Publications by authors named "Fernando Santiago"

45 Publications

Mesenchymal stem cell-derived extracellular vesicles reduce senescence and extend health span in mouse models of aging.

Aging Cell 2021 Mar 16:e13337. Epub 2021 Mar 16.

Center on Aging and Departments of Molecular Medicine, Scripps Research, Jupiter, Florida, USA.

Aging drives progressive loss of the ability of tissues to recover from stress, partly through loss of somatic stem cell function and increased senescent burden. We demonstrate that bone marrow-derived mesenchymal stem cells (BM-MSCs) rapidly senescence and become dysfunctional in culture. Injection of BM-MSCs from young mice prolonged life span and health span, and conditioned media (CM) from young BM-MSCs rescued the function of aged stem cells and senescent fibroblasts. Extracellular vesicles (EVs) from young BM-MSC CM extended life span of Ercc1 mice similarly to injection of young BM-MSCs. Finally, treatment with EVs from MSCs generated from human ES cells reduced senescence in culture and in vivo, and improved health span. Thus, MSC EVs represent an effective and safe approach for conferring the therapeutic effects of adult stem cells, avoiding the risks of tumor development and donor cell rejection. These results demonstrate that MSC-derived EVs are highly effective senotherapeutics, slowing the progression of aging, and diseases driven by cellular senescence.
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http://dx.doi.org/10.1111/acel.13337DOI Listing
March 2021

Truncated YY1 interacts with BASP1 through a 339KLK341 motif in YY1 and suppresses vascular smooth muscle cell growth and intimal hyperplasia after vascular injury.

Cardiovasc Res 2021 Jan 28. Epub 2021 Jan 28.

Vascular Biology and Translational Research Laboratory, School of Medical Sciences, UNSW Medicine, University of New South Wales, Sydney NSW 2052, Australia.

Aims: In-stent restenosis and late stent thrombosis are complications associated with the use of metallic and drug-coated stents. Strategies that inhibit vascular smooth muscle cell (SMC) proliferation without affecting endothelial cell (EC) growth would be helpful in reducing complications arising from percutaneous interventions. Our group previously showed that the forced expression of the injury-inducible zinc finger (ZNF) transcription factor, yin yang-1 (YY1) comprising 414 residues inhibits neointima formation in carotid arteries of rabbits and rats. YY1 inhibits SMC proliferation without affecting EC growth. Identifying a shorter version of YY1 retaining cell-selective inhibition would make it more amenable for potential use as a gene therapeutic agent.

Methods And Results: We dissected YY1 into a range of shorter fragments (YY1A-D, YY1Δ) and found that the first two ZNFs in YY1 (construct YY1B, spanning 52 residues) repressed SMC proliferation. Receptor Binding Domain analysis predicts a three residue (339KLK341) interaction domain. Mutation of 339KLK341 to 339AAA341 in YY1B (called YY1Bm) abrogated YY1B's ability to inhibit SMC but not EC proliferation and migration. Incubation of recombinant GST-YY1B and GST-YY1Bm with SMC lysates followed by precipitation with glutathione-agarose beads and mass spectrometric analysis identified a novel interaction between YY1B and BASP1. Overexpression of BASP1, like YY1, inhibited SMC but not EC proliferation and migration. BASP1 siRNA partially rescued SMC from growth inhibition by YY1B. In the rat carotid balloon injury model, adenoviral overexpression of YY1B, like full-length YY1, reduced neointima formation, whereas YY1Bm had no such effect. CD31 immunostaining suggested YY1B could increase re-endothelialization in a 339KLK341-dependent manner.

Conclusions: These studies identify a truncated form of YY1 (YY1B) that can interact with BASP1 and inhibits SMC proliferation, migration and intimal hyperplasia after balloon injury of rat carotid arteries as effectively as full length YY1. We demonstrate the therapeutic potential of YY1B in vascular proliferative disease.
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http://dx.doi.org/10.1093/cvr/cvab021DOI Listing
January 2021

Thermostable small-molecule inhibitor of angiogenesis and vascular permeability that suppresses a pERK-FosB/ΔFosB-VCAM-1 axis.

Sci Adv 2020 Jul 29;6(31):eaaz7815. Epub 2020 Jul 29.

Vascular Biology and Translational Research, School of Medical Sciences and UNSW Medicine, University of New South Wales, Sydney, NSW 2052, Australia.

Vascular permeability and angiogenesis underpin neovascular age-related macular degeneration and diabetic retinopathy. While anti-VEGF therapies are widely used clinically, many patients do not respond optimally, or at all, and small-molecule therapies are lacking. Here, we identified a dibenzoxazepinone BT2 that inhibits endothelial cell proliferation, migration, wound repair in vitro, network formation, and angiogenesis in mice bearing Matrigel plugs. BT2 interacts with MEK1 and inhibits ERK phosphorylation and the expression of FosB/ΔFosB, VCAM-1, and many genes involved in proliferation, migration, angiogenesis, and inflammation. BT2 reduced retinal vascular leakage following rat choroidal laser trauma and rabbit intravitreal VEGF-A administration. BT2 suppressed retinal CD31, pERK, VCAM-1, and VEGF-A expression. BT2 reduced retinal leakage in rats at least as effectively as aflibercept, a first-line therapy for nAMD/DR. BT2 withstands boiling or autoclaving and several months' storage at 22°C. BT2 is a new small-molecule inhibitor of vascular permeability and angiogenesis.
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http://dx.doi.org/10.1126/sciadv.aaz7815DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7450479PMC
July 2020

Ancient genomes in South Patagonia reveal population movements associated with technological shifts and geography.

Nat Commun 2020 08 3;11(1):3868. Epub 2020 Aug 3.

Department of Genetics, Harvard Medical School, Boston, MA, 02115, USA.

Archaeological research documents major technological shifts among people who have lived in the southern tip of South America (South Patagonia) during the last thirteen millennia, including the development of marine-based economies and changes in tools and raw materials. It has been proposed that movements of people spreading culture and technology propelled some of these shifts, but these hypotheses have not been tested with ancient DNA. Here we report genome-wide data from 20 ancient individuals, and co-analyze it with previously reported data. We reveal that immigration does not explain the appearance of marine adaptations in South Patagonia. We describe partial genetic continuity since ~6600 BP and two later gene flows correlated with technological changes: one between 4700-2000 BP that affected primarily marine-based groups, and a later one impacting all <2000 BP groups. From ~2200-1200 BP, mixture among neighbors resulted in a cline correlated to geographic ordering along the coast.
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http://dx.doi.org/10.1038/s41467-020-17656-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7400565PMC
August 2020

Predicting habitat use by the Argentine hake Merluccius hubbsi in a warmer world: inferences from the Middle Holocene.

Oecologia 2020 Jun 18;193(2):461-474. Epub 2020 May 18.

Department of Evolutionary Biology, Ecology and Environmental Science, Biodiversity Research Institute (IRBio), University of Barcelona, Barcelona, Spain.

Fish skeletal remains recovered from two archaeological sites dated in the Middle Holocene of Tierra del Fuego (Argentina) were analysed to describe habitat use patterns by hake in the past and predict changes in a warmer world. Mitochondrial DNA was successfully extracted and amplified from 42 out of 45 first vertebra from ancient hake and phylogenetic analysis assigned all haplotypes to Argentine hake (Merluccius hubbsi). According to osteometry, the Argentine hake recovered from the archaeological site were likely adults ranging 37.2-58.1 cm in standard length. C and N stable isotope analysis showed that currently Argentine hake use foraging grounds deeper than those of Patagonian blenny and pink cusk-eel. Argentine hake, however, had a much broader isotopic niche during the Middle Holocene, when a large part of the population foraged much shallower than contemporary pink cusk-eel. The overall evidence suggests the presence of large numbers of Argentine hake onshore Tierra del Fuego during the Middle Holocene, which allowed exploitation by hunter-gatherer-fisher groups devoid of fishing technology. Interestingly, average SST off Tierra del Fuego during the Middle Holocene was higher than currently (11 °C vs 7 °C) and matched SST in the current southernmost onshore spawning aggregations, at latitude 47 °S. This indicates that increasing SST resulting from global warming will likely result into an increased abundance of adult Argentine hake onshore Tierra del Fuego, as during the Middle Holocene. Furthermore, stable isotope ratios from mollusc shells confirmed a much higher marine primary productivity during the Middle Holocene off Tierra del Fuego.
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http://dx.doi.org/10.1007/s00442-020-04667-zDOI Listing
June 2020

SA-β-Galactosidase-Based Screening Assay for the Identification of Senotherapeutic Drugs.

J Vis Exp 2019 06 28(148). Epub 2019 Jun 28.

Department of Molecular Medicine and the Center on Aging, The Scripps Research Institute; Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota; Institute on the Biology of Aging and Metabolism, University of Minnesota;

Cell senescence is one of the hallmarks of aging known to negatively influence a healthy lifespan. Drugs able to kill senescent cells specifically in cell culture, termed senolytics, can reduce the senescent cell burden in vivo and extend healthspan. Multiple classes of senolytics have been identified to date including HSP90 inhibitors, Bcl-2 family inhibitors, piperlongumine, a FOXO4 inhibitory peptide and the combination of Dasatinib/Quercetin. Detection of SA-β-Gal at an increased lysosomal pH is one of the best characterized markers for the detection of senescent cells. Live cell measurements of senescence-associated β-galactosidase (SA-β-Gal) activity using the fluorescent substrate C12FDG in combination with the determination of the total cell number using a DNA intercalating Hoechst dye opens the possibility to screen for senotherapeutic drugs that either reduce overall SA-β-Gal activity by killing of senescent cells (senolytics) or by suppressing SA-β-Gal and other phenotypes of senescent cells (senomorphics). Use of a high content fluorescent image acquisition and analysis platform allows for the rapid, high throughput screening of drug libraries for effects on SA-β-Gal, cell morphology and cell number.
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http://dx.doi.org/10.3791/58133DOI Listing
June 2019

Extracellular signal-regulated kinase-1 phosphorylates early growth response-1 at serine 26.

Biochem Biophys Res Commun 2019 03 31;510(3):345-351. Epub 2019 Jan 31.

Vascular Biology and Translational Research Laboratory, School of Medical Sciences, University of New South Wales, Sydney, Australia; UNSW Medicine, University of New South Wales, Sydney, Australia. Electronic address:

Egr-1, an immediate-early gene product and master regulator was originally described as a phosphoprotein following its discovery in the 1980s. However specific residue(s) phosphorylated in Egr-1 remain elusive. Here we phosphorylated recombinant Egr-1 in vitro with ERK1 prior to mass spectrometry, which identified phosphorylation of Ser and Ser with the latter ∼12 times more abundant than Ser. Phosphorylation of wild-type recombinant Egr-1 (as compared with Ser>Ala mutant Egr-1) revealed that Ser accounts for the majority of phosphorylation of Egr-1 by ERK1. N-FGSFPH(pS)PTMDNYC-C was used as an antigen to generate mouse monoclonal antibodies (pS26 MAb). pS26 MAb recognised ERK1-phosphorylated Egr-1 but not Egr-1 bearing a point mutation at Ser. pS26 MAb recognised inducible ∼75 kDa and 100 kDa species in nuclear extracts of cells exposed to FGF-2. Peptide blocking revealed both inducible species were phosphosite-specific. Immunoprecipitation of nuclear extracts of cells exposed to FGF-2 with pS26 MAb followed by SDS-PAGE and mass spectrometry identified Egr-1 sequences corresponding to the ∼75 kDa species but not ∼100 kDa species. This study identifies a specific amino acid phosphorylated in endogenous Egr-1.
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http://dx.doi.org/10.1016/j.bbrc.2019.01.019DOI Listing
March 2019

Role of imaging methods in diagnosis and treatment of Morton's neuroma.

World J Radiol 2018 Sep;10(9):91-99

Orthopaedic Department, Hospital of Neuro-Traumatology (Virgen de las Nieves), Granada 18014, Spain.

Among the many causes of forefoot pain, Morton's neuroma (MN) is often suspected, particularly in women, due to its high incidence. However, there remain controversies about its relationship with symptomatology and which diagnostic and treatment choices to choose. This article mainly focuses on the role of the various imaging methods and their abilities to support an accurate diagnosis of MN, ruling out other causes of forefoot pain, and as a way of providing targeted imaging-guided therapy for patients with MN.
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http://dx.doi.org/10.4329/wjr.v10.i9.91DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6177560PMC
September 2018

Osteoporotic vertebral endplate and cortex fractures: A pictorial review.

J Orthop Translat 2018 Oct 6;15:35-49. Epub 2018 Sep 6.

Department of Radiology, Hospital of Traumatology, Carretera de Jaen SN, Granada, Spain.

Despite years' research, the radiographic criteria for osteoporotic vertebral fracture and its grading remain debated. The importance of identifying vertebral endplate/cortex fracture (ECF) is being recognised; however, evaluation of osteoporotic ECF requires training and experience. This article aims to serve as a teaching material for radiologists/physicians or researchers to evaluate osteoporotic ECF. Emphasis is particularly dedicated to identifying ECF that may not be associated with apparent vertebral body collapse. We suggest a combined approach based on standardised radiologic evaluation by experts and morphometry measurement is the most appropriate approach to detect and classify osteoporotic vertebral fractures.

The Translational Potential: A good understanding of radiologic anatomy of vertebrae and fracture signs of endplate/cortex are essential for spine fragility fracture assessment.
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http://dx.doi.org/10.1016/j.jot.2018.08.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6169255PMC
October 2018

CT-guided radiofrequency ablation in patients with aneurysmal bone cysts.

Eur J Radiol 2018 Mar 4;100:116-123. Epub 2018 Feb 4.

Radiology Department, South Egypt Cancer Institute (SECI), Assiut University, 71515, Assiut, Egypt.

Introduction: Aneurysmal bone cyst (ABC) is one of most therapeutic challenging lesions for orthopedic surgeons specially in large-sized lesions and lesions, which are very close to important neurovascular structures. In the present study, we express our experience in the treatment of aneurysmal bone cyst by radiofrequency thermal ablation (RFTA).

Methods: In the last two years, we have treated 20 cases (12 males & 8 females) presented with painful aneurysmal bone cysts in different anatomical locations, the age mean (±SD) is 18.95 ± 8.02 years and median is 17.5 years, the mean size of the lesions (±SD) is: 32.25 ± 7.15 mm & the median (range) is 33.5 mm (18.0-43.0) mm. The treatment was done by (RFTA) only in 11 cases and by (RFTA) with cementation in the other 9 cases, then the patients underwent close clinical follow-up for clinical symptoms by using visual analogue scale (VAS) pain score & radiological follow-up for one month, six months & one year after the procedure.

Results: Close follow-up for the patients proved that (RFTA) is a clinically successful &curative treatment as there was significant reduction in the mean (±SD) of the (VAS) pain score in all treated cases from 8.40 ± 1.23 before the intervention to 0.20 ± 0.41 at the end of follow-up period. No recorded post-procedural complications or recurrence during or at the end of the follow-up period.
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http://dx.doi.org/10.1016/j.ejrad.2018.01.020DOI Listing
March 2018

Developing Neolignans as Proangiogenic Agents: Stereoselective Total Syntheses and Preliminary Biological Evaluations of the Four Guaiacylglycerol 8--4'-Coniferyl Ethers.

ACS Omega 2017 Oct 30;2(10):7375-7388. Epub 2017 Oct 30.

School of Medical Sciences, Faculty of Medicine, The University of New South Wales, Sydney, NSW 2052, Australia.

Stereoselective total syntheses of the four stereoisomeric forms of guaiacylglycerol 8--4'-coniferyl ether, viz., compounds , -, , and -, have been established. The key step involves an Evans/Seebach auxiliary-controlled and syn-selective aldol process followed, in the reaction sequences leading to the anti-compounds, by a Mitsunobu reaction involving a benzylic alcohol residue. The proangiogenic properties of the synthetic materials were evaluated in a human microvascular endothelial cell tubule formation assay, thus revealing that they are all active, with the 8S-configured compounds and being the most potent.
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http://dx.doi.org/10.1021/acsomega.7b01459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5724931PMC
October 2017

Identifying osteoporotic vertebral endplate and cortex fractures.

Quant Imaging Med Surg 2017 Oct;7(5):555-591

Department of Radiology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.

Osteoporosis is the most common metabolic bone disease, and vertebral fractures (VFs) are the most common osteoporotic fracture. A single atraumatic VF may lead to the diagnosis of osteoporosis. Prevalent VFs increase the risk of future vertebral and non-vertebral osteoporotic fracture independent of bone mineral density (BMD). The accurate and clear reporting of VF is essential to ensure patients with osteoporosis receive appropriate treatment. Radiologist has a vital role in the diagnosis of this disease. Several morphometrical and radiological methods for detecting osteoporotic VF have been proposed, but there is no consensus regarding the definition of osteoporotic VF. A vertebra may fracture yet not ever result in measurable changes in radiographic height or area. To overcome these difficulties, algorithm-based qualitative approach (ABQ) was developed with a focus on the identification of change in the vertebral endplate. Evidence of endplate fracture (rather than variation in vertebral shape) is the primary indicator of osteoporotic fracture according to ABQ criteria. Other changes that may mimic osteoporotic fractures should be systemically excluded. It is also possible that vertebral cortex fracture may not initially occur in endplate. Particularly, vertebral cortex fracture can occur in anterior vertebral cortex without gross vertebral deformity (VD), or fractures deform the anterior vertebral cortex without endplate disruption. This article aims to serve as a teaching material for physicians or researchers to identify vertebral endplate/cortex fracture (ECF). Emphasis is particularly dedicated to identifying ECF which may not be associated apparent vertebral body collapse. We believe a combined approach based on standardized radiologic evaluation by experts and morphometry measurement is the most appropriate approach to detect and classify VFs.
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http://dx.doi.org/10.21037/qims.2017.10.05DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5682396PMC
October 2017

Taking advantage of an unerupted third molar: a case report.

Dental Press J Orthod 2017 Jul-Aug;22(4):97-101

Universidade Federal de Minas Gerais, Faculdade de Odontologia, Centro de Ciências da Saúde, Departamento de Clínica, Patologia e Cirurgia Odontológicas (Belo Horizonte/MG, Brasil).

Introduction:: Treatments with dental surgery seek to displace tooth to the correct position within the dental arch.

Objective:: To report a clinical case that took advantage of an unerupted third molar.

Case History: : A male patient, 18 years of age, was referred by his dentist to evaluate the third molars. The clinical exam revealed no visible lower third molars. The computed tomography (CT) exam showed the presence of a supernumerary tooth in the region of the mandibular ramus, on the left side, and impaction of the third molar, which was causing root resorption on the second molar, thus making it impossible to remain in the buccal cavity. The preferred option, therefore, was to remove both second molar and the supernumerary tooth, in addition to attaching a device to the third molar during surgery for further traction.

Results: : After 12 months, the third molar reached the proper position.

Conclusion: : When a mandibular second permanent molar shows an atypical root resorption, an impacted third molar can effectively substitute the tooth by using an appropriate orthodontic-surgical approach.
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http://dx.doi.org/10.1590/2177-6709.22.4.097-101.oarDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5573016PMC
July 2018

The Association between t-PA Administration and In-Hospital Mortality following Acute Ischemic Stroke in Puerto Rican Patients.

P R Health Sci J 2016 Dec;35(4):215-219

Herbert Wertheim College of Medicine, Florida International University, Miami, Florida.

Objective: Despite being the standard of care, thrombolytic therapy with tissue plasminogen activator (t-PA) is currently administered to only 5% of acute ischemic stroke (AIS) patients in the United States. Published scientific information regarding both the use of t-PA for AIS in Hispanic patients and its impact on short-term mortality is scarce. The objectives of this study are to investigate, among Puerto Rican patients hospitalized with AIS, the rate of t-PA administration, and the risk of in-hospital mortality in patients who received t-PA vs. those patients who did not receive t-PA.

Methods: We performed a secondary analysis of data from patients with AIS admitted to acute care facilities throughout Puerto Rico in study years 2007, 2009, and 2011who were participating in the Puerto Rico Cardiovascular Disease Surveillance System. Multivariate logistic regression was used to determine the independent association between treatment with t-PA within 4.5 hours of symptom onset and in-hospital mortality.

Results: Of the 1968 study patients hospitalized with AIS, 104 (5%) received t-PA treatment. After adjustments for demographic and clinical confounders, patients receiving t-PA had similar odds of in-hospital mortality as patients not receiving t-PA did (OR = 2.49, 95% CI = 0.81-7.66). The receipt of concomitant anticoagulation medication was independently associated with relatively lower odds of in-hospital mortality (OR = 0.42, 95% CI = 0.20-0.88). Being over 80 years of age (OR = 2.03, 95% CI = 1.13-3.68), being obese (OR = 1.88, 95% CI = 1.01-3.49), and arriving in an ambulance (OR = 3.61, 95% CI = 1.95-6.68) were all independently associated with relatively higher odds of in-hospital mortality.

Conclusion: Among patients hospitalized in Puerto Rico with acute ischemic stroke, t-PA treatment was not significantly associated with in-hospital mortality.
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December 2016

Temperature and toxic Tau in Alzheimer's disease: new insights.

Temperature (Austin) 2015 Oct-Dec;2(4):491-8. Epub 2015 Oct 19.

Graduate Program in Neuroscience and Cognition; Universidade Federal do ABC; São Bernardo do Campo, Brasil; Center for Natural Sciences and Humanities; Universidade Federal do ABC; São Bernardo do Campo, Brasil.

Alzheimer's disease (AD), the most common dementia in the elderly, is characterized by cognitive impairment and severe autonomic symptoms such as disturbance in core body temperature (Tc), which may be predictors or early events in AD onset. Inclusions of phosphorylated Tau (p-Tau) are a hallmark of AD and other neurodegenerative disorders called "Tauopathies." Animal and human studies show that anesthesia augments p-Tau levels through reduction of Tc, with implications for AD. Additionally, hypothermia impairs memory and cognitive function. The molecular networks related to Tc that are associated with AD remain poorly characterized. Under physiological conditions, Tau binds microtubules, promoting their assembly and stability. The dynamically regulated Tau-microtubule interaction plays an important role in structural remodeling of the cytoskeleton, having important functions in neuronal plasticity and memory in the hippocampus. Hypothermia-induced increases in p-Tau levels are significant, with an 80% increase for each degree Celsius below normothermic conditions. Although the effects of temperature on Tau phosphorylation are evident, its effects on p-Tau degradation remain poorly understoodWe review information concerning the mechanisms of Tau regulation of neuron plasticity via its effects on microtubule dynamics, with focus on pathways regulating the abundance of phosphorylated Tau species.  We highlight the effects of temperature on molecular mechanisms influencing the development of Tau-related diseases. Specifically, we argue that cold might preferentially affects central nervous system structures that are highly reliant upon plasticity, such as the hippocampus, and that the effect of cold on Tau phosphorylation may constitute a pathology-initiating trigger leading to neurodegeneration.
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http://dx.doi.org/10.1080/23328940.2015.1096438DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4843920PMC
May 2016

BAG2 expression dictates a functional intracellular switch between the p38-dependent effects of nicotine on tau phosphorylation levels via the α7 nicotinic receptor.

Exp Neurol 2016 Jan 21;275 Pt 1:69-77. Epub 2015 Oct 21.

Center of Natural and Human Sciences, Universidade Federal do ABC, São Bernardo do Campo, SP, Brazil. Electronic address:

The histopathological hallmarks present in Alzheimer's disease (AD) brain are plaques of Aβ peptide, neurofibrillary tangles of hyperphosphorylated tau protein, and a reduction in nicotinic acetylcholine receptor (nAChR) levels. The role of nAChRs in AD is particularly controversial. Tau protein function is regulated by phosphorylation, and its hyperphosphorylated forms are significantly more abundant in AD brain. Little is known about the relationship between nAChR and phospho-tau degradation machinery. Activation of nAChRs has been reported to increase and decrease tau phosphorylation levels, and the mechanisms responsible for this discrepancy are not presently understood. The co-chaperone BAG2 is capable of regulating phospho-tau levels via protein degradation. In SH-SY5Y cell line and rat primary hippocampal cell culture low endogenous BAG2 levels constitute an intracellular environment conducive to nicotine-induced accumulation of phosphorylated tau protein. Further, nicotine treatment inhibited endogenous expression of BAG2, resulting in increased levels of phosphorylated tau indistinguishable from those induced by BAG2 knockdown. Conversely, overexpression of BAG2 is conducive to a nicotine-induced reduction in cellular levels of phosphorylated tau protein. In both cases the effect of nicotine was p38MAPK-dependent, while the α7 antagonist MLA was synthetic to nicotine treatment, either increasing levels of phospho-Tau in the absence of BAG2, or further decreasing the levels of phospho-Tau in the presence of BAG2. Taken together, these findings reconcile the apparently contradictory effects of nicotine on tau phosphorylation by suggesting a role for BAG2 as an important regulator of p38-dependent tau kinase activity and phospho-tau degradation in response to nicotinic receptor stimulation. Thus, we report that BAG2 expression dictates a functional intracellular switch between the p38-dependent functions of nicotine on tau phosphorylation levels via the α7 nicotinic receptor.
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http://dx.doi.org/10.1016/j.expneurol.2015.10.005DOI Listing
January 2016

Impact of Day of the Week and Time of Arrival on Ischemic Stroke Management.

P R Health Sci J 2015 Sep;34(3):164-9

Section of Neurosurgery, Department of Surgery, School of Medicine, University of Puerto Rico Medical Sciences Campus, San Juan, PR.

Objective: The purpose of this study was to evaluate the association between measures of patient arrival day (weekday or weekend day), day part (nighttime vs. daytime) and hour (regular hours vs. off hours) at the stroke unit of the Emergency Department of the Puerto Rico Medical Center and the following time-to-treatment measures: door-to-CT-scan, door-to-needle, and stroke-onset-to-treatment.

Methods: In this retrospective study, the data of 54 patients was obtained from the stroke unit of the Puerto Rico Medical Center through the Get With The Guidelines- Stroke Registry. Inclusion criteria were as follows: having an ischemic stroke within the period covering from August 2008 through February 2010 and being at least 18 years old. Associations between patient arrival time and timeliness of interventions were assessed using t-tests/Mann-Whitney tests and chi-square tests/Fisher's exact tests, as appropriate.

Results: The majority of the patients (74%) were men. The mean and standard deviation of age was 67±14 years. The median of times for door-to-CT-scan and onset to treatment were 15 minutes (interquartile range=15) and 2.7 hours (interquartile range=0.6), respectively. The mean and standard deviation for door-to-needle time was 77±18 minutes. No differences were found for any of the variables in terms of arrival date, day part or hour (p>0.05). The median time for door-to-CT- scan was shorter for patients receiving intravenous tissue plasminogen activator treatment than it was for those not receiving such treatment (12 minutes vs. 20 minutes; p=0.02).

Conclusion: The timeliness of the stroke management interventions did not differ significantly in terms of arrival day, day part, or hour.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4633410PMC
September 2015

The Co-chaperone BAG2 Mediates Cold-Induced Accumulation of Phosphorylated Tau in SH-SY5Y Cells.

Cell Mol Neurobiol 2016 May 25;36(4):593-602. Epub 2015 Jul 25.

Universidade Federal do ABC, São Bernardo do Campo, São Paulo, Brazil.

Inclusions of phosphorylated tau (p-tau) are a hallmark of many neurodegenerative disorders classified as "tauopathy," of which Alzheimer's disease is the most prevalent form. Dysregulation of tau phosphorylation disrupts neuron structure and function, and hyperphosphorylated tau aggregates to form neurotoxic inclusions. The abundance of ubiquitin in tau inclusions suggests a defect in ubiquitin-mediated tau protein degradation by the proteasome. Under the temperature of 37 °C, the co-chaperone BAG2 protein targets phosphorylated tau for degradation via by a more-efficient, ubiquitin-independent pathway. In both in vivo and in vitro studies, cold exposure induces the accumulation of phosphorylated tau protein. The SH-SY5Y cell line differentiates into neuron-like cells on treatment with retinoic acid and is an established model for research on the effects of cold on tau phosphorylation. The aim of the present study was to investigate whether BAG2 mediates the cold-induced accumulation of phosphorylated tau protein. Our findings show that cold exposure causes a decrease in BAG2 expression in undifferentiated cells. Conversely, BAG2 expression is increased in differentiated cells exposed to cold. Further, undifferentiated cells exposed to cold had an increased proportion of p-tau to total tau, suggesting an accumulation of p-tau that is consistent with decreased levels of BAG2. Overexpression of BAG2 in cold-exposed undifferentiated cells restored levels of p-tau to those of 37 °C undifferentiated control. Interestingly, although BAG2 expression increased in differentiated cells, this increase was not accompanied by a decrease in the proportion of p-tau to total tau. Further, overexpression of BAG2 in cold exposed differentiated cells showed no significant difference in p-tau levels compared to 37 °C controls. Taken together, these data show that expression of BAG2 is differently regulated in a differentiation-dependent context. Our results suggest that repression of BAG2 expression or BAG2 activity by cold-sensitive pathways, as modeled in undifferentiated and differentiated cells, respectively, may be a causal factor in the accumulation of cytotoxic hyperphosphorylated tau protein via restriction of BAG2-mediated clearance of cellular p-tau.
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http://dx.doi.org/10.1007/s10571-015-0239-xDOI Listing
May 2016

BAG2 Is Repressed by NF-κB Signaling, and Its Overexpression Is Sufficient to Shift Aβ1-42 from Neurotrophic to Neurotoxic in Undifferentiated SH-SY5Y Neuroblastoma.

J Mol Neurosci 2015 Sep 19;57(1):83-9. Epub 2015 May 19.

Pós-graduação em Neurociência e Cognição, Universidade Federal do ABC, São Bernardo do Campo, Brazil,

Amyloid-beta (Aβ) binds to various neuronal receptors and elicits a context- and dose-dependent toxic or trophic response from neurons. The molecular mechanisms for this phenomenon are presently unknown. The cochaperone BAG2 has been shown to mediate important cellular responses to stress, including cell cycle arrest and apoptosis. Here, we use SH-SY5Y neuroblastoma cells to characterize BAG2 expression and regulation and investigate the involvement of BAG2 in Aβ1-42-mediated neurotrophism or neurotoxicity in the context of differentiation. We report that BAG2 is upregulated on differentiation of SH-SY5Y cells into neuron-like cells. This increase in BAG2 expression is accompanied by a change in response to treatment with Aβ1-42 from neurotrophic to neurotoxic. Further, overexpression of BAG2 in undifferentiated SH-SY5Y cells was sufficient to induce the change from neurotrophic to neurotoxic response. Of several transcription factors queried, the putative BAG2 promoter had a higher-than-expected occurrence of response elements (RE) for nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Treatment with JSH-23, a potent inhibitor of NF-κB, caused a marked increase in BAG2 mRNA expression, suggesting that NF-κB is a repressor of BAG2 transcription in undifferentiated SH-SY5Y cells. Together, these data suggest that NF-κB-mediated modulation of BAG2 expression constitutes a "switch" that regulates the shift between the neurotrophic and neurotoxic effects of Aβ1-42.
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http://dx.doi.org/10.1007/s12031-015-0579-5DOI Listing
September 2015

Uncommon localization of pathologic vertebral fracture in ankylosing spondylitis.

Joint Bone Spine 2015 Oct 13;82(5):371. Epub 2015 Mar 13.

Rheumatology Department, San Cecilio Universitary Hospital, 18012 Granada, Spain.

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http://dx.doi.org/10.1016/j.jbspin.2015.01.012DOI Listing
October 2015

Alpha2-adrenoceptor and adenosine A1 receptor within the nucleus tractus solitarii in hypertension development.

Auton Neurosci 2015 Jan 7;187:36-44. Epub 2014 Nov 7.

Universidade Federal do ABC (UFABC), Centro de Ciências Naturais e Humanas, Santo André, SP, Brazil. Electronic address:

Alpha2-adrenoceptor and A1 adenosine receptor systems within the nucleus tractus solitarii (NTS) play an important role in cardiovascular control. Deregulation of these systems may result in an elevated sympathetic tone, one of the root causes of neurogenic hypertension. The dorsomedial/dorsolateral and subpostremal NTS subnuclei of spontaneously hypertensive rats (SHR) show density changes in both receptors, even at 15 days of age, prior to the onset of hypertension. In addition, adenosine A1 receptors have been specifically reported to modulate alpha2-adrenoceptors in several brain regions, including the NTS, via a PLC-dependent pathway involving cross regulation between sympathetic neurons and astrocytes. The physiological cross talk between these receptor systems is also deregulated in SHR suggesting that alpha2-adrenoceptor and A1 adenosine receptor might be germane to the development of hypertension. In this review, we will focus on these systems within the NTS during development, pointing out some interesting modulations in processes, and chemical changes within specific subnuclei of NTS circuitry, that might have implications for neurogenic hypertension.
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http://dx.doi.org/10.1016/j.autneu.2014.11.002DOI Listing
January 2015

Burden of stroke in Puerto Rico.

Int J Stroke 2015 Jan 20;10(1):117-9. Epub 2014 Aug 20.

FIU Herbert Wertheim College of Medicine, Florida International University, Miami, Florida, USA.

Stroke is the fifth leading cause of death and the first cause of long-term disability in Puerto Rico. Trained staff reviewed and independently validated the medical records of patients who had been hospitalized with possible stroke at any of the 20 largest hospitals located in Puerto Rico during 2007, 2009, and 2011. The mean age of the 5005 newly diagnosed stroke patients (51·2% female) was 70 years. At the time of hospitalization, women were 4½ years older, were less likely to be married (60·2% vs. 39·9%, P < 0·001), smoked less (5·8% vs. 13·4%, P < 0·001), and had significantly higher proportion of diabetes (56·0% vs. 54·8%), hypertension (89·1% vs. 85·0%), and low density lipoprotein-cholesterol (LDL-Chol) > 100 mg/dL (65·7% vs. 57·5%) P < 0·05. Ischemic stroke represented 75% of all types of strokes. Atrial fibrillation was mentioned in 7·9% of the medical records. The risk for dying before discharge was similar for both genders, but was 40% higher for women than for men at one-year follow-up: age-adjusted odds ratio = 1·4 (95% confidence interval = 1·2-1·5).
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http://dx.doi.org/10.1111/ijs.12350DOI Listing
January 2015

Interventional procedures of the spine.

Semin Musculoskelet Radiol 2014 Jul 4;18(3):309-17. Epub 2014 Jun 4.

2nd Radiology Department, University General Hospital "ATTIKON," Athens, Greece.

Different interventional procedures performed under imaging guidance permit the diagnosis and treatment of the many causes of back pain. Sources of pain amenable to be treated include facet joints, vertebral body, intervertebral disk, and paraspinal structures including nerves and ganglion roots. These procedures may be merely diagnostic, therapeutic, or intended for both purposes. We review the main indications, advantages, and complications of these techniques.
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http://dx.doi.org/10.1055/s-0034-1375572DOI Listing
July 2014

DNAzyme targeting c-jun suppresses skin cancer growth.

Sci Transl Med 2012 Jun;4(139):139ra82

Centre for Vascular Research, University of New South Wales, Sydney, New South Wales 2052, Australia.

Worldwide, one in three cancers is skin-related, with increasing incidence in many populations. Here, we demonstrate the capacity of a DNAzyme-targeting c-jun mRNA, Dz13, to inhibit growth of two common skin cancer types-basal cell and squamous cell carcinomas-in a therapeutic setting with established tumors. Dz13 inhibited tumor growth in both immunodeficient and immunocompetent syngeneic mice and reduced lung nodule formation in a model of metastasis. In addition, Dz13 suppressed neovascularization in tumor-bearing mice and zebrafish and increased apoptosis of tumor cells. Dz13 inhibition of tumor growth, which required an intact catalytic domain, was due in part to the induction of tumor immunity. In a series of good laboratory practice-compliant toxicology studies in cynomolgus monkeys, minipigs, and rodents, the DNAzyme was found to be safe and well tolerated. It also did not interfere in more than 70 physiologically relevant in vitro bioassays, suggesting a reduced propensity for off-target effects. If these findings hold true in clinical trials, Dz13 may provide a safe, effective therapy for human skin cancer.
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http://dx.doi.org/10.1126/scitranslmed.3003960DOI Listing
June 2012

Yin Yang-1 inhibits tumor cell growth and inhibits p21WAF1/Cip1 complex formation with cdk4 and cyclin D1.

Int J Oncol 2012 May 9;40(5):1575-80. Epub 2012 Feb 9.

Centre for Vascular Research, University of New South Wales, Sydney, Australia.

The GLI-Krüppel zinc finger factor yin yang-1 (YY1) is a complex protein that regulates a variety of processes including transcription, proliferation, development and differentiation. YY1 inhibits cell growth in a cell type-specific manner. The role played by YY1 in its control of tumor cell growth is unclear and controversial. We show here that YY1 can suppress the growth of different tumor cell types in vitro, including human breast carcinoma cells and glioblastoma cells. YY1 also blocked the growth of 13762 MAT mammary adenocarcinoma isografts in rats. YY1 inhibited 13762 MAT tumor growth by approximately 80% compared with the GFP alone group 21 days after injection. YY1 inhibited proliferating cell nuclear antigen (PCNA) expression and pRbSer249/Thr252 phosphorylation without influencing tumor microvascular density. Moreover, YY1 inhibited p21WAF1/Cip1 complex formation with cdk4 and cyclin D1. These findings demonstrate that YY1 can negatively regulate the growth of multiple malignant cell types.
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http://dx.doi.org/10.3892/ijo.2012.1362DOI Listing
May 2012

Interplay between heme oxygenase-1 and the multifunctional transcription factor yin yang 1 in the inhibition of intimal hyperplasia.

Circ Res 2010 Dec 28;107(12):1490-7. Epub 2010 Oct 28.

Centre for Vascular Research, School of Medical Sciences and Bosch Institute, Medical Foundation Building (K25), University of Sydney, 92-94 Parramatta Rd, Camperdown, NSW 2006, Australia.

Rationale: induction of heme oxygenase (HO)-1 protects against experimental atherosclerotic diseases, and certain pharmacological HO-1 inducers, like probucol, inhibit the proliferation of vascular smooth muscle cells and, at the same time, promote the growth of endothelial cells in vivo and in vitro.

Objective: because such cell-specific effects are reminiscent of the action of the transcription factor Yin Yang (YY)1, we tested the hypothesis that there is a functional relationship between HO-1 and YY1.

Methods And Results: we report that probucol increases the number of YY1(+) cells in rat carotid artery following balloon injury at a time coinciding with increased HO-1 expression. The drug also induces the expression of YY1 mRNA and protein in rat aortic smooth muscle cells (RASMCs) in vitro, as do other known HO-1 inducers (tert-butylhydroquinone and hemin) and overexpression of HO-1 using a human HMOX1 cDNA plasmid. Conversely, overexpression of YY1 induces expression of HO-1 in RASMCs. Induction of YY1 expression is dependent on HO-1 enzyme activity and its reaction product CO, because pharmacological inhibition of heme oxygenase activity or CO scavenging block, whereas exposure of RASMCs to a CO-releasing molecule increases, YY1 expression. Furthermore, RNA interference knockdown of YY1 prevents probucol or adeno-HO-1 from inhibiting RASMC proliferation in vitro and neointimal formation in vivo.

Conclusions: our findings show, for the first time, that HO-1 functionally interplays with the multifunctional transcription factor YY1 and that this interplay explains some of the protective activities of HO-1.
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http://dx.doi.org/10.1161/CIRCRESAHA.110.231985DOI Listing
December 2010

Macrophage migration inhibitory factor increases leukocyte-endothelial interactions in human endothelial cells via promotion of expression of adhesion molecules.

J Immunol 2010 Jul 16;185(2):1238-47. Epub 2010 Jun 16.

Department of Medicine, Monash Medical Centre, Centre for Inflammatory Diseases, Monash University, Clayton, Victoria, Australia.

Macrophage migration inhibitory factor (MIF) has been shown to promote leukocyte-endothelial cell interactions, although whether this occurs via an effect on endothelial cell function remains unclear. Therefore, the aims of this study were to examine the ability of MIF expressed by endothelial cells to promote leukocyte adhesion and to investigate the effect of exogenous MIF on leukocyte-endothelial interactions. Using small interfering RNA to inhibit HUVEC MIF production, we found that MIF deficiency reduced the ability of TNF-stimulated HUVECs to support leukocyte rolling and adhesion under flow conditions. These reductions were associated with decreased expression of E-selectin, ICAM-1, VCAM-1, IL-8, and MCP-1. Inhibition of p38 MAPK had a similar effect on adhesion molecule expression, and p38 MAPK activation was reduced in MIF-deficient HUVECs, suggesting that MIF mediated these effects via promotion of p38 MAPK activation. In experiments examining the effect of exogenous MIF, application of MIF to resting HUVECs failed to induce leukocyte rolling and adhesion, whereas addition of MIF to TNF-treated HUVECs increased these interactions. This increase was independent of alterations in TNF-induced expression of E-selectin, VCAM-1, and ICAM-1. However, combined treatment with MIF and TNF induced de novo expression of P-selectin, which contributed to leukocyte rolling. In summary, these experiments reveal that endothelial cell-expressed MIF and exogenous MIF promote endothelial adhesive function via different pathways. Endogenous MIF promotes leukocyte recruitment via effects on endothelial expression of several adhesion molecules and chemokines, whereas exogenous MIF facilitates leukocyte recruitment induced by TNF by promoting endothelial P-selectin expression.
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http://dx.doi.org/10.4049/jimmunol.0904104DOI Listing
July 2010

Pain and functional outcome after vertebroplasty and kyphoplasty. A comparative study.

Eur J Radiol 2010 Aug 6;75(2):e108-13. Epub 2010 Feb 6.

Department of Radiology, Hospital of Traumatology, Ciudad Sanitaria Virgen de las Nieves, Carretera de Jaén SN, 18014 Granada, Spain.

Purpose: The aim of this study was to compare the effectiveness of percutaneous vertebroplasty and kyphoplasty to treat pain from non-neoplastic vertebral fractures and improve functional outcomes.

Materials And Methods: We compared 30 patients treated by vertebroplasty for non-neoplastic vertebral fractures with 30 patients treated by kyphoplasty for the same condition. Pain was measured with a visual analogue scale (VAS) and functional outcome with the Oswestry disability index (ODI). Baseline data were compared with measurements on the day after the procedure (for pain alone) and at 1 month, 6 months, and 1 year.

Results: The VAS pain score was reduced by 4-5 points on the day after either type of treatment, a statistically significant improvement. The global ODI was significantly improved (by 13-18 points) at 1 month after either procedure. These improvements persisted at 6 months and 1 year. No significant differences in functional outcome were observed between the techniques.

Conclusion: Vertebroplasty and kyphoplasty obtain similar improvements in pain and functional outcomes in these patients. The choice of technique must therefore depend on other factors. An initial improvement with either technique is a good predictor of long-term improvement.
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http://dx.doi.org/10.1016/j.ejrad.2010.01.010DOI Listing
August 2010

Pilot study of the characteristics of acute stroke events in patients discharged from the Carolina University Hospital, Puerto Rico in 2007.

Bol Asoc Med P R 2009 Jul-Sep;101(3):11-3

Office of Clinical Research, Endowed Health Services Research Center, San Juan, PR 00936-5067.

Background: Stroke is the third leading cause of death in Puerto Rico. We examined the pre-hospital phase, management and case-fatality-rates (CFR) of patients discharged with acute stroke from the Carolina University of Puerto Rico Hospital during 2007.

Methods: Trained personnel collected information on demographics, delay-time, mode-of-transportation, management, and mortality from all medical records. STATAâ was utilized to conduct univariate comparison of demographics, mode-of-transportation, therapeutics and diagnostic characteristics. Logistic regression analysis assessed cohort effect and controlled for confounders.

Results: The average age was 69.1 years, and 53% were males. The average delay between onset of symptoms suggestive of stroke and arrival at the emergency department was 4.5 hours. Only 62% of patients utilized Emergency Medical Services (EMS). Intravenous thrombolysis was not administered. Stroke mortality increased with age. Ischemic vs. hemorrhagic CFR was significantly higher (63.9% vs. 36.10%; p = 0.034).

Conclusions: These findings highlight the potential benefit of evidence-based therapeutics and EMS use among stroke patients.
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April 2010

Phosphorylation and acetylation of histone H3 and autoregulation by early growth response 1 mediate interleukin 1beta induction of early growth response 1 transcription.

Arterioscler Thromb Vasc Biol 2010 Mar 17;30(3):536-45. Epub 2009 Dec 17.

Centre for Vascular Research, University of New South Wales, Sydney NSW 2052, Australia.

Objective: The transcription factor early growth response (EGR)-1 has been implicated as a key vascular phenotypic switch through its control of inducible transcription. EGR-1 autoregulation, and histone modification in the EGR-1 promoter, represent key mechanisms in EGR-1 control, but have not been explored.

Methods And Results: We demonstrate that EGR-1 regulates its own transcription and that this involves histone H3 phosphorylation and acetylation. EGR-1 transactivates its promoter in smooth muscle cells exposed to interleukin (IL) 1beta through a novel cis-acting element (-211/-203). PD98059, which inhibits mitogen-activated protein kinase kinase/extracellular regulated kinase (MEK/ERK) attenuates IL-1beta-inducible phosphorylation of extracellular signal-regulated kinase 1/2 and mitogen and stress-activated protein kinases 1/2; and reduces levels of phosphorylated and acetylated histone H3. Histone deacetylase inhibition enhances EGR-1 transcription in response to cytokine. Conversely, suppression of histone modification with mitogen and stress-activated protein kinase 1/2 short interfering RNA, or the histone H3 acetyltransferase inhibitor Garcinol, inhibits IL-1beta-inducible EGR-1 transcription. EGR-1 interacts with the acetyltransferase p300. Acetylated H3 and phosphorylated H3 are enriched at the promoter of EGR-1; and EGR-1 is enriched at the promoters of tissue factor and plasminogen activator inhibitor 1 in response to IL-1beta, and attenuated by PD98059, Garcinol, and mitogen and stress-activated protein kinase 1/2 short interfering RNA.

Conclusions: IL-1beta induction of EGR-1 transcription involves histone H3 phosphorylation, acetylation, and autoregulation by EGR-1.
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http://dx.doi.org/10.1161/ATVBAHA.109.193821DOI Listing
March 2010