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Dive into the research topics where Matthew P. Keasey is active.

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Featured researches published by Matthew P. Keasey.


Neurobiology of Disease | 2013

Endogenous CNTF mediates stroke-induced adult CNS neurogenesis in mice

Seong Su Kang; Matthew P. Keasey; Sheila A. Arnold; Rollie Reid; Justin T. Geralds; Theo Hagg

Focal brain ischemia in adult rats rapidly and robustly induces neurogenesis in the subventricular zone (SVZ) but there are few and inconsistent reports in mice, presenting a hurdle to genetically investigate the endogenous neurogenic regulators such as ciliary neurotrophic factor (CNTF). Here, we first provide a platform for further studies by showing that middle cerebral artery occlusion in adult male C57BL/6 mice robustly enhances neurogenesis in the SVZ only under very specific conditions, i.e., 14days after a 30min occlusion. CNTF expression paralleled changes in the number of proliferated, BrdU-positive, SVZ cells. Stroke-induced proliferation was absent in CNTF-/- mice, suggesting that it is mediated by CNTF. MCAO-increased CNTF appears to act on C cell proliferation and by inducing FGF2 expression but not via EGF expression or Notch1 signaling of neural stem cells in the SVZ. CNTF is unique, as expression of other gp130 ligands, IL-6 and LIF, did not predict SVZ proliferation or showed no or only small compensatory increases in CNTF-/- mice. Expression of tumor necrosis factor-α, which can inhibit neurogenesis, and the presence of leukocytes in the SVZ were inversely correlated with neurogenesis, but pro-inflammatory cytokines did not affect CNTF expression in cultured astrocytes. These results suggest that slowly up-regulated CNTF in the SVZ mediates stroke-induced neurogenesis and is counteracted by inflammation. Further pharmacological stimulation of endogenous CNTF might be a good therapeutic strategy for cell replacement after stroke as CNTF regulates normal patterns of neurogenesis and is expressed almost exclusively in the nervous system.


The Journal of Neuroscience | 2012

Loss of Neuron-Astroglial Interaction Rapidly Induces Protective CNTF Expression after Stroke in Mice

Seong Su Kang; Matthew P. Keasey; Jun Cai; Theo Hagg

Ciliary neurotrophic factor (CNTF) is a potent neural cytokine with very low expression in the CNS, predominantly by astrocytes. CNTF increases rapidly and greatly following traumatic or ischemic injury. Understanding the underlying mechanisms would help to design pharmacological treatments to increase endogenous CNTF levels for neuroprotection. Here, we show that astroglial CNTF expression in the adult mouse striatum is increased twofold within 1 h and increases up to >30-fold over 2 weeks following a focal stroke caused by a transient middle cerebral artery occlusion (MCAO). Selective neuronal loss caused by intrastriatal injection of quinolinic acid resulted in a comparable increase. Cocultured neurons reduced CNTF expression in astrocytes, which was prevented by light trypsinization. RGD (arginine-glycine-aspartic acid) blocking peptides induced CNTF expression, which was dependent on transcription. Astroglial CNTF expression was not affected by diffusible neuronal molecules or by neurotransmitters. The transient ischemia does not seem to directly increase CNTF, as intrastriatal injection of an ischemic solution or exposure of naive mice or cultured cells to severe hypoxia had minimal effects. Inflammatory mechanisms were probably also not involved, as intrastriatal injection of proinflammatory cytokines (IFNγ, IL6) in naive mice had no or small effects, and anti-inflammatory treatments did not diminish the increase in CNTF after MCAO. CNTF−/− mice had more extensive tissue loss and similar astrocyte activation after MCAO than their wild-type littermates. These data suggest that contact-mediated integrin signaling between neurons and astrocytes normally represses CNTF expression and that neuronal dysfunction causes a rapid protective response by the CNS.


International Review of Neurobiology | 2013

An update on primary familial brain calcification.

R. R. Lemos; João Ferreira; Matthew P. Keasey; João Ricardo Mendes de Oliveira

Patients with primary familial brain calcifications (PFBC) present bilateral calcifications, often affecting basal ganglia, thalamus, and cerebellum, inherited in an autosomal dominant pattern of segregation. Affected individuals display a wide variety of motor and cognitive impairments such as parkinsonism, dystonia, migraine, dementia, psychosis, and mood symptoms. Worldwide growth in the availability of neuroimaging procedures, combined with careful screening of patients and their relatives, has increased detection of PFBC. Recently, mutations in the SLC20A2 gene coding for the inorganic phosphate transporter PiT2 were linked to PFBC, thereby implicating impaired phosphate transport as an underlying disease mechanism. To date, around 20 families of various ethnicities carry different mutations in SLC20A2 correlate with ~40% of PFBC cases. More recently, two French families were recently reported with mutations in PDGFRB: c.1973T>C, p.L658P and c.2959C>T, p.R987W, a class III tyrosine kinase receptor. Six other families were found with mutations in PDGFB, and, in general, mutations at the PDGF pathway add a new dimension to the physiopathology of PFBC so far explained by a disturbance in phosphate homeostasis with SLC20A2. The identification of SLC20A2, PDGFRB, and PDGFB provides a new avenue for potential treatments based on compounds such as bisphosphonates and those modulating the PDGFB pathway.


Cellular Signalling | 2017

Reduced FAK-STAT3 signaling contributes to ER stress-induced mitochondrial dysfunction and death in endothelial cells

Kalpita Banerjee; Matthew P. Keasey; Vladislav Razskazovskiy; Nishant P. Visavadiya; Cuihong Jia; Theo Hagg

Excessive endoplasmic reticulum (ER) stress leads to cell loss in many diseases, e.g., contributing to endothelial cell loss after spinal cord injury. Here, we determined whether ER stress-induced mitochondrial dysfunction could be explained by interruption of the focal adhesion kinase (FAK)-mitochondrial STAT3 pathway we recently discovered. ER stress was induced in brain-derived mouse bEnd5 endothelial cells by thapsigargin or tunicamycin and caused apoptotic cell death over a 72h period. In concert, ER stress caused mitochondrial dysfunction as shown by reduced bioenergetic function, loss of mitochondrial membrane potential and increased mitophagy. ER stress caused a reduction in mitochondrial phosphorylated S727-STAT3, known to be important for maintaining mitochondrial function. Normal activation or phosphorylation of the upstream cytoplasmic FAK was also reduced, through mechanisms that involve tyrosine phosphatases and calcium signaling, as shown by pharmacological inhibitors, bisperoxovanadium (bpV) and 2-aminoethoxydiphenylborane (APB), respectively. APB mitigated the reduction in FAK and STAT3 phosphorylation, and improved endothelial cell survival caused by ER stress. Transfection of cells rendered null for STAT3 using CRISPR technology with STAT3 mutants confirmed the specific involvement of S727-STAT3 inhibition in ER stress-mediated cell loss. These data suggest that loss of FAK signaling during ER stress causes mitochondrial dysfunction by reducing the protective effects of mitochondrial STAT3, leading to endothelial cell death. We propose that stimulation of the FAK-STAT3 pathway is a novel therapeutic approach against pathological ER stress.


International Journal of Primatology | 2014

Camera Trap Observations of Nonhabituated Critically Endangered Wild Blonde Capuchins, Sapajus flavius (Formerly Cebus flavius)

Bruna M. Bezerra; Monique Bastos; Antonio Souto; Matthew P. Keasey; Perri K. Eason; Nicola Schiel; Gareth J. F. Jones

Habituation presents major challenges for the study of wild primates, particularly in areas where threats such as hunting pressure and increasing forest fragmentation exist. This study describes the use of ground camera trapping to investigate nonhabituated blonde capuchins. Capuchins are arboreal animals, but often use the ground when foraging. Thus, we hypothesized that a ground-baited camera trapping station would be an efficient method to document the presence of capuchins, and to collect information about aspects of their social behavior and ecology. We conducted 92 systematic trapping days over 15 months (from December 2010 to February 2011 and from August 2011 to July 2012). The capuchins visited the trapping stations 43 times. All visits occurred between 05:13h and 17:32h, and lasted 3 min-2:03 h. Sixty-five percent of the photographs included our target species. Groups contained up to 46 individuals and were multimale-multifemale. We recorded no monkeys at the trapping stations during August and November (2011) and January (2012). Infants were more likely to be carried than not. Infants were carried by both sexes; however, 96% of photographs showed females as carriers. Adult males always arrived first at the camera trapping stations, suggesting that males led the group’s movements. The ground-baited camera trapping stations proved effective for confirming the presence of the blonde capuchins in the study site and for documenting aspects of their social behavior. The technique could potentially be used to provide comparative data among populations of this and other primate species in areas where habituation is difficult or risky to the primates.


Journal of Molecular Neuroscience | 2016

MiR-132 Is Upregulated by Ischemic Preconditioning of Cultured Hippocampal Neurons and Protects them from Subsequent OGD Toxicity

Matthew P. Keasey; Helen L. Scott; Ioannis Bantounas; James B. Uney; Stephen Kelly

We explored the response of a panel of selected microRNAs (miRNAs) in neuroprotection produced by ischemic preconditioning. Hippocampal neuronal cultures were exposed to a 30-min oxygen–glucose deprivation (OGD). In our hands, this duration of OGD does not result in neuronal loss in vitro but significantly reduces neuronal death from a subsequent ‘lethal’ OGD insult. RT-qPCR was used to determine the expression of 16 miRNAs of interest at 1 and 24-h post-OGD. One miRNA (miR-98) was significantly decreased at 1-h post-OGD. Ten miRNAs (miR-9, miR-21, miR-29b, miR-30e, miR-101a, miR-101b, miR-124a, miR-132, miR-153, miR-204) were increased significantly at 24-h post-OGD. No miRNAs were decreased at 24-h. The increases observed in the 24-h group suggested that these miRNAs might play a role in preconditioning-induced neuroprotection. We selected the widely studied miR-132, a brain enriched, CREB regulated miRNA, to explore its role in simulated ischemic insults. We found that hippocampal neurons transduced with lentiviral vectors expressing miR-132 were protected from OGD and NMDA treatment, but not hydrogen peroxide. These findings add to the growing literature that targeting neuroprotective pathways controlled by miRNAs may represent a therapeutic strategy for the treatment of ischemic brain injury.


Scientific Reports | 2016

Vitamin-D receptor agonist calcitriol reduces calcification in vitro through selective upregulation of SLC20A2 but not SLC20A1 or XPR1

Matthew P. Keasey; R. R. Lemos; Theo Hagg; João Ricardo Mendes de Oliveira

Vitamin D deficiency (hypovitaminosis D) causes osteomalacia and poor long bone mineralization. In apparent contrast, hypovitaminosis D has been reported in patients with primary brain calcifications (“Fahr’s disease”). We evaluated the expression of two phosphate transporters which we have found to be associated with primary brain calcification (SLC20A2, whose promoter has a predicted vitamin D receptor binding site, and XPR1), and one unassociated (SLC20A1), in an in vitro model of calcification. Expression of all three genes was significantly decreased in calcifying human bone osteosarcoma (SaOs-2) cells. Further, we confirmed that vitamin D (calcitriol) reduced calcification as measured by Alizarin Red staining. Cells incubated with calcitriol under calcifying conditions specifically maintained expression of the phosphate transporter SLC20A2 at higher levels relative to controls, by RT-qPCR. Neither SLC20A1 nor XPR1 were affected by calcitriol treatment and remained suppressed. Critically, knockdown of SLC20A2 gene and protein with CRISPR technology in SaOs2 cells significantly ablated vitamin D mediated inhibition of calcification. This study elucidates the mechanistic importance of SLC20A2 in suppressing the calcification process. It also suggests that vitamin D might be used to regulate SLC20A2 gene expression, as well as reduce brain calcification which occurs in Fahr’s disease and normal aging.


Psychoneuroendocrinology | 2019

Ciliary neurotrophic factor is a key sex-specific regulator of depressive-like behavior in mice

Cuihong Jia; Russell W. Brown; Hannah M. Malone; Katherine C. Burgess; W. Drew Gill; Matthew P. Keasey; Theo Hagg

Ciliary neurotrophic factor (CNTF) is produced by astrocytes and promotes neurogenesis and neuroprotection. Little is known about the role of CNTF in affective behavior. We investigated whether CNTF affects depressive- and anxiety-like behavior in adult mice as tested in the forced swim, sucrose preference and elevated-T maze tests. Female wild type CNTF+/+ mice more readily developed behavioral despair with increased immobility time and decreased latency to immobility in the forced swim test than male CNTF+/+ littermates. The lack of CNTF in CNTF-/- mice had an opposite effect on depressive-like behavior in female mice (reduced immobility time and increased sucrose preference) vs. male mice (increased immobility time). Female wildtype mice expressed more CNTF in the amygdala than male mice. Ovariectomy increased CNTF expression, as well as immobility time, which was significantly reduced in CNTF-/- mice, suggesting that CNTF mediates overiectomy-induced immobility time, possibly in the amygdala. Progesterone but not 17-β estradiol inhibited CNTF expression in cultured C6 astroglioma cells. Progesterone treatment also reduced CNTF expression in the amygdala and decreased immobility time in female CNTF+/+ but not in CNTF-/- mice. Castration did not alter CNTF expression in males nor their behavior. Lastly, there were no effects of CNTF on the elevated T-maze, a behavioral test of anxiety, suggesting that a different mechanism may underlie anxiety-like behavior. This study reveals a novel CNTF-mediated mechanism in stress-induced depressive-like behavior and points to opportunities for sex-specific treatments for depression, e.g. progesterone in females and CNTF-stimulating drugs in males.


Journal of Cell Science | 2018

Blood vitronectin is a major activator of LIF and IL-6 in the brain through integrin–FAK and uPAR signaling

Matthew P. Keasey; Cuihong Jia; Lylyan F. Pimentel; Richard R. T. Sante; Chiharu Lovins; Theo Hagg

ABSTRACT We defined how blood-derived vitronectin (VTN) rapidly and potently activates leukemia inhibitory factor (LIF) and pro-inflammatory interleukin 6 (IL-6) in vitro and after vascular injury in the brain. Treatment with VTN (but not fibrinogen, fibronectin, laminin-111 or collagen-I) substantially increased LIF and IL-6 within 4 h in C6-astroglioma cells, while VTN−/− mouse plasma was less effective than that from wild-type mice. LIF and IL-6 were induced by intracerebral injection of recombinant human (rh)VTN in mice, but induction seen upon intracerebral hemorrhage was less in VTN−/− mice than in wild-type littermates. In vitro, VTN effects were inhibited by RGD, αvβ3 and αvβ5 integrin-blocking peptides and antibodies. VTN activated focal adhesion kinase (FAK; also known as PTK2), whereas pharmacological- or siRNA-mediated inhibition of FAK, but not PYK2, reduced the expression of LIF and IL-6 in C6 and endothelial cells and after traumatic cell injury. Dominant-negative FAK (Y397F) reduced the amount of injury-induced LIF and IL-6. Pharmacological inhibition or knockdown of uPAR (also known as PLAUR), which binds VTN, also reduced cytokine expression, possibly through a common target of uPAR and integrins. We propose that VTN leakage into tissues promotes inflammation. Integrin–FAK signaling is therefore a novel IL-6 and LIF regulation mechanism relevant to the inflammation and stem cell fields. Summary: Blood vitronectin is a unique and key inducer of pro-inflammatory IL-6 and LIF, through integrin and uPAR signaling, which had not been previously indicated as having a role in cytokine expression.


Journal of Molecular Neuroscience | 2017

Erratum to: MiR-9-5p Down-Regulates PiT2, but not PiT1 in Human Embryonic Kidney 293 Cells

D. P. Bezerra; Matthew P. Keasey; Jaline Melo Oliveira

PiT1 (SLC20A1) and PiT2 (SLC20A2) are members of the mammalian type-III inorganic phosphate transporters and recent studies linked SLC20A2 mutations with primary brain calcifications. MicroRNAs (miRNAs) are endogenous noncoding regulatory RNAs and MicroRNA-9 (miR-9) modulates neurogenesis but is also involved with different types of cancer. We evaluated possible interactions between miR-9 and the phosphate transporters (PiT1 and PiT2). SLC20A2, platelet-derived growth factor receptor beta (PDGFRB) and Fibrillin-2 (FBN2) showed binding sites with high affinity for mir-9, In silico. miR-9 mimic was transfected into HEK293 cells and expression was confirmed by RT-qPCR. Overexpression of miR-9 in these cells caused a significant reduction in PiT2 and FBN2. PDGFRB appeared to be decreased, but was not significantly down-regulated. PiT1 showed no significant difference relative to controls. The down-regulation of PiT2 protein by miR-9 was confirmed by western blotting. In conclusion, we showed that miR-9 can down-regulate PiT2, in HEK293 cells. The online version of the original article can be found at http://dx.doi. org/10.1007/s12031-017-0906-0 * D. P. Bezerra [email protected] * M. Keasey [email protected] * J. R. M. Oliveira [email protected] 1 Keizo Asami Laboratory, Federal University of Pernambuco, Recife, PE, Brazil 2 Neuropsychiatry Department, Federal University of Pernambuco, Recife, PE, Brazil 3 Department of Biomedical Sciences – Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA J Mol Neurosci (2017) 62:34 DOI 10.1007/s12031-017-0913-1

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Theo Hagg

University of Louisville

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Cuihong Jia

East Tennessee State University

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Chiharu Lovins

East Tennessee State University

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Kalpita Banerjee

East Tennessee State University

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Nishant P. Visavadiya

East Tennessee State University

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Seong Su Kang

University of Louisville

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Vladislav Razskazovskiy

East Tennessee State University

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Jaline Melo Oliveira

Federal University of Pernambuco

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R. R. Lemos

Federal University of Pernambuco

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Gary L. Wright

East Tennessee State University

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