Publications by authors named "Yuji Kaneko"

102 Publications

Rhynchophylline promotes stem cell autonomous metabolic homeostasis.

Cytotherapy 2020 02 24;22(2):106-113. Epub 2020 Jan 24.

Center of Excellence for Aging and Brain, Department of Neurosurgery and Brain Repair, University of South Florida College of Medicine, Tampa Florida, USA. Electronic address:

Rhynchophylline (Rhy) effectively obstructs the expansive signaling pathways of degenerative diseases, including Alzheimer disease, Parkinson disease, epilepsy and amyotrophic lateral sclerosis, and stimulates neurogenesis. Maintenance of stemness and cell proliferation requires sophisticated intracellular environments to achieve pluripotency via specific expression of genes and proteins. We examined whether Rhy promotes this regulation in bone marrow human mesenchymal stromal cells (BM-hMSCs). Results revealed (i) Rhy modulated biological activity by regulating the mitochondria, N-methyl-D-aspartate receptor subunit, and levels of FGFβ (basic fibroblast growth factor), BDNF (brain-derived neurotrophic factor), OXTR (oxytocin receptor) and ATP (Adenosine triphosphate); (ii) Rhy altered expression level of BM-MSC proliferation/differentiation-related transcription genes; and (iii) interestingly, Rhy amplified the glycolytic flow ratio and lactate dehydrogenase activity while reducing pyruvate dehydrogenase activity, indicating a BM-hMSC metabolic shift of mitochondrial oxidative phosphorylation into aerobic glycolysis. Altogether, we demonstrated a novel mechanism of action for Rhy-induced BM-hMSC modification, which can enhance the cell transplantation approach by amplifying the metabolic activity of stem cells.
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http://dx.doi.org/10.1016/j.jcyt.2019.12.008DOI Listing
February 2020

Translating intracarotid artery transplantation of bone marrow-derived NCS-01 cells for ischemic stroke: Behavioral and histological readouts and mechanistic insights into stem cell therapy.

Stem Cells Transl Med 2020 02 18;9(2):203-220. Epub 2019 Nov 18.

Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida College of Medicine, Tampa, Florida.

The present study used in vitro and in vivo stroke models to demonstrate the safety, efficacy, and mechanism of action of adult human bone marrow-derived NCS-01 cells. Coculture with NCS-01 cells protected primary rat cortical cells or human neural progenitor cells from oxygen glucose deprivation. Adult rats that were subjected to middle cerebral artery occlusion, transiently or permanently, and subsequently received intracarotid artery or intravenous transplants of NCS-01 cells displayed dose-dependent improvements in motor and neurological behaviors, and reductions in infarct area and peri-infarct cell loss, much better than intravenous administration. The optimal dose was 7.5 × 10 cells/mL when delivered via the intracarotid artery within 3 days poststroke, although therapeutic effects persisted even when administered at 1 week after stroke. Compared with other mesenchymal stem cells, NCS-01 cells ameliorated both the structural and functional deficits after stroke through a broad therapeutic window. NCS-01 cells secreted therapeutic molecules, such as basic fibroblast growth factor and interleukin-6, but equally importantly we observed for the first time the formation of filopodia by NCS-01 cells under stroke conditions, characterized by cadherin-positive processes extending from the stem cells toward the ischemic cells. Collectively, the present efficacy readouts and the novel filopodia-mediated mechanism of action provide solid lab-to-clinic evidence supporting the use of NCS-01 cells for treatment of stroke in the clinical setting.
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http://dx.doi.org/10.1002/sctm.19-0229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6988762PMC
February 2020

Selective endovascular cooling for stroke entails brain-derived neurotrophic factor and splenic IL-10 modulation.

Brain Res 2019 11 12;1722:146380. Epub 2019 Aug 12.

Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, 12901 Bruce B. Downs Blvd., Tampa, FL 33612, USA. Electronic address:

Stroke poses a serious health and economic burden, and the lack of treatment options necessitates a viable therapy. Hypothermia represents a promising stroke therapy, yet side effects of full-body cooling, such as pneumonia, limit its clinical application. Selective endovascular cooling (SEC), via infusion of cold saline through the intraarterial artery, represents an attractive alternative by locally cooling the brain while preserving body temperature. However, the mechanisms underlying SEC are poorly understood. Brain-derived neurotrophic factor (BDNF) is a widely recognized promotor of neuroplasticity and biomarker of stroke outcomes, as well as its association with inflammation, such as IL-10. Stroke-induced neuroinflammation exacerbates damage and stems from peripheral organs, namely the spleen. The spleen has emerged as a therapeutic target for stroke, yet the effect of SEC on the splenic inflammatory response is unknown. Here, we aimed to elucidate the local and peripheral mechanisms driving SEC as a neuroprotective stroke therapy by examining brain BDNF and splenic IL-10 expression. Animals that received SEC prior to stroke displayed elevated brain BDNF expression ipsilaterally and contralaterally across the cortex, striatum, and hippocampus. SEC also upregulated splenic IL-10, suggesting alteration of the peripheral inflammatory response. The oxygen-glucose deprivation in vitro model of stroke further demonstrated that "cold" rat splenocytes protected rat primary neurons by upregulating BDNF and IL-10. Altogether these data support BDNF- and IL-10-based mechanisms underlying the neuroprotective potential of SEC therapy for stroke, and further advance the concept of exploiting the pathological link between brain and spleen as therapeutic targets.
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http://dx.doi.org/10.1016/j.brainres.2019.146380DOI Listing
November 2019

Empathy in stroke rats is modulated by social settings.

J Cereb Blood Flow Metab 2020 06 1;40(6):1182-1192. Epub 2019 Aug 1.

Center of Excellence for Aging and Brain Repair, Department of Neurosurgery, USF Morsani College of Medicine, Tampa, FL, USA.

Rodents display "empathy" defined as perceived physical pain or psychological stress by cagemates when co-experiencing socially distinct traumatic events. The present study tested the hypothesis that empathy occurs in adult rats subjected to an experimental neurological disorder, by allowing co-experience of stroke with cagemates. Psychological stress was measured by general locomotor activity, Rat Grimace Scale (RGS), and plasma corticosterone. Physiological correlates were measured by Western blot analysis of advanced glycation endproducts (AGE)-related proteins in the thymus. General locomotor activity was impaired in stroke animals and in non-stroke rats housed with stroke rats suggesting transfer of behavioral manifestation of psychological stress from an injured animal to a non-injured animal leading to social inhibition. RGS was higher in stroke rats regardless of social settings. Plasma corticosterone levels at day 3 after stroke were significantly higher in stroke animals housed with stroke rats, but not with non-stroke rats, indicating that empathy upregulated physiological stress level. The expression of five proteins related to AGE in the thymus reflected the observed pattern of general locomotor activity, RGS, and plasma corticosterone levels. These results indicate that stroke-induced psychological stress manifested on both the behavioral and physiological levels and appeared to be affected by empathy-associated social settings.
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http://dx.doi.org/10.1177/0271678X19867908DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7238373PMC
June 2020

48-hour interruption of agitation: effect on quality of washed PLT suspended in BRS-A.

Transfusion 2019 07;59(7):2477-2478

Central Blood Institute, Japanese Red Cross Society, Tokyo, Japan.

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http://dx.doi.org/10.1111/trf.15299DOI Listing
July 2019

T-Regulatory Cells Confer Increased Myelination and Stem Cell Activity after Stroke-Induced White Matter Injury.

J Clin Med 2019 Apr 19;8(4). Epub 2019 Apr 19.

Center of Excellence for Aging and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, FL 33612, USA.

Stroke-induced hypoxia causes oligodendrocyte death due to inflammation, lack of oxygen and exacerbation of cell death. Bone marrow-derived stem cells (BMSCs) possess an endogenous population of T-regulatory cells (T) which reduce secretion of pro-inflammatory cytokines that lead to secondary cell death. Here, we hypothesize that oligodendrocyte progenitor cells (OPCs) cultured with BMSCs containing their native T population show greater cell viability, less pro-inflammatory cytokine secretion and greater myelin production after exposure to oxygen-glucose deprivation and reoxygenation (OGD/R) than OPCs cultured without T. OPCs were cultured and then exposed to OGD/R. BMSCs with or without T were added to the co-culture immediately after ischemia. The T were depleted by running the BMSCs through a column containing a magnetic substrate. Fibroblast growth factor beta (FGF-β) and interleukin 6 (IL-6) ELISAs determined BMSC activity levels. Immunohistochemistry assessed OPC differentiation. OPCs cultured with BMSCs containing their endogenous T showed increased myelin production compared to the BMSCs with depleted T. IL-6 and FGF-β were increased in the group cultured with T. Collectively, these results suggest that BMSCs containing T are more therapeutically active, and that T have beneficial effects on OPCs subjected to ischemia. T play an important role in stem cell therapy and can potentially treat white matter injury post-stroke.
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http://dx.doi.org/10.3390/jcm8040537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518209PMC
April 2019

Endothelial Progenitor Cells Modulate Inflammation-Associated Stroke Vasculome.

Stem Cell Rev Rep 2019 04;15(2):256-275

Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, 12901 Bruce B. Downs Blvd., Tampa, FL, 33612, USA.

Stroke remains a major unmet clinical need that warrants novel therapies. Following an ischemic insult, the cerebral vasculature secretes inflammatory molecules, creating the stroke vasculome profile. The present study evaluated the therapeutic effects of endothelial cells on the inflammation-associated stroke vasculome. qRT-PCR analysis revealed that specific inflammation-related vasculome genes BRM, IκB, Foxf1, and ITIH-5 significantly upregulated by oxygen glucose deprivation (OGD. Interestingly, co-culture of human endothelial cells (HEN6) with human endothelial cells (EPCs) during OGD significantly blocked the elevations of BRM, IκB, and Foxf1, but not ITIH-5. Next, employing the knockdown/antisense technology, silencing the inflammation-associated stroke vasculome gene, IκB, as opposed to scrambled knockdown, blocked the EPC-mediated protection of HEN6 against OGD. In vivo, stroke animals transplanted with intracerebral human EPCs (300,000 cells) into the striatum and cortex 4 h post ischemic stroke displayed significant behavioral recovery up to 30 days post-transplantation compared to vehicle-treated stroke animals. At 7 days post-transplantation, quantification of the fluorescent staining intensity in the cortex and striatum revealed significant upregulation of the endothelial marker RECA1 and a downregulation of the stroke-associated vasculome BRM, IKB, Foxf1, ITIH-5 and PMCA2 in the ipsilateral side of cortex and striatum of EPC-transplanted stroke animals relative to vehicle-treated stroke animals. Altogether, these results demonstrate that EPCs exert therapeutic effects in experimental stroke possibly by modulating the inflammation-plagued vasculome.
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http://dx.doi.org/10.1007/s12015-019-9873-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6441406PMC
April 2019

Central and Peripheral Secondary Cell Death Processes after Transient Global Ischemia in Nonhuman Primate Cerebellum and Heart.

Methods Mol Biol 2019 ;1919:215-225

Department of Neurosurgery and Brain Repair, Center of Excellence for Aging and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, FL, USA.

Cerebral ischemia and its pathological sequelae are responsible for severe neurological deficits generally attributed to the neural death within the infarcted tissue and adjacent regions. Distal brain regions, and even peripheral organs, may be subject to more subtle consequences of the primary ischemic event which can initiate parallel disease processes and promote comorbid symptomology. In order to characterize the susceptibility of cerebellar brain regions and the heart to transient global ischemia (TGI) in nonhuman primates (NHP), brain and heart tissues were harvested 6 months post-TGI injury. Immunostaining analysis with unbiased stereology revealed significant cell death in lobule III and IX of the TGI cerebellum when compared to sham cerebellum, coinciding with an increase in inflammatory and apoptotic markers. Cardiac tissue analysis showed similar increases in inflammatory and apoptotic cells within TGI hearts. A progressive inflammatory response and cell death within the cerebellum and heart of chronic TGI NHPs indicate secondary injury processes manifesting both centrally and peripherally. This understanding of distal disease processes of cerebral ischemia underscores the importance of the chronic aberrant inflammatory response and emphasizes the needs for therapeutic options tailored to target these pathways. Here, we discuss the protocols for characterizing the histopathological effects of transient global ischemia in nonhuman primate cerebellum and heart, with an emphasis on the inflammatory and apoptotic cell death processes.
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http://dx.doi.org/10.1007/978-1-4939-9007-8_17DOI Listing
June 2019

Neuroprotective effects of human bone marrow mesenchymal stem cells against cerebral ischemia are mediated in part by an anti-apoptotic mechanism.

Neural Regen Res 2019 Apr;14(4):597-604

Department of Neurosurgery and Brain Repair, Center of Excellence for Aging and Brain Repair, University of South Florida, Tampa, FL, USA.

Transplantation of human bone marrow mesenchymal stem cells (hMSCs) stands as a potent stroke therapy, but its exact mechanism remains unknown. This study investigated the anti-apoptotic mechanisms by which hMSCs exert neuroprotective effects on cerebral ischemia. Primary mixed cultures of rat neurons and astrocytes were cultured and exposed to oxygen-glucose deprivation. A two-hour period of "reperfusion" in standard medium and normoxic conditions was allowed and immediately followed by hMSCs and/or Bcl-2 antibody treatment. Cell viability of primary rat neurons and astrocytes was determined by 3-(4,5-dimethylthianol-2-yl)-2,5 diphenyl tetrazolium bromide and trypan blue exclusion methods. hMSC survival and differentiation were characterized by immunocytochemistry, while the concentration of Bcl-2 in the supernatant was measured by enzyme-linked immunosorbent assay to reveal the secretory anti-apoptotic function of hMSCs. Cultured hMSCs expressed embryonic-like stem cell phenotypic markers CXCR4, Oct4, SSEA4, and Nanog, as well as immature neural phenotypic marker Nestin. Primary rat neurons and astrocytes were protected from oxygen-glucose deprivation by hMSCs, which was antagonized by the Bcl-2 antibody. However, Bcl-2 levels in the supernatants did not differ between hMSC- and non-treated cells exposed to oxygen-glucose deprivation. Neuroprotective effects of hMSCs against cerebral ischemia were partially mediated by the anti-apoptotic mechanisms. However, further studies are warranted to fully elucidate this pathway.
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http://dx.doi.org/10.4103/1673-5374.247464DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6352592PMC
April 2019

β-Eudesmol, an Oxygenized Sesquiterpene, Reduces the Increase in Saliva 3-Methoxy-4-Hydroxyphenylglycol After the "Trier Social Stress Test" in Healthy Humans: A Randomized, Double-Blind, Placebo-Controlled Cross-Over Study.

Nutrients 2018 Dec 20;11(1). Epub 2018 Dec 20.

Department of Psychology, Kurume University, 1635 Mii-machi, Kurume, Fukuoka 839-8502, Japan.

Hops, the immature inflorescences of the female hop plant ( L.) are one of the main components of beer and provides flavor and bitterness. β-Eudesmol, an oxygenated sesquiterpene, is reported to accumulate in a particular hop cultivar. Recently, we revealed that β-Eudesmol ingestion affected autonomic nerve activity in an animal model. The effect on humans has not been elucidated, therefore, we investigated the effects of β-Eudesmol on reducing objective and subjective markers related to sympathetic nerve activity after the application of mental stress in healthy participants. Fifty participants (male and female aged 20 to 50 years) were randomly assigned to two groups. Five minutes before taking the Trier Social Stress Test (TSST) as a mental stressor, participants in each group ingested a beverage containing β-Eudesmol, the active beverage, or a placebo beverage that did not contain β-Eudesmol. Saliva 3-methoxy-4-hydroxyphenylglycol (MHPG), a major product of noradrenaline breakdown and a representative marker of sympathetic nerve activity, was significantly lower just after the TSST in the active group compared with the placebo group. Saliva cortisol, a marker of the endocrine stress response system, was not significantly different between the two groups. No adverse events related to test beverage ingestion were observed. This is the first experimental evidence of β-Eudesmol effect for mental stress in human.
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http://dx.doi.org/10.3390/nu11010009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6356403PMC
December 2018

Human stem cells transplanted into the rat stroke brain migrate to the spleen via lymphatic and inflammation pathways.

Haematologica 2019 05 4;104(5):1062-1073. Epub 2018 Dec 4.

Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida College of Medicine, Tampa, FL, USA

Despite mounting evidence of a massive peripheral inflammatory response accompanying stroke, the ability of intracerebrally transplanted cells to migrate to the periphery and sequester systemic inflammation remains unexamined. Here, we tested the hypothesis that human bone marrow mesenchymal stromal cells intracerebrally transplanted in the brain of adult rats subjected to experimental stroke can migrate to the spleen, a vital organ that confers peripheral inflammation after stroke. Sham or experimental stroke was induced in adult Sprague-Dawley rats by a 1 hour middle cerebral artery occlusion model. One hour after surgery, rats were intracerebrally injected with human bone marrow mesenchymal stromal cells (3×10/9 μL), then euthanized on day 1, 3, or 7 for immunohistochemical assays. Cell migration assays were performed for human bone marrow mesenchymal stromal cells using Boyden chambers with the bottom plate consisting of microglia, lymphatic endothelial cells, or both, and treated with different doses of tumor necrosis factor-α. Plates were processed in a fluorescence reader at different time points. Immunofluorescence microscopy on different days after the stroke revealed that stem cells engrafted in the stroke brain but, interestingly, homed to the spleen via lymphatic vessels, and were propelled by inflammatory signals. Experiments using human bone marrow mesenchymal stromal cells co-cultured with lymphatic endothelial cells or microglia, and treated with tumor necrosis factor-α, further indicated the key roles of the lymphatic system and inflammation in directing stem cell migration. This study is the first to demonstrate brain-to-periphery migration of stem cells, advancing the novel concept of harnessing the lymphatic system in mobilizing stem cells to sequester peripheral inflammation as a brain repair strategy.
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http://dx.doi.org/10.3324/haematol.2018.206581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518907PMC
May 2019

Pituitary Adenylate Cyclase Activating Polypeptide Elicits Neuroprotection Against Acute Ischemic Neuronal Cell Death Associated with NMDA Receptors.

Cell Physiol Biochem 2018 4;51(4):1982-1995. Epub 2018 Dec 4.

Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida College of Medicine, Tampa, Florida,

Background/aims: The endogenous neurotrophic peptides pituitary adenylate cyclase-activating polypeptides (PACAP-27/38) protect against stroke, but the molecular mechanism remains unknown.

Methods: Primary rat neural cells were exposed to PACAP-27 or PACAP-38 before induction of experimental acute ischemic stroke via oxygen-glucose deprivation-reperfusion (OGD/R) injury. To reveal PACAP's role in neuroprotection, we employed fluorescent live/dead cell viability and caspase 3 assays, optical densitometry of mitochondrial dehydrogenase and cell growth, glutathione disulfide luciferase activity, ELISA for high mobility group box1 extracellular concentration, ATP bioluminescence, Western blot analysis of PACAP, NMDA subunits, apoptosis regulator Bcl-2, social interaction hormone oxytocin, and trophic factor BDNF, and immunocytochemical analysis of PACAP.

Results: Both PACAP-27 and PACAP-38 (PACAP-27/38) increased cell viability, decreased oxidative stress-induced cell damage, maintained mitochondrial activity, prevented the release of high mobility group box1, and reduced cytochrome c/caspase 3-induced apoptosis. PACAP-27/38 increased the protein expression levels of BDNF, Bcl-2, oxytocin, and precursor PACAP. N-methyl-D-aspartate receptor (NMDAR)-induced excitotoxicity contributes to the cell death associated with stroke. PACAP-27/38 modulated the protein expression levels of NMDAR subunits. PACAP-27/38 increased the protein expression levels of the GluN1 subunit, and decreased that of the GluN2B and GluN2D subunits. PACAP-27, but not PACAP-38, increased the expression level of the GluN2C subunit.

Conclusion: This study provides evidence that PACAP regulated NMDAR subunits, affording neuroprotection after OGD/R injury.
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http://dx.doi.org/10.1159/000495722DOI Listing
January 2019

The relationship between the effect of matured hop extract and physical activity on reducing body fat: re-analysis of data from a randomized, double-blind, placebo-controlled parallel group study.

Nutr J 2018 10 30;17(1):98. Epub 2018 Oct 30.

Research Laboratories for Health Science and Food Technologies, Kirin Co., Ltd. 1-13-5, Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan.

Background: We recently reported that successive ingestion of matured hop extract (MHE), produced by oxidation of hops, results in a reduction of body fat in healthy overweight participants. A combined effect of MHE and physical activity on body fat has not been investigated. Thus, we re-analyzed data from the previous study to explore the relationship between the effect of MHE and walking as an index of physical activity.

Methods: This analysis uses existing data from a randomized, double-blind, placebo-controlled parallel group study in which MHE (active) or placebo was given for 12 w to 200 healthy overweight Japanese, from May to December 2014. Correlation between the change in abdominal fat areas at 12 w and the number of steps taken per day was tested by Spearman's correlation coefficient test. The subjects were stratified using the average number of steps per day of Japanese into walking less and walking more subgroups (WL and WM, respectively) as follows: placebo (WL, n = 43; WM, n = 44) and active (WL, n = 49; WM, n = 42). Reductions in total, visceral, and subcutaneous fat area (TFA, VFA and SFA, respectively) were evaluated. The interaction effect between ingestion (active/placebo) and walking (WL/WM) was analyzed using two-way analysis of variance (ANOVA).

Results: There was a significant negative correlation between the change in VFA and daily steps taken in the active group (r = - 0.208, P = 0.048). No significant correlation in TFA or SFA. Although the interaction effect in TFA was not significant, the main effect of ingestion was significant (P = 0.045). In contrast, the interaction effect in VFA was suggested to be synergistic (P = 0.055).

Conclusion: The results suggested that MHE ingestion combined with light intensity exercise would induce a greater reduction in VFA which would be beneficial for obese or overweight individuals in reducing obesity and obesity-related diseases.

Trial Registration: UMIN-CTR UMIN000014185 registered 6 June 2014.
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http://dx.doi.org/10.1186/s12937-018-0405-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6208082PMC
October 2018

May the force be with you: Transfer of healthy mitochondria from stem cells to stroke cells.

J Cereb Blood Flow Metab 2019 02 30;39(2):367-370. Epub 2018 Oct 30.

2 Department of Molecular Biosciences, University of California Davis, Davis, CA, USA.

Stroke is a major cause of death and disability in the United States and around the world with limited therapeutic option. Here, we discuss the critical role of mitochondria in stem cell-mediated rescue of stroke brain by highlighting the concept that deleting the mitochondria from stem cells abolishes the cells' regenerative potency. The application of innovative approaches entailing generation of mitochondria-voided stem cells as well as pharmacological inhibition of mitochondrial function may elucidate the mechanism underlying transfer of healthy mitochondria to ischemic cells, thereby providing key insights in the pathology and treatment of stroke and other brain disorders plagued with mitochondrial dysfunctions.
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http://dx.doi.org/10.1177/0271678X18811277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6365599PMC
February 2019

Regulatory T-cells within bone marrow-derived stem cells actively confer immunomodulatory and neuroprotective effects against stroke.

J Cereb Blood Flow Metab 2019 09 23;39(9):1750-1758. Epub 2018 Mar 23.

1 Department of Neurosurgery and Brain Repair, Center of Excellence for Aging and Brain Repair, USF Morsani College of Medicine, Tampa, FL, USA.

Regulatory T-cells (T) may exert a neuroprotective effect on ischemic stroke by inhibiting both inflammation and effector T-cell activation. Transplantation of human bone marrow-derived stem cells (BMSCs) in ischemic stroke affords neuroprotection that results in part from the cells' anti-inflammatory property. However, the relationship between T and BMSCs in treatment of ischemic stroke has not been fully elucidated. Here, we tested the hypothesis that T within the BMSCs represent active mediators of immunomodulation and neuroprotection in experimental stroke. Primary rat neuronal cells were subjected to an oxygen-glucose deprivation and reperfusion (OGD/R) condition. The cells were re-perfused and co-cultured with T and/or BMSCs. We detected a minority population of T within BMSCs with both immunocytochemistry (ICC) and flow cytometry identifying cells expressing phenotypic markers of CD4, CD25, and FoxP3 protein. BMSCs with the native population of T conferred maximal neuroprotection compared to the treatment conditions containing 0%, 10%, and 100% relative ratio T. Increasing the T population resulted in increased IL6 secretion and decreased FGF-β secretion by BMSCs. This study shows that a minority population of T exists within the therapeutic BMSC population, which serves as robust mediators of the immunomodulatory and neuroprotective effect provided by BMSC transplantation.
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http://dx.doi.org/10.1177/0271678X18766172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6727132PMC
September 2019

Histopathological and Behavioral Assessments of Aging Effects on Stem Cell Transplants in an Experimental Traumatic Brain Injury.

Methods Mol Biol 2019 ;2045:299-310

Center of Excellence for Aging & Brain Repair, Morsani College of Medicine, University of South Florida, 12901 Bruce B. Downs Blvd., MDC 78, Tampa, FL, 33612, USA.

Traumatic brain injury (TBI) displays cognitive and motor symptoms following the initial injury which can be exacerbated by secondary cell death. Aging contributes significantly to the morbidity of TBI, with higher rates of negative neurological and behaviors outcomes. In the recent study, young and aged animals were injected intravenously with human adipose-derived mesenchymal stem cells (hADSCs) (Tx), conditioned media (CM), or vehicle (unconditioned media) following TBI. The beneficial effects of hADSCs were analyzed using various molecular and behavioral techniques. More specially, DiR-labeled hADSCs were used to observe the biodistribution of the transplanted cells. In addition, a battery of behavior tests was conducted to evaluate the neuromotor function for each treatment group and various regions of the brain were analyzed utilizing Nissl, hematoxylin and eosin (H&E), and human nuclei (HuNu) staining. Finally, flow cytometry was also performed to determine the levels of various proteins in the spleen. Here, we discuss the protocols for characterizing the histopathological and behavioral effects of transplanted stem cells in an animal model of TBI, with an emphasis on the role of aging in the therapeutic outcomes.
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http://dx.doi.org/10.1007/7651_2018_121DOI Listing
April 2020

Translating regenerative medicine techniques for the treatment of epilepsy.

Brain Circ 2017 Jul-Sep;3(3):156-162. Epub 2017 Oct 12.

Department of Neurosurgery and Brain Repair, USF Morsani College of Medicine, Tampa, FL 33612, USA.

Epilepsy is considered a chronic neurological disorder and is accompanied by persistent and diverse disturbances in electrical brain activity. While antiepileptic pharmaceuticals are still the predominant treatment for epilepsy, the advent of numerous surgical interventions has further improved outcomes for patients. Despite these advancements, a subpopulation continues to experience intractable seizures which are resistant to current conventional and nonconventional therapeutic options. In this review, we begin with an introduction to the clinical presentation of epilepsy before discussing the clinically relevant laboratory models of epilepsy. Finally, we explore the implications of regenerative medicine - including cell therapy, neuroprotective agents, and electrical stimulation - for epilepsy, supplemented with our laboratory's data. This paper is a review article. Referred literature in this paper has been listed in the references section. The datasets supporting the conclusions of this article are available online by searching various databases, including PubMed. Some original points in this article come from the laboratory practice in our research center and the authors' experiences.
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http://dx.doi.org/10.4103/bc.bc_21_17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6057691PMC
October 2017

Extracellular HMGB1 Modulates Glutamate Metabolism Associated with Kainic Acid-Induced Epilepsy-Like Hyperactivity in Primary Rat Neural Cells.

Cell Physiol Biochem 2017 20;41(3):947-959. Epub 2017 Feb 20.

Background/aims: Neuroinflammatory processes have been implicated in the pathophysiology of seizure/epilepsy. High mobility group box 1 (HMGB1), a non-histone DNA binding protein, behaves like an inflammatory cytokine in response to epileptogenic insults. Kainic acid (KA) is an excitotoxic reagent commonly used to induce epilepsy in rodents. However, the molecular mechanism by which KA-induced HMGB1 affords the initiation of epilepsy, especially the role of extracellular HMGB1 in neurotransmitter expression, remains to be elucidated.

Methods: Experimental early stage of epilepsy-related hyperexcitability was induced in primary rat neural cells (PRNCs) by KA administration. We measured the localization of HMGB1, cell viability, mitochondrial activity, and expression level of glutamate metabolism-associated enzymes.

Results: KA induced the translocation of HMGB1 from nucleus to cytosol, and its release from the neural cells. The translocation is associated with post-translational modifications. An increase in extracellular HMGB1 decreased PRNC cell viability and mitochondrial activity, downregulated expression of glutamate decarboxylase67 (GAD67) and glutamate dehydrogenase (GLUD1/2), and increased intracellular glutamate concentration and major histocompatibility complex II (MHC II) level.

Conclusions: That a surge in extracellular HMGB1 approximated seizure initiation suggests a key pathophysiological contribution of HMGB1 to the onset of epilepsy-related hyperexcitability.
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http://dx.doi.org/10.1159/000460513DOI Listing
June 2017

NSI-189, a small molecule with neurogenic properties, exerts behavioral, and neurostructural benefits in stroke rats.

J Cell Physiol 2017 Oct 25;232(10):2731-2740. Epub 2017 Apr 25.

Department of Neurosurgery and Brain Repair, Center of Excellence for Aging and Brain Repair, University South Florida College of Medicine, Tampa, Florida.

Enhancing neurogenesis may be a powerful stroke therapy. Here, we tested in a rat model of ischemic stroke the beneficial effects of NSI-189, an orally active, new molecular entity (mol. wt. 366) with enhanced neurogenic activity, and indicated as an anti-depressant drug in a clinical trial (Fava et al., , Molecular Psychiatry, DOI: 10.1038/mp.2015.178) and being tested in a Phase 2 efficacy trial (ClinicalTrials.gov, , ClinicalTrials.gov Identifier: NCT02695472) for treatment of major depression. Oral administration of NSI-189 in adult Sprague-Dawley rats starting at 6 hr after middle cerebral artery occlusion, and daily thereafter over the next 12 weeks resulted in significant amelioration of stroke-induced motor and neurological deficits, which was maintained up to 24 weeks post-stroke. Histopathological assessment of stroke brains from NSI-189-treated animals revealed significant increments in neurite outgrowth as evidenced by MAP2 immunoreactivity that was prominently detected in the hippocampus and partially in the cortex. These results suggest NSI-189 actively stimulated remodeling of the stroke brain. Parallel in vitro studies further probed this remodeling process and demonstrated that oxygen glucose deprivation and reperfusion (OGD/R) initiated typical cell death processes, which were reversed by NSI-189 treatment characterized by significant attenuation of OGD/R-mediated hippocampal cell death and increased Ki67 and MAP2 expression, coupled with upregulation of neurogenic factors such as BDNF and SCF. These findings support the use of oral NSI-189 as a therapeutic agent well beyond the initial 6-hr time window to accelerate and enhance the overall functional improvement in the initial 6 months post stroke.
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http://dx.doi.org/10.1002/jcp.25847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5518191PMC
October 2017

pH-gradient ion-exchange microbial cell chromatography as a simple method for microbial separation.

J Biosci Bioeng 2017 Apr 4;123(4):431-436. Epub 2016 Dec 4.

Department of Life Science and Medical Bio-Science, Waseda University, Shinjuku-ku, Tokyo 162-8480, Japan.

Selective separation of specific microbial types from a heterogeneous microbial population, such as an environmental microbial community, is an important process for microbial research and biotechnological industries. In the present study, pH-gradient ion-exchange microbial cell chromatography (PIE-MCC) was developed as a new method for microbial separation. The proposed method enables target microorganisms to be separated from a microbial community based on differences in microbial surface characteristics, because these characteristics, such as the ζ (zeta)-potential, vary among microbial cells. PIE-MCC was conducted by controlling the adhesion and detachment of microbial cells to and from the carrier surface by manipulating the pH of the running buffer. As a proof of concept, microbial cell separation via PIE-MCC was demonstrated using pure-cultured strains, model mixtures of two different pure-cultured strains, and an environmental sample targeting uncultivated microorganisms; i.e., each pure-cultured strain showed unique chromatograms; specific single species were separated from the model mixture; and a specific, uncultivated target was separated from the environmental sample. The ζ-potential of several tested strains suggested that not only electrostatic interactions, but also other factors affected microbial adhesion to the carrier surface. The newly developed method has several potential advantages compared with other techniques, not only in terms of its microbial separation capability, but also in terms of its simplicity and ability to be scaled up. Thus, the method has the potential to be widely used for a variety of purposes in the microbiology and biotechnology fields.
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http://dx.doi.org/10.1016/j.jbiosc.2016.10.012DOI Listing
April 2017

Oxytocin modulates GABAR subunits to confer neuroprotection in stroke in vitro.

Sci Rep 2016 10 21;6:35659. Epub 2016 Oct 21.

Center of Excellence for Aging and Brain, Department of Neurosurgery and Brain Repair, University of South Florida College of Medicine, 12901 Bruce B Downs Blvd, Tampa FL 33612, USA.

Oxytocin protects against ischemia-induced inflammation and oxidative stress, and is associated with GABA (γ-aminobutyric acid, an inhibitory neurotransmitter) signaling transduction in neurons. However, the molecular mechanism by which oxytocin affords neuroprotection, especially the interaction between oxytocin receptor and GABA receptor (GABAR), remains to be elucidated. Primary rat neural cells were exposed to oxytocin before induction of experimental acute stroke model via oxygen-glucose deprivation-reperfusion (OGD/R) injury. Pretreatment with oxytocin increased cell viability, decreased the cell damage against oxidative stress, and prevented the release of high mobility group box1 during OGD/R. However, introduction of oxytocin during OGD/R did not induce neuroprotection. Although oxytocin did not affect the glutathione-related cellular metabolism before OGD, oxytocin modulated the expression levels of GABAR subunits, which function to remove excessive neuronal excitability via chloride ion influx. Oxytocin-pretreated cells significantly increased the chloride ion influx in response to GABA and THIP (δ-GABAR specific agonist). This study provides evidence that oxytocin regulated GABAR subunits in affording neuroprotection against OGD/R injury.
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http://dx.doi.org/10.1038/srep35659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5073361PMC
October 2016

Increased Amyloid Precursor Protein and Tau Expression Manifests as Key Secondary Cell Death in Chronic Traumatic Brain Injury.

J Cell Physiol 2017 Mar 19;232(3):665-677. Epub 2016 Oct 19.

Department of Neurosurgery and Brain Repair, Center of Excellence for Aging and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, Florida.

In testing the hypothesis of Alzheimer's disease (AD)-like pathology in late stage traumatic brain injury (TBI), we evaluated AD pathological markers in late stage TBI model. Sprague-Dawley male rats were subjected to moderate controlled cortical impact (CCI) injury, and 6 months later euthanized and brain tissues harvested. Results from H&E staining revealed significant 33% and 10% reduction in the ipsilateral and contralateral hippocampal CA3 interneurons, increased MHCII-activated inflammatory cells in many gray matter (8-20-fold increase) and white matter (6-30-fold increased) regions of both the ipsilateral and contralateral hemispheres, decreased cell cycle regulating protein marker by 1.6- and 1-fold in the SVZ and a 2.3- and 1.5-fold reductions in the ipsilateral and contralateral dentate gyrus, diminution of immature neuronal marker by two- and onefold in both the ipsilateral and contralateral SVZ and dentate gyrus, and amplified amyloid precursor protein (APP) distribution volumes in white matter including corpus callosum, fornix, and internal capsule (4-38-fold increase), as well as in the cortical gray matter, such as the striatum hilus, SVZ, and dentate gyrus (6-40-fold increase) in TBI animals compared to controls (P's < 0.001). Surrogate AD-like phenotypic markers revealed a significant accumulation of phosphorylated tau (AT8) and oligomeric tau (T22) within the neuronal cell bodies in ipsilateral and contralateral cortex, and dentate gyrus relative to sham control, further supporting the rampant neurodegenerative pathology in TBI secondary cell death. These findings indicate that AD-like pathological features may prove to be valuable markers and therapeutic targets for late stage TBI. J. Cell. Physiol. 232: 665-677, 2017. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/jcp.25629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5484295PMC
March 2017

Cyclosporine A Treatment Abrogates Ischemia-Induced Neuronal Cell Death by Preserving Mitochondrial Integrity through Upregulation of the Parkinson's Disease-Associated Protein DJ-1.

CNS Neurosci Ther 2016 07 1;22(7):602-10. Epub 2016 Jun 1.

Center of Excellence for Aging & Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, FL, USA.

Aims: Hypoxic-ischemia alters mitochondrial membrane potential (Δψm), respiratory-related enzymes, and mitochondrial DNA (mtDNA). Drugs acting on mitochondria, such as cyclosporine A (CsA), may reveal novel mitochondria-based cell death signaling targets for stroke. Our previous studies showed that Parkinson's disease-associated protein DJ-1 participates in the acute endogenous neuroprotection after stroke via mitochondrial pathway. DJ-1 was detected immediately after stroke and efficiently translocated into the mitochondria offering a new venue for developing treatment strategies against stroke. Here, we examined a molecular interaction between CsA and mitochondrial integrity in the in vitro acute stroke model of oxygen glucose deprivation/reperfusion (OGD/R) injury with emphasis on DJ-1.

Methods: Primary rat neuronal cells (PRNCs) were exposed to OGD/R injury and processed for immunocytochemistry, ELISA, and mitochondria-based molecular assays to reveal the role of DJ-1 in CsA modulation of mitochondrial integrity.

Results: Administration of CsA before stroke onset (24 h pre-OGD/R) afforded significantly much more robust neuroprotective effects than when CsA was initiated after stroke (2 h post-OGD/R), revealing that CsA exerted neuroprotection in the early phase of ischemic stroke. CsA prevented the mitochondria-dependent cell death signaling pathway involved in cytochrome c (Cyt c)-induced intrinsic apoptotic process. CsA preserved cellular ATP content, but not hexokinase activity under hypoxic conditions. CsA prevented both mtDNA decrement and Δψm degradation after reperfusion, and enhanced secretion of DJ-1 in the mitochondria, coupled with reduced oxidative stress.

Conclusion: These observations provided evidence that CsA maintained mitochondrial integrity likely via DJ-1 upregulation, supporting the concept that mitochondria-based treatments targeting the early phase of disease progression may prove beneficial in stroke.
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http://dx.doi.org/10.1111/cns.12546DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5189675PMC
July 2016

Detrimental effects of physical inactivity on neurogenesis.

Brain Circ 2016 Apr-Jun;2(2):80-85. Epub 2016 Jul 13.

Department of Neurosurgery and Brain Repair, University of South Florida, Tampa, FL, USA.

Patients diagnosed with neurological disorders exhibit a variety of physical and psychiatric symptoms, including muscle atrophy, general immobility, and depression. Patients who participate in physical rehabilitation at times show unexpected clinical improvement, which includes diminished depression and other stress-related behaviors. Regenerative medicine has advanced two major stem cell-based therapies for central nervous system (CNS) disorders, transplantation of exogenous stem cells, and enhancing the endogenous neurogenesis. The latter therapy utilizes a natural method of re-innervating the injured brain, which may mend neurological impairments. In this study, we examine how inactivity-induced atrophy, using the hindlimb suspension model, alters neurogenesis in rats. The hypothesis is that inactivity inhibits neurogenesis by decreasing circulation growth or trophic factors, such as vascular endothelial growth or neurotrophic factors. The restriction modifies neurogenesis and stem cell differentiation in the CNS, the stem cell microenvironment is examined by the trophic and growth factors, including stress-related proteins. Despite growing evidence revealing the benefits of "increased" exercise on neurogenesis, the opposing theory involving "physical inactivity," which simulates pathological states, continues to be neglected. This novel theory will allow us to explore the effects on neurogenesis by an intransigent stem cell microenvironment likely generated by inactivity. 5-bromo-2-deoxyuridine labeling of proliferative cells, biochemical assays of serum, cerebrospinal fluid, and brain levels of trophic factors, growth factors, and stress-related proteins are suggested identifiers of neurogenesis, while evaluation of spontaneous movements will give insight into the psychomotor effects of inactivity. Investigations devised to show how stimulation, or lack thereof, affects the stem cell microenvironment are necessary to establish treatment methods to boost neurogenesis in bedridden patients.
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http://dx.doi.org/10.4103/2394-8108.186278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6126252PMC
July 2016

Matured hop extract reduces body fat in healthy overweight humans: a randomized, double-blind, placebo-controlled parallel group study.

Nutr J 2016 Mar 9;15:25. Epub 2016 Mar 9.

Fukushima Healthcare Center, Kensyokai Medical Corporation, 2-12-16, Tamakawa, Fukushima-ku, Osaka, 553-0004, Japan.

Background: Hops are the main components of beer that provide flavor and bitterness. Iso-α-acids, the bitter components of beer, have been reported to reduce body fat in humans, but the bitterness induced by effective doses of iso-α-acids precludes their acceptance as a nutrient. The matured hop bitter acids (MHBA) of oxidized hops appear to have a more pleasant bitterness compared to the sharper bitterness of iso-α-acids. While there has been little information concerning the identity of the MHBA compounds and their physiological effects, MHBA was recently found to be primarily composed of oxides derived from α-acids, and structurally similar to iso-α-acids. Here, we investigated the effects of matured hop extract (MHE) containing MHBA on reducing abdominal body fat in healthy subjects with a body mass index (BMI) of 25 to below 30 kg/m(2), classified as "obese level 1" in Japan or as "overweight" by the WHO.

Trial Design: A randomized, double-blind, placebo-controlled parallel group study.

Methods: Two hundred subjects (male and female aged 20 to below 65 years with a BMI of 25 or more and less than 30 kg/m(2)) were randomly assigned to two groups. During a 12-week ingestion period, the subjects in each group ingested daily 350 mL of test-beverage, either containing MHE (with 35 mg MHBA), i.e. the namely active beverage, or a placebo beverage without MHE. The primary endpoint was reduction of the abdominal fat area as determined by CT scanning after continual ingestion of MHE for 12 weeks.

Results: Compared to the placebo group, a significant reduction was observed in the visceral fat area after 8 and 12 w, and in the total fat area after 12 w in the active group. There was also a concomitant decrease in body fat ratio in the active group compared to the placebo group. No adverse events related to the test beverages or clinically relevant abnormal changes in the circulatory, blood and urine parameters were observed in either group.

Conclusions: The present study suggests that continual ingestion of MHE safely reduces body fat, particularly the abdominal visceral fat of healthy overweight subjects.

Trial Registration: UMIN-CTR UMIN000014185.
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http://dx.doi.org/10.1186/s12937-016-0144-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4784395PMC
March 2016

Stroke and cardiac cell death: Two peas in a pod.

Clin Neurol Neurosurg 2016 Mar 21;142:145-147. Epub 2016 Jan 21.

University of South Florida, Department of Neurosurgery and Brain Repair, Tampa, FL, USA. Electronic address:

A close pathological link between stroke brain and heart failure may exist. Here, we discuss relevant laboratory and clinical reports demonstrating neural and cardiac myocyte cell death following ischemic stroke. Although various overlapping risk factors exist between cerebrovascular incidents and cardiac incidents, stroke therapy has largely neglected the cardiac pathological consequences. Recent preclinical stroke studies have implicated an indirect cell death pathway, involving toxic molecules, that originates from the stroke brain and produces cardiac cell death. In concert, previous laboratory reports have revealed a reverse cell death cascade, in that cardiac arrest leads to ischemic cell death in the brain. A deeper understanding of the crosstalk of cell death pathways between stroke and cardiac failure will facilitate the development of novel treatments designed to arrest the global pathology of both diseases thereby improving the clinical outcomes of patients diagnosed with stroke and heart failure.
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http://dx.doi.org/10.1016/j.clineuro.2016.01.001DOI Listing
March 2016

A Nuclear Attack on Traumatic Brain Injury: Sequestration of Cell Death in the Nucleus.

CNS Neurosci Ther 2016 Apr 4;22(4):306-15. Epub 2016 Feb 4.

Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, FL, USA.

Background: Exportin 1 (XPO1/CRM1) plays prominent roles in the regulation of nuclear protein export. Selective inhibitors of nuclear export (SINE) are small orally bioavailable molecules that serve as drug-like inhibitors of XPO1, with potent anti-cancer properties. Traumatic brain injury (TBI) presents with a secondary cell death characterized by neuroinflammation that is putatively regulated by nuclear receptors.

Aims And Results: Here, we report that the SINE compounds (KPT-350 or KPT-335) sequestered TBI-induced neuroinflammation-related proteins (NF-(k)B, AKT, FOXP1) within the nucleus of cultured primary rat cortical neurons, which coincided with protection against TNF-α (20 ng/mL)-induced neurotoxicity as shown by at least 50% and 100% increments in preservation of cell viability and cellular enzymatic activity, respectively, compared to non-treated neuronal cells (P's < 0.05). In parallel, using an in vivo controlled cortical impact (CCI) model of TBI, we demonstrate that adult Sprague-Dawley rats treated post-injury with SINE compounds exhibited significant reductions in TBI-induced behavioral and histological deficits. Animals that received KPT-350 orally starting at 2 h post-TBI and once a day thereafter over the next 4 days exhibited significantly better motor coordination, and balance in the rotorod test and motor asymmetry test by 100-200% improvements, as early as 4 h after initial SINE compound injection that was sustained during subsequent KPT-350 dosing, and throughout the 18-day post-TBI study period compared to vehicle treatment (P's < 0.05). Moreover, KPT-350 reduced cortical core impact area and peri-impact cell death compared to vehicle treatment (P's < 0.05).

Conclusions: Both in vitro and in vivo experiments revealed that KPT-350 increased XPO1, AKT, and FOXP1 nuclear expression and relegated NF-(k)B expression within the neuronal nuclei. Altogether, these findings advance the utility of SINE compounds to stop trafficking of cell death proteins within the nucleus as an efficacious treatment for TBI.
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http://dx.doi.org/10.1111/cns.12501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5067638PMC
April 2016

Brain Region-Specific Histopathological Effects of Varying Trajectories of Controlled Cortical Impact Injury Model of Traumatic Brain Injury.

CNS Neurosci Ther 2016 Mar 18;22(3):200-11. Epub 2016 Jan 18.

Department of Neurosurgery and Brain Repair, Morsani College of Medicine, University of South Florida College of Medicine, Tampa, FL, USA.

Aims: Traumatic brain injury (TBI) occurs when the head is impacted by an external force causing either a closed or penetrating head injury through a direct or accelerating impact. In laboratory research, most of the TBI animal models focus on a specific region to cause brain injury, but traumatic injuries in patients do not always impact the same brain regions. The aim of this study was to examine the histopathological effects of different angles of mechanical injury by manipulating the trajectory of the controlled cortical impact injury (CCI) model in adult Sprague-Dawley rats.

Methods: The CCI model was manipulated as follows: conventional targeting of the frontal cortex, farthest right angle targeting the frontal cortex, closest right angle targeting the frontal cortex, olfactory bulb injury, and cerebellar injury. Three days after TBI, brains were harvested to analyze cortical and hippocampal cell loss, neuroinflammatory response, and neurogenesis via immunohistochemistry.

Results: Results revealed cell death in the M1 region of the cortex across all groups, and in the CA3 area from olfactory bulb injury group. This observed cell death involved upregulation of inflammation as evidenced by rampant MHCII overexpression in cortex, but largely spared Ki-67/nestin neurogenesis in the hippocampus during this acute phase of TBI.

Conclusion: These results indicate a trajectory-dependent injury characterized by exacerbation of inflammation and different levels of impaired cell proliferation and neurogenesis. Such multiple brain areas showing varying levels of cell death after region-specific CCI model may closely mimic the clinical manifestations of TBI.
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http://dx.doi.org/10.1111/cns.12485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4849201PMC
March 2016

Enhancing endogenous stem cells in the newborn via delayed umbilical cord clamping.

Neural Regen Res 2015 Sep;10(9):1359-62

Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida College of Medicine, Tampa, FL, USA.

There is currently no consensus among clinicians and scientists over the appropriate or optimal timing for umbilical cord clamping. However, many clinical studies have suggested that delayed cord clamping is associated with various neonatal benefits including increased blood volume, reduced need for blood transfusion, increased cerebral oxygenation in pre-term infants, and decreased frequency of iron deficiency anemia in term infants. Human umbilical cord blood contains significant amounts of stem and progenitor cells and is currently used in the treatment of several life-threatening diseases. We propose that delayed cord clamping be encouraged as it enhances blood flow from the placenta to the neonate, which is accompanied by an increase supply of valuable stem and progenitor cells, as well as may improve blood oxygenation and increase blood volume, altogether reducing the infant's susceptibility to both neonatal and age-related diseases.
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http://dx.doi.org/10.4103/1673-5374.165218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4625484PMC
September 2015

Nutraceutical intervention reverses the negative effects of blood from aged rats on stem cells.

Age (Dordr) 2015 Oct 26;37(5):103. Epub 2015 Sep 26.

Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, MDC-78, USF Morsani College of Medicine, 12901 Bruce B Downs Blvd, Tampa, FL, 33620, USA.

Aging is associated with a decline in function in many of the stem cell niches of the body. An emerging body of literature suggests that one of the reasons for this decline in function is due to cell non-autonomous influences on the niche from the body. For example, studies using the technique of parabiosis have demonstrated a negative influence of blood from aged mice on muscle satellite cells and neurogenesis in young mice. We examined if we could reverse this effect of aged serum on stem cell proliferation by treating aged rats with NT-020, a dietary supplement containing blueberry, green tea, vitamin D3, and carnosine that has been shown to increase neurogenesis in aged rats. Young and aged rats were administered either control NIH-31 diet or one supplemented with NT-020 for 28 days, and serum was collected upon euthanasia. The serum was used in cultures of both rat hippocampal neural progenitor cells (NPCs) and rat bone marrow-derived mesenchymal stem cells (MSCs). Serum from aged rats significantly reduced cell proliferation as measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and 5-bromo-2'-deoxyuridine (BrdU) assays in both NPCs and MSCs. Serum from aged rats treated with NT-020 was not different from serum from young rats. Therefore, NT-020 rescued the effect of serum from aged rats to reduce stem cell proliferation.
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http://dx.doi.org/10.1007/s11357-015-9840-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5005857PMC
October 2015