Maraviroc promotes recovery from traumatic brain injury in mice by suppression of neuroinflammation and activation of neurotoxic reactive astrocytes

Neuroinflammation and the NACHT,LRR,and PYD domains-containing protein 3 inflammasome play crucial roles in secondary tissue damage following an initial insult in patients with traumatic brain injury(TBI).Maraviroc,a C-C chemokine receptor type 5 antagonist,has been viewed as a new therapeutic strategy for many neuroinflammatory diseases.We studied the effect of maraviroc on TBI-induced neuroinflammation.A moderate-TBI mouse model was subjected to a controlled cortical impact device.Maraviroc or vehicle was injected intraperitoneally 1 hour after TBI and then once per day for 3 consecutive days.Western blot,immunohistochemistry,and TUNEL(terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling)analyses were performed to evaluate the molecular mechanisms of maraviroc at 3 days post-TBI.Our results suggest that maraviroc administration reduced NACHT,LRR,and PYD domains-containing protein 3 inflammasome activation,modulated microglial polarization from M1 to M2,decreased neutrophil and macrophage infiltration,and inhibited the release of inflammatory factors after TBI.Moreover,maraviroc treatment decreased the activation of neurotoxic reactive astrocytes,which,in turn,exacerbated neuronal cell death.Additionally,we confirmed the neuroprotective effect of maraviroc using the modified neurological severity score,rotarod test,Morris water maze test,and lesion volume measurements.In summary,our findings indicate that maraviroc might be a desirable pharmacotherapeutic strategy for TBI,and C-C chemokine receptor type 5 might be a promising pharmacotherapeutic target to improve recovery after TBI.

Atorvastatin combined with low-dose dexamethasone for vascular endothelial cell dysfunction induced by chronic subdural hematoma

Atorvastatin has been shown to be a safe and effective non-surgical treatment option for patients with chronic subdural hematoma.However,treatment with atorvastatin is not effective in some patients,who must undergo further surgical treatment.Dexamethasone has anti-inflammatory and immunomodulatory effects,and low dosages are safe and effective for the treatment of many diseases,such as ankylosing spondylitis and community-acquired pneumonia.However,the effects of atorvastatin and low-dose dexamethasone for the treatment of chronic subdural hematoma remain poorly understood.Hematoma samples of patients with chronic subdural hematoma admitted to the General Hospital of Tianjin Medical University of China were collected and diluted in endothelial cell medium at 1:1 as the hematoma group.Atorvastatin,dexamethasone,or their combination was added to the culture medium.The main results were as follows:hopping probe ion conductance microscopy and permeability detection revealed that the best dosages to improve endothelial cell permeability were 0.1μM atorvastatin and 0.1μM dexamethasone.Atorvastatin,dexamethasone,or their combination could markedly improve the recovery of injured endothelial cells.Mice subcutaneously injected with diluted hematoma solution and then treated with atorvastatin,dexamethasone,or their combination exhibited varying levels of rescue of endothelial cell function.Hopping probe ion conductance microscopy,western blot assay,and polymerase chain reaction to evaluate the status of human cerebral endothelial cell status and expression level of tight junction protein indicated that atorvastatin,dexamethasone,or their combination could reduce subcutaneous vascular leakage caused by hematoma fluid.Moreover,the curative effect of the combined treatment was significantly better than that of either single treatment.Expression of Krüppel-like factor 2 protein in human cerebral endothelial cells was significantly increased,as was expression of the tight junction protein and vascular permeability marker vascular endothelial cadherin in each treatment group compared with the hematoma stimulation group.Hematoma fluid in patients with chronic subdural hematoma may damage vascular endothelial cells.However,atorvastatin combined with low-dose dexamethasone could rescue endothelial cell dysfunction by increasing the expression of tight junction proteins after hematoma injury.The effect of combining atorvastatin with low-dose dexamethasone was better than that of atorvastatin alone.Increased expression of Krüppel-like factor 2 may play an important role in the treatment of chronic subdural hematoma.The animal protocols were approved by the Animal Care and Use Committee of Tianjin Medical University of China on July 31,2016(approval No.IRB2016-YX-036).The study regarding human hematoma samples was approved by the Ethics Committee of Tianjin Medical University of China on July 31,2018(approval No.IRB2018-088-01).

Blast response of clay brick masonry unit walls unreinforced and reinforced with polyurea elastomer

Clay brick masonry unit(CBMU) walls are widely used in building structures,and its damage and protection under explosion loads have been a matter of concern in the field of engineering protection.In this paper,a series of full-scale experiments of the response characteristics of 24 cm CMBU walls unreinforced and reinforced with polyurea elastomer subjected to blast loading were carried out.Through setting 5.0 kg TNT charges at different stand-off distances,the damage characteristics of masonry walls at different scaled distances were obtained.The reinforcement effect of different polyurea coating thicknesses and methods on the blast resistance performance of masonry walls under single and repeated loads were also explored.Five failure grades were summarized according to the dynamic response features of masonry walls.Based on the stress wave propagation pattern in multi-media composite structures,the internal stress distribution of masonry walls were analyzed,and the division basis of the masonry walls’ failure grades was then quantified.Combined with Scanning Electron Microscope(SEM)images,the deformation characteristics of soft and hard segments of polyurea and effects of detonation products on microstructures were revealed respectively,which provides an important reference for the design and application of polyurea in the blast resistance of clay brick masonry walls.

Counterbalance: modulation of VEGF/VEGFR activities byTNFSF15

Vascular hyperpermeability occurs in angiogenesis and several pathobiological conditions,producing elevated interstitial fluid pressure and lymphangiogenesis.How these closely related events are modulated is a fundamentally important question regarding the maintenance of vascular homeostasis and treatment of disease conditions such as cancer,stroke,and myocardial infarction.Signals mediated by vascular endothelial growth factor receptors,noticeably VEGFR-1,−2,and−3,are centrally involved in the promotion of both blood vessel and lymphatic vessel growth.These signaling pathways are counterbalanced or,in the case of VEGFR3,augmented by signals induced by tumor necrosis factor superfamily-15(TNFSF15).TNFSF15 can simultaneously downregulate membrane-bound VEGFR1 and upregulate soluble VEGFR1,thus changing VEGF/VEGFR1 signals from pro-angiogenic to anti-angiogenic.In addition,TNFSF15 inhibits VEGF-induced VEGFR2 phosphorylation,thereby curbing VEGFR2-mediated enhancement of vascular permeability.Third,and perhaps more interestingly,TNFSF15 is capable of stimulating VEGFR3 gene expression in lymphatic endothelial cells,thus augmenting VEGF-C/D-VEGFR3-facilitated lymphangiogenesis.We discuss the intertwining relationship between the actions of TNFSF15 and VEGF in this review.