The outbreak of coronavirus disease 2019 (COVID-19) has considerably burdened the healthcare system in the Hubei Province, the most severely affected region in China. The aim of our study was to assess the psychological effects of COVID-19 epidemic on the healthcare workers in Hubei. Methods: A total of 2737 healthcare workers were sampled using a two-dimensional code shared online between Mar 4 and Mar 9, 2020. The questionnaires consisted of three elements: baseline characteristics, Pittsburgh Sleep Quality Index (PSQI), and Hospital Anxiety and Depression Scale (HADS). The primary outcome variables were PQSI, anxiety and depression scores of non-medical staff, non-frontline medical staff and frontline medical staff. Binary logistical regression analyses were used to compare between respondents with and without sleep disturbance. Results: About 61.6% of the respondents reported sleep problems, 22.6% experienced anxiety, and 35% exhibited depressive symptoms. The prevalence of sleep disorders was higher among the frontline healthcare workers compared to the non-frontline and nonmedical staff, while anxiety and depression were prevalent in the entire cohort. Logistic regression analysis identified medical occupation, family burden, bereavement, anxiety, and depression as significantly predictive of poor sleep quality. Conclusions: Frontline medical staff are more vulnerable to sleep disturbances. Psychosocial interventions are needed to help allied healthcare personnel to better respond to COVID-19 and future outbreaks.

Itaconate, a metabolite produced during inflammatory macrophage activation, has been extensively described to be involved in immunoregulation, oxidative stress, and lipid peroxidation. As a form of iron and lipid hydroperoxide-dependent regulated cell death, ferroptosis plays a critical role in sepsis-induced acute lung injury (ALI). However, the relationship between itaconate and ferroptosis remains unclear. This study aims to explore the regulatory role of itaconate on ferroptosis in sepsis-induced ALI. In in vivo experiments, mice were injected with LPS (10 mg/kg) for 12 h to generate experimental sepsis models. Differential gene expression analysis indicated that genes associated with ferroptosis existed significant differences after itaconate pretreatment. 4-octyl itaconate (4-OI), a cell-permeable derivative of endogenous itaconate, can significantly alleviate lung injury, increase LPS-induced levels of glutathione peroxidase 4 (GPX4) and reduce prostaglandin-endoperoxide synthase 2 (PTGS2), malonaldehyde (MDA), and lipid ROS. In vitro experiments showed that both 4-OI and ferrostatin-1 inhibited LPS-induced lipid peroxidation and injury of THP-1 macrophage. Mechanistically, we identified that 4-OI inhibited the GPX4-dependent lipid peroxidation through increased accumulation and activation of Nrf2. The silence of Nrf2 abolished the inhibition of ferroptosis from 4-OI in THP-1 cells. Additionally, the protection of 4-OI for ALI was abolished in Nrf2-knockout mice. We concluded that ferroptosis was one of the critical mechanisms contributing to sepsis-induced ALI. Itaconate is promising as a therapeutic candidate against ALI through inhibiting ferroptosis.

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Objective-Notch signaling has been implicated in the development of pulmonary arterial hypertension (PH) as reflected by increased expression of Notch member proteins that induce the proliferation of pulmonary arterial smooth muscle cells (PASMCs). Soluble Jagged1 (sJag1) has been shown to inhibit Notch signaling in vitro and in vivo; however, its capacity to suppress PH remains unknown. Approach and Results-Notch1, Notch3, Jagged1, and Herp2 protein were highly expressed in both the mouse model of hypoxia-induced PH and the rat model of monocrotaline-induced PH. By attenuation and reversal of multiple pathological processes that were associated with PH, adenoviral sJag1 transfection significantly reduced the proliferation and enhanced the apoptosis of PASMCs in PH, whereas vehicle had no effect. The sJag1 inhibitory effect on Notch activation is likely related to its interference with ligand-induced signaling. Importantly, the administration with adenoviral sJag1 improved the survival rate of PH rats. Furthermore, sJag1 can restore the PH-PASMCs phenotype from the dedifferentiated to the differentiated state, by giving a positive effect on the physical binding of myocardin to the CC(A/T) n GG (CArG)-containing regions of vascular smooth muscle cells-specific promoters. Conclusions-Our results demonstrated that the potential therapeutic use of the sJag1 may not only inhibit the proliferation of PASMCs but also restore the PH-PASMCs phenotype from the dedifferentiated to the differentiated state through interference with Notch-Herp2 signaling. Because proliferation of PASMCs is a prerequisite for all kinds of PH, we hypothesized that blockage of Notch signaling could inhibit formation and development of PH. Soluble Jagged1 (sJag1) has been shown to inhibit Notch signaling in vitro and in vivo 16,17 ; however, its capacity to suppress PH remains unknown. Here, we showed that 2 kinds of rodent PH models, including the hypoxia-induced mouse and the monocrotaline (MCT)-induced rat, were inhibited by administration of sJag1 treatment. Accordingly, sJag1 was able to reduce the PASMCs proliferation and restore the phenotype by interfering with Notch signaling involving depression of Herp2 expression. Materials and MethodsMaterials and Methods are available in the online-only Supplement. Results Notch/Jagged1 Signaling Was Highly Activated in PHTo investigate the expression pattern of Notch signaling pathway in normal and PH lungs, we studied 2 kinds of PH rodent models including hypoxia-induced mouse and MTC-induced rat. The Verhoeff-Van Gieson stain sections for lung tissue clearly showed that there was significantly increased vascular medial thickening in the PH models of rat ( Figure 1A) and mouse. Consistent with this observation, our studies showed that the mean pulmonary arterial pressures (mPAP) by day 35 in hypoxia-mouse and by day 42 in MTC-rat were significantly higher than those in normal ( Figure 2B). Collectively, it was suggested that PH has been successfully induced in the hypoxia-treated mouse and MTC-tr...

Circulating exosomal microRNAs (ex-miRNAs) are reflective of the characteristics of the tumor and are valuable biomarkers in different types of tumor. In addition, miRNAs serve important roles in tumor progression and metastasis. The present study aimed to investigate the circulating ex-miRNA-21 and miRNA-210 as novel biomarkers for patients with pancreatic cancer (PC). For this purpose, serum ex-miRNAs were extracted from the serum of patients with PC (n=30) and chronic pancreatitis (CP) (n=10) using an RNA isolation kit. For exosome identification in serum, transmission electron micrographs were used to determine crystalline structure, western blotting was used to identify exosomal markers, and NanoSight was used for nanoparticle characterization. The relative expression levels of ex-miRNAs were quantified using quantitative PCR and compared between patients with PC and CP. The expression levels of both ex-miRNA-21 and miRNA-210 were significantly higher in patients with PC compared with patients with CP (both P<0.001). However, no significant difference in the relative serum levels of free miR-21 and miR-210 was observed between the 2 groups of patients (both P>0.05). ex-miRNA-21 and miRNA-210 were associated with tumor stage, as well as other factors. The diagnostic potential of ex-miRNA-21 and miRNA-210 levels was 83 and 85%, respectively. In addition, when ex-miRNA and serum carbohydrate antigen 19-9 expression levels were combined, the accuracy increased to 90%. The present study identified that serum ex-miRNAs, miRNA-21 and miRNA-210 may be of value as potential biomarkers and therapeutic targets for the diagnosis and treatment of PC.

Long intergenic nonprotein coding RNA p53‐induced transcript (LINC‐PINT) has been reported to participate in various cancers. Here, we investigated the effects of LINC‐PINT on lung cancer progression. Firstly, in our study, we implied that LINC‐PINT was obviously decreased in NSCLC. Thereafter, in A549 and H1299 cells, LINC‐PINT was upregulated via transfecting LV‐LINC‐PINT. As exhibited, LINC‐PINT repressed cell proliferation and cell colony formation of A549 and H1299 cells. Subsequently, flow cytometry evidenced that A549 and H1299 cell apoptosis was obviously triggered and the cell cycle was arrested in G1 phase. Then, migration and transwell invasion experiments were carried out to detect the cell migration and invasion capacity. We found A549 and H1299 cell migration and invasion capacity were restrained by the upregulation of LINC‐PINT. Meanwhile, we predicted that miR‐543 could function as the target of LINC‐PINT and the association was verified. Moreover, we exhibited that miR‐543 was remarkably increased in lung cancer, which could be regulated by LINC‐PINT negatively. Furthermore, PTEN could act as the downstream target of miR‐543 and upregulation of miR‐543 repressed PTEN, which was reversed by LV‐PINT in A549 and H1299 cells. Finally, xenografts were utilized to confirm the function of LINC‐PINT on lung cancer. All these findings concluded that LINC‐PINT exerted crucial biological roles in NSCLC through sponging miR‐543 and inducing PTEN.

Stroke remains the leading cause of death and disability worldwide. This fact highlights the need to search for potential drug targets that can reduce stroke-related brain damage. We showed recently that a glycogen synthase kinase-3β (GSK-3β) inhibitor attenuates tissue plasminogen activator-induced hemorrhagic transformation after permanent focal cerebral ischemia. Here, we examined whether GSK-3β inhibition mitigates early ischemia-reperfusion stroke injury and investigated its potential mechanism of action. We used the rat middle cerebral artery occlusion (MCAO) model to mimic transient cerebral ischemia. At 3.5 h after MCAO, cerebral blood flow was restored, and rats were administered DMSO (vehicle, 1% in saline) or GSK-3β inhibitor TWS119 (30 mg/kg) by intraperitoneal injection. Animals were sacrificed 24 h after MCAO. TWS119 treatment reduced neurologic deficits, brain edema, infarct volume, and blood-brain barrier permeability compared with those in the vehicle group. TWS119 treatment also increased the protein expression of β-catenin and zonula occludens-1 but decreased β-catenin phosphorylation while suppressing the expression of GSK-3β. These results indicate that GSK-3β inhibition protects the blood-brain barrier and attenuates early ischemia-reperfusion stroke injury. This protection may be related to early activation of the Wnt/β-catenin signaling pathway.