/or C16 : 1ω7c) and C16 : 0. The polar lipid profile contained phosphatidylglycerol, phosphatidylethanolamine and two unidentified lipids. The genomic DNA G+C content of strain TP462T was 48.7 mol%. On the basis of the evidence presented in this study, strain TP462T represents a novel species of the genus Rheinheimera, for which we propose the name Rheinheimera marina sp. nov. (type strain TP462T=KACC 18560T=CGMCC 1.15399T).