43 results on '"CESARIO, V."'
Search Results
2. Effects of Lovastatin on Brain Cancer Cells
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Efosa Amadasu, Richard Kang, Ahsan Usmani, and Cesario V. Borlongan
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Medicine - Abstract
Although brain tumors occur less frequently than other forms of cancer, they have one of the bleakest prognoses with low survival rates. The conventional treatment for brain tumors includes surgery, radiotherapy, and chemotherapy. However, resistance to treatment remains a problem with recurrence shortly following. The resistance to treatment may be caused by cancer stem cells (CSCs), a subset of brain tumor cells with the affinity for self-renewal and differentiation into multiple cell lineages. An emerging approach to targeting CSCs in brain tumors is through repurposing the lipid-lowering medication, lovastatin. Lovastatin is a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor that impacts the mevalonate pathway. The inhibition of intermediates in the mevalonate pathway affects signaling cascades and oncogenes associated with brain tumor stem cells (BTSC). In this review, we show the possible mechanisms where lovastatin can target BTSC for different varieties of malignant brain tumors.
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- 2022
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3. Retracted: Lovastatin Inhibits RhoA to Suppress Canonical Wnt/β-Catenin Signaling and Alternative Wnt-YAP/TAZ Signaling in Colon Cancer
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Yi Xiao, Qin Liu, Nanyin Peng, Yuzhang Li, Danyang Qiu, Tianlun Yang, Richard Kang, Ahsan Usmani, Efosa Amadasu, Cesario V. Borlongan, and Guolong Yu
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Medicine - Published
- 2022
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4. Advancing Stem Cell Therapy for Repair of Damaged Lung Microvasculature in Amyotrophic Lateral Sclerosis
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Svitlana Garbuzova-Davis, Robert Shell, Hilmi Mustafa, Surafuale Hailu, Alison E. Willing, Paul R. Sanberg, and Cesario V. Borlongan
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Medicine - Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal disease of motor neuron degeneration in the brain and spinal cord. Progressive paralysis of the diaphragm and other respiratory muscles leading to respiratory dysfunction and failure is the most common cause of death in ALS patients. Respiratory impairment has also been shown in animal models of ALS. Vascular pathology is another recently recognized hallmark of ALS pathogenesis. Central nervous system (CNS) capillary damage is a shared disease element in ALS rodent models and ALS patients. Microvascular impairment outside of the CNS, such as in the lungs, may occur in ALS, triggering lung damage and affecting breathing function. Stem cell therapy is a promising treatment for ALS. However, this therapeutic strategy has primarily targeted rescue of degenerated motor neurons. We showed functional benefits from intravenous delivery of human bone marrow (hBM) stem cells on restoration of capillary integrity in the CNS of an superoxide dismutase 1 (SOD1) mouse model of ALS. Due to the widespread distribution of transplanted cells via this route, administered cells may enter the lungs and effectively restore microvasculature in this respiratory organ. Here, we provided preliminary evidence of the potential role of microvasculature dysfunction in prompting lung damage and treatment approaches for repair of respiratory function in ALS. Our initial studies showed proof-of-principle that microvascular damage in ALS mice results in lung petechiae at the late stage of disease and that systemic transplantation of mainly hBM-derived endothelial progenitor cells shows potential to promote lung restoration via re-established vascular integrity. Our new understanding of previously underexplored lung competence in this disease may facilitate therapy targeting restoration of respiratory function in ALS.
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- 2020
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5. Genetic and Histological Alterations Reveal Key Role of Prostaglandin Synthase and Cyclooxygenase 1 and 2 in Traumatic Brain Injury–Induced Neuroinflammation in the Cerebral Cortex of Rats Exposed to Moderate Fluid Percussion Injury
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Hideki Shojo, Cesario V. Borlongan, and Tadashi Mabuchi
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Medicine - Abstract
After the initial insult in traumatic brain injury (TBI), secondary neurodegeneration occurs that is intimately associated with neuroinflammation. Prostaglandin (PG) synthases and cyclooxygenase (COX) 1 and 2 may contribute to inflammation in the brain. Temporal and spatial expression features of PG and COX1 and 2 following trauma may guide the development of antineuroinflammation strategies. Here, we examined PG synthase signaling and COX1 and 2 gene expression levels and COX- 1 - and 2-positive cell types and their temporal localization in TBI-induced brain in an effort to reveal their participation in the disease’s evolving neuroinflammation. Using brain samples from the cerebral cortex of rats subjected to TBI model of lateral moderate fluid percussion injury (FPI), we sought to characterize the temporal (subacute TBI) and spatial (lateral cortical lesion) brain alterations accompanying the disease progression. Temporal gene expression changes of PG synthase signaling were compared between sham-operated and TBI-treated rats using microarray pathway analysis. Moreover, we examined COX1 and 2 expression patterns and their intracellular distribution in sham-operated and TBI-treated rats by immunohistochemistry. After FPI, COX1 and 2 gene expression levels, and PGE 2 synthase increased while PGD 2 synthase decreased, suggesting that PGE 2 and PGD 2 afforded contraindicative effects of inflammation and anti-inflammation, respectively. Immunohistochemical analyses showed that both COX1 and COX2 increased in a time-dependent manner in the brain, specifically in degenerating neurons of the cortex. Interestingly, the expression of COX cell type was cell-specific, in that COX1 was particularly increased in degenerating neurons while COX2 was expressed in macrophages. In view of the dynamic temporal and spatial expression of PG, COX1 and 2 gene expression and localization in the injured brain regulating PG synthase and COX1 and 2 activity will require a careful disease-specific tailoring of treatments to abrogate the neuroinflammation-plagued secondary cell death due to TBI.
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- 2017
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6. Extracardiac-Lodged Mesenchymal Stromal Cells Propel an Inflammatory Response against Myocardial Infarction via Paracrine Effects
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Yi Peng, Wei Pan, Yali Ou, Weifang Xu, Sussannah Kaelber, Cesario V. Borlongan Ph.D., Meiqin Sun, and Guolong Yu
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Medicine - Abstract
Transplantation of stem cells, including mesenchymal stromal cells (MSCs), improves the recovery of cardiac function after myocardial infarction (MI) in experimental studies using animal models and in patients. However, the improvement of cardiac function following MSC transplantation remains suboptimal in both preclinical and clinical studies. Understanding the mechanism of cell therapy may improve its therapeutic outcomes, but the mode of action mediating stem cell promotion of cardiac repair is complex and not fully understood. Recent studies suggest that the immunomodulatory effects of MSCs on the macrophage M1/M2 subtype transition allow the transplanted stem cells to inhibit inflammation-induced injury and promote cardiac repair in acute MI. However, equally compelling evidence shows that there is poor survival and minimal graft persistence of transplanted MSCs within the infarcted heart tissues, negating the view that graft survival per se is required for the observed high rate and long duration of the transition from proinflammatory M1 to reparative M2 macrophages in the infarcted myocardium. Therefore, we raised a novel hypothesis that the therapeutic effects of MSC transplantation for acute MI depends not primarily on the grafted cells in infarct myocardium, but that MSCs migrating to and being lodged in the extracardiac organs, demonstrating good graft survival and persistence, may render the therapeutic effects in MI. More specifically, MSC transplantation promotes the transition from M1 to M2 in extracardiac organs, such as spleen and bone marrow, and therapeutic effects are conferred to the infarcted myocardium via paracrine effects. In MSC transplantation, the conversion from proinflammatory M1 to anti-inflammatory M2 monocytes may occur remotely from the heart and may serve as one of the major pathways in regulating the dual effects of inflammation. This hypothesis, if proven valid, may represent an important new mechanism of action to be considered for the future of MSC transplantation in the treatment of MI.
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- 2016
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7. Safety and Feasibility of Remote Limb Ischemic Preconditioning in Patients with Unilateral Middle Cerebral Artery Stenosis and Healthy Volunteers
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Sijie Li, Chun Ma, Guo Shao, Fatema Esmail, Yang Hua, Lingyun Jia, Jian Qin, Changhong Ren, Yumin Luo, Yuchun Ding, Cesario V. Borlongan, and Xunming Ji
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Medicine - Abstract
Previous studies have indicated a neuroprotective effect of remote limb ischemic preconditioning. The aim of the present study was to assess whether upper arm ischemic preconditioning is feasible and safe in patients with unilateral middle cerebral artery (MCA) stenosis compared to healthy volunteers. Ten patients with unilateral MCA stenosis and 24 healthy volunteers underwent limb ischemic preconditioning, consisting of five cycles of 5-min inflations of a blood pressure cuff to 200 mmHg around an upper limb followed by 5 min of reperfusion. Limb ischemic preconditioning has no significant effect on the heart rate, oxygenation index, or mean flow velocity in patients with unilateral MCA stenosis or healthy volunteers. However, healthy volunteers showed a reduction in blood pressure 30 min following reperfusion of the last cycle. Limb ischemic preconditioning was found to be safe and well tolerated in both patients and healthy volunteers. We highlight the potential of limb ischemic preconditioning as an adjunct to neuroprotective treatment.
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- 2015
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8. Suppression of Astrocyte Lineage in Adult Hippocampal Progenitor Cells Expressing Hippocampal Cholinergic Neurostimulating Peptide Precursor in an in Vivo Ischemic Model
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Takanari Toyoda, Noriyuki Matsukawa M.D., Ph.D., Takafumi Sagisaka, Norihiko Uematsu, Tetsuko Kanamori, Daisuke Kato, Masayuki Mizuno, Hiroaki Wake, Hideki Hida, Cesario V. Borlongan, and Kosei Ojika
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Medicine - Abstract
Hippocampal cholinergic neurostimulating peptide (HCNP) is known to promote differentiation of septohippocampal cholinergic neurons. The HCNP precursor protein (HCNP-pp) may play several roles, for example, as an ATP-binding protein, a Raf kinase inhibitor protein, and a phosphatidylethanolamine-binding protein, as well as a precursor for HCNP. This study therefore aimed to elucidate the involvement of HCNP-pp in specific neural lineages after stroke using a hypoxic–ischemic (HI) rat model of brain ischemia. The specific neural lineages in the hippocampus were investigated 14 days after ischemia. Some bromodeoxyuridine (BrdU) + neural progenitor cells in the hippocampus of hypoxic, HI, or sham-operated rats expressed HCNP-pp. Almost half of the BrdU + /HCNP-pp + cells also expressed the oligodendrocyte lineage marker 2′,3′-cyclic nucleotide 3′-phosphodiesterase, whereas only a few BrdU + /HCNP-pp + cells in the hippocampus in HI brains expressed the neuronal lineage marker, doublecortin (DCX). Interestingly, no BrdU + /HCNP-pp + progenitor cells in hypoxic, HI, or sham-operated brains expressed the astrocyte lineage marker, glial fibrillary acidic protein. Together with previous in vitro data, the results of this study suggest that the expression level of HCNP-pp regulates the differentiation of neural progenitor cells into specific neural lineages in the HI hippocampus, indicating that neural stem cell fate can be controlled via the HCNP-pp mediating pathway.
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- 2012
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9. Striatal Stimulation Nurtures Endogenous Neurogenesis and Angiogenesis in Chronic-Phase Ischemic Stroke Rats
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Takamasa Morimoto, Takao Yasuhara M.D., Ph.D., Masahiro Kameda, Tanefumi Baba, Satoshi Kuramoto, Akihiko Kondo, Kazuya Takahashi, Naoki Tajiri, Feifei Wang, Jing Meng, Yuan Wen Ji, Tomohito Kadota, Tomoko Maruo, Kazushi Kinugasa, Yasuyuki Miyoshi, Tetsuro Shingo, Cesario V. Borlongan, and Isao Date
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Medicine - Abstract
Deep brain stimulation (DBS) is used to treat a variety of neurological disorders including Parkinson's disease. In this study, we explored the effects of striatal stimulation (SS) in a rat model of chronic-phase ischemic stroke. The stimulation electrode was implanted into the ischemic penumbra at 1 month after middle cerebral artery occlusion (MCAO) and thereafter continuously delivered SS over a period of 1 week. Rats were evaluated behaviorally coupled with neuroradiological assessment of the infarct volumes using magnetic resonance imaging (MRI) at pre- and post-SS. The rats with SS showed significant behavioral recovery in the spontaneous activity and limb placement test compared to those without SS. MRI visualized that SS also significantly reduced the infarct volumes compared to that at pre-SS or without SS. Immunohistochemical analyses revealed a robust neurogenic response in rats that received SS characterized by a stream of proliferating cells from the subventricular zone migrating to and subsequently differentiating into neurons in the ischemic penumbra, which exhibited a significant GDNF upregulation. In tandem with this SS-mediated neurogenesis, enhanced angiogenesis was also recognized as revealed by a significant increase in VEGF levels in the penumbra. These results provide evidence that SS affords neurorestoration at the chronic phase of stroke by stimulating endogenous neurogenesis and angiogenesis.
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- 2011
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10. Article Commentary: Who's in Favor of Translational Cell Therapy for Stroke: STEPS Forward Please?
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Michael Chopp, Gary K. Steinberg, Douglas Kondziolka, Mei Lu, Tonya M. Bliss, Yi Li, David C. Hess, and Cesario V. Borlongan Ph.D.
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Medicine - Abstract
A consortium of translational stem cell and stroke experts from multiple academic institutes and biotechnology companies, under the guidance of the government (FDA/NIH), is missing. Here, we build a case for the establishment of this consortium if cell therapy for stroke is to advance from the laboratory to the clinic.
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- 2009
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11. Transplants of Encapsulated Rat Choroid Plexus Cells Exert Neuroprotection in a Rodent Model of Huntington's Disease
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Cesario V. Borlongan, Christopher G. Thanos, Steven J. M. Skinner, Marilyn Geaney, and Dwaine F. Emerich
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Medicine - Abstract
Choroid plexus (CP) epithelial cells secrete several neurotrophic factors and have been used in transplantation studies designed to impart neuroprotection against central nervous system (CNS) trauma. In the present study, CP was isolated from adult rats, encapsulated within alginate microcapsules, and transplanted unilaterally into the rat striatum. Three days later, unilateral injections of quinolinic acid (QA; 225 nmol) were made into the ipsilateral striatum to mimic the pathology observed in Huntington's disease (HD). After surgery, animals were tested for motor function using the placement test. Rats receiving CP transplants were significantly less impaired on this test. Nissl-stained sections demonstrated that CP transplants significantly reduced the volume of the striatal lesion produced by QA. Quantitative analysis of striatal neurons further demonstrated that choline acetyltransferase-immunoreactive, but not diaphorase-positive, neurons were protected by CP transplants. These data demonstrate that transplanted CP cells can be used to protect striatal neurons from excitotoxic damage and that the pattern of neuroprotection varies across specific neuronal populations.
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- 2007
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12. Transplantation of Bone Marrow-Derived Stem Cells: A Promising Therapy for Stroke
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Yamei Tang, Takao Yasuhara, Koichi Hara, Noriyuki Matsukawa, Mina Maki, Guolong Yu, Lin Xu, David C. Hess, and Cesario V. Borlongan Ph.D.
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Medicine - Abstract
Stroke remains a major cause of death in the US and around the world. Over the last decade, stem cell therapy has been introduced as an experimental treatment for stroke. Transplantation of stem cells or progenitors into the injured site to replace the nonfunctional cells, and enhancement of proliferation or differentiation of endogenous stem or progenitor cells stand as the two major cell-based strategies. Potential sources of stem/progenitor cells for stroke include fetal neural stem cells, embryonic stem cells, neuroteratocarcinoma cells, umbilical cord blood-derived nonhematopoietic stem cells, and bone marrow-derived stem cells. The goal of this article is to provide an update on the preclinical use of bone marrow-derived stem cells with major emphasis on mesenchymal stem cells (MSCs) and multipotent adult progenitor cells (MAPCs) because they are currently most widely applied in experimental stroke studies and are now being phased into early clinical trials. The phenotypic features of MSCs and MAPCs, as well as their application in stroke, are described.
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- 2007
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13. A Role of the Choroid Plexus in Transplantation Therapy
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Dwaine F. Emerich, Stephen J. M. Skinner, Cesario V. Borlongan, and Christopher G. Thanos
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Medicine - Abstract
The choroid plexuses (CPs) play pivotal roles in the most basic aspects of neural function. Some of the roles of the CP include maintaining the extracellular milieu of the brain by actively modulating chemical exchange between the CSF and brain parenchyma, surveying the chemical and immunological status of the brain, detoxifying the brain, secreting a nutritive “cocktail” of polypeptides, and participating in repair processes following trauma. This diversity of functions suggests that even modest changes in the CP can have far reaching effects. Indeed, changes in the anatomy and physiology of the CP have been linked to several CNS diseases. It is also possible that replacing diseased CP or transplanting healthy CP might be useful for treating acute and chronic brain diseases. Here we describe the wide-ranging functions of the CP, alterations of these functions in aging and neurodegeneration, and recent demonstrations of the therapeutic potential of transplanted CP for neural trauma.
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- 2005
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14. Transplantation of Fetal Kidney Cells: Neuroprotection and Neuroregeneration
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Yung-Hsiao Chiang, Cesario V. Borlongan, Feng C. Zhou, Barry J. Hoffer, and Yun Wang M.D., Ph.D.
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Medicine - Abstract
Various trophic factors in the transforming growth factor-β (TGF-β) superfamily have been reported to have neuroprotective and neuroregenerative effects. Intracerebral administration of glial cell line-derived neurotrophic factor (GDNF) or bone morphogenetic proteins (BMPs), both members of the TGF-β family, reduce ischemia- or 6-hydroxydopamine (6-OHDA)-induced injury in adult rat brain. Because BMPs and GDNF are highly expressed in fetal kidney cells, transplantation of fetal kidney tissue could serve as a cellular reservoir for such molecules and protect against neuronal injury induced by ischemia, neurotoxins, or reactive oxygen species. In this review, we discuss preclinical evidence for the efficacy of fetal kidney cell transplantation in neuroprotection and regeneration models.
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- 2005
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15. Article Commentary: Neural Transplantation in the New Millenium
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Cesario V. Borlongan and Paul R. Sanberg
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Medicine - Published
- 2002
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16. T155g-Immortalized Kidney Cells Produce Growth Factors and Reduce Sequelae of Cerebral Ischemia
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Ora Dillon-Carter, Rowena E. Johnston, Cesario V. Borlongan Ph.D., Mary Ellen Truckenmiller, Mark Coggiano, and William J. Freed
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Medicine - Abstract
Fetal rat kidney cells produce high levels of glial-derived neurotrophic factor (GDNF) and exert neuroprotective effects when transplanted into the brain in animal models of Parkinson's disease and stroke. The purpose of the present experiment was to produce kidney cell lines that secrete GDNF. Genes encoding two truncated N-terminal fragments of SV40 large T antigen, T155g and T155c, which does not code for small t antigen, were used. T155g was transduced into E17 cultured fetal Sprague-Dawley rat kidney cortex cells using a plasmid vector, and T155c was transduced with a plasmid and a retroviral vector. Sixteen clones were isolated from cultures transfected with the T155g-expressing plasmid. No cell lines were obtained with T155c. Four clones produced GDNF at physiological concentrations ranging from 55 to 93 pg/ml of medium. These four clones were transplanted into the ischemic core or penumbra of rats that had undergone middle cerebral artery occlusion (MCAO). Three of the four clones reduced the volume of infarction and the behavioral abnormalities normally resulting from MCAO. Blocking experiments with antibodies to GDNF and platelet-derived growth factor (PDGF) suggested that these growth factors contributed only minimally to the reduction in infarct volume and behavioral abnormality. These cell lines may be useful for intracerebral transplantation in animal models of brain injury, stroke, or Parkinson's disease.
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- 2002
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17. Delta Opioid Peptide Augments Functional Effects and Intrastriatal Graft Survival of Rat Fetal Ventral Mesencephalic Cells
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Cesario V. Borlongan, Tsung-Ping Su, and Yun Wang
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Medicine - Abstract
Delta enkephalin analogue [d-Ala(2),d-Leu(5)]enkephalin (DADLE) has been shown to protect dopamine transporters from methamphetamine-induced neurotoxicity. In the present study, we demonstrate that exposure of embryonic ventral mesencephalic cells to DADLE (0.01 g/ml), prior to intrastriatal transplantation, enhanced functional recovery and graft survival in 6-hydroxydopamine-induced hemiparkinsonian rats. At 6 and 8 weeks posttransplantation, animals that received DADLE-treated cell grafts exhibited significantly higher (near normal) spontaneous locomotor behaviors, as well as trends of greater reversal of motor asymmetrical behaviors compared with animals that received nontreated cell grafts. Histological examination revealed that animals transplanted with DADLE-treated cell grafts exhibited about twice the number of surviving tyrosine hydroxylase-immunoreactive grafted neurons compared with those animals that received nontreated cell grafts. These results suggest that DADLE should be considered as an adjunctive agent for neural transplantation therapy in Parkinson's disease.
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- 2001
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18. Cyclosporine A-Induced Hyperactivity in Rats: Is it Mediated by Immunosuppression, Neurotrophism, or Both?
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Cesario V. Borlongan, Christine E. Stahl, Tomoko Fujisaki, Paul R. Sanberg, and Shigeru Watanabe
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Medicine - Abstract
Cyclosporine A (CsA) immunosuppressive treatment has become an adjunctive therapy in neural transplantation of dopamine-secreting cells for treatment of Parkinson's disease (PD). Recently, CsA and its analogues have been shown to promote trophic effects against neurodegenerative disorders, and therefore CsA may have direct beneficial effects on dopaminergic neurons and dopamine-mediated behaviors. The present study examined the interaction between the reported CsA-induced hyperactivity and the possible alterations in nigral tyrosine hydroxylase (TH)-immunoreactive neurons in rats with damaged blood–brain barrier. CsA was administered at a therapeutic dose (10 mg/kg/day, IP, for 9 days) used in neural transplantation protocol for PD animal models. CsA-treated animals displayed significantly higher general spontaneous locomotor activity than control animals at drug injection days 7 and 9. Histological assays at day 9 revealed that there was a significant increase in TH-immunoreactive neurons in the nigra of CsA-treated rats compared to that of the vehicle-treated rats. The nigral TH elevation was accompanied by suppressed calcium-phosphotase calcineurin activity, indicating an inhibition of host immune response. This is the first report of CsA exerting simultaneous immunosuppressive and neurotrophic effects, as well as increasing general spontaneous locomotor behavior. These results support the utility of CsA as a therapeutic agent for PD and other movement disorders.
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- 1999
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19. Bilateral Fetal Striatal Grafts in the 3-Nitropropionic Acid-Induced Hypoactive Model of Huntington's Disease
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Cesario V. Borlongan, Theodore K. Koutouzis, Stephen G. Poulos, Samuel Saporta, and Paul R. Sanberg
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Medicine - Abstract
We investigated the 3-nitropropionic acid (3-NP)–induced hypoactive model of Huntington's disease (HD) to demonstrate whether fetal tissue transplantation can ameliorate behavioral deficits associated with a more advanced stage of HD. Twelve-week-old Sprague–Dawley rats were introduced to the 3-NP dosing regimen (10 mg/kg, i.p., once every 4 days for 28 consecutive days), and were then tested for general spontaneous locomotor activity in the Digiscan locomotor apparatus. All rats displayed significant hypoactivity compared to their pre-3-NP injection locomotor activity. Randomly selected rats then received bilateral intrastriatal solid grafts of fetal striatal (lateral ganglionic eminence, LGE) tissues from embryonic day 14 rat fetuses. Approximately 1/3 of each LGE in hibernation medium was infused into each lesioned host striatum. In control rats, medium alone was infused intrastriatally. A 3-mo posttransplant maturation period was allowed prior to locomotor activity testing. Animals receiving fetal LGE grafts exhibited a significant increase in locomotor activity compared to their post-3-NP injection activity or to the controls’ posttransplant activity. Surviving striatal grafts were noted in functionally recovered animals. This observation supports the use of fetal striatal transplants to correct the akinetic stage of HD. To the best of our knowledge, this is the first study that has investigated the effects of fetal striatal transplantation in a hypoactive model of HD.
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- 1998
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20. Article Commentary: The Testis-Derived Cultured Sertoli Cell as a Natural Fas-L Secreting Cell for Immunosuppressive Cellular Therapy
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Paul R. Sanberg, Samuel Saporta, Cesario V. Borlongan, Agneta I. Othberg, Richard C. Allen, and Don F. Cameron
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Medicine - Published
- 1997
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21. Book Review: Microtransplantation of Nigral Dopamine Neurons in a Rat Model of Parkinson's Disease
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Guido Nikkhah, Cesario V. Borlongan, and Paul R. Sanberg
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Medicine - Published
- 1995
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22. Cyclosporine-A Increases Spontaneous and Dopamine Agonist-Induced Locomotor Behavior in Normal Rats
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Cesario V. Borlongan, Thomas B. Freeman, Theresa A. Scorcia, Kathleen A. Sherman, Warren C. Olanow, David W. Cahill, and Paul R. Sanberg
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Medicine - Abstract
Cyclosporine-A (CsA) has been increasingly used as an immunosuppressant concomitant with neural transplantation treatment for different degenerative disorders. However, the possible role that CsA itself may have in the recovery of transplant patients is not known. Some investigators have argued that clinical improvement following transplantation (e.g., myoblast) may be confounded by CsA administration. The present study was conducted to delineate CsA-induced behavioral alterations. Four groups of normal 5-wk old Sprague-Dawley rats (n = 8 per group) were utilized in two separate experiments. In both experiments, two groups of animals were used; each group either received daily injections of 15 mg/kg of CsA or olive oil for 32 days (experiment 1) and 21 days (experiment 2). Animals in both experiments were subsequently tested for nocturnal locomotor behavior. Animals in experiment 2 were further tested in passive avoidance task, motor coordination, and amphetamine-induced locomotor activity. Results demonstrated that CsA-treated animals were significantly hyperactive compared to controls across the 12-h nocturnal activity periods and in amphetamine-induced locomotor activity. No significant differences between the CsA- and vehicle-treated animals were observed in passive avoidance or in motor coordination. Postmortem analyses of dopamine and its metabolites in the striatum and olfactory tubercle did not show any significant differences between the CsA- and the vehicle-treated groups. In summary, CsA significantly increased nocturnal spontaneous and amphetamine-induced locomotor behavior, but the neurochemical correlates for these effects need to be investigated. In addition, while the present study demonstrated that CsA induced motor alterations, any possible effects CsA may have on neurological or dystrophic patients with motor dysfunctions remain to be determined.
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- 1995
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23. Article Commentary: Who's in Favor of Translational Cell Therapy for Stroke: STEPS Forward Please?
- Author
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Mei Lu, Douglas Kondziolka, Gary K. Steinberg, Tonya M. Bliss, Cesario V. Borlongan, Yi Li, David C. Hess, and Michael Chopp
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Transplantation ,medicine.medical_specialty ,Government ,business.industry ,lcsh:R ,Biomedical Engineering ,Alternative medicine ,lcsh:Medicine ,Cell Biology ,medicine.disease ,Private sector ,Cell therapy ,medicine ,cardiovascular diseases ,Stem cell ,Intensive care medicine ,business ,Stroke - Abstract
A consortium of translational stem cell and stroke experts from multiple academic institutes and biotechnology companies, under the guidance of the government (FDA/NIH), is missing. Here, we build a case for the establishment of this consortium if cell therapy for stroke is to advance from the laboratory to the clinic.
- Published
- 2009
24. Melatonin-Secreting Pineal Gland: A Novel Tissue Source for Neural Transplantation Therapy in Stroke
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Terumi Sakurai, Hideki Hida, Isabel C. Sumaya, Donald E. Moss, Cesario V. Borlongan, Michiko Kumazaki, and Hitoo Nishino
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0301 basic medicine ,Male ,endocrine system ,medicine.medical_specialty ,Cell Transplantation ,medicine.medical_treatment ,Biomedical Engineering ,Pinealectomy ,lcsh:Medicine ,Pineal Gland ,Melatonin ,Rats, Sprague-Dawley ,03 medical and health sciences ,Pineal gland ,0302 clinical medicine ,medicine.artery ,Internal medicine ,medicine ,Animals ,cardiovascular diseases ,Stroke ,Neurons ,Transplantation ,Behavior, Animal ,Cerebral infarction ,business.industry ,lcsh:R ,Infarction, Middle Cerebral Artery ,Cell Biology ,medicine.disease ,Free radical scavenger ,Rats ,surgical procedures, operative ,030104 developmental biology ,medicine.anatomical_structure ,Endocrinology ,Regional Blood Flow ,Cerebrovascular Circulation ,Middle cerebral artery ,business ,hormones, hormone substitutes, and hormone antagonists ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Chronic systemic melatonin treatment attenuates abnormalities produced by occlusion of middle cerebral artery (MCA) in adult rats. Because the pineal gland secretes high levels of melatonin, we examined in the present study whether transplantation of pineal gland exerted similar protective effects in MCA-occluded adult rats. Animals underwent same-day MCA occlusion and either intrastriatal transplantation of pineal gland (harvested from 2-month-old rats) or vehicle infusion. Behavioral tests (from day of surgery to 3 days posttransplantation) revealed that transplanted stroke rats displayed significantly less motor asymmetrical behaviors than vehicle-infused stroke rats. Histological analysis at 3 days posttransplantation revealed that transplanted stroke rats had significantly smaller cerebral infarction than vehicle-infused rats. Additional experiments showed that pinealectomy affected transplantation outcome, in that transplantation of pineal gland only protected against stroke-induced deficits in stroke animals with intact pineal gland, but not in pinealectomized stroke rats. Interestingly, nonpinealectomized vehicle-infused stroke rats, as well as pinealectomized transplanted stroke rats, had significantly lower melatonin levels in the cerebrospinal fluid than nonpinealectomized transplanted stroke rats. We conclude that intracerebral transplantation of pineal gland, in the presence of host intact pineal gland, protected against stroke, possibly through secretion of melatonin.
- Published
- 2003
25. Cyclosporine-A Increases Spontaneous and Dopamine Agonist-Induced Locomotor Behavior in Normal Rats
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Thomas B. Freeman, David W. Cahill, Theresa Scorcia, Warren C. Olanow, Cesario V. Borlongan, Kathleen A. Sherman, and Paul R. Sanberg
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Dopamine ,Biomedical Engineering ,lcsh:Medicine ,Striatum ,Dopamine agonist ,Rats, Sprague-Dawley ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Animals ,Amphetamine ,Transplantation ,Behavior, Animal ,business.industry ,Olfactory tubercle ,lcsh:R ,Dystrophy ,Cell Biology ,Corpus Striatum ,Motor coordination ,Rats ,030104 developmental biology ,Endocrinology ,Anesthesia ,Dopamine Agonists ,Cyclosporine ,business ,030217 neurology & neurosurgery ,Locomotion ,medicine.drug - Abstract
Cyclosporine-A (CsA) has been increasingly used as an immunosuppressant concomitant with neural transplantation treatment for different degenerative disorders. However, the possible role that CsA itself may have in the recovery of transplant patients is not known. Some investigators have argued that clinical improvement following transplantation (e.g., myoblast) may be confounded by CsA administration. The present study was conducted to delineate CsA-induced behavioral alterations. Four groups of normal 5-wk old Sprague-Dawley rats (n = 8 per group) were utilized in two separate experiments. In both experiments, two groups of animals were used; each group either received daily injections of 15 mg/kg of CsA or olive oil for 32 days (experiment 1) and 21 days (experiment 2). Animals in both experiments were subsequently tested for nocturnal locomotor behavior. Animals in experiment 2 were further tested in passive avoidance task, motor coordination, and amphetamine-induced locomotor activity. Results demonstrated that CsA-treated animals were significantly hyperactive compared to controls across the 12-h nocturnal activity periods and in amphetamine-induced locomotor activity. No significant differences between the CsA- and vehicle-treated animals were observed in passive avoidance or in motor coordination. Postmortem analyses of dopamine and its metabolites in the striatum and olfactory tubercle did not show any significant differences between the CsA- and the vehicle-treated groups. In summary, CsA significantly increased nocturnal spontaneous and amphetamine-induced locomotor behavior, but the neurochemical correlates for these effects need to be investigated. In addition, while the present study demonstrated that CsA induced motor alterations, any possible effects CsA may have on neurological or dystrophic patients with motor dysfunctions remain to be determined.
- Published
- 1995
26. Lovastatin Inhibits RhoA to Suppress Canonical Wnt/β-Catenin Signaling and Alternative Wnt-YAP/TAZ Signaling in Colon Cancer.
- Author
-
Xiao Y, Liu Q, Peng N, Li Y, Qiu D, Yang T, Kang R, Usmani A, Amadasu E, Borlongan CV, and Yu G
- Subjects
- Animals, Humans, Lovastatin pharmacology, Lovastatin therapeutic use, Mice, Wnt Signaling Pathway, YAP-Signaling Proteins, rhoA GTP-Binding Protein metabolism, rhoA GTP-Binding Protein pharmacology, Colonic Neoplasms drug therapy, beta Catenin metabolism
- Abstract
Statins are first-line drugs used to control patient lipid levels, but there is recent evidence that statin treatment can lower colorectal cancer (CRC) incidence by 50% and prolong CRC patient survival through mechanisms that are poorly understood. In this study, we found that the treatment of APC
min mice by the mevalonate pathway inhibitor lovastatin significantly reduced the number of colonic masses and improved hypersplenism and peripheral anemia. Furthermore, reverse transcription polymerase chain reaction (RT-PCR) analysis of colonic mass tissues showed a potent inhibitory effect in both Wnt/β-catenin signaling and YAP/TAZ signaling in the lovastatin treatment group. The results of our transcriptomic analyses in RKO indicated that lovastatin regulated several proliferation-related signaling pathways. Moreover, lovastatin suppressed important genes and proteins related to the canonical Wnt/β-catenin and alternative Wnt-YAP/TAZ signaling pathways in RKO and SW480 cells, and these effects were rescued by mevalonic acid (MVA), as confirmed through a series of Western blotting, RT-PCR, and reporter assays. Given that statins suppress oncogenic processes primarily through the inhibition of Rho GTPase in the mevalonate pathway, we speculate that lovastatin can inhibit certain Rho GTPases to suppress both canonical Wnt/β-catenin signaling and alternative Wnt-YAP/TAZ signaling. In RKO cells, lovastatin showed similar inhibitory properties as the RhoA inhibitor CCG1423, being able to inhibit β-catenin, TAZ, and p-LATS1 protein activity. Our results revealed that lovastatin inhibited RhoA activity, thereby suppressing the downstream canonical Wnt/β-catenin and alternative Wnt-YAP/TAZ pathways in colon cancer cells. These inhibitory properties suggest the promise of statins as a treatment for CRC. Altogether, the present findings support the potential clinical use of statins in non-cardiovascular contexts and highlight novel targets for anticancer treatments.- Published
- 2022
- Full Text
- View/download PDF
27. Effects of Lovastatin on Brain Cancer Cells.
- Author
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Amadasu E, Kang R, Usmani A, and Borlongan CV
- Subjects
- Brain metabolism, Humans, Lovastatin pharmacology, Lovastatin therapeutic use, Mevalonic Acid metabolism, Mevalonic Acid pharmacology, Brain Neoplasms drug therapy, Hydroxymethylglutaryl-CoA Reductase Inhibitors pharmacology, Hydroxymethylglutaryl-CoA Reductase Inhibitors therapeutic use
- Abstract
Although brain tumors occur less frequently than other forms of cancer, they have one of the bleakest prognoses with low survival rates. The conventional treatment for brain tumors includes surgery, radiotherapy, and chemotherapy. However, resistance to treatment remains a problem with recurrence shortly following. The resistance to treatment may be caused by cancer stem cells (CSCs), a subset of brain tumor cells with the affinity for self-renewal and differentiation into multiple cell lineages. An emerging approach to targeting CSCs in brain tumors is through repurposing the lipid-lowering medication, lovastatin. Lovastatin is a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor that impacts the mevalonate pathway. The inhibition of intermediates in the mevalonate pathway affects signaling cascades and oncogenes associated with brain tumor stem cells (BTSC). In this review, we show the possible mechanisms where lovastatin can target BTSC for different varieties of malignant brain tumors.
- Published
- 2022
- Full Text
- View/download PDF
28. Exosomes Derived From Mesenchymal Stem Cells Pretreated With Ischemic Rat Heart Extracts Promote Angiogenesis via the Delivery of DMBT1.
- Author
-
Xiao Y, Zhang Y, Li Y, Peng N, Liu Q, Qiu D, Cho J, Borlongan CV, and Yu G
- Subjects
- Animals, Human Umbilical Vein Endothelial Cells, Humans, Neovascularization, Pathologic, Neovascularization, Physiologic, Proteomics, Rats, Vascular Endothelial Growth Factor A metabolism, Exosomes metabolism, Mesenchymal Stem Cells metabolism, Myocardial Infarction metabolism, Myocardial Infarction therapy
- Abstract
Mesenchymal stem cell-derived exosomes (MSC-Exos) have been shown to promote angiogenesis. Treating MSCs with ischemic rat brain extracts was sufficient to augment their benefits in stroke. However, no similar analyses of ischemic heart extracts have been performed to date. We aim to determine whether MSC-Exos derived from MSCs pretreated with ischemic rat heart extract were able to promote angiogenesis and to clarify underlying mechanisms. ELISA (enzyme-linked immunosorbent assay) of heart extracts revealed a significant increase of vascular endothelial growth factor (VEGF) at 24 h post-MI (myocardial infarction) modeling, and time-dependent decreases in hypoxia inducible factor-1α (HIF-1α). MTT and wound healing assays revealed human umbilical vein endothelial cells (HUVECs) migration and proliferation increased following MSC
E -Exo treatment (exosomes derived from MSC pretreated with ischemic heart extracts of 24 h post-MI) relative to MSCN -Exo treatment (exosomes derived from MSC pretreated with normal heart extracts). Proteomic analyses of MSCE -Exo and MSCN -Exo were conducted to screen for cargo proteins promoting angiogenesis. Result revealed several angiogenesis-related proteins were upregulated in MSCE -Exo, including DMBT1 (deleted in malignant brain tumors 1). When DMBT1 was silenced in MSCs, HUVECs with MSCDMBT1 RNAi -Exo treatment exhibited impaired proliferative and migratory activity and reductions of DMBT1, p-Akt, β-catenin, and VEGF. To explore how ischemic heart extracts took effects, ELISA was conducted showing a significant increase of IL-22 at 24 h post-MI modeling. P-STAT3, IL22RA1, DMBT1, and VEGF proteins were increased in MSCE relative to MSCN , and VEGF and DMBT1 were increased in MSCE -Exos. Together, these suggest that IL-22 upregulation in ischemic heart extracts can increase DMBT1 in MSCs. Exosomes derived from those MSCs deliver DMBT1 to HUVECs, thereby enhancing their migratory and proliferative activity.- Published
- 2022
- Full Text
- View/download PDF
29. Advancing Stem Cell Therapy for Repair of Damaged Lung Microvasculature in Amyotrophic Lateral Sclerosis.
- Author
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Garbuzova-Davis S, Shell R, Mustafa H, Hailu S, Willing AE, Sanberg PR, and Borlongan CV
- Subjects
- Animals, Humans, Lung pathology, Spinal Cord pathology, Amyotrophic Lateral Sclerosis therapy, Microvessels pathology, Motor Neurons metabolism, Stem Cell Transplantation
- Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal disease of motor neuron degeneration in the brain and spinal cord. Progressive paralysis of the diaphragm and other respiratory muscles leading to respiratory dysfunction and failure is the most common cause of death in ALS patients. Respiratory impairment has also been shown in animal models of ALS. Vascular pathology is another recently recognized hallmark of ALS pathogenesis. Central nervous system (CNS) capillary damage is a shared disease element in ALS rodent models and ALS patients. Microvascular impairment outside of the CNS, such as in the lungs, may occur in ALS, triggering lung damage and affecting breathing function. Stem cell therapy is a promising treatment for ALS. However, this therapeutic strategy has primarily targeted rescue of degenerated motor neurons. We showed functional benefits from intravenous delivery of human bone marrow (hBM) stem cells on restoration of capillary integrity in the CNS of an superoxide dismutase 1 (SOD1) mouse model of ALS. Due to the widespread distribution of transplanted cells via this route, administered cells may enter the lungs and effectively restore microvasculature in this respiratory organ. Here, we provided preliminary evidence of the potential role of microvasculature dysfunction in prompting lung damage and treatment approaches for repair of respiratory function in ALS. Our initial studies showed proof-of-principle that microvascular damage in ALS mice results in lung petechiae at the late stage of disease and that systemic transplantation of mainly hBM-derived endothelial progenitor cells shows potential to promote lung restoration via re-established vascular integrity. Our new understanding of previously underexplored lung competence in this disease may facilitate therapy targeting restoration of respiratory function in ALS.
- Published
- 2020
- Full Text
- View/download PDF
30. Genetic and Histological Alterations Reveal Key Role of Prostaglandin Synthase and Cyclooxygenase 1 and 2 in Traumatic Brain Injury-Induced Neuroinflammation in the Cerebral Cortex of Rats Exposed to Moderate Fluid Percussion Injury.
- Author
-
Shojo H, Borlongan CV, and Mabuchi T
- Subjects
- Animals, Antigens, CD metabolism, Antigens, Differentiation, Myelomonocytic metabolism, Brain Injuries, Traumatic complications, Brain Injuries, Traumatic enzymology, Cell Shape, Cerebral Cortex enzymology, Glial Fibrillary Acidic Protein metabolism, Inflammation complications, Inflammation enzymology, Male, Neuroglia enzymology, Neuroglia pathology, Neurons enzymology, Neurons pathology, Rats, Wistar, Brain Injuries, Traumatic genetics, Brain Injuries, Traumatic pathology, Cerebral Cortex pathology, Cyclooxygenase 1 metabolism, Cyclooxygenase 2 metabolism, Inflammation genetics, Inflammation pathology, Percussion, Prostaglandin-Endoperoxide Synthases metabolism
- Abstract
After the initial insult in traumatic brain injury (TBI), secondary neurodegeneration occurs that is intimately associated with neuroinflammation. Prostaglandin (PG) synthases and cyclooxygenase (COX) 1 and 2 may contribute to inflammation in the brain. Temporal and spatial expression features of PG and COX1 and 2 following trauma may guide the development of antineuroinflammation strategies. Here, we examined PG synthase signaling and COX1 and 2 gene expression levels and COX-1- and 2-positive cell types and their temporal localization in TBI-induced brain in an effort to reveal their participation in the disease's evolving neuroinflammation. Using brain samples from the cerebral cortex of rats subjected to TBI model of lateral moderate fluid percussion injury (FPI), we sought to characterize the temporal (subacute TBI) and spatial (lateral cortical lesion) brain alterations accompanying the disease progression. Temporal gene expression changes of PG synthase signaling were compared between sham-operated and TBI-treated rats using microarray pathway analysis. Moreover, we examined COX1 and 2 expression patterns and their intracellular distribution in sham-operated and TBI-treated rats by immunohistochemistry. After FPI, COX1 and 2 gene expression levels, and PGE
2 synthase increased while PGD2 synthase decreased, suggesting that PGE2 and PGD2 afforded contraindicative effects of inflammation and anti-inflammation, respectively. Immunohistochemical analyses showed that both COX1 and COX2 increased in a time-dependent manner in the brain, specifically in degenerating neurons of the cortex. Interestingly, the expression of COX cell type was cell-specific, in that COX1 was particularly increased in degenerating neurons while COX2 was expressed in macrophages. In view of the dynamic temporal and spatial expression of PG, COX1 and 2 gene expression and localization in the injured brain regulating PG synthase and COX1 and 2 activity will require a careful disease-specific tailoring of treatments to abrogate the neuroinflammation-plagued secondary cell death due to TBI.- Published
- 2017
- Full Text
- View/download PDF
31. Extracardiac-Lodged Mesenchymal Stromal Cells Propel an Inflammatory Response Against Myocardial Infarction via Paracrine Effects.
- Author
-
Peng Y, Pan W, Ou Y, Xu W, Kaelber S, Borlongan CV, Sun M, and Yu G
- Subjects
- Animals, Heart physiopathology, Humans, Macrophages metabolism, Neovascularization, Physiologic physiology, Cell- and Tissue-Based Therapy methods, Inflammation immunology, Macrophages immunology, Mesenchymal Stem Cell Transplantation methods, Mesenchymal Stem Cells cytology, Myocardial Infarction therapy
- Abstract
Transplantation of stem cells, including mesenchymal stromal cells (MSCs), improves the recovery of cardiac function after myocardial infarction (MI) in experimental studies using animal models and in patients. However, the improvement of cardiac function following MSC transplantation remains suboptimal in both preclinical and clinical studies. Understanding the mechanism of cell therapy may improve its therapeutic outcomes, but the mode of action mediating stem cell promotion of cardiac repair is complex and not fully understood. Recent studies suggest that the immunomodulatory effects of MSCs on the macrophage M1/M2 subtype transition allow the transplanted stem cells to inhibit inflammation-induced injury and promote cardiac repair in acute MI. However, equally compelling evidence shows that there is poor survival and minimal graft persistence of transplanted MSCs within the infarcted heart tissues, negating the view that graft survival per se is required for the observed high rate and long duration of the transition from proinflammatory M1 to reparative M2 macrophages in the infarcted myocardium. Therefore, we raised a novel hypothesis that the therapeutic effects of MSC transplantation for acute MI depends not primarily on the grafted cells in infarct myocardium, but that MSCs migrating to and being lodged in the extracardiac organs, demonstrating good graft survival and persistence, may render the therapeutic effects in MI. More specifically, MSC transplantation promotes the transition from M1 to M2 in extracardiac organs, such as spleen and bone marrow, and therapeutic effects are conferred to the infarcted myocardium via paracrine effects. In MSC transplantation, the conversion from proinflammatory M1 to anti-inflammatory M2 monocytes may occur remotely from the heart and may serve as one of the major pathways in regulating the dual effects of inflammation. This hypothesis, if proven valid, may represent an important new mechanism of action to be considered for the future of MSC transplantation in the treatment of MI.
- Published
- 2016
- Full Text
- View/download PDF
32. Safety and Feasibility of Remote Limb Ischemic Preconditioning in Patients With Unilateral Middle Cerebral Artery Stenosis and Healthy Volunteers.
- Author
-
Li S, Ma C, Shao G, Esmail F, Hua Y, Jia L, Qin J, Ren C, Luo Y, Ding Y, Borlongan CV, and Ji X
- Subjects
- Adult, Aged, Blood Flow Velocity, Blood Pressure, Constriction, Pathologic, Female, Healthy Volunteers, Heart Rate, Hemodynamics, Humans, Male, Middle Aged, Oxygen Consumption, Reperfusion, Ultrasonography, Doppler, Transcranial, Extremities blood supply, Ischemic Preconditioning, Middle Cerebral Artery physiology
- Abstract
Previous studies have indicated a neuroprotective effect of remote limb ischemic preconditioning. The aim of the present study was to assess whether upper arm ischemic preconditioning is feasible and safe in patients with unilateral middle cerebral artery (MCA) stenosis compared to healthy volunteers. Ten patients with unilateral MCA stenosis and 24 healthy volunteers underwent limb ischemic preconditioning, consisting of five cycles of 5-min inflations of a blood pressure cuff to 200 mmHg around an upper limb followed by 5 min of reperfusion. Limb ischemic preconditioning has no significant effect on the heart rate, oxygenation index, or mean flow velocity in patients with unilateral MCA stenosis or healthy volunteers. However, healthy volunteers showed a reduction in blood pressure 30 min following reperfusion of the last cycle. Limb ischemic preconditioning was found to be safe and well tolerated in both patients and healthy volunteers. We highlight the potential of limb ischemic preconditioning as an adjunct to neuroprotective treatment.
- Published
- 2015
- Full Text
- View/download PDF
33. Suppression of astrocyte lineage in adult hippocampal progenitor cells expressing hippocampal cholinergic neurostimulating Peptide precursor in an in vivo ischemic model.
- Author
-
Toyoda T, Matsukawa N, Sagisaka T, Uematsu N, Kanamori T, Kato D, Mizuno M, Wake H, Hida H, Borlongan CV, and Ojika K
- Subjects
- Animals, Astrocytes metabolism, Brain Ischemia metabolism, Cell Differentiation physiology, Cell Growth Processes physiology, Cell Lineage, Disease Models, Animal, Doublecortin Protein, Female, Immunohistochemistry, Male, Neural Stem Cells metabolism, Rats, Rats, Sprague-Dawley, Astrocytes cytology, Brain Ischemia pathology, Neural Stem Cells cytology, Phosphatidylethanolamine Binding Protein biosynthesis
- Abstract
Hippocampal cholinergic neurostimulating peptide (HCNP) is known to promote differentiation of septohippocampal cholinergic neurons. The HCNP precursor protein (HCNP-pp) may play several roles, for example, as an ATP-binding protein, a Raf kinase inhibitor protein, and a phosphatidylethanolamine-binding protein, as well as a precursor for HCNP. This study therefore aimed to elucidate the involvement of HCNP-pp in specific neural lineages after stroke using a hypoxic-ischemic (HI) rat model of brain ischemia. The specific neural lineages in the hippocampus were investigated 14 days after ischemia. Some bromodeoxyuridine (BrdU)(+) neural progenitor cells in the hippocampus of hypoxic, HI, or sham-operated rats expressed HCNP-pp. Almost half of the BrdU(+)/HCNP-pp(+) cells also expressed the oligodendrocyte lineage marker 2',3'-cyclic nucleotide 3'-phosphodiesterase, whereas only a few BrdU(+)/HCNP-pp(+) cells in the hippocampus in HI brains expressed the neuronal lineage marker, doublecortin (DCX). Interestingly, no BrdU(+)/HCNP-pp(+) progenitor cells in hypoxic, HI, or sham-operated brains expressed the astrocyte lineage marker, glial fibrillary acidic protein. Together with previous in vitro data, the results of this study suggest that the expression level of HCNP-pp regulates the differentiation of neural progenitor cells into specific neural lineages in the HI hippocampus, indicating that neural stem cell fate can be controlled via the HCNP-pp mediating pathway.
- Published
- 2012
- Full Text
- View/download PDF
34. Striatal stimulation nurtures endogenous neurogenesis and angiogenesis in chronic-phase ischemic stroke rats.
- Author
-
Morimoto T, Yasuhara T, Kameda M, Baba T, Kuramoto S, Kondo A, Takahashi K, Tajiri N, Wang F, Meng J, Ji YW, Kadota T, Maruo T, Kinugasa K, Miyoshi Y, Shingo T, Borlongan CV, and Date I
- Subjects
- Animals, Behavior, Animal, Brain blood supply, Brain physiopathology, Brain Ischemia metabolism, Brain Ischemia pathology, Chronic Disease, Disease Models, Animal, Electrodes, Glial Cell Line-Derived Neurotrophic Factor metabolism, Magnetic Resonance Imaging, Male, Rats, Rats, Wistar, Stroke metabolism, Stroke pathology, Vascular Endothelial Growth Factor A metabolism, Brain Ischemia therapy, Deep Brain Stimulation, Neovascularization, Physiologic physiology, Neurogenesis, Stroke therapy
- Abstract
Deep brain stimulation (DBS) is used to treat a variety of neurological disorders including Parkinson's disease. In this study, we explored the effects of striatal stimulation (SS) in a rat model of chronic-phase ischemic stroke. The stimulation electrode was implanted into the ischemic penumbra at 1 month after middle cerebral artery occlusion (MCAO) and thereafter continuously delivered SS over a period of 1 week. Rats were evaluated behaviorally coupled with neuroradiological assessment of the infarct volumes using magnetic resonance imaging (MRI) at pre- and post-SS. The rats with SS showed significant behavioral recovery in the spontaneous activity and limb placement test compared to those without SS. MRI visualized that SS also significantly reduced the infarct volumes compared to that at pre-SS or without SS. Immunohistochemical analyses revealed a robust neurogenic response in rats that received SS characterized by a stream of proliferating cells from the subventricular zone migrating to and subsequently differentiating into neurons in the ischemic penumbra, which exhibited a significant GDNF upregulation. In tandem with this SS-mediated neurogenesis, enhanced angiogenesis was also recognized as revealed by a significant increase in VEGF levels in the penumbra. These results provide evidence that SS affords neurorestoration at the chronic phase of stroke by stimulating endogenous neurogenesis and angiogenesis.
- Published
- 2011
- Full Text
- View/download PDF
35. Who's in favor of translational cell therapy for stroke: STEPS forward please?
- Author
-
Chopp M, Steinberg GK, Kondziolka D, Lu M, Bliss TM, Li Y, Hess DC, and Borlongan CV
- Subjects
- Academies and Institutes, Animals, Clinical Trials as Topic standards, Drug Evaluation, Preclinical standards, Humans, National Institutes of Health (U.S.), Private Sector, Stem Cell Transplantation, United States, United States Food and Drug Administration, Cell- and Tissue-Based Therapy, Stroke therapy, Translational Research, Biomedical organization & administration
- Abstract
A consortium of translational stem cell and stroke experts from multiple academic institutes and biotechnology companies, under the guidance of the government (FDA/NIH), is missing. Here, we build a case for the establishment of this consortium if cell therapy for stroke is to advance from the laboratory to the clinic.
- Published
- 2009
- Full Text
- View/download PDF
36. Transplants of encapsulated rat choroid plexus cells exert neuroprotection in a rodent model of Huntington's disease.
- Author
-
Borlongan CV, Thanos CG, Skinner SJ, Geaney M, and Emerich DF
- Subjects
- Alginates, Animals, Capsules, Corpus Striatum pathology, Glucuronic Acid, Hexuronic Acids, Huntington Disease chemically induced, Huntington Disease pathology, Male, Motor Activity, Nerve Degeneration chemically induced, Nerve Degeneration therapy, Neurons pathology, Quinolinic Acid, Rats, Rats, Wistar, Choroid Plexus cytology, Epithelial Cells transplantation, Huntington Disease therapy
- Abstract
Choroid plexus (CP) epithelial cells secrete several neurotrophic factors and have been used in transplantation studies designed to impart neuroprotection against central nervous system (CNS) trauma. In the present study, CP was isolated from adult rats, encapsulated within alginate microcapsules, and transplanted unilaterally into the rat striatum. Three days later, unilateral injections of quinolinic acid (QA; 225 nmol) were made into the ipsilateral striatum to mimic the pathology observed in Huntington's disease (HD). After surgery, animals were tested for motor function using the placement test. Rats receiving CP transplants were significantly less impaired on this test. Nissl-stained sections demonstrated that CP transplants significantly reduced the volume of the striatal lesion produced by QA. Quantitative analysis of striatal neurons further demonstrated that choline acetyltransferase-immunoreactive, but not diaphorase-positive, neurons were protected by CP transplants. These data demonstrate that transplanted CP cells can be used to protect striatal neurons from excitotoxic damage and that the pattern of neuroprotection varies across specific neuronal populations.
- Published
- 2008
37. Transplants of Encapsulated Rat Choroid Plexus Cells Exert Neuroprotection in a Rodent Model of Huntington's Disease.
- Author
-
Borlongan CV, Thanos CG, Skinner SJM, Geaney M, and Emerich DF
- Abstract
Choroid plexus (CP) epithelial cells secrete several neurotrophic factors and have been used in transplantation studies designed to impart neuroprotection against central nervous system (CNS) trauma. In the present study, CP was isolated from adult rats, encapsulated within alginate microcapsules, and transplanted unilaterally into the rat striatum. Three days later, unilateral injections of quinolinic acid (QA; 225 nmol) were made into the ipsilateral striatum to mimic the pathology observed in Huntington's disease (HD). After surgery, animals were tested for motor function using the placement test. Rats receiving CP transplants were significantly less impaired on this test. Nissl-stained sections demonstrated that CP transplants significantly reduced the volume of the striatal lesion produced by QA. Quantitative analysis of striatal neurons further demonstrated that choline acetyltransferase-immunoreactive, but not diaphorase-positive, neurons were protected by CP transplants. These data demonstrate that transplanted CP cells can be used to protect striatal neurons from excitotoxic damage and that the pattern of neuroprotection varies across specific neuronal populations.
- Published
- 2007
- Full Text
- View/download PDF
38. Transplantation of bone marrow-derived stem cells: a promising therapy for stroke.
- Author
-
Tang Y, Yasuhara T, Hara K, Matsukawa N, Maki M, Yu G, Xu L, Hess DC, and Borlongan CV
- Subjects
- Animals, Humans, Multipotent Stem Cells cytology, Pluripotent Stem Cells cytology, Bone Marrow Cells cytology, Stem Cell Transplantation, Stroke therapy
- Abstract
Stroke remains a major cause of death in the US and around the world. Over the last decade, stem cell therapy has been introduced as an experimental treatment for stroke. Transplantation of stem cells or progenitors into the injured site to replace the nonfunctional cells, and enhancement of proliferation or differentiation of endogenous stem or progenitor cells stand as the two major cell-based strategies. Potential sources of stem/progenitor cells for stroke include fetal neural stem cells, embryonic stem cells, neuroteratocarcinoma cells, umbilical cord blood-derived nonhematopoietic stem cells, and bone marrow-derived stem cells. The goal of this article is to provide an update on the preclinical use of bone marrow-derived stem cells with major emphasis on mesenchymal stem cells (MSCs) and multipotent adult progenitor cells (MAPCs) because they are currently most widely applied in experimental stroke studies and are now being phased into early clinical trials. The phenotypic features of MSCs and MAPCs, as well as their application in stroke, are described.
- Published
- 2007
39. A role of the choroid plexus in transplantation therapy.
- Author
-
Emerich DF, Skinner SJ, Borlongan CV, and Thanos CG
- Subjects
- Aging, Animals, Brain physiology, Brain physiopathology, Brain Diseases physiopathology, Central Nervous System physiology, Central Nervous System physiopathology, Cerebrospinal Fluid physiology, Choroid Plexus cytology, Choroid Plexus physiology, Humans, Neurodegenerative Diseases physiopathology, Neurodegenerative Diseases surgery, Brain Diseases surgery, Brain Tissue Transplantation methods, Choroid Plexus surgery
- Abstract
The choroid plexuses (CPs) play pivotal roles in the most basic aspects of neural function. Some of the roles of the CP include maintaining the extracellular milieu of the brain by actively modulating chemical exchange between the CSF and brain parenchyma, surveying the chemical and immunological status of the brain, detoxifying the brain, secreting a nutritive "cocktail" of polypeptides, and participating in repair processes following trauma. This diversity of functions suggests that even modest changes in the CP can have far reaching effects. Indeed, changes in the anatomy and physiology of the CP have been linked to several CNS diseases. It is also possible that replacing diseased CP or transplanting healthy CP might be useful for treating acute and chronic brain diseases. Here we describe the wide-ranging functions of the CP, alterations of these functions in aging and neurodegeneration, and recent demonstrations of the therapeutic potential of transplanted CP for neural trauma.
- Published
- 2005
- Full Text
- View/download PDF
40. Transplantation of fetal kidney cells: neuroprotection and neuroregeneration.
- Author
-
Chiang YH, Borlongan CV, Zhou FC, Hoffer BJ, and Wang Y
- Subjects
- Animals, Bone Morphogenetic Proteins metabolism, Bone Morphogenetic Proteins pharmacology, Bone Morphogenetic Proteins physiology, Brain Injuries metabolism, Brain Injuries prevention & control, Glial Cell Line-Derived Neurotrophic Factor, Humans, Kidney metabolism, Nerve Growth Factors metabolism, Nerve Growth Factors pharmacology, Nerve Growth Factors physiology, Neuroprotective Agents pharmacology, Parkinson Disease therapy, Rats, Stroke therapy, Cell Transplantation physiology, Fetal Tissue Transplantation physiology, Kidney cytology, Nerve Degeneration prevention & control, Nerve Regeneration physiology
- Abstract
Various trophic factors in the transforming growth factor-beta (TGF-beta) superfamily have been reported to have neuroprotective and neuroregenerative effects. Intracerebral administration of glial cell line-derived neurotrophic factor (GDNF) or bone morphogenetic proteins (BMPs), both members of the TGF-beta family, reduce ischemia- or 6-hydroxydopamine (6-OHDA)-induced injury in adult rat brain. Because BMPs and GDNF are highly expressed in fetal kidney cells, transplantation of fetal kidney tissue could serve as a cellular reservoir for such molecules and protect against neuronal injury induced by ischemia, neurotoxins, or reactive oxygen species. In this review, we discuss preclinical evidence for the efficacy of fetal kidney cell transplantation in neuroprotection and regeneration models.
- Published
- 2005
- Full Text
- View/download PDF
41. Neural transplantation in the new millenium.
- Author
-
Borlongan CV and Sanberg PR
- Subjects
- Animals, Cell Transplantation statistics & numerical data, Fetal Tissue Transplantation statistics & numerical data, Humans, Periodicals as Topic, Transplantation, Heterologous statistics & numerical data, Cell Transplantation methods, Cell Transplantation trends, Nervous System
- Published
- 2002
42. T155g-immortalized kidney cells produce growth factors and reduce sequelae of cerebral ischemia.
- Author
-
Dillon-Carter O, Johnston RE, Borlongan CV, Truckenmiller ME, Coggiano M, and Freed WJ
- Subjects
- Animals, Antibodies immunology, Antigens, Polyomavirus Transforming metabolism, Behavior, Animal physiology, Cell Line, Cell Line, Transformed, Cell Transplantation, Cerebral Cortex surgery, Disease Models, Animal, Fetal Tissue Transplantation, Glial Cell Line-Derived Neurotrophic Factor, Humans, Infarction, Middle Cerebral Artery physiopathology, Kidney Cortex embryology, Kidney Cortex metabolism, Male, Motor Activity, Neuroprotective Agents metabolism, Rats, Rats, Sprague-Dawley, Stroke physiopathology, Transfection, Antigens, Polyomavirus Transforming genetics, Growth Substances metabolism, Infarction, Middle Cerebral Artery surgery, Kidney Cortex cytology, Nerve Growth Factors metabolism, Stroke surgery
- Abstract
Fetal rat kidney cells produce high levels of glial-derived neurotrophic factor (GDNF) and exert neuroprotective effects when transplanted into the brain in animal models of Parkinson's disease and stroke. The purpose of the present experiment was to produce kidney cell lines that secrete GDNF. Genes encoding two truncated N-terminal fragments of SV40 large T antigen, T155g and T155c, which does not code for small t antigen, were used. T155g was transduced into E17 cultured fetal Sprague-Dawley rat kidney cortex cells using a plasmid vector, and T155c was transduced with a plasmid and a retroviral vector. Sixteen clones were isolated from cultures transfected with the T155g-expressing plasmid. No cell lines were obtained with T155c. Four clones produced GDNF at physiological concentrations ranging from 55 to 93 pg/ml of medium. These four clones were transplanted into the ischemic core or penumbra of rats that had undergone middle cerebral artery occlusion (MCAO). Three of the four clones reduced the volume of infarction and the behavioral abnormalities normally resulting from MCAO. Blocking experiments with antibodies to GDNF and platelet-derived growth factor (PDGF) suggested that these growth factors contributed only minimally to the reduction in infarct volume and behavioral abnormality. These cell lines may be useful for intracerebral transplantation in animal models of brain injury, stroke, or Parkinson's disease.
- Published
- 2002
43. MICROTRANSPLANTATION OF NIGRAL DOPAMINE NEURONS IN A RAT MODEL OF PARKINSON'S DISEASE.
- Author
-
Borlongan CV and Sanberg PR
- Published
- 1995
- Full Text
- View/download PDF
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