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  • 1.

    【2hr】The Protective Roles of Urinary Trypsin Inhibitor in Brain Injury Following Fat Embolism Syndrome in a Rat Model

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    机译 尿胰蛋白酶抑制剂在大鼠脂肪栓塞综合征后脑损伤中的保护作用
    摘要：Fat embolism syndrome (FES) is a common complication following long bone fracture; fat droplets are released into the blood circulation and form embolisms, mainly in lung and brain. However, the potential mechanisms involved remain to be clarified. In this study, the mechanism of brain injury following FES and the protective effects of urinary trypsin inhibitor (UTI)—a serine protease inhibitor—were investigated. Sixty male Sprague-Dawley rats were divided randomly into sham, FES and FES+UTI treatment groups. The FES model was established using tail vein injection of glycerol trioleate, and UTI was administered by intraperitoneal injection immediately following FES. Brain/lung water content evaluation, Evans blue content and magnetic resonance imaging examination were used to assess the effects of UTI. Furthermore, immunohistochemistry and western blot were also applied to explore the protective mechanism of UTI following FES. The results of oil red O staining indicated that the FES model was successfully established. UTI could significantly attenuate blood-brain-barrier (BBB) disruption, as seen through brain edema evaluation and Evans blue content examination. Immunofluorescence staining results indicated that the TLR4-JNK pathway was involved in brain injury after FES; this effect could be quenched by UTI treatment. Furthermore, UTI could decrease the levels of downstream target proteins of the TLR4-JNK pathway, phosphorylated-NF- κB (p65) and p53 in brain. Our results showed that UTI could alleviate BBB injury after FES through blocking activity of the TLR4-JNK pathway.
  • 2.

    【2hr】Inflammatory Smooth Muscle Cells Induce Endothelial Cell Alterations to Influence Cerebral Aneurysm Progression via Regulation of Integrin and VEGF Expression

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    机译 炎性平滑肌细胞通过调节整联蛋白和VEGF的表达诱导内皮细胞改变，从而影响脑动脉瘤的进展。
    摘要：Cerebral aneurysm growth is characterized by vessel wall frailness, although the underlying cellular mechanisms are unclear. Here, we examined the relationship between inflammatory smooth muscle cells (SMCs) and endothelial cells (ECs) in cerebral aneurysms, including the mechanisms underlying inflammatory SMC-induced changes in ECs. Five saccular cerebral aneurysms were collected and five temporal artery samples were used as controls. Cells and cytokines were detected by immunohistochemistry and TUNEL (transferase dUTP nick end labeling) assays performed to evaluate apoptosis. Human umbilical vein endothelial cells (HUVECs) were seeded on collagen I, IV, and VI-coated plates for cell adhesion assays and inflammatory SMCs (iSMCs) were established by culture in flexible silicone chambers subjected to cyclic mechanical stretch. HUVECs were cultured in iSMC-conditioned medium, followed by evaluation of their viability, apoptosis, and function, and determination of VEGF (vascular endothelial growth factor) -A and integrin levels by western blotting. Aneurysm tissue contained fewer SMCs and lacked ECs. In aneurysm walls, more matrix metalloproteinase (MMP) -1, MMP-3, and apoptotic cells were detected, accompanied by decreased collagen IV and VI levels. Cell adhesion assays revealed that more HUVECs were attached in collagen IV and VI-coated plates compared with controls. iSMC-conditioned medium significantly reduced HUVEC viability and apoptosis showed an increased trend; however, the difference was not significant. iSMC medium also reduced tube formation and migration of HUVECs. Moreover, iSMC medium reduced HUVEC expression of VEGF-A, integrin α1, integrin α2, and integrin β. Our data demonstrate a lack of SMCs and ECs in aneurysm walls, accompanied by elevated MMP and decreased collagen levels. In vitro assays showed that iSMCs induced reduction in EC adhesion, and caused EC dysfunction. Understanding of the relationships among SMC, EC, and collagens during aneurysm progression provides an additional therapeutic option for prevention of cerebral aneurysm progression.
  • 3.

    【2hr】Detrimental Role of miRNA-144-3p in Intracerebral Hemorrhage Induced Secondary Brain Injury is Mediated by Formyl Peptide Receptor 2 Downregulation Both In Vivo and In Vitro

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    机译 miRNA-144-3p在脑出血引起的继发性脑损伤中的有害作用是由体内和体外的甲酰肽受体2下调介导的。
    摘要：Although microRNA-144-3p (miRNA-144-3p) has been shown to suppress tumor proliferation and invasion, its function in intracerebral hemorrhage (ICH)-induced secondary brain injury (SBI) remains unclear. Thus, this study was designed to investigate the role of miRNA-144-3p in ICH. To accomplish this, we used adult male Sprague-Dawley rats to establish an in vivo ICH model by injecting autologous blood, while cultured primary rat cortical neurons were exposed to oxyhemoglobin (OxyHb) to mimic ICH in vitro. To examine the role of miRNA-144-3p in ICH-induced SBI, we used an miRNA-144-3p mimic and inhibitor both in vivo and in vitro. Following ICH induction, we found miRNA-144-3p expression to increase. Additionally, we predicted the formyl peptide receptor 2 (FPR2) to be a potential miRNA-144-3p target, which we validated experimentally, with FPR2 expression downregulated when miRNA-144-3p was upregulated. Furthermore, elevated miRNA-144-3p levels aggravated brain edema and neurobehavioral disorders and induced neuronal apoptosis via the downregulation of FPR2 both in vivo and in vitro. We suspected that these beneficial effects provided by FPR2 were associated with the PI3K/AKT pathway. We validated this finding by overexpressing FPR2 while inhibiting PI3K/AKT in vitro and in vivo. In conclusion, miRNA-144-3p aggravated ICH-induced SBI by targeting and downregulating FPR2, thereby contributing to neurological dysfunction and neural apoptosis via PI3K/AKT pathway activation. These findings suggest that inhibiting miRNA-144-3p may offer an effective approach to attenuating brain damage incurred after ICH and a potential therapy to improve ICH-induced SBI.
  • 4.

    【2hr】Size, Aspect Ratio and Anatomic Location of Ruptured Intracranial Aneurysms: Consecutive Series of 415 Patients from a Prospective, Multicenter, Observational Study

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    机译 破裂颅内动脉瘤的大小，长宽比和解剖位置：一项来自前瞻性，多中心，观察性研究的415例患者的连续研究
    摘要：To analyze the size and location distribution of ruptured intracranial aneurysms (IAs) helps to provide evidence for clinical treatment of unruptured IAs using this feature of aneurysms. In this study, 415 patients who presented with an acute subarachnoid hemorrhage caused by IAs were enrolled from eight tertiary referral centers between June 2016 and March 2018. The size, aspect ratio and anatomic location of ruptured IAs were defined and reported by patient sex. In the study cohort of 415 patients (60.5% women) with saccular ruptured IAs, the three most common locations of ruptured IAs were posterior communicating artery (32.0%), anterior communicating artery (28.7%), and middle cerebral artery (13.5%). The mean size of all ruptured IAs was 5.3±3.1 mm (range 1.1–28.5 mm), but the size varied considerably by location. For example, ruptured IAs of the posterior communicating artery had a mean size of 5.8±3.1 mm, whereas the mean size of ruptured anterior communicating artery aneurysms was 4.6±1.7 mm. The mean AR in all ruptured IAs was 1.66±0.76. Of those aneurysms, 243 (58.6%) had an AR smaller than 1.6 and 318 (76.6%) had an AR smaller than 2.0. Our results suggested that the size of the most ruptured IAs are smaller than 7 mm or even 5 mm. The size and AR varied by sex and location. With the knowledge of size, location and AR, multiplicity should be considered for treatment strategies of unruptured IAs.
  • 5.

    【2hr】MRI Tracking of iPS Cells-Induced Neural Stem Cells in Traumatic Brain Injury Rats

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    机译 颅脑损伤大鼠中iPS细胞诱导的神经干细胞的MRI追踪
    摘要：Induced pluripotent stem cells (iPS cells) are promising cell source for stem cell replacement strategy applied to brain injury caused by traumatic brain injury (TBI) or stroke. Neural stem cell (NSCs) derived from iPS cells could aid the reconstruction of brain tissue and the restoration of brain function. However, tracing the fate of iPS cells in the host brain is still a challenge. In our study, iPS cells were derived from skin fibroblasts using the four classic factors Oct4, Sox2, Myc, and Klf4. These iPS cells were then induced to differentiate into NSCs, which were incubated with superparamagnetic iron oxides (SPIOs) in vitro. Next, 30 TBI rat models were prepared and divided into three groups (n = 10). One week after brain injury, group A&B rats received implantation of NSCs (labeled with SPIOs), while group C rats received implantation of non-labeled NSCs. After cell implantation, all rats underwent T2*-weighted magnetic resonance imaging (MRI) scan at day 1, and 1 week to 4 weeks, to track the distribution of NSCs in rats’ brains. One month after cell implantation, manganese-enhanced MRI (ME-MRI) scan was performed for all rats. In group B, diltiazem was infused during the ME-MRI scan period. We found that (1) iPS cells were successfully derived from skin fibroblasts using the four classic factors Oct4, Sox2, Myc, and Klf4, expressing typical antigens including SSEA4, Oct4, Sox2, and Nanog; (2) iPS cells were induced to differentiate into NSCs, which could express Nestin and differentiate into neural cells and glial cells; (3) NSCs were incubated with SPIOs overnight, and Prussian blue staining showed intracellular particles; (4) after cell implantation, T2*-weighted MRI scan showed these implanted NSCs could migrate to the injury area in chronological order; (5) the subsequent ME-MRI scan detected NSCs function, which could be blocked by diltiazem. In conclusion, using an in vivo MRI tracking technique to trace the fate of iPS cells-induced NSCs in host brain is feasible.
  • 6.

    【2hr】Administration of rCTRP9 Attenuates Neuronal Apoptosis ThroughAdipoR1/PI3K/Akt Signaling Pathway after ICH in Mice

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    机译 rCTRP9的给药通过减轻神经细胞凋亡ICH后小鼠的AdipoR1 / PI3K / Akt信号通路
    摘要：Targeting neuronal apoptosis after intracerebral hemorrhage (ICH) may be an important therapeutic strategy for ICH patients. Emerging evidence indicates that C1q/TNF-Related Protein 9 (CTRP9), a newly discovered adiponectin receptor agonist, exerts neuroprotection in cerebrovascular disease. The aim of this study was to investigate the anti-apoptotic role of CTRP9 after experimental ICH and to explore the underlying molecular mechanisms. ICH was induced in mice via intrastriatal injection of bacterial collagenase. Recombinant CTRP9 (rCTRP9) was administrated intranasally at 1 h after ICH. To elucidate the underlying mechanisms, adiponectin receptor1 small interfering ribonucleic acid (AdipoR1 siRNA) and selective PI3 K inhibitor were administered prior to rCTRP9 treatment. Western blots, neurofunctional assessments, immunofluorescence staining, and Fluoro-Jade C (FJC) staining experiments were performed. Administration of rCTRP9 significantly improved both short- and long-term neurofunctional behavior after ICH. RCTRP9 treatment significantly increased the expression of AdipoR1, PI3 K, p-Akt, and Bcl-2, while at the same time was found to decrease the expression of Bax in the brain, which was reversed by inhibition of AdipoR1 and PI3 K. The neuroprotective effect of rCTRP9 after ICH was mediated by attenuation of neuronal apoptosis via the AdipoR1/PI3K/Akt signaling pathway; therefore, rCTRP9 should be further evaluated as a potential therapeutic agent for ICHpatients.
  • 7.

    【2hr】Treatment Strategy for Unruptured Intracranial Aneurysm in ElderlyPatients: Coiling, Clipping, or Conservative?

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    机译 老年人颅内动脉瘤破裂的治疗策略患者：卷曲，修剪还是保守？
    摘要：An increasing number of unruptured intracranial aneurysms (UIAs) has been discovered in elderly patients in recent years, but the optimal treatment strategy for these patients remains controversial. We report our six-year experience treating UIAs in elderly patients (≥ 70 years old). A retrospective review was conducted of elderly patients who harbored UIAs treated by conservative observation, microsurgical clipping, or endovascular coiling between January 2009 and December 2014. The patients’ clinical and imaging information was recorded. Treating methods, procedure-related complications, imaging results, and clinical outcomes were analyzed. A total of 141 consecutive elderly patients with 166 UIAs were enrolled in our study. In all, 64 patients with 79 aneurysms were treated with coiling, and 14 patients with 14 aneurysms were treated with clipping. The remaining 63 patients with 73 aneurysms were placed under conservative observation. The average modified Rankin scale was 0.99 (range 0–6) in the full cohort after a mean follow-up of 50.4 months (range 0–70 months). There was no significant difference of modified Rankin scale in patients with UIAs treated by different methods. Multivariate analysis showed that age (p=0.030) and aneurysm size (p=0.011)were independent risk factors for unfavorable outcome of UIAs in the elderly.Patient age (p=0.010) and aneurysm size(p=0.020) were also significantly associated with unfavorableoutcome of UIAs managed with observation initially. Our results indicated thatendovascular coil embolization and clipping were both safe and effectivetreatment methods for UIAs in the elderly. Aggressive treatment for UIAs inelderly patients with risk factors of aneurysm rupture should be consideredpositively.
  • 8.

    【2hr】Delta Opioid Peptide [d-Ala2, d-Leu5] Enkephalin (DADLE) Exerts a Cytoprotective Effect in Astrocytes Exposed to Oxygen-Glucose Deprivation by Inducing Autophagy

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    机译 三角洲阿片肽[d-Ala2，d-Leu5]脑啡肽（DADLE）通过诱导自噬作用，在星形胶质细胞暴露于氧-葡萄糖剥夺的情况下发挥细胞保护作用
    摘要：Astrocytes protection and functional regulation are important strategies to protect against neuronal damage caused by ischemia. Activation of the delta opioid receptor (DOR) could reduce astrocytes damage, although the mechanism remains unclear. The present study aimed to test the effect of DOR activation on autophagy in astrocytes exposed to oxygen-glucose deprivation (OGD), and to further investigate whether this effect has a protective effect on astrocytes. Primary cultured rat cortical astrocytes were treated with various doses of [d-Ala2, d-Leu5]-Enkephalin (DADLE, a selective DOR agonist) followed by 6 h OGD. Cell viability was evaluated by CCK-8 assay and lactate dehydrogenase release. Autophagic vacuole was analyzed with LC3 immunofluorescent staining. The levels of autophagy and apoptosis-related proteins were analyzed by western blot. Results demonstrated that treatment with 10 nM DADLE was sufficient to increase cell viability and induced autophagy in astrocytes. The DADLE-induced autophagy displayed a cytoprotective effect on astrocytes. Inhibition of autophagy by 3-methyladenine (3-MA, an autophagy inhibitor) reversed the protective effect of DADLE. Naltrindole (a DOR antagonist) only partially antagonized the role of DADLE, which indicated that DADLE might have a cytoprotective mechanism independent of DOR. Further results showed that DADLE significantly enhanced the level of Bcl-2 protein and reduced the level of Bax protein in astrocytes exposed to OGD. Our results suggest a novel mechanism in which DADLE induces autophagy in astrocytes and exerts cytoprotective effects by inhibiting apoptosis.
  • 9.

    【2hr】Novel Insights into MSK1 Phosphorylation by MRKβ in Intracerebral Hemorrhage-Induced Neuronal Apoptosis

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    机译 MRKβ对脑出血引起的神经元凋亡的MSK1磷酸化的新见解。
    摘要：Neuronal apoptosis is regarded as one of the most important pathophysiological changes of intracerebral hemorrhagic (ICH) stroke—a major public health problem that leads to high mortality rates and functional dependency. Mitogen-and stress-activated kinase (MSK) 1 is implicated in various biological functions in different cell types, including proliferation, tumorigenesis and responses to stress. Our previous study showed that MSK1 phosphorylation (p-MSK1) is related to the regulation of LPS-induced astrocytic inflammation, and possibly acts as a negative regulator of inflammation. In this study, we identified a specific interaction between MSK1 and MRKβ (MLK-related kinase)—a member of the MAPK pathway—during neuronal apoptosis. In an ICH rat model, western blotting and immunohistochemical analysis revealed that both MRKβ and phosphorylation of MSK1 (p-MSK1 Ser376) were significantly upregulated in cells surrounding the hematoma. Triple-immunofluorescent labeling demonstrated the co-localization of MRKβ and p-MSK1 in neurons, but not astrocytes. Furthermore, MRKβ was partially transported into the nucleus, and interacted with p-MSK1 in hemin-treated neurons. Immunoprecipitation showed that MRKβ and p-MSK1 exhibited an enhanced interaction during the pathophysiology process. Utilizing small interfering RNAs to knockdown MRKβ or MSK1, we verified that MSK1 Ser376 is a phosphorylation site targeted by MRKβ. We also observed that the phosphorylation of NF-κB p65 at Ser276 was mediated by the MRKβ-p-MSK1 complex. Furthermore, it was found that the neuronal apoptosis marker, active caspase-3, was co-localized with MRKβ and p-MSK1. In addition, flow cytometry analysis revealed that knockdown of MRKβ or MSK1 specifically resulted in increased neuronal apoptosis, which suggested that the MRKβ-p-MSK1 complex might exert a neuroprotective function against ICH-induced neuronal apoptosis. Taken together, our data suggest that MRKβ translocated into the nucleus and phosphorylated MSK1 to protect neurons via phosphorylation of p65—a subunit of nuclear factor κB.
  • 10.

    【2hr】CDNF Protein Therapy in Parkinson’s Disease

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    机译 帕金森氏病的CDNF蛋白疗法
    摘要：Neurotrophic factors (NTF) are a subgroup of growth factors that promote survival and differentiation of neurons. Due to their neuroprotective and neurorestorative properties, their therapeutic potential has been tested in various neurodegenerative diseases. Bioavailability of NTFs in the target tissue remains a major challenge for NTF-based therapies. Various intracerebral delivery approaches, both protein and gene transfer-based, have been tested with varying outcomes. Three growth factors, glial cell-line derived neurotrophic factor (GDNF), neurturin (NRTN) and platelet-derived growth factor (PDGF-BB) have been tested in clinical trials in Parkinson’s disease (PD) during the past 20 years. A new protein can now be added to this list, as cerebral dopamine neurotrophic factor (CDNF) has recently entered clinical trials. Despite their misleading names, CDNF, together with its closest relative mesencephalic astrocyte-derived neurotrophic factor (MANF), form a novel family of unconventional NTF that are both structurally and mechanistically distinct from other growth factors. CDNF and MANF are localized mainly to the lumen of endoplasmic reticulum (ER) and their primary function appears to be modulation of the unfolded protein response (UPR) pathway. Prolonged ER stress, via the UPR signaling pathways, contributes to the pathogenesis in a number of chronic degenerative diseases, and is an important target for therapeutic modulation.Intraputamenally administered recombinant human CDNF has shown robust neurorestorativeeffects in a number of small and large animal models of PD, and had a good safety profilein preclinical toxicology studies. Intermittent monthly bilateral intraputamenal infusionsof CDNF are currently being tested in a randomized placebo-controlled phase I–II clinicalstudy in moderately advanced PD patients. Here, we review the history of growthfactor-based clinical trials in PD, and discuss how CDNF differs from the previouslytested growth factors.
  • 11.

    【2hr】Transplanting Cells for Spinal Cord Repair: Who, What, When, Where and Why?

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    机译 脊髓修复移植细胞：谁，什么，何时，何地以及为什么？
    摘要：Cellular transplantation for repair of the injured spinal cord has a rich history with strategies focused on neuroprotection, immunomodulation, and neural reconstruction. The goal of the present review is to provide a concise overview and discussion of five key themes that have become important considerations for rebuilding functional neural networks. The questions raised include: (i) who are the donor cells selected for transplantation, (ii) what is the intended target for repair, (iii) when is the optimal time for transplantation, (iv) where should the cells be delivered, and lastly (v) why does cell transplantation remain an attractive candidate for promoting neural repair after injury? Recent developments in neurobiology and engineering now enable us to start addressing these questions with multidisciplinary expertise and methods.
  • 12.

    【2hr】Endothelial Progenitor Cells Conditioned Medium Supports Number of GABAergic Neurons and Exerts Neuroprotection in Cultured Striatal Neuronal Progenitor Cells

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    机译 内皮祖细胞条件培养基支持GABA能神经元的数量，并在培养的纹状体神经元祖细胞中发挥神经保护作用
    摘要：There is growing evidence that stem and progenitor cells exert regenerative actions by means of paracrine factors. In line with these notions, we recently demonstrated that endothelial progenitor cell (EPC)-derived conditioned medium (EPC-CM) substantially increased viability of brain microvascular cells. In the present study, we aimed at investigating whether EPC-CM supports cell survival of cultured striatal progenitor cells. For that purpose, primary cultures from fetal rat embryonic (E14) ganglionic eminence were prepared and grown for 7 days in vitro (DIV). EPC-CM was administered from DIV5–7. Treatment of the striatal cultures with EPC-CM resulted in significantly increased densities of GABA-immunoreactive (-ir) neurons. Inhibition of mitogen-activated protein kinase and phosphatidylinositol-3-kinase, but not of the ROCK pathway, significantly attenuated the EPC-CM induced increase in GABA-ir cell densities. Similar results were observed when EPC-CM was subjected to proteolytic digestion and lipid extraction. Furthermore, inhibition of translation abolished the EPC-CM induced effects. Importantly, EPC-CM displayed neuroprotection against 3-nitropropionic acid induced toxicity. These findings demonstrate that EPC-derived paracrine factors substantially promote survival and/or differentiation of cultured striatal progenitor cells involving both proteinaceous factors and lipidic factors. In sum, EPC-CM constituents might lead to a novel cell-free therapeutic strategy to challenge neuronal degeneration.
  • 13.

    【2hr】α-Synuclein Expression Is Preserved in Substantia Nigra GABAergic Fibers ofYoung and Aged Neurotoxin-Treated Rhesus Monkeys

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    机译 α-突触核蛋白的表达在黑质的GABA能级纤维中得以保留幼龄和老年神经毒素处理过的恒河猴
    摘要：α-Synuclein (α-syn) is a small presynaptic protein distributed ubiquitously in the central and peripheral nervous system. In normal conditions, α-syn is found in soluble form, while in Parkinson’s disease (PD) it may phosphorylate, aggregate, and combine with other proteins to form Lewy bodies. The purpose of this study was to evaluate, in nonhuman primates, whether α-syn expression is affected by age and neurotoxin challenge. Young adult (n = 5, 5–10 years old) and aged (n = 4, 23–25 years old) rhesus monkeys received a single unilateral carotid artery injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Three months post-MPTP the animals were necropsied by transcardiac perfusion, and their brains extracted and processed with immunohistochemical methods. Quantification of tyrosine hydroxylase (TH)-positive substantia nigra (SN) neurons showed a significant 80–89% decrease in the side ipsilateral to MPTP administration in young and old animals. Optical density of TH- immunoreactivity (-ir) in the caudate and putamen presented a 60–70% loss compared with the contralateral side. α-Syn-ir was present in both ipsi- and contra- lateral MPTP-treated nigra, caudate, and putamen, mostly in fibers; its intracellular distribution was not affected by age. Comparison of α-syn-ir between MPTP-treated young and aged monkeys revealed significantly higher optical density for both the ipsi- and contralateral caudate and SN in the agedanimals. TH and α-syn immunofluorescence confirmed the loss of nigral TH-ir dopaminergicneurons in the MPTP-treated side of intoxicated animals, but bilateral α-syn expression.Colabeling of GAD67 and α-syn immunofluorescence showed that α-syn expression was presentmainly in GABAergic fibers. Our results demonstrate that, 3 months post unilateralintracarotid artery infusion of MPTP, α-syn expression in the SN is largely present inGABAergic fibers, regardless of age. Bilateral increase of α-syn expression in SN fibersof aged, compared with young rhesus monkeys, suggests that α-syn-ir may increase with age,but not after neurotoxin-induced dopaminergic nigral cell loss.
  • 14.

    【2hr】The Effect of iPS-Derived Neural Progenitors Seeded on Laminin-Coated pHEMA-MOETACl Hydrogel with Dual Porosity in a Rat Model of Chronic Spinal Cord Injury

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    机译 iPS衍生的神经祖细胞对层粘连蛋白包覆的pHEMA-MOETACl水凝胶的双重孔隙作用在慢性脊髓损伤大鼠模型中的影响
    摘要：Spinal cord injury (SCI), is a devastating condition leading to the loss of locomotor and sensory function below the injured segment. Despite some progress in acute SCI treatment using stem cells and biomaterials, chronic SCI remains to be addressed. We have assessed the use of laminin-coated hydrogel with dual porosity, seeded with induced pluripotent stem cell-derived neural progenitors (iPSC-NPs), in a rat model of chronic SCI. iPSC-NPs cultured for 3 weeks in hydrogel in vitro were positive for nestin, glial fibrillary acidic protein (GFAP) and microtubule-associated protein 2 (MAP2). These cell-polymer constructs were implanted into a balloon compression lesion, 5 weeks after lesion induction. Animals were behaviorally tested, and spinal cord tissue was immunohistochemically analyzed 28 weeks after SCI. The implanted iPSC-NPs survived in the scaffold for the entire experimental period. Host axons, astrocytes and blood vessels grew into the implant and an increased sprouting of host TH+ fibers was observed in the lesion vicinity. The implantation of iPSC-NP-LHM cell-polymer construct into the chronic SCI led to the integration of material into the injured spinal cord, reduced cavitation and supported the iPSC-NPs survival, but did not result in a statistically significant improvement of locomotor recovery.
  • 15.

    【2hr】Characterization of CDNF-Secreting ARPE-19 Cell Clones for Encapsulated Cell Therapy

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    机译 CDNF分泌的ARPE-19细胞克隆用于封装细胞治疗的表征
    摘要：Cerebral dopamine neurotrophic factor (CDNF) shows beneficial effects in rodent models of Parkinson’s and Alzheimer’s disease. The brain is a challenging target for protein therapy due to its exclusive blood–brain barrier. Hence, the therapeutic protein should be delivered directly to the brain parenchyma. Implantation of encapsulated mammalian cells that constantly secrete CDNF is a potential approach for targeted and long-term protein delivery to the brain. In this study, we generated several CDNF-secreting cell clones derived from human retinal pigment epithelial cell line ARPE-19, and studied CDNF secretion from the clones maintained as monolayers and in polymeric microcapsules. The secretion of wild type (wt) CDNF transgene was low and the majority of the produced protein remained intracellular, locating mainly to the endoplasmic reticulum (ER). The secretion of wtCDNF decreased to even lower levels when the clones were in a non-dividing state, as in the microcapsules. Both codon optimization and deletion of the putative ER-retrieval signal (four last amino acids: KTEL) improved CDNF secretion. More importantly, the secretion of KTEL-deleted CDNF remained constant in the non-dividing clones. Thus, cells expressing KTEL-deleted CDNF, in contrast to wtCDNF, can be considered for cell encapsulation applications if the KTEL-deleted CDNF is proven to be biologically active in vivo.
  • 16.

    【2hr】Secondary Pathology of the Thalamus after Focal Cortical Stroke in Rats isnot Associated with Thermal or Mechanical Hypersensitivity and is Not Alleviated byIntra-Thalamic Post-Stroke Delivery of Recombinant CDNF or MANF

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    机译 大鼠局灶性皮质中风后丘脑的继发病理是与热或机械超敏反应无关，并不能缓解脑卒中后重组CDNF或MANF的输送
    摘要：A stroke affecting the somatosensory pathway can trigger central post-stroke pain syndrome (CPSP). The symptoms often include hyperalgesia, which has also been described in rodents after the direct damage of the thalamus. Previous studies have shown that hemorrhagic stroke or ischemia caused by vasoconstriction in the thalamus induces increased pain sensitivity. We investigated whether inducing secondary damage in the thalamus by a cortical stroke causes similar pain hypersensitivity as has previously been reported with direct ischemic injury. We induced a focal cortical ischemia-reperfusion injury in male rats, quantified the amount of secondary neurodegeneration in the thalamus, and measured whether the thalamic neurodegeneration is associated with thermal or mechanical hypersensitivity. After one month, we observed extensive neuronal degeneration and found approximately 40% decrease in the number of NeuN+ cells in the ipsilateral thalamus. At the same time, there was a massive accumulation—a 30-fold increase—of phagocytic cells in the ipsilateral thalamus. However, despite the evident damage in the thalamus, we did not observe thermal or mechanical sensitization. Thus, thalamic neurodegeneration after cortical ischemia-reperfusion does not induce CPSP-like symptoms in rats, and these results suggest that direct ischemic damage is needed for CPSP induction. Despite not observing hyperalgesia, we investigated whether administration ofcerebral dopamine neurotrophic factor (CDNF) and mesencephalic astrocyte-derivedneurotrophic factor (MANF) into the ipsilateral thalamus would reduce the secondarydamage. We gave a single injection (10 µg) of recombinant CDNF or MANF protein into thethalamus at 7 days post-stroke. Both CDNF and MANF treatment promoted the functionalrecovery but had no effect on the neuronal loss or the amount of phagocytic cells in thethalamus.
  • 17.

    【2hr】Pomalidomide Reduces Ischemic Brain Injury in Rodents

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    机译 泊马利度胺减少啮齿动物的缺血性脑损伤
    摘要：Stroke is a leading cause of death and severe disability worldwide. After cerebral ischemia, inflammation plays a central role in the development of permanent neurological damage. Reactive oxygen species (ROS) are involved in the mechanism of post-ischemic inflammation. The activation of several inflammatory enzymes produces ROS, which subsequently suppress mitochondrial activity, leading to further tissue damage. Pomalidomide (POM) is a clinically available immunomodulatory and anti-inflammatory agent. Prior cellular studies demonstrate that POM can mitigate oxidative stress and lower levels of pro-inflammatory cytokines, particularly TNF-α, which plays a prominent role in ischemic stroke-induced brain damage and functional deficits. To evaluate the potential value of POM in cerebral ischemia, POM was initially administered to transgenic mice chronically over-expressing TNF-α surfactant protein (SP)-C promoter (SP-C/TNF-α mice) to assess whether systemically administered drug could lower systemic TNF-α level. POM significantly lowered serum levels of TNF-α and IL-5. Pharmacokinetic studies were then undertaken in mice to evaluate brain POM levels following systemic drug administration. POM possessed a brain/plasma concentration ratio of 0.71. Finally, rats were subjected to transient middle cerebral artery occlusion (MCAo) for 60 min, and subsequently treated with POM 30 min thereafter to evaluate action on cerebral ischemia. POM reduced thecerebral infarct volume in MCAo-challenged rats and improved motor activity, as evaluatedby the elevated body swing test. POM’s neuroprotective actions on ischemic injuryrepresent a potential therapeutic approach for ischemic brain damage and relateddisorders, and warrant further evaluation.
  • 18.

    【2hr】Functional Multipotency of Stem Cells and Recovery Neurobiology of InjuredSpinal Cords

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    机译 干细胞的功能多能性和损伤的恢复神经生物学脊髓
    • 作者：Yang D. Teng
    • 刊名：Cell Transplantation
    • 2019年第4期
    摘要：This invited concise review was written for the special issue of Cell Transplantation to celebrate the 25th anniversary of the American Society for Neural Therapy and Repair (ASNTR). I aimed to present a succinct summary of two interweaved lines of research work carried out by my team members and collaborators over the past decade. Since the middle of the 20th century, biomedical research has been driven overwhelmingly by molecular technology-based focal endeavors. Our investigative undertakings, however, were orchestrated to define and propose novel theoretical frameworks to enhance the field’s ability to overcome complex neurological disorders. The effort has engendered two important academic concepts: Functional Multipotency of Stem Cells, and Recovery Neurobiology of Injured Spinal Cords. Establishing these theories was facilitated by academic insight gleaned from stem cell-based multimodal cross-examination studies using tactics of material science, systems neurobiology, glial biology, and neural oncology. It should be emphasized that the collegial environment cultivated by the mission of the ASNTR greatly promoted the efficacy of inter-laboratory collaborations. Notably, our findings have shed new light on fundamentals of stem cell biology and adult mammalian spinal cord neurobiology. Moreover, the novel academic leads have enabled determination of potential therapeutic targets to restore function for spinal cord injury andneurodegenerative diseases.
  • 19.

    【2hr】Silencing of the Mutant Huntingtin Gene through CRISPR-Cas9 Improves theMitochondrial Biomarkers in an In Vitro Model of Huntington’s Disease

    包量

    机译 通过CRISPR-Cas9沉默Huntingtin突变基因可改善亨廷顿舞蹈病体外模型中的线粒体生物标志物
    摘要：During the 25-year history of the American Society for Neural Therapy and Repair (ASNTR) there have been several breakthroughs in the area of neurotherapeutics, which was the case during the 2014–2105 year when one of us (GLD) had the privilege of serving as its president. During that year, the use of a newly developed gene-editing tool, the CRISPR-Cas9 system, started to skyrocket. Although scientists unraveled the use of “clustered regularly interspaced short palindromic repeats” (CRISPR) and its associated genes from the Cas family as an evolved mechanism of some bacterial and archaeal genomes to protect themselves from being hijacked by invasive viral genes, its use as a therapeutic tool was not fully appreciated until further research revealed how this system operated and how it might be developed technologically to manipulate genes of any species. By 2015, this technology had exploded to the point that close to 2,000 papers that used this technology were published during that year alone.
  • 20.

    【2hr】ASNTR Abstracts 2019

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    机译 ASNTR摘要2019
    • 作者：
    • 刊名：Cell Transplantation
    • 2019年第4期
    摘要：
题名 作者 来源 发表时间

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