Interaction of major facilitator superfamily domain containing 2A with the blood-brain barrier

The functional and structural integrity of the blood-brain barrier is crucial in maintaining homeostasis in the brain microenvironment;however,the molecular mechanisms underlying the formation and function of the blood-brain barrier remain poorly understood.The major facilitator superfamily domain containing 2A has been identified as a key regulator of blood-brain barrier function.It plays a critical role in promoting and maintaining the formation and functional stability of the blood-brain barrier,in addition to the transport of lipids,such as docosahexaenoic acid,across the blood-brain barrier.Furthermore,an increasing number of studies have suggested that major facilitator superfamily domain containing 2A is involved in the molecular mechanisms of blood-brain barrier dysfunction in a variety of neurological diseases;however,little is known regarding the mechanisms by which major facilitator superfamily domain containing 2A affects the blood-brain barrier.This paper provides a comprehensive and systematic review of the close relationship between major facilitator superfamily domain containing 2A proteins and the blood-brain barrier,including their basic structures and functions,cross-linking between major facilitator superfamily domain containing 2A and the blood-brain barrier,and the in-depth studies on lipid transport and the regulation of blood-brain barrier permeability.This comprehensive systematic review contributes to an in-depth understanding of the important role of major facilitator superfamily domain containing 2A proteins in maintaining the structure and function of the blood-brain barrier and the research progress to date.This will not only help to elucidate the pathogenesis of neurological diseases,improve the accuracy of laboratory diagnosis,and optimize clinical treatment strategies,but it may also play an important role in prognostic monitoring.In addition,the effects of major facilitator superfamily domain containing 2A on blood-brain barrier leakage in various diseases and the research progress on cross-blood-brain barrier drug delivery are summarized.This review may contribute to the development of new approaches for the treatment of neurological diseases.

Effects of Minimally Invasive Puncture and Drainage of Intracranial Hematoma on the Blood-brain Barrier in Patients with Cerebral Hemorrhage

The effects of minimally invasive surgery on the blood-brain barrier （BBB） of 30 patients with cerebral hemorrhage were investigated. Difference of the BBB index and serum MBP concentration were assessed in 15 cases of conservative treatment group and 15 cases of minimally invasive surgery group. The BBB index in minimally invasive surgery group was significantly lower than in conservative treatment group （P〈0.05）, and the BBB index in the two treatment groups was significantly higher than in control group （P〈0.01）. Serum MBP concentration in minimally invasive surgery group was significantly lower than in conservative treatment group （P〈0.05）, and that in the two treatment groups was significantly higher than in control group （P〈0.01）. It was suggested the permeability of BBB in patients with cerebral hemorrhage was increased, and BBB index and serum MBP concentration in patients with cerebral hemorrhage were increased. Minimally invasive surgery can reduce the lesion of cytotoxicity to BBB and cerebral edema.

Blood-brain barrier modeling: challenges and perspectives

The blood-brain barrier （BBB） forms a highly selective inter- face between blood and brain. Extensive research efforts have completely changed our view of the BBB in the last years, from a static, impermeable barrier to a dynamic, highly regulated and specific cellular system. The BBB ultrastructurally consists of specialized brain microvascular endothelial cells （BMEC） characterized by low pinocytic activity,

Studying Molecular Aspects of the Blood-Brain Barrier Using an in Vitro Model: Contribution of a Global Proteomics Strategy

A global proteomics strategy was initiated to decipher molecular mechanisms associated with the blood-brain barrier (BBB) phenotype of the brain capillary endothelial cells. The different methods implemented were shown complementarily. The main results obtained using an in vitro BBB model allowed highlighting the role of several protein actors of cytoskeleton remodelling, the involvement of the asymmetric dimethylarginine pathway in regulating endothelial function and the role of tissue non-specific alkaline phosphatase in the regulation of endothelial permeability.

Human induced pluripotent stem cell based in vitro models of the blood-brain barrier： the future standard？

There is an urgent and tremendous need for human dis- ease models in drug development in order to improve pre- clinical predictability. In the case of brain disorders drugs have to cross the blood-brain barrier （BBB） to enter the central nervous system （CNS）. It was estimated that more than 95% of the drugs cannot cross the BBB.

开窍药对血脑屏障影响的实验研究进展

开窍药的主要功效为芳香开窍,醒神回苏,临床用以治疗脑卒中、神志昏迷等证。近年来研究发现开窍药能通过影响血脑屏障(blood-brain barrier,BBB)发挥其治疗脑部疾患的作用,有些开窍药或药物单体能迅速通过BBB,有些开窍药则可以促进其它药物通透,是其发挥开窍醒神回苏的主要作用机制,推测其也许是该类药归心经的理论基础。

脑泰方提取物干预大鼠脑缺血后MMP-9-mRNA及PA-mRNA表达研究

目的研究大鼠脑缺血后益气活血中药脑泰方提取物(黄芪、川芎、地龙、僵蚕)干预对缺血区脑水肿及MMP-9-mRNA、PA-mRNA表达的影响。方法随机将SD大鼠分为假手术组、模型组、脑泰方提取物(NTE)低、中、高剂量组(3,9,27g/kg)。各组大鼠预处理ig给药连续3d,每日1次,MCAO模型制备术后ig给药1d。术后1d取材检测各组脑组织含水量,RT-PCR检测MMP-9-mRNA及PA-mRNA表达。结果实验表明高、中NTE组与模型组比较,脑含水量均有明显降低(P<0.05)。NTE高剂量组脑缺血区MMP-9-mRNA、PA-mRNA表达明显降低(P<0.05)。结论脑泰方提取物干预可减轻脑水肿的发生,可能是通过降低MMP-9-mRNA及PA-mRNA的表达,减少MMP-9、PA的生成,发挥保护急性脑缺血血脑屏障的作用。

Development of targeted therapies in treatment of glioblastoma

Glioblastoma （GBM） is a type of tumor that is highly lethal despite maximal therapy. Standard therapeutic approaches provide modest improvement in progression-free and overall survival, necessitating the investigation of novel therapies. Oncologic therapy has recently experienced a rapid evolution toward ＂targeted therapy＂, with drugs directed against specific targets which play essential roles in the proliferation, survival, and invasiveness of GBM cells, including numerous molecules involved in signal transduction pathways. Inhihitors of these molecules have already entered or are undergoing clinical trials. However, significant challenges in their development remain because several preclinical and clinical studies present conflicting results. In this article, we will provide an up-to-date review of the current targeted therapies in GBM.

Localization of Inhibin in Some Rat Tissues and Exploration of Its Transport Mechanism

The aims of the study were to determine the distribution of inhibin and its α subunit in some rat tissues by an immunohistochemical method of streptavidin-biotin complex （SABC） and to assess the transport mechanism of inhibin by investigating the localization of inhibin and α subunits in the central nervous system （mainly in hypothalamus and pituitary） of ovariectomized rats. Investigations on the extragonadal tissues of ovariectomized rats showed positive expression of inhibin and its α subunit in heart, kidney, spleen, pancreatic gland cells, but no positive reaction sites were seen in lung, liver, submaxillary gland, and adrenal gland. After injection with inhibin α subunit fragment or inhibin extract, positive reaction sites were observed in hypothalamus and pituitary of ovariectomized rats by SABC. Inhibin and its subunit was present in a wide variety of nonreproductive organs and tissues, and its expression was tissue specific, which indicated that inhibin might play a role in regulating tissue function through autocrine/paracrine mechanisms. Inhibin dimer and α subunit could be transported through the BBB by the method of “separation and reconstruction”.

Methemoglobinemia—A biomarker and a link to ferric iron accumulation in Alzheimer’s disease

Understanding the mechanism of oxidative stress is likely to yield new insights regarding the pathogenesis of Alzheimer’s disease (AD). Our earlier work focused on the difference between hemoglobin and methemoglobin degradation, respectively leading to ferrous (Fe2+) iron, or ferric (Fe3+) iron. Methemoglobin has the role of carrier, the donor of cytotoxic and redox-active ferric (Fe3+) iron, which can directly accumulate and increase the rate of capillary endothelial cell apoptosis, and may cross into the brain parenchyma, to the astrocytes, glia, neurons, and other neuronal cells (neurovascular unit). This supposition helps us to understand the transport and neuronal accumulation process of ferric iron, and determine how iron is transported and accumulated intracellularly, identifiable as “Brain rust”. Earlier research found that the incidences of neonatal jaundice (p = 0.034), heart murmur (p = 0.011) and disorders such as dyslalia and learning/memory impairments (p = 0.002) were significantly higher in those children born from mothers with methemoglobinemia. Our hypothesis suggests that prenatal iron abnormalities could lead to greater neuronal death, the disease ageing process, and neurodegenerative disorders such as AD and other neurodegenerative diseases.

Nanotechnology-based therapeutics: new hope for ischemic cerebral stroke intervention

Ischemic cerebral stroke is a leading cause of death and disability globally.At present,thrombolytics,such as recombinant tissue-type plasminogen activator,are the only effective treatment for acute stroke.However,usage of thrombolytics has a strict therapeutic window and cannot be applied to a number of patients.Despite the promising effects of some neuroprotectants in preclinical studies,they failed in clinical trials as a result of poor pharmacokinetic properties,particularly with regard to solubility and permeability across the blood-brain barrier(BBB).Approaches for delivering these drugs by nanotechnologies may overcome these pharmacokinetic deficits and enhance their neuroprotective effects.However,issues such as potential side effects and biosafety properties currently limit clinical application of these approaches.In this article,we reviewed recent progress of nanotechnology-based interventions for stroke treatment,and in particular,summarized novel materials applied to synthesize nanocarriers,encapsulation with neuroprotectants,and factors impacting nanodrug bioactivities to provide a theoretical basis for the development of anti-stroke drugs.

Carrier-free programmed spherical nucleic acid for effective ischemic stroke therapy via self-delivery antisense oligonucleotide

Antisense oligonucleotide(ASO)for anti-apoptosis is emerging as a highly promising therapeutic agents for ischemic stroke with complex pathological environment.However,its therapeutic efficacy is seriously limited by a number of challenges including inefficient internalization,low blood-brain barrier(BBB)penetration,poor stability,and potential toxicity of the carrier.Herein,a carrier-free programmed spherical nucleic acid nanostructure is developed for effective ischemic stroke therapy via integrating multifunctional modules into one DNA structure.By co-encoding caspase-3-ASO and transferrin receptor(TfR)aptamer into circle template,the spherical nucleic acid nanostructure(TD)was obtained via self-assembly.The experimental results demonstrated that the developed TD displayed efficient BBB penetration capability(6.4 times)and satisfactory caspase-3 silence effect(2.3 times)due to the dense DNA packaging in TD.Taken together,our study demonstrated that the carrier-free programmed spherical nucleic acid nanostructure could significantly improve the therapeutic efficacy of ischemic stroke and was a promising therapeutic tool for various brain damage-related diseases.

LAT1 targeted brain delivery of temozolomide and sorafenib for effective glioma therapy

Glioma is the most common primary craniocerebral tumor caused by the cancerous growth of glial cells in the brain and spinal cord.Currently,standard treatment is the surgical resection followed by concurrent radiation and chemotherapy.However,the blood-brain barrier(BBB)prevents most antitumor drugs from entering the brain and reduces their efficacy,especially in lowgrade glioma.Since L-type amino acid transporter 1(LAT1)is highly expressed in glioma cells and mediates drug transport across the BBB,it is a promising target for drug delivery and treatment of glioma.Temozolomide(TMZ)is the first-line treatment for glioma,however,patients often exhibit drug resistance at advanced stage.A multikinase inhibitor and inducer of ferroptosis,sorafenib can improve the therapeutic effects of TMZ.Therefore,to optimize the glioma treatment and cross the BBB,we designed LAT1-targeting nanoparticles co-loaded with TMZ and sorafenib.Our results from both in vitro and in vivo studies confirmed that LAT1-targeting nanoparticles significantly increased the cellular uptake,cytotoxicity,accumulation at tumor site,and the anti-tumor efficacy compared to the non-target nanoparticles.Therefore,LAT1 can be used as a potential target for braintargeted drug delivery,and sorafenib-induced ferroptosis can aid the anti-glioma efficacy of TMZ.

Reduction of Brain Injury After Stroke in Hyperglycemic Rats via Fasudil Pretreatment

Diabetes is usually associated with cerebrovascular disease,especially stroke.In practice,fasudil is widely accepted to be applied for the treatment of vascular disease.This article demonstrates the study concentrating on the effects of fasudil pretreatment on the prognosis of diabetic stroke.250—300 g SpragueDawley rats were randomly divided into three groups,non-diabetic stroke group,diabetic stroke group,and fasudil pretreatment group.The rats of diabetes group were treated with intraperitoneal injection of streptozotocin(60 mg/kg),in the meantime the same dose of citrate buffer was injected into those of the control group.The rats of the fasudil group received daily fasudil intraperitoneal injection at 10 mg/kg for three consecutive weeks.After four weeks,all the rats of the experimental group were treated with middle cerebral artery occlusion for 90 min.After sacrifice,the fresh brain samples were collected for following experiments,including infarct volume,edema volume,blood-brain barrier(BBB),which were detected by immunohistochemistry.Inflammatory factors were examined by real-time polymerase chain reaction(RT-PCR)using tissue Ribonucleic Acid(RNA).The concentration of blood glucose is 15 mmol/L or more,which proved that the diabetes model was a success.Fasudil pretreatment decreases the percentage of stroke mortality of diabetes from 43.75%to 31.25%,while the infarction volume decreases from 52.95%±12.7%to 45.97%±6.7%.Gap formation of tight junction and Immunoglobulin G(Ig G)leakage were reduced(P<0.05),and the expression of inflammatory factors decreases(P<0.05)in fasudil pretreatment after diabetic stroke.Diabetes aggravates the mortality of cerebral ischemic rats.Prolonged fasudil pretreatment can reduce mortality of diabetic stroke,decrease cerebral infarction volume and undermine inflammatory factors expression,and protect the BBB.