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Browsing by Author "Ruan, Yiwen"
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Item Carbon nanotube multilayered nanocomposites as multifunctional substrates for actuating neuronal differentiation and functions of neural stem cells(Elsevier, 2018-08) Shao, Han; Li, Tingting; Zhu, Rong; Xu, Xiaoting; Yu, Jiandong; Chen, Shengfeng; Song, Li; Ramakrishna, Seeram; Lei, Zhigang; Ruan, Yiwen; He, Liumin; Anatomy and Cell Biology, School of MedicineCarbon nanotubes (CNTs) have shown potential applications in neuroscience as growth substrates owing to their numerous unique properties. However, a key concern in the fabrication of homogeneous composites is the serious aggregation of CNTs during incorporation into the biomaterial matrix. Moreover, the regulation mechanism of CNT-based substrates on neural differentiation remains unclear. Here, a novel strategy was introduced for the construction of CNT nanocomposites via layer-by-layer assembly of negatively charged multi-walled CNTs and positively charged poly(dimethyldiallylammonium chloride). Results demonstrated that the CNT-multilayered nanocomposites provided a potent regulatory signal over neural stem cells (NSCs), including cell adhesion, viability, differentiation, neurite outgrowth, and electrophysiological maturation of NSC-derived neurons. Importantly, the dynamic molecular mechanisms in the NSC differentiation involved the integrin-mediated interactions between NSCs and CNT multilayers, thereby activating focal adhesion kinase, subsequently triggering downstream signaling events to regulate neuronal differentiation and synapse formation. This study provided insights for future applications of CNT-multilayered nanomaterials in neural fields as potent modulators of stem cell behavior.Item Characterization of dendritic morphology and neurotransmitter phenotype of thoracic descending propriospinal neurons after complete spinal cord transection and GDNF treatment(Elsevier, 2016-03) Deng, Lingxiao; Ruan, Yiwen; Chen, Chen; Frye, Christian Corbin; Xiong, Wenhui; Jin, Xiaoming; Jones, Kathryn; Sengelaub, Dale; Xu, Xiao-Ming; Department of Anatomy & Cell Biology, IU School of MedicineAfter spinal cord injury (SCI), poor regeneration of damaged axons of the central nervous system (CNS) causes limited functional recovery. This limited spontaneous functional recovery has been attributed, to a large extent, to the plasticity of propriospinal neurons, especially the descending propriospinal neurons (dPSNs). Compared with the supraspinal counterparts, dPSNs have displayed significantly greater regenerative capacity, which can be further enhanced by glial cell line-derived neurotrophic factor (GDNF). In the present study, we applied a G-mutated rabies virus (G-Rabies) co-expressing green fluorescence protein (GFP) to reveal Golgi-like dendritic morphology of dPSNs. We also investigated the neurotransmitters expressed by dPSNs after labeling with a retrograde tracer Fluoro-Gold (FG). dPSNs were examined in animals with sham injuries or complete spinal transections with or without GDNF treatment. Bilateral injections of G-Rabies and FG were made into the 2nd lumbar (L2) spinal cord at 3 days prior to a spinal cord transection performed at the 11th thoracic level (T11). The lesion gap was filled with Gelfoam containing either saline or GDNF in the injury groups. Four days post-injury, the rats were sacrificed for analysis. For those animals receiving G-rabies injection, the GFP signal in the T7-9 spinal cord was visualized via 2-photon microscopy. Dendritic morphology from stack images was traced and analyzed using a Neurolucida software. We found that dPSNs in sham injured animals had a predominantly dorsal-ventral distribution of dendrites. Transection injury resulted in alterations in the dendritic distribution with dorsal-ventral retraction and lateral-medial extension. Treatment with GDNF significantly increased the terminal dendritic length of dPSNs. The density of spine-like structures was increased after injury, and treatment with GDNF enhanced this effect. For the group receiving FG injections, immunohistochemistry for glutamate, choline acetyltransferase (ChAT), glycine, and GABA was performed in the T7-9 spinal cord. We show that the majority of FG retrogradely-labeled dPSNs were located in the Rexed Lamina VII. Over 90% of FG-labeled neurons were glutamatergic, with the other three neurotransmitters contributing less than 10% of the total. To our knowledge this is the first report describing the morphologic characteristics of dPSNs and their neurotransmitter expressions, as well as the dendritic response of dPSNs after transection injury and GDNF treatment.Item In vivo Two-Photon Imaging Reveals Acute Cerebral Vascular Spasm and Microthrombosis After Mild Traumatic Brain Injury in Mice(Frontiers Media, 2020-03) Han, Xinjia; Chai, Zhi; Ping, Xingjie; Song, Li-Juan; Ma, Cungen; Ruan, Yiwen; Jin, Xiaoming; Anatomy and Cell Biology, School of MedicineMild traumatic brain injury (mTBI), or concussion, is reported to interfere with cerebral blood flow and microcirculation in patients, but our current understanding is quite limited and the results are often controversial. Here we used longitudinal in vivo two-photon imaging to investigate dynamic changes in cerebral vessels and velocities of red blood cells (RBC) following mTBI. Closed-head mTBI induced using a controlled cortical impact device resulted in a significant reduction of dwell time in a Rotarod test but no significant change in water maze test. Cerebral blood vessels were repeatedly imaged through a thinned skull window at baseline, 0.5, 1, 6 h, and 1 day following mTBI. In both arterioles and capillaries, their diameters and RBC velocities were significantly decreased at 0.5, 1, and 6 h after injury, and recovered in 1 day post-mTBI. In contrast, decreases in the diameter and RBC velocity of venules occurred only in 0.5–1 h after mTBI. We also observed formation and clearance of transient microthrombi in capillaries within 1 h post-mTBI. We concluded that in vivo two-photon imaging is useful for studying earlier alteration of vascular dynamics after mTBI and that mTBI induced reduction of cerebral blood flow, vasospasm, and formation of microthrombi in the acute stage following injury. These changes may contribute to early brain functional deficits of mTBI.Item Increased Sestrin3 Contributes to Post-ischemic Seizures in the Diabetic Condition(Frontiers Media, 2021-01-15) Shi, Zhongshan; Lei, Zhigang; Wu, Fan; Xia, Luoxing; Ruan, Yiwen; Xu, Zao C.; Anatomy and Cell Biology, School of MedicineSeizures are among the most common neurological sequelae of stroke, and diabetes notably increases the incidence of post-ischemic seizures. Recent studies have indicated that Sestrin3 (SESN3) is a regulator of a proconvulsant gene network in human epileptic hippocampus. But the association of SESN3 and post-ischemic seizures in diabetes remains unclear. The present study aimed to reveal the involvement of SESN3 in seizures following transient cerebral ischemia in diabetes. Diabetes was induced in adult male mice and rats via intraperitoneal injection of streptozotocin (STZ). Forebrain ischemia (15 min) was induced by bilateral common carotid artery occlusion, the 2-vessel occlusion (2VO) in mice and 4-vessel occlusion (4VO) in rats. Our results showed that 59% of the diabetic wild-type mice developed seizures after ischemia while no seizures were observed in non-diabetic mice. Although no apparent cell death was detected in the hippocampus of seizure mice within 24 h after the ischemic insult, the expression of SESN3 was significantly increased in seizure diabetic mice after ischemia. The post-ischemic seizure incidence significantly decreased in SESN3 knockout mice. Furthermore, all diabetic rats suffered from post-ischemic seizures and non-diabetic rats have no seizures. Electrophysiological recording showed an increased excitatory synaptic transmission and intrinsic membrane excitability in dentate granule cells of the rat hippocampus, together with decreased IA currents and Kv4.2 expression levels. The above results suggest that SESN3 up-regulation may contribute to neuronal hyperexcitability and seizure generation in diabetic animals after ischemia. Further studies are needed to explore the molecular mechanism of SESN3 in seizure generation after ischemia in diabetic conditions.Item Neuroprotective Mechanisms of Lycium barbarum Polysaccharides Against Ischemic Insults by Regulating NR2B and NR2A Containing NMDA Receptor Signaling Pathways(Frontiers, 2017-09-27) Shi, Zhongshan; Zhu, Lihui; Li, Tingting; Tang, Xiaoya; Xiang, Yonghui; Han, Xinjia; Xia, Luoxing; Zeng, Ling; Nie, Junhua; Huang, Yongxia; Tsang, Chi Kwan; Wang, Ying; Lei, Zhigang; Xu, Zaocheng; So, Kwok-fai; Ruan, Yiwen; Anatomy and Cell Biology, School of MedicineGlutamate excitotoxicity plays an important role in neuronal death after ischemia. However, all clinical trials using glutamate receptor inhibitors have failed. This may be related to the evidence that activation of different subunit of NMDA receptor will induce different effects. Many studies have shown that activation of the intrasynaptic NR2A subunit will stimulate survival signaling pathways, whereas upregulation of extrasynaptic NR2B will trigger apoptotic pathways. A Lycium barbarum polysaccharide (LBP) is a mixed compound extracted from Lycium barbarum fruit. Recent studies have shown that LBP protects neurons against ischemic injury by anti-oxidative effects. Here we first reported that the effect of LBP against ischemic injury can be achieved by regulating NR2B and NR2A signaling pathways. By in vivo study, we found LBP substantially reduced CA1 neurons from death after transient global ischemia and ameliorated memory deficit in ischemic rats. By in vitro study, we further confirmed that LBP increased the viability of primary cultured cortical neurons when exposed to oxygen-glucose deprivation (OGD) for 4 h. Importantly, we found that LBP antagonized increase in expression of major proteins in the NR2B signal pathway including NR2B, nNOS, Bcl-2-associated death promoter (BAD), cytochrome C (cytC) and cleaved caspase-3, and also reduced ROS level, calcium influx and mitochondrial permeability after 4 h OGD. In addition, LBP prevented the downregulation in the expression of NR2A, pAkt and pCREB, which are important cell survival pathway components. Furthermore, LBP attenuated the effects of a NR2B co-agonist and NR2A inhibitor on cell mortality under OGD conditions. Taken together, our results demonstrated that LBP is neuroprotective against ischemic injury by its dual roles in activation of NR2A and inhibition of NR2B signaling pathways, which suggests that LBP may be a superior therapeutic candidate for targeting glutamate excitotoxicity for the treatment of ischemic stroke.Item Unilateral Microinjection of Acrolein into Thoracic Spinal Cord Produces Acute and Chronic Injury and Functional Deficits(Elsevier, 2016-06-21) Gianaris, Alexander; Liu, Nai-Kui; Wang, Xiao-Fei; Oakes, Eddie; Brenia, John; Gianaris, Thomas; Ruan, Yiwen; Deng, Ling-Xiao; Goetz, Maria; Vega-Alvarez, Sasha; Lu, Qing-Bo; Shi, Riyi; Xu, Xiao-Ming; Neurological Surgery, School of MedicineAlthough lipid peroxidation has long been associated with spinal cord injury (SCI), the specific role of lipid peroxidation-derived byproducts such as acrolein in mediating damage remains to be fully understood. Acrolein, an α-β unsaturated aldehyde, is highly reactive with proteins, DNA, and phospholipids and is considered as a second toxic messenger that disseminates and augments initial free radical events. Previously, we showed that acrolein increased following traumatic SCI and injection of acrolein induced tissue damage. Here, we demonstrate that microinjection of acrolein into the thoracic spinal cord of adult rats resulted in dose-dependent tissue damage and functional deficits. At 24 h (acute) after the microinjection, tissue damage, motoneuron loss, and spinal cord swelling were observed on sections stained with Cresyl Violet. Luxol fast blue staining further showed that acrolein injection resulted in dose-dependent demyelination. At 8 weeks (chronic) after the microinjection, cord shrinkage, astrocyte activation, and macrophage infiltration were observed along with tissue damage, neuron loss, and demyelination. These pathological changes resulted in behavioral impairments as measured by both the Basso, Beattie, and Bresnahan (BBB) locomotor rating scale and grid walking analysis. Electron microscopy further demonstrated that acrolein induced axonal degeneration, demyelination, and macrophage infiltration. These results, combined with our previous reports, strongly suggest that acrolein may play a critical causal role in the pathogenesis of SCI and that targeting acrolein could be an attractive strategy for repair after SCI.