Cyclophilin D-induced mitochondrial impairment confers axonal injury after intracerebral hemorrhage in mice

The mitochondrial permeability transition pore is a nonspecific transmembrane channel.Inhibition of mitochondrial permeability transition pore opening has been shown to alleviate mitochondrial swelling,calcium overload,and axonal degeneration.Cyclophilin D is an important component of the mitochondrial permeability transition pore.Whether cyclophilin D participates in mitochondrial impairment and axonal injury after intracerebral hemorrhage is not clear.In this study,we established mouse models of intracerebral hemorrhage in vivo by injection of autologous blood and oxyhemoglobin into the striatum in Thy1-YFP mice,in which pyramidal neurons and axons express yellow fluorescent protein.We also simulated intracerebral hemorrhage in vitro in PC12 cells using oxyhemoglobin.We found that axonal degeneration in the early stage of intracerebral hemorrhage depended on mitochondrial swelling induced by cyclophilin D activation and mitochondrial permeability transition pore opening.We further investigated the mechanism underlying the role of cyclophilin D in mouse models and PC12 cell models of intracerebral hemorrhage.We found that both cyclosporin A inhibition and short hairpin RNA interference of cyclophilin D reduced mitochondrial permeability transition pore opening and mitochondrial injury.In addition,inhibition of cyclophilin D and mitochondrial permeability transition pore opening protected corticospinal tract integrity and alleviated motor dysfunction caused by intracerebral hemorrhage.Our findings suggest that cyclophilin D is used as a key mediator of axonal degeneration after intracerebral hemorrhage;inhibition of cyclophilin D expression can protect mitochondrial structure and function and further alleviate corticospinal tract injury and motor dysfunction after intracerebral hemorrhage.Our findings provide a therapeutic target for preventing axonal degeneration of white matter injury and subsequent functional impairment in central nervous diseases.

Effects of ulinastatin therapy in deep vein thrombosis prevention after brain tumor surgery:A single-center randomized controlled trial

BACKGROUND Venous thromboembolism(VTE)is a common neurosurgical complication after brain tumor resection,and its prophylaxis has been widely studied.There are no effective drugs in the clinical management of venous thromboembolism,and there is an absence of evidence-based medicine concerning the treatment of severe multiple traumas.AIM To explore whether ulinastatin(UTI)can prevent VTE after brain tumor resection.METHODS The present research included patients who underwent brain tumor resection.Patients received UTIs(400,000 IU)or placebos utilizing computer-based random sequencing(in a 1:1 ratio).The primary outcome measures were the incidence of VTE,coagulation function,pulmonary emboli,liver function,renal function,and drug-related adverse effects.RESULTS A total of 405 patients were evaluated between January 2019 and December 2021,and 361 of these were initially enrolled in the study to form intention-to-treat,which was given UTI(n=180)or placebo(n=181)treatment in a random manner.There were no statistically significant differences in baseline clinical data between the two groups.The incidence of VTE in the UTI group was remarkably improved compared with that in the placebo group.UTI can improve coagulation dysfunction,pulmonary emboli,liver function,and renal function.No significant difference was identified between the two groups in the side effects of UTI-induced diarrhea,vomiting,hospital stays,or hospitalization costs.The incidence of allergies was higher in the UTI group than in the placebo group.CONCLUSION The findings from the present research indicated that UTI can decrease the incidence of VTE and clinical outcomes of patients after brain tumor resection and has fewer adverse reactions.

Expression signatures of long non-coding RNA and mRNA in human traumatic brain injury

Long non-coding RNAs(lncRNAs) play a key role in craniocerebral disease, although their expression profiles in human traumatic brain injury are still unclear. In this regard, in this study, we examined brain injury tissue from three patients of the 101 st Hospital of the People's Liberation Army, China(specifically, a 36-year-old male, a 52-year-old female, and a 49-year-old female), who were diagnosed with traumatic brain injury and underwent brain contusion removal surgery. Tissue surrounding the brain contusion in the three patients was used as control tissue to observe expression characteristics of lncRNAs and mRNAs in human traumatic brain injury tissue. Volcano plot filtering identified 99 lncRNAs and 63 mRNAs differentially expressed in frontotemporal tissue of the two groups(P < 0.05, fold change > 1.2). Microarray analysis showed that 43 lncRNAs were up-regulated and 56 lncRNAs were down-regulated. Meanwhile, 59 mRNAs were up-regulated and 4 mRNAs were down-regulated. Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) analyses revealed 27 signaling pathways associated with target genes and, in particular, legionellosis and influenza A signaling pathways. Subsequently, a lncRNA-gene network was generated, which showed an absolute correlation coefficient value > 0.99 for 12 lncRNA-mRNA pairs. Finally, quantitative real-time polymerase chain reaction confirmed different expression of the five most up-regulated mRNAs within the two groups, which was consistent with the microarray results. In summary, our results show that expression profiles of mRNAs and lncRNAs are significantly different between human traumatic brain injury tissue and surrounding tissue, providing novel insight regarding lncRNAs' involvement in human traumatic brain injury. All participants provided informed consent. This research was registered in the Chinese Clinical Trial Registry(registration number: ChiCTR-TCC-13004002) and the protocol version number is 1.0.

An early neuroprotective effect of atorvastatin against subarachnoid hemorrhage

Atorvastatin has been shown to reduce early brain edema and neuronal death after subarachnoid hemorrhage,but its mechanism is not clear.In this study,rat models of subarachnoid hemorrhage were established by autologous blood injection in the cisterna magna.Rat models were intragastrically administered 20 mg/kg atorvastatin 24 hours before subarachnoid hemorrhage,12 and 36 hours after subarachnoid hemorrhage.Compared with the controls,atorvastatin treatment demonstrated that at 72 hours after subarachnoid hemorrhage,neurological function had clearly improved;brain edema was remarkably relieved;cell apoptosis was markedly reduced in the cerebral cortex of rats;the number of autophagy-related protein Beclin-1-positive cells and the expression levels of Beclin-1 and LC3 were increased compared with subarachnoid hemorrhage only.The ultrastructural damage of neurons in the temporal lobe was also noticeably alleviated.The similarities between the effects of atorvastatin and rapamycin were seen in all the measured outcomes of subarachnoid hemorrhage.However,these were contrary to the results of 3-methyladenine injection,which inhibits the signaling pathway of autophagy.These findings indicate that atorvastatin plays an early neuroprotective role in subarachnoid hemorrhage by activating autophagy.The experimental protocol was approved by the Animal Ethics Committee of Anhui Medical University,China(904 Hospital of Joint Logistic Support Force of PLA;approval No.YXLL-2017-09)on February 22,2017.

Bioinformatics-based Identification of Key Pathways and Hub Genes of Traumatic Brain Injury in a Rat Model

Traumatic brain injury(TBI)is a common injury caused by external forces that lead to damaged brain function or pathological changes in the brain tissue.To explore the molecular mechanism and the hub genes of TBI,we downloaded gene expression profiles of the TBI model of rat and the sham control for the subsequent gene set enrichment analysis,pathway analysis and protein-protein interactions analysis.The results of Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis indicated that multiple biological pathways,including immune response,inflammatory response and cellular response to interleukin-1,as well as signaling pathways,such as tumor necrosis factor signaling pathway,chcmokine signaling pathway,cytokine-cytokine receptor interaction,Toll-like receptor signaling pathway and nuclear factor kappa B signaling pathway were implicated in the TBI.In conclusion,this study provides insights into the molecular mechanism of TBI by screening the differentially expressed genes and hub genes that can be used as biomarkers and therapeutic targets.

Forniceal deep brain stimulation in severe Alzheimer's disease:A case report

BACKGROUND Forniceal deep brain stimulation(DBS)has been proposed as an alternative treatment for Alzheimer's disease(AD).Previous studies on mild to moderate AD patients demonstrated improvements in cognitive functions brought about by forniceal DBS.Here,we report our longitudinal findings in one severe AD patient for whom the activities of daily living(ADL)rather than cognitive function significantly improved after 3 mo of continuous stimulation.CASE SUMMARY In 2011,a 62-year-old Chinese male with no previous history of brain injury or other neuropsychological diseases and no family history of dementia developed early symptoms of memory decline and cognitive impairment.Five years later,the symptoms had increased to the extent that they affected his daily living.He lost the ability to work as a businessman and to take care of himself.The patient was given a clinical diagnosis of probable AD and was prescribed donepezil and subsequently memantine,but no improvement in symptoms was observed.The patient then received DBS surgery.After 3 mo of continuous stimulation,the patient's ADL score decreased from 65 points to 47 points,indicating the quality of the patient's daily living improved distinctly.Other scores remained unchanged,suggesting no significant improvement in cognitive function.A follow-up positron emission tomography scan demonstrated perceivable increased glucose metabolism in the classical AD-related brain regions.CONCLUSION Based on this case we hypothesize that forniceal DBS may improve ADL through elevating regional glucose metabolism in the brain.

Up-regulation of circular RNA hsa_circ_01844 induces apoptosis and suppresses proliferation and migration of glioblastoma cells

Background:Previous studies have demonstrated that various circular RNAs are involved in the malignant proliferation of cancers,such as liver cancer,lung cancer,breast cancer,and others.The potential role of circular RNAs in glioblastoma,however,is still uncertain.In this study,we aimed to study the potential role of hsa_circ_01844 in glioblastoma.Methods:Using reverse transcription-polymerase chain reaction(RT-PCR)method,hsa_circ_01844 expression was measured in five glioblastoma samples and five normal brain samples.To evaluate the potential function of hsa_circ_01844 in glioblastoma,hsa_circ_01844 was overexpressed in glioblastoma cell lines(U251 and U87 cells).Using these two cell lines,in vitro experiments including the flow cytometry assay,3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay,Transwell assay,and cell apoptosis assay were performed to investigate the role of hsa_circ_01844 in glioblastoma.Student t test and one-way analysis of variance were used for statistical analysis.Results:The expression of circular RNA hsa_circ_01844 was lower in glioblastoma tissues when compared with the normal brain tissues by RT-PCR method(0.034±0.036 vs.1.630±0.891,P<0.001).Using two glioblastoma cell lines,we found that overexpression of hsa_circ_01844 in glioblastoma cells suppressed their proliferation,colony formation,migration,and increased the apoptotic rate compared with empty vector group and blank control group(all P<0.05).Conclusion:Hsa_circ_01844 shows decreased expression in glioblastoma and its overexpression induces apoptosis and inhibits proliferation,migration,and invasion of glioblastoma cells.