Enhanced liver X receptor signalling reduces brain injury and promotes tissue regeneration following experimental intracerebral haemorrhage:roles of microglia/macrophages

background Inflammation-exacerbated secondary brain injury and limited tissue regeneration are barriers to favourable prognosis after intracerebral haemorrhage(ICH).As a regulator of inflammation and lipid metabolism,Liver X receptor(LXR)has the potential to alter microglia/macrophage(M/M)phenotype,and assist tissue repair by promoting cholesterol efflux and recycling from phagocytes.To support potential clinical translation,the benefits of enhanced LXR signalling are examined in experimental ICH.Methods Collagenase-induced ICH mice were treated with the LXR agonist GW3965 or vehicle.Behavioural tests were conducted at multiple time points.Lesion and haematoma volume,and other brain parameters were assessed using multimodal MRI with T2-weighted,diffusion tensor imaging and dynamic contrast-enhanced MRI sequences.The fixed brain cryosections were stained and confocal microscopy was applied to detect LXR downstream genes,M/M phenotype,lipid/cholesterol-laden phagocytes,oligodendrocyte lineage cells and neural stem cells.Western blot and real-time qPCR were also used.CX3CR1^(CreER):Rosa26^(iDTR) mice were employed for M/M-depletion experiments.results GW3965 treatment reduced lesion volume and white matter injury,and promoted haematoma clearance.Treated mice upregulated LXR downstream genes including ABCA1 and Apolipoprotein E,and had reduced density of M/M that apparently shifted from proinflammatory interleukin-1β+to Arginase1+CD206+regulatory phenotype.Fewer cholesterol crystal or myelin debris-laden phagocytes were observed in GW3965 mice.LXR activation increased the number of Olig2+PDGFRα+precursors and Olig2+CC1+mature oligodendrocytes in perihaematomal regions,and elevated SOX2+or nestin+neural stem cells in lesion and subventricular zone.MRI results supported better lesion recovery by GW3965,and this was corroborated by return to pre-ICH values of functional rotarod activity.The therapeutic effects of GW3965 were abrogated by M/M depletion in CX3CR1^(CreER):Rosa26^(iDTR) mice.Conclusions LXR agonism using GW3965 reduced brain injury,promoted beneficial properties of M/M and facilitated tissue repair correspondent with enhanced cholesterol recycling.

Intracerebral haemorrhage: from clinical settings to animal models

Spontaneous intracerebral haemorrhage(ICH)is a devastating type of stroke with high mortality and morbidity and for which no effective treatments are available to date.Much experimental and clinical research have been performed to explore its mechanisms regard the subsequent inflammatory cascade and to seek the potential therapeutic strategies.The aim of this review is to discuss insights from clinical settings that have led to the development of numerous animal models of ICH.Some of the current and future challenges for clinicians to understand ICH are also surveyed.

Light-guided tumor diagnosis and therapeutics:From nanoclusters to polyoxometalates

Malignant tumors,with the characteristics of easy metastasis and recurrence,are a serious threat to health of mankind.It is urgent to develop promising clinical cancer targeted agents with combination of rapid diagnosis and efficient therapies.Compared with the conventional photosensitizing agents,the recent advances of nanoagents based on transition metal-oxide clusters possess unique structural and electronic properties,greatly improving cancer survival rate,meanwhile,keeping high contrast imaging.This review provides a brief introduction of metal-oxide clusters,including both nanoclusters to molecular clusters,specifically polyoxometalates(POMs).Subsequently,biocompatibility of metal-oxide clusters is emphasized from aspects of endocytosis,macropinocytosis,and phagocytosis.Through the classification of late and early transition metals oxide clusters,recent outcomes of light-guided nanoagents are represented with their intriguing chemical and optical properties in their diagnosing and photochemotherapy performance.It shed light on the summary of next generation multifunctional cancer targeting agents'developments as well as outlook of materials selection trends and research direction in the future.