This article summarizes the likely benefits of melatonin in the attenuation of COVID-19 based on its putative pathogenesis. The recent outbreak of Journal Pre-proof
Elucidation of the mechanism of action for drug candidates is fundamental to drug development, and it is strongly facilitated by metabolomics. Herein, we developed an imaging metabolomics method based on air-flow-assisted desorption electrospray ionization mass spectrometry imaging (AFADESI-MSI) under ambient conditions. This method was subsequently applied to simultaneously profile a novel anti-insomnia drug candidate, N(6)-(4-hydroxybenzyl)-adenosine (NHBA), and various endogenous metabolites in rat whole-body tissue sections after the administration of NHBA. The principal component analysis (PCA) represented by an intuitive color-coding scheme based on hyperspectral imaging revealed in situ molecular profiling alterations in response to stimulation of NHBA, which are in a very low intensity and hidden in massive interferential peaks. We found that the abundance of six endogenous metabolites changed after drug administration. The spatiotemporal distribution indicated that five altered molecules—including neurotransmitter γ-aminobutyric acid, neurotransmitter precursors choline and glycerophosphocholine, energy metabolism-related molecules adenosine (an endogenous sleep factor), and creatine—are closely associated with insomnia or other neurological disorders. These findings not only provide insights into a deep understanding on the mechanism of action of NHBA, but also demonstrate that the AFADESI-MSI-based imaging metabolomics is a powerful technique to investigate the molecular mechanism of drug action, especially for drug candidates with multitarget or undefined target in the preclinical study stage.
The aim of this study was to investigate the safety and effectiveness of endovascular stenting for extracranial carotid artery aneurysms (ECAAs) and evaluate the mid-term outcomes.Twelve consecutive symptomatic patients (mean age 43.8 ± 14.9 years; 8 men) with ECAAs who were treated with endovascular stenting between 1997 and 2015 were retrospectively analyzed. Clinical follow-up data including symptoms and neurological events were obtained from outpatient records. Imaging follow-up with duplex ultrasound and/or computed tomographic angiography (CTA) was performed to examine the aneurysm obliteration and patency of the stents at 3, 6, 12 months and yearly thereafter.A total of 5 true aneurysms and 7 pseudoaneurysms were included in our series. Neurological symptoms (n = 5, 41.7%) and a pulsatile neck mass (n = 5, 41.7%) were the most common presenting symptoms. Endovascular stenting procedures were technically successful in all cases; 3 patients received bare stents, and 9 patients received covered stents. No perioperative neurologic or cardiopulmonary complications occurred. Over a period of follow-ups (mean 21.8 ± 25.1 months), all patients were alive and free from neurological or other adverse events. All aneurysms were completely excluded except for 1 patient who was exposed to a residual medium leaking into the aneurysm sac. No reintervention was performed in this specific patient because aneurysm growth or significant clinical symptoms did not occur. Recurrent restenosis assessed by CTA imaging at 12 months occurred in 1 (8.3%) patient in our series. Target lesion revascularization for this hemodynamic restenosis was treated with placement of an additional stent.In our series, endovascular stenting for ECAAs was found to be safe, effective, and proved to have promising mid-term results. Although long-term results need to be further explored, advantages including less procedure-related complications and a shorter recovery time make endovascular stenting an attractive option for ECAAs, especially for the patients who are unfit for traditional open surgery.
Background Emerging clinical evidence has shown that COVID-19 patients are complicated with venous thromboembolism (VTE), consisting of deep vein thrombosis (DVT) and pulmonary embolism (PE). The prevalence of VTE in hospitalized COVID-19 patients is unclear. Methods Eligible studies on COVID-19 were collected from PubMed, Web of Science, and Embase. Patient characteristics and information were extracted for three categories of patients: Consecutive, ICU, and non-ICU group. All PEs and DVTs were diagnosed by computed tomographic pulmonary arteriography and duplex ultrasound, respectively. A subgroup analysis of testing strategies in ICU and non-ICU patients for PE and DVT was also performed. Results Forty clinical studies involving 7966 hospitalized COVID-19 patients were included. Pooled VTE prevalence was 13% in consecutive patients (95%CI: 0.05–0.24; I 2 =97%), 7% in non-ICU patients (95%CI: 0.01-0.18; I 2 =93%), and 31% in ICU patients (95%CI: 0.22–0.42; I 2 =91%). ICU patients had the highest prevalence of PE among the three groups (17%, 95%CI: 0.12-0.23, vs. 8% in consecutive patients with 95%CI: 0.04-0.13, 4% in non-ICU with 95%CI: 0.01-0.08). ICU patients also had the highest DVT prevalence (25%, 95%CI: 0.14-0.37, vs. 7% in consecutive patients with 95%CI: 0.03-0.14, 7% in non-ICU with 95%CI: 0.02-0.14). The subgroup analysis showed a 3-fold improvement in PE and DVT detections rate in both ICU and non-ICU patients with COVID-19 when screening test for VTE was applied. In the settings of screening tests for VTE, ICU patients have a significantly higher prevalence of PE (37% vs. 10%, p<0.0001) and DVT (40% vs. 12%, p=0.0065) compared to non-ICU patients. Conclusions VTE is common in hospitalized COVID-19 patients, especially among ICU patients. Screening tests for PE and DVT may significantly improve detection rates in both ICU and non-ICU patients with COVID-19 than tests based on clinical suspicion.
Tumor necrosis factor receptor-associated factor 1 (TRAF1), an adapter in signal transduction, is involved in immunity and in apoptotic processes in various cell types. However, little is known about its function and the molecular mechanism of its activation during liver injury. This study tested the hypothesis that TRAF1 is a mediator of cell injury after hepatic ischemia/reperfusion injury (I/R). In a mouse hepatic I/R injury model, we found that TRAF1 expression was highly induced. TRAF1 deficiency was liver protective, whereas sustained TRAF1 overexpression aggravated liver injury in response to hepatic I/R injury. Mechanistic studies demonstrated that a deficiency of TRAF1 in cultured hepatocytes led to the inhibition of NF-κB-mediated inflammatory responses, suppression of the ASK/JNK pro-death pathway and promotion of cellular regeneration capacity. In contrast, the converse occurred in hepatocyte-specific TRAF1 transgenic mice. TRAF1 activated the ASK1/JNK pathway and promoted hepatic injury. Our study demonstrates that TRAF1 is a crucial early mediator of hepatic I/R injury and suggests that TRAF1 may be a potential gene therapy target for the treatment of liver injury.
Epidemiology survey indicated that cigarette smoking is a risk factor of diabetes. However, the precise mechanisms remain to be clarified. In this study, we found that smoking caused metabolic malfunctions on pancreas and liver in experimental animal model. These were indicated by hyperglycemia, increased serum hemoglobin A1c level and decreased insulin secretion, inhibition of liver glycogen synthase (LGS), and hepatic glycogen synthesis. Mechanistic studies revealed that all these alterations were caused by the inflammatory reaction and reactive oxygen species (ROS) induced by the smoking. Melatonin treatment significantly preserved the functions of both pancreas and liver by reducing β cell apoptosis, CD68‐cell infiltration, ROS production, and caspase‐3 expression. The siRNA‐knockdown model identified that the protective effects of melatonin were mediated by melatonin receptor‐2 (MT2). This study uncovered potentially underlying mechanisms related to the association between smoking and diabetes. In addition, it is, for first time, to report that melatonin effectively protects against smoking‐induced glucose metabolic alterations and the signal transduction pathway of melatonin is mainly mediated by its MT2 receptor. These observations provide solid evidence for the clinically use of melatonin to reduce smoking‐related diabetes, and the therapeutic regimens are absent currently.
Background Cigarette smoke (CS) exposure impairs serum lipid profiles and the function of vascular endothelial cells, which accelerates the atherosclerosis. However, the precise mechanism and effect on the expression of low-density lipoprotein receptor (LDLR) in the liver by CS exposure is still unclear. Methods In this study, adult male C57BL/6 J mice were divided into three groups, with one group being exposed to CS for 6 weeks. HepG2 cells were treated with CS extract at concentrations of 1, 2.5, 5, and 10%. Results The serum levels of total cholesterol (TC), triglycerides (TGs), and low-density lipoprotein cholesterol (LDL-C) for the CS-exposure group were significantly higher than those in the control group (P < 0.05). Moreover, CS exposure decreased the LDLR expression in the hepatocytes and promoted inflammation in the blood vessel walls. Melatonin was intraperitoneally injected at 10 mg/kg/d for 6 weeks alongside CS exposure, and this significantly decreased the levels of TC, TGs, and LDL-C and decreased the expression of intercellular adhesion molecule-1 and the infiltration of cluster determinant 68-cells. In vitro, CS extract prepared by bubbling CS through phosphate-buffered saline decreased the LDLR expression in HepG2 cells in a time- and concentration-dependent manner, and this effect was prevented by pretreatment with 100 μM melatonin. Conclusions In conclusion, CS exposure impaired lipid metabolism and decreased LDLR expression in hepatocytes, and these effects could be prevented by melatonin supplementation. These findings implied that melatonin has the potential therapeutic applicability in the prevention of lipid metabolic disorder in smokers.
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