Melatonin attenuates restenosis after vascular injury in diabetic rats through activation of the Nrf2 signaling pathway.

Diabetes is a major risk factor for the development of cardiovascular disease. Diabetic patients have a higher incidence of restenosis following endovascular therapy than non-diabetic patients. Melatonin is primarily synthesized and secreted by the pineal gland and plays an important protective anti-inflammatory and antioxidant role in a variety of cardiovascular diseases. However, no studies to date have evaluated the underlying effects and molecular mechanisms of melatonin on diabetes-related restenosis. Herein, we used an in vivo model of diabetes-related restenosis and an in vitro model of high glucose-cultured vascular smooth muscle cells to investigate the anti-restenosis effect and signaling mechanisms induced by melatonin treatment. The present study provides the first evidence that melatonin attenuates restenosis following vascular injury in diabetic rats. We further investigated the underlying molecular mechanisms both in vivo and in vitro. The data suggest that the Nrf2 signaling pathway is an important molecular target for melatonin-mediated inhibition of diabetes-related restenosis after vascular injury. These findings indicate that melatonin may represent a potential candidate for the prevention or treatment of vascular diseases and restenosis following endovascular therapy, especially in diabetic patients.

An indirect comparison by Bayesian network meta-analysis of drug-coated devices versus saphenous vein graft bypass in femoropopliteal arterial occlusive disease.

OBJECTIVE: To compare the efficacy and safety between drug-coated devices (DCDs) and bypass surgery with saphenous vein graft (BSV) in femoropopliteal arterial occlusive disease. METHODS: A Bayesian network meta-analysis and indirect comparison were performed. Randomized controlled trials of BSV, bypass surgery with prosthetic graft, bare metal stents, endoluminal bypass (covered stent), percutaneous transluminal angioplasty, and DCDs treating femoropopliteal arterial occlusive disease were collected. The primary end point was target lesion revascularization/target vessel revascularization, and secondary end points were all-cause mortality, limb salvage, and early complications (PROSPERO registry number: CRD42019136530). RESULTS: Forty-two trials and 6867 patients were included. The comparison of DCDs and BSV revealed no significant difference in the 1-year target lesion revascularization/target vessel revascularization (DCDs vs BSV: odds ratio [OR], 0.60; 95% credible interval [CrI], 0.16-2.39). Total early complications from BSV were significantly higher than those from DCDs (DCDs vs BSV: OR, 0.14; 95% CrI, 0.05-0.45), and the main complications of BSV were not death related. There was also no significant difference in systemic early complications (DCDs vs BSV: OR, 0.19; 95% CrI, 0.00-7.82) and 1-year amputation rate (DCDs vs BSV: OR, 2.81; 95% CrI, 0.16-89.53). The 30-day (DCDs vs BSV: OR, 0.38; 95% CrI, 0.00-110.46), 1-year (DCDs vs BSV: OR, 0.96; 95% CrI, 0.24-3.29), 2-year (DCDs vs BSV: OR, 1.60; 95% CrI, 0.64-4.95), and 5-year all-cause mortality rates (DCDs vs BSV: OR, 2.05; 95% CrI, 0.92-4.39) showed no significant differences between DCDs and BSV, although there was a noticeable tendency toward significant results of a higher 5-year mortality rate. CONCLUSIONS: There is no significant difference between DCDs and BSV in short-term efficacy or short- and long-term mortality. Despite traditional BSV remaining the gold standard, DCDs provide a reasonable alternative therapy. In addition, the DCDs have a lower short-term morbidity associated with the procedure at the cost of the possible risk of higher long-term mortality. Clinical trials with more validity are required for a direct comparison between BSV and DCDs.

Potential Role of Melatonin as an Adjuvant for Atherosclerotic Carotid Arterial Stenosis.

Carotid artery stenosis (CAS) is an atherosclerotic disease characterized by a narrowing of the artery lumen and a high risk of ischemic stroke. Risk factors of atherosclerosis, including smoking, hypertension, hyperglycemia, hyperlipidemia, aging, and disrupted circadian rhythm, may potentiate atherosclerosis in the carotid artery and further reduce the arterial lumen. Ischemic stroke due to severe CAS and cerebral ischemic/reperfusion (I/R) injury after the revascularization of CAS also adversely affect clinical outcomes. Melatonin is a pluripotent agent with potent anti-inflammatory, anti-oxidative, and neuroprotective properties. Although there is a shortage of direct clinical evidence demonstrating the benefits of melatonin in CAS patients, previous studies have shown that melatonin may be beneficial for patients with CAS in terms of reducing endothelial damage, stabilizing arterial plaque, mitigating the harm from CAS-related ischemic stroke and cerebral I/R injury, and alleviating the adverse effects of the related risk factors. Additional pre-clinical and clinical are required to confirm this speculation.

Cigarette smoke exposure impairs lipid metabolism by decreasing low-density lipoprotein receptor expression in hepatocytes.

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.

Diagnosis and treatment of low T3 syndrome in neurocritical patients.

WHAT IS KNOWN AND OBJECTIVE: Low levels of serum triiodothyronine (T3) are a strong predictor of mortality and poor prognosis in critical care patients. Few reports, however, have focused on neurocritical patients. The application of hormone replacement therapy (HRT) in the treatment of neurocritical patients with low T3 syndrome remains controversial. We studied the role of low T3 state as a predictor of outcomes in neurocritical patients and examined the effect of HRT on prognosis. METHODS: A retrospective analysis was performed on the data of 32 neurocritical patients with low T3 syndrome who were admitted to the neuro-intensive care unit of Peking Union Medical College Hospital between January 2012 and October 2018. While 18/32 (56.25%) patients received HRT (HRT group; n = 18), 14/32 (43.75%) patients did not receive HRT (non-HRT group; n = 14). Patients were followed up for periods ranging from 3 months to 72 months. Baseline clinical and laboratory data were compared between the two groups using Mann-Whitney U tests or the t tests. Overall survival was assessed by Kaplan-Meier curve and compared by log-rank tests. Univariate and multivariate regression analyses were performed to identify the factors associated with prognosis and estimate the effect of HRT. We also assessed the influence of HRT on final neurological function, using the Glasgow Coma Scale (GCS) and the Glasgow Outcome Scale (GOS) scores. RESULTS AND DISCUSSION: The neurocritical events in our cohort included post-operative complications (n = 18), traumatic brain injury (n = 8) and spontaneous intracerebral haemorrhage (n = 6). Mean GCS score in the cohort was 6.41 (6.44 ± 3.14 in HRT group vs 6.36 ± 2.06 in non-HRT group). A total of 15/32 (46.87%) deaths were recorded (7 in the HRT group, 8 in the non-HRT group). In the HRT group, 15 patients underwent repeat thyroid function tests after completion of HRT; the low T3 situation was corrected in only 5/15 (33.3%) patients. Overall survival was significantly shorter in the non-HRT group than in the HRT group (16.45 months vs 47.47 months; P = .034). In univariate regression analysis, the HRT group has the lower mortality risk than the non-HRT group (HR = 0.301, 95% Cl: 0.094-0.964; P = .043). However, multivariate regression analysis showed no significant difference in mortality risk between the two groups (HR = 0.340 95% CI: 0.099-1.172; P = .087). There was no significant difference in effects of HRT on the short- and long-term neurological function between the groups. WHAT IS NEW AND CONCLUSION: Low T3 syndrome may influence the prognosis of neurocritical patients, attention should be paid to the changes in serum T3 levels during treatment. Although it is unclear to what extent HRT can improve the short or long-term outcomes of neurological function, it can significantly improve the survival rates of neurocritical patients.

Melatonin alleviates cigarette smoke-induced endothelial cell pyroptosis through inhibiting ROS/NLRP3 axis.

Endothelial dysfunction (ED) is a crucial and initial stage for the development of cardiovascular diseases. Accumulated evidence has demonstrated causative links between cigarette smoke (CS) and ED. However, the underlying mechanisms remain largely unknown. Pyroptosis is a unique form of inflammatory cell death. In this study, we found that cigarette smoke extract (CSE) increased pyroptosis in endothelial cells (ECs) as evidenced by increasing lactate dehydrogenase release and the number of propidium iodide (PI) positive cells. A specific NOD-like receptor family, pyrin domain-containing 3 (NLRP3) inhibitor (MCC950) pretreatment dramatically reduced CSE-induced pyroptosis. Additionally, we also observed that N-Acetylcysteine (NAC, a ROS scavenger) pretreatment inhibited NLRP3 inflammasome activation as evidenced by suppressing the upregulation of NLRP3, ASC, cleaved-caspase-1, GSDMD-N, IL-1ß and IL-18 protein levels in CSE-treated ECs. Meanwhile, NAC pretreatment also remarkably inhibited CSE-induced EC pyroptosis. Melatonin is a hormone synthesized and secreted by mammalian pineal gland and plays a protective role in various cardiovascular diseases through its powerful anti-inflammatory and antioxidant properties. In this study, melatonin was observed to inhibit ROS production, NLRP3 inflammasome activation and pyroptosis in CSE-treated ECs. Moreover, oxidative stress and NLRP3 inflammasome activation in carotid arteries of smoking rats was also inhibited by melatonin. In conclusion, our study generated two novel findings, (i) CS activates ROS/NLRP3 axis and induces EC pyroptosis; (ii) melatonin attenuates CS-induced EC pyroptosis by inhibiting ROS/NLRP3 axis.

Protection of Nerve Injury with Exosome Extracted from Mesenchymal Stem Cell.

OBJECTIVE: To investigate the protective effect of Exosomes from human adipose-derived mesenchymal stem cells (hAMSCs) in neural injury induced by glutamate and its possible mechanism. METHODS: Characteristics of Exosomes from hAMSCs were identified by electron microscopy and Western blot analysis. Cytokines that might play a major role in the protective effect were tested by enzyme-linked immunosorbent assay (ELISA). The protective action of Exosome and its possible signaling pathway were researched by the in vitro neural injury induced by glutamate, including control group (without Glu), Glu group (dealing with Glu), Glu+Exo group (dealing with Glu +100 ng/ml Exo), Glu+Exo+Akt group (dealing with Glu+100 ng/ml Exo+10 µmol/L Akt), Glu+Exo+Erk group (dealing with 100 ng/ml Glu+100 ng/ml Exo+10 µmol/L Erk), and Glu+Exo+TrkB group (dealing with Glu+100 ng/ml Exo +10 µmol/L TrkB). RESULTS: Exosomes from hAMSCs had similar sizes to those isolated from other kinds of cells, and expressed the characteristic proteins such as CD63, CD81, HSP70, and HSP90. Cytokines that had neurotrophic effects on Exosomes were mainly insulin-like growth factor and hepatocyte growth factor, with the concentration being 9336.49±258.63 and 58,645.50±16,014.62, respectively; brain derived neurotrophic factor, nerve growth factor,and vascular endothelial growth factor had lower levels, with the concentration being 1928.25±385.47, 1136.94±5.99, and 33.34±9.43, respectively. MTS assay showed that the PC12 cell survival rates were 0.842±0.047, 0.306±0.024, 0.566±0.026, 0.461±0.016, 0.497±0.003, and 0.515±0.034 in the control group, Glu group, Glu+Exo group, Glu+Exo+Akt group, Glu+Exo+Erk group, and Glu+Exo+TrkB group; obviously, it was significantly lower in Glu group than in control group (P=0.02), significantly higher in Glu+Exo group than in Glu group (P=0.01), and significantly lower in Glu+Exo+Akt group than in Glu+Exo group (P=0.01). CONCLUSION: Exosomes secreted from hAMSCs have protective effect against neuron damage induced by glutamate, which may be mediated through activating the PI3/K-Akt signalling pathway.

Fetal endothelial colony-forming cells: Possible targets for prevention of the fetal origins of adult diseases.

Endothelial colony-forming cells (ECFCs), a subset of circulating and resident endothelial progenitor cells, are capable of self-renewal and de novo vessel formation, and are known key regulators of vascular integrity and homeostasis. Numerous studies have found that exposure to hostile environment during the fetal development exerts a profound influence on the level and function of ECFCs, which may be the underlying factor linking endothelial dysfunction to cardiovascular disease of the offspring in later life. Herein, we focus on the latest findings regarding the effects of pregnancy-related disorders on the frequency and function of fetal ECFCs. Subsequently, we discuss about placental ECFCs and put forward some details that should be paid attention to in the process of ECFC isolation and culture. Overall, the information presented in this review highlight the potential of ECFCs as a future biomarker or even therapeutic targets for the pregnancy-related adverse maternal and fetal outcomes.

Melatonin attenuates high glucose­induced endothelial cell pyroptosis by activating the Nrf2 pathway to inhibit NLRP3 inflammasome activation.

Endothelial injury induced by hyperglycemia is the most critical initial step in the development of diabetic vasculopathy. The aim of this present study was to explore the prevention and treatment strategies and elucidate the specific mechanism of diabetes­induced vascular endothelial injury. Melatonin, a hormone secreted by the pineal gland to regulate biological rhythm, serves an important role in maintaining human physiological function. Pyroptosis is a type of newly discovered inflammatory cell death. The current study first found by western blotting that melatonin could activate nuclear factor erythroid 2­related factor 2 (Nrf2) pathway in human umbilical vein endothelial cells (HUVECs) under high glucose (HG) condition. Second, it found that pretreatment with Luzindole, a specific inhibitor of melatonin receptor (MT1/MT2), significantly reduced the activation of Nrf2 pathway by melatonin in HUVECs. It also found that pretreatment with melatonin or a specific NOD­like receptor family, pyrin domain­containing 3 (NLRP3) inhibitor (MCC950) pretreatment reduced HG­induced endothelial cell pyroptosis. Finally, it was found that the protective effect of melatonin against reactive oxygen species/NLRP3 inflammasome pathway activation induced by HG in HUVECs was decreased after Nrf2 knockdown. In conclusion, the present study showed that melatonin may serve a protective role in HG­induced vascular endothelial cell pyroptosis by activating the Nrf2 pathway to inhibit NLRP3 inflammasome activation. In addition, it was further found that melatonin attenuated HG­induced vascular endothelial cell injury by interacting with its receptors (MT1/MT2) to promote activation of Nrf2 pathway.

Systematic review and meta-analysis of the prevalence of venous thromboembolic events in novel coronavirus disease-2019 patients.

BACKGROUND: Emerging clinical evidence has shown that patients with the novel coronavirus disease-2019 (COVID-19) have complications that include venous thromboembolism (VTE), consisting of deep vein thrombosis (DVT) and pulmonary embolism (PE). The prevalence of VTE in patients hospitalized with COVID-19 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 examination, 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 patients hospitalized with COVID-19 were included. Pooled VTE prevalence was 13% in consecutive patients (95% confidence interval [CI], 0.05-0.24; I2 = 97%), 7% in non-ICU patients (95% CI, 0.01-0.18; I2 = 93%), and 31% in ICU patients (95% CI, 0.22-0.42; I2 = 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 [95% CI, 0.04-0.13], 4% in non-ICU patients [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 [95% CI, 0.03-0.14], and 7% in non-ICU [95% CI, 0.02-0.14]). The subgroup analysis showed a three-fold improvement in the PE and DVT detection rates in both ICU and non-ICU patients with COVID-19 when the 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 < .0001) and DVT (40% vs 12%; P = .0065) compared with non-ICU patients. CONCLUSIONS: VTE is common in patients hospitalized with COVID-19, 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.

Melatonin attenuates smoking-induced atherosclerosis by activating the Nrf2 pathway via NLRP3 inflammasomes in endothelial cells.

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.

Cigarette smoke extract stimulates PCSK9 production in HepG2 cells via ROS/NF­κB signaling.

Cigarette smoke (CS) exposure is a risk factor for dyslipidemia and atherosclerosis. Reduced expression of low­density lipoprotein receptor (LDLR) in hepatocytes may be one of the underlying mechanisms for these disorders. The aim of the present study was to investigate the molecular mechanism underlying the regulatory effect of CS extract (CSE) on proprotein convertase subtilisin/kexin type 9 (PCSK9) and low LDLR expression in HepG2 cells. PCSK9 and LDLR mRNA and protein expression levels in HepG2 cells were evaluated after CSE treatment via reverse transcription­quantitative polymerase chain reaction and western blotting, respectively. In addition, total intracellular reactive oxygen species (ROS) production was determined via 2,7­dichlorofluorescein diacetate fluorescence. CSE significantly increased PCSK9 expression and inhibited LDLR expression in a time­ and concentration­dependent manner. Furthermore, CSE significantly induced ROS production and nuclear factor κB (NF­κB) activation. However, pretreatment with a ROS scavenger or an NF­κB inhibitor significantly attenuated the CSE­induced changes in PCSK9 and LDLR expression. In addition, pretreatment with melatonin markedly reduced ROS production, NF­κB activation and PCSK9 expression, and increased LDLR expression in the CSE­treated cells. These data suggest that melatonin inhibits CSE­regulated PCSK9 and LDLR production in HepG2 cells via ROS/NF­κB signaling.

Construction and Validation of a New Model for the Prediction of Rupture in Patients with Intracranial Aneurysms.

BACKGROUND: Despite progress in the detection of biological molecules that contribute to intracranial aneurysm (IA) development, many pathophysiological mechanisms remain unclear, particularly with regard to predicting IA rupture. In this study, we aimed to identify hub genes and construct a new model to predict IA rupture. METHODS: Four datasets (62 ruptured IAs, 16 unruptured IAs, and 31 normal controls) were downloaded from the Gene Expression Omnibus. Differentially expressed genes (DEGs) were identified between the IAs and normal controls. All overlapping genes were analyzed using weighted gene co-expression network analysis. Functional enrichment analyses were performed using key modules. We then intersected the key module genes with DEGs. Protein-protein interaction networks were assessed to identify key hub genes. Least absolute shrinkage and selection operator logistic regression analysis was performed to construct a prediction model. A receiver operating characteristic curve was constructed to evaluate the reliability of the scoring system. RESULTS: After intersection and normalization, 433 DEGs were identified and 15,388 genes were selected for weighted gene co-expression network analysis. The black module with 1145 genes exhibited the highest correlation with IA rupture. Many potential mechanisms are involved, such as the inflammatory response, innate immune response, extracellular exosome, and extracellular space. Thirty hub genes were selected from the protein-protein interaction, and 4 independent risk genes, TNFAIP6, NCF2, OSM, and IRAK3, were identified in the least absolute shrinkage and selection operator logistic regression model. CONCLUSIONS: Our prediction model not only serves as a useful tool for assessing the risk of IA rupture, but the key genes identified herein could also serve as biomarkers and therapeutic targets.

Hypothalamus-Pituitary Dysfunction as an Independent Risk Factor for Postoperative Central Nervous System Infections in Patients With Sellar Region Tumors.

Objective: The purpose of this study was to verify that hypothalamus-pituitary dysfunction is one of the risk factors for postoperative central nervous system infections (PCNSIs). Method: We performed a retrospective analysis of all patients with sellar region lesions who underwent surgery between January 2016 and November 2019 at Peking Union Medical College Hospital. In total, 44 age- and sex-matched controls were enrolled. Univariate and multivariate analyses were performed to identify risk factors for PCNSIs. Result: We enrolled 88 patients, 44 of whom had PCNSIs. Surgical approach (TCS) (P<0.001), previous surgery on the same site (P=0.001), intraoperative cerebral spinal fluid (CSF) leakage (P<0.001), postoperative adrenal insufficiency (P=0.017), postoperative DI (P=0.004) and the maximum Na+ levels(<0.001) correlated significantly with PCNSIs. Multivariate analysis showed that Surgery approach (TCS)(OR: 77.588; 95%CI: 7.981-754.263; P<0.001), intraoperative CSF leakage (OR: 12.906; 95%CI: 3.499-47.602; P<0.001), postoperative DI (OR: 6.999; 95%CI:1.371-35.723; P=0.019) and postoperative adrenal insufficiency (OR: 6.115; 95%CI: 1.025-36.469; P=0.047) were independent influencing factors for PCNSIs. Conclusion: TCS, intraoperative CSF leakage, postoperative DI and postoperative adrenal insufficiency are risk factors for PCNSIs in patients with sellar region tumors.

Differential roles of Scavenger receptor class B type I: A protective molecule and a facilitator of atherosclerosis (Review).

The scavenger receptor class B type I (SR­BI) is a multi­ligand membrane protein receptor that binds to high­density lipoprotein (HDL) under physiological conditions, promoting the selective uptake of cholesterol esters from HDL into cells. SR­BI also promotes the reverse transport of excess cholesterol from peripheral tissues to the liver, contributing to the synthesis of bile acids for excretion and the removal of excess cholesterol from the body, thereby lowering the cholesterol load and exerting anti­atherosclerotic effects. Studies in mice and humans have demonstrated that a functional defect of SR­BI can cause atherosclerotic lesions and cardiovascular diseases, such as myocardial infarction and stroke. Additionally, SR­BI in vascular endothelial cells promoted the deposition of low­density lipoprotein under the endothelium. Although SR­BI is widely expressed in various tissues and cell types throughout the body, its expression level and function vary accordingly. The present review focuses on the biological functions and mechanisms of SR­BI in regulating atherosclerosis.

MSC-derived exosomes promote recovery from traumatic brain injury via microglia/macrophages in rat.

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.

COVID-19: Melatonin as a potential adjuvant treatment.

This article summarizes the likely benefits of melatonin in the attenuation of COVID-19 based on its putative pathogenesis. The recent outbreak of COVID-19 has become a pandemic with tens of thousands of infected patients. Based on clinical features, pathology, the pathogenesis of acute respiratory disorder induced by either highly homogenous coronaviruses or other pathogens, the evidence suggests that excessive inflammation, oxidation, and an exaggerated immune response very likely contribute to COVID-19 pathology. This leads to a cytokine storm and subsequent progression to acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) and often death. Melatonin, a well-known anti-inflammatory and anti-oxidative molecule, is protective against ALI/ARDS caused by viral and other pathogens. Melatonin is effective in critical care patients by reducing vessel permeability, anxiety, sedation use, and improving sleeping quality, which might also be beneficial for better clinical outcomes for COVID-19 patients. Notably, melatonin has a high safety profile. There is significant data showing that melatonin limits virus-related diseases and would also likely be beneficial in COVID-19 patients. Additional experiments and clinical studies are required to confirm this speculation.

Combined Strategy for Post-Operative Patients with Central Nervous System Infections Caused by Extensively Drug-Resistant/Pan-Drug-Resistant Acinetobacter baumannii: A Retrospective Study.

Background: Post-operative central nervous system infections (PCNSIs) caused by extensively drug-resistant (XDR) or pan-drug-resistant (PDR) Acinetobacter baumannii are rare but intractable problems. To investigate a potential combined strategy to treat Acinetobacter baumannii organisms that are resistant to not only meropenem but also colistin. Methods: We retrospectively reviewed cerebrospinal fluid positive culture isolates of Acinetobacter baumannii in patients who underwent neurosurgery. Medical records were collected by standard forms and analyzed. Results: Sixteen patients met the criteria and most patients were middle-aged males who had undergone craniotomy or endonasal trans-sphenoidal surgery. A total of 68.8% Acinetobacter baumannii isolates were XDR bacteria, and 18.8% of isolates were PDR bacteria. Twelve patients were treated by meropenem-based regimen strategy. Another four patients were administered tetracycline-based regimens. A total of 93.8% patients were treated with therapeutic drainage and strict hygiene rules were followed. Finally, 12 patients survived their infections, and the average Glasgow Outcome Scale score was 2.9 ± 1.4 at discharge. The mortality rates of carbapenem-resistant Acinetobacter baumannii (CRAB) were 8.3%. Conclusions: Post-operative central nervous system infections caused by XDR/PDR Acinetobacter baumannii are a rare and serious complication. Combined therapy based on the individual situation, including appropriate antimicrobial agents, surgical management, and strict hygiene management might be an effective therapeutic strategy.

Therapeutic Potential of Endothelial Colony Forming Cells Derived from Human Umbilical Cord Blood.

Endothelial progenitor cells (EPCs) are implicated in multiple biologic processes such as vascular homeostasis, neovascularization and tissue regeneration, and tumor angiogenesis. A subtype of EPCs is referred to as endothelial colony-forming cells (ECFCs), which display robust clonal proliferative potential and can form durable and functional blood vessels in animal models. In this review, we provide a brief overview of EPCs' characteristics, classification and origins, a summary of the progress in preclinical studies with regard to the therapeutic potential of human umbilical cord blood derived ECFCs (CB-ECFCs) for ischemia repair, tissue engineering and tumor, and highlight the necessity to select high proliferative CB-ECFCs and to optimize their recovery and expansion conditions.

Prevalence and antibiotic resistance of bacteria isolated from the cerebrospinal fluid of neurosurgical patients at Peking Union Medical College Hospital.

Background: Postoperative 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. Methods: We 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. Results: A 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. Conclusion: PCNSIs 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.