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

Angiogenesis is a complicated and sequential process that plays an important role in different physiological processes. Mesenchymal stem cells (MSCs), which are pluripotent stem cells, are widely used for the treatment of ischemic and traumatic diseases, and exosomes derived from these cells can also promote angiogenesis. Therefore, we aimed to uncover mechanisms to improve MSC exosome-mediated angiogenesis. For this study, we isolated human adipose-derived MSCs (hAD-MSCs) and assessed differentiation ability and markers. Cells were divided into hypoxia-treated MSCs (H-MSCs) and normoxia-treated MSCs (N-MSC), and exosomes were extracted by ultrafiltration. Exosomes (100 μg/mL) from H-MSCs and N-MSCs were added to human umbilical vein endothelial cells (HUVECs). Exosome uptake and the ability of endothelial cells to form tubes were detected in real time. Protein samples were collected at different time points to detect the expression of inhibitors (Vash1) and enhancers (Angpt1 and Flk1) of angiogenesis; we also assessed their related signaling pathways. We found that exosomes from the hypoxia group were more easily taken up by HUVECs; furthermore, their angiogenesis stimulatory activity was also significantly enhanced compared to that with exosomes from the normoxia group. HUVECs exposed to exosomes from H-MSCs significantly upregulated angiogenesis-stimulating genes and deregulated angiogenesis-inhibitory genes. The expression of vascular endothelial growth factor (VEGF) and activation of the protein kinase A (PKA) signaling pathway in HUVECs were significantly increased by hypoxia-exposed exosomes. Moreover, a PKA inhibitor was shown to significantly suppress angiogenesis. Finally, we concluded that hypoxia-exposed exosomes derived from hAD-MSCs can improve angiogenesis by activating the PKA signaling pathway and promoting the expression of VEGF. These results could be used to uncover safe and effective treatments for traumatic diseases.

Traumatic brain injury (TBI) is a leading cause of morbidity and mortality in young individuals worldwide. There is currently no effective clinical treatment for TBI, but mesenchymal stem cell-derived exosomes have exhibited promising therapeutic effects. In this study, we performed intracerebroventricular microinjection of human adipose mesenchymal stem cell (hADSC)-derived exosomes (hADSC-ex) in a weight-drop-induced TBI rat model. We found that hADSC-ex promoted functional recovery, suppressed neuroinflammation, reduced neuronal apoptosis, and increased neurogenesis in TBI rats. The therapeutic effects of hADSC-ex were comparable to those of hADSC. Sequential in vivo imaging revealed increasing aggregation of DiR-labeled hADSC-ex in the lesion area. Immunofluorescent staining of coronal brain sections and primary mixed neural cell cultures revealed distinct overlap between CM-DiI-labeled hADSC-ex and microglia/macrophages, indicating that hADSC-ex were mainly taken up by microglia/macrophages. In a lipopolysaccharide-induced inflammatory model, hADSC-ex suppressed microglia/macrophage activation by inhibiting nuclear factor κB and P38 mitogen-activated protein kinase signaling. These data suggest that hADSC-ex specifically enter microglia/macrophages and suppress their activation during brain injury, thereby inhibiting inflammation and facilitating functional recovery. They also offer new insight into the cellular targeting, uptake and migration of hADSC-ex, and provide a theoretical basis for new therapeutic strategies for central nervous system diseases.

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BackgroundPostoperative central nervous system infections (PCNSIs) represent a serious complication, and the timely use of antibiotics guided by the identification of the causative pathogens and their antibiotic sensitivities is essential for treatment. However, there are little data regarding the prevalence of PCNSI pathogens in China. The aim of this study is to investigate the features of pathogens in patients with PCNSIs, which could help clinicians to choose the appropriate empirical antibiotic therapy.MethodsWe retrospectively examined the positive CSF cultures in patients who underwent craniotomy between January 2010 and December 2015. We collected data, including demographic characteristics, type of neurosurgery, laboratory data, causative organisms and antimicrobial susceptibility testing results.ResultsA total of 62 patients with 90 isolates out of 818 patients with 2433 CSF culture samples were available for data analysis. The estimated incidence and culture-positive rate of PCNSIs were approximately 0.9 and 7.5%, respectively. The predominant organism was coagulase-negative staphylococci, of which most were methicillin-resistant coagulase-negative staphylococci (MRCoNS). All were susceptible to vancomycin, linezolid, rifampicin and amoxicillin-clavulanate. Acinetobacter baumannii was the most frequent causative Gram-negative agent and was resistant to 12 out of 18 antimicrobials tested. The sensitivity rates for tigecycline and minocycline were only 40 and 33%, respectively.ConclusionPCNSIs could lead to high mortality. Although the MRCoNS were the predominant organism, the management of Acinetobacter baumannii was a major clinical challenge with few effective antimicrobials in PCNSIs.Electronic supplementary materialThe online version of this article (10.1186/s13756-018-0323-3) contains supplementary material, which is available to authorized users.

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.

Substantial evidence suggests that the effects of smoking in atherosclerosis are associated with inflammation mediated by endothelial cells. However, the mechanisms and potential drug therapies for smoking-induced atherosclerosis remain to be clarified. Considering that melatonin exerts beneficial effects in cardiovascular diseases, we examined its effects on cigarette smoke-induced vascular injury. We found that cigarette smoke extract (CSE) treatment induced NLRP3-related pyroptosis in human aortic endothelial cells (HAECs). CSE also induced ROS generation and upregulated the Nrf2 pathway in HAECs. Furthermore, pretreatment of HAECs with Nrf2-specific siRNA and an Nrf2 activator revealed that Nrf2 can inhibit CSE-induced ROS/NLRP3 activation. Nrf2 also improved cell viability and the expression of VEGF and eNOS in CSE-treated HAECs. In balloon-induced carotid artery injury model rats exposed to cigarette smoke, melatonin treatment reduced intimal hyperplasia in the carotid artery. Mechanistic studies revealed that compared with the control group, Nrf2 activation was increased in the melatonin group, whereas ROS levels and the NLRP3 inflammasome pathway were inhibited. These results reveal that melatonin might effectively protect against smoking-induced vascular injury and atherosclerosis through the Nrf2/ROS/NLRP3 signaling pathway. Overall, these observations provide compelling evidence for the clinical use of melatonin to reduce smoking-related inflammatory vascular injury and atherosclerosis.

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.