Interferon-α stimulates DExH-box helicase 58 to prevent hepatocyte ferroptosis.

BACKGROUND: Liver ischemia/reperfusion (I/R) injury is usually caused by hepatic inflow occlusion during liver surgery, and is frequently observed during war wounds and trauma. Hepatocyte ferroptosis plays a critical role in liver I/R injury, however, it remains unclear whether this process is controlled or regulated by members of the DEAD/DExH-box helicase (DDX/DHX) family. METHODS: The expression of DDX/DHX family members during liver I/R injury was screened using transcriptome analysis. Hepatocyte-specific Dhx58 knockout mice were constructed, and a partial liver I/R operation was performed. Single-cell RNA sequencing (scRNA-seq) in the liver post I/R suggested enhanced ferroptosis by Dhx58hep-/-. The mRNAs and proteins associated with DExH-box helicase 58 (DHX58) were screened using RNA immunoprecipitation-sequencing (RIP-seq) and IP-mass spectrometry (IP-MS). RESULTS: Excessive production of reactive oxygen species (ROS) decreased the expression of the IFN-stimulated gene Dhx58 in hepatocytes and promoted hepatic ferroptosis, while treatment using IFN-α increased DHX58 expression and prevented ferroptosis during liver I/R injury. Mechanistically, DHX58 with RNA-binding activity constitutively associates with the mRNA of glutathione peroxidase 4 (GPX4), a central ferroptosis suppressor, and recruits the m6A reader YT521-B homology domain containing 2 (YTHDC2) to promote the translation of Gpx4 mRNA in an m6A-dependent manner, thus enhancing GPX4 protein levels and preventing hepatic ferroptosis. CONCLUSIONS: This study provides mechanistic evidence that IFN-α stimulates DHX58 to promote the translation of m6A-modified Gpx4 mRNA, suggesting the potential clinical application of IFN-α in the prevention of hepatic ferroptosis during liver I/R injury.

Impacts of androgen deprivation therapy on the risks and outcomes of SARS-CoV-2 infection in patients with prostate cancer.

Studies have investigated the effects of androgen deprivation therapy (ADT) use on the incidence and clinical outcomes of coronavirus disease 2019 (COVID-19); however, the results have been inconsistent. We searched the PubMed, Medline, Cochrane, Scopus, and Web of Science databases from inception to March 2022; 13 studies covering 84 003 prostate cancer (PCa) patients with or without ADT met the eligibility criteria and were included in the meta-analysis. We calculated the pooled risk ratios (RRs) with 95% confidence intervals (CIs) to explore the association between ADT use and the infection risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and severity of COVID-19. After synthesizing the evidence, the pooled RR in the SARS-CoV-2 positive group was equal to 1.17, and the SARS-CoV-2 positive risk in PCa patients using ADT was not significantly different from that in those not using ADT (P = 0.544). Moreover, no significant results concerning the beneficial effect of ADT on the rate of intensive care unit admission (RR = 1.04, P = 0.872) or death risk (RR = 1.23, P = 0.53) were found. However, PCa patients with a history of ADT use had a markedly higher COVID-19 hospitalization rate (RR = 1.31, P = 0.015) than those with no history of ADT use. These findings indicate that ADT use by PCa patients is associated with a high risk of hospitalization during infection with SARS-CoV-2. A large number of high quality studies are needed to confirm these results.

A Novel Mutant of rLj-RGD3 (rLj-112) Suppressed the Proliferation and Metastasis of B16 Cells through the EGFR Signaling Pathway.

Lj-RGD3, which contains three Arg⁻Gly⁻Asp (RGD) motifs, was first identified from the buccal glands of Lampetra japonica and has been shown to suppress the tumor progression in the previous studies. Apart from the three RGD motifs, Lj-RGD3 is also characterized by its high content of histidine in its amino acid sequence. In order to clarify whether the histidine-rich characterization of Lj-RGD3 is also associated with its anti-tumor activity, mutants were designed in which the three RGD motifs (Lj-112), or all histidines (Lj-27) or both (Lj-26) were deleted. Furthermore, a mutant (Lj-42) in which all histidines and three RGD motifs were respectively substituted with alanines and three Ala⁻Gly⁻Asp (AGD) motifs, as well as a mutant (Lj-41) in which all histidines were substituted with alanines was synthesized to avoid alterations in structure which might further cause changes in the peptides' functions. After recombination and purification, recombinant Lj-112 (rLj-112), recombinant Lj-27 (rLj-27), recombinant Lj-41 (rLj-41), and recombinant Lj-RGD3 (rLj-RGD3) exhibited anti-proliferative activity in B16 cells, respectively; while recombinant Lj-26 (rLj-26) and recombinant Lj-42 (rLj-42) did not affect the proliferation of B16 cells significantly. In addition, the anti-proliferative activity of rLj-112 in B16 cells was due to apoptosis. Typical apoptosis features were observed, including chromatin condensation, fragmented DNA, and increased levels of cleaved caspase 3/caspase 7/nuclear enzyme poly (ADP-ribose) polymerase (PARP) in B16 cells. Similar to rLj-RGD3, rLj-112 was also capable of suppressing the migration and invasion of B16 cells by disturbing the F-actin arrangement. After labeling with FITC, rLj-112 was found localized in the cytoplasm of B16 cells, which induced the internalization of epidermal growth factor receptor (EGFR), suggesting that rLj-112 might block the EGFR mediated signaling pathway. Actually, the phosphorylation level of EGFR and its downstream signal molecules including Akt, PI3K, p38, and ERK1/2 was reduced in the rLj-112 treated B16 cells. In vivo, rLj-112 also inhibited the growth, weight, and volume of the tumors in B16 xenografted C57BL/6 mice without reducing their body weight, indicating that rLj-112 might be safe and might be used as an effective anti-tumor drug in the near future.

[Determination of 1, 1-dichloro-l-nitroethane in air of workplaces by gas chromatography].

OBJECTIVE: To establish a gas chromatography method for detecting the concentration of 1,1-dichloro-1-nitroethane in air of workplaces. METHOD: 1,1-dichloro-1-nitroethane in air of workplaces was collected by activated charcoal tube, absorbed using carbon disulfide and analyzed by Gas Chromatography (FID) with FFAP capillary column. RESULTS: The linear rang of 1,1-dichloro-1-nitroethane in this method was 4.0-858.2 microg/ml, the linear regression formula was Y = 283X-1076, the correlation coefficient was 0.9999, the lowest detection concentration was 0.4 mg/m3 (3L sampling air), the relative standard deviation (RSD) was 1.8%-4.1%, the desorption efficiency was 88.5%-90.6%, the breakthrough volume was > 0.7 mg, the sampling efficiency was 100%, the samples could be kept at ambient temperature for at least 7 days. CONCLUSION: The indicators of this method were conformed to the requirements of "Guide for establishing occupational health standards--Determination methods of air chemicals in workplace". This method could be used to detect 1,1-dichloro-1-nitroethane in air of workplaces.

[Expression of FasL and apoptosis in pulmonary tissue of rats exposed to silica at different time].

OBJECTIVE: To investigate the change of the expression of the FasL receptor and apoptosis in the pathology of silicosis of the rats exposed to silica and their roles. METHODS: Ninety-six wistar rats were randomizedly divided into the control group and the experimental group. The silicotic animal model was established by the direct tracheal instillation of silica into rat lungs surgically. The control rats underwent directly tracheal instillation of saline into lungs surgically. Eight rats from each group were sacrificed at different days. The expression of FasL receptor in the tissue of the model rats was detected by tissuechip microarray and immunohistochemistry and the cell apoptosis induced by silica was determined by TdT-mediated dUTP nick end-labeling method. The integral optical density of positive cells were quantitatively analyzed using Image-Pro Plus Version 4.5 for windows. RESULTS: The expression of FasL in the lung tissue of the model rats on the 7th, the 14th, the 21st, and the 28th day was significantly higher than that in the control group (P < 0.05), and peaked at the 14th day after exposure to silica. Apoptotic cells in the lung tissue of the model rats on the 1st, the 3rd, the 7th, the 14th, the 21st, and the 28th day were significantly more than those in the control group, and peaked at the 7th and the 14th day after exposure to silica. CONCLUSION: Silica can lead to apoptosis in lung tissues. FasL is expressed in all kinds of cells in the pulmonary tissues of the rats exposed to silica and leads to apoptosis. From the 7th day to 14th day, inflammatory cells dominate in apoptotic cells.