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1.
J Therm Biol ; 87: 102466, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31999601

RESUMO

To date, hypothermia has focused on improving rates of resuscitation to increase survival in patients sustaining cardiac arrest (CA). Towards this end, the role of body temperature in neuronal damage or death during CA needs to be determined. However, few studies have investigated the effect of regional temperature variation on survival rate and neurological outcomes. In this study, adult male rats (12 week-old) were used under the following four conditions: (i) whole-body normothermia (37 ± 0.5 °C) plus (+) no asphyxial CA, (ii) whole-body normothermia + CA, (iii) whole-body hypothermia (33 ± 0.5 °C)+CA, (iv) body hypothermia/brain normothermia + CA, and (v) brain hypothermia/body normothermia + CA. The survival rate after resuscitation was significantly elevated in groups exposed to whole-body hypothermia plus CA and body hypothermia/brain normothermia plus CA, but not in groups exposed to whole-body normothermia combined with CA and brain hypothermia/body normothermia plus CA. However, the group exposed to hypothermia/brain normothermia combined with CA exhibited higher neuroprotective effects against asphyxial CA injury, i.e. improved neurological deficit and neuronal death in the hippocampus compared with those involving whole-body normothermia combined with CA. In addition, neurological deficit and neuronal death in the group of rat exposed to brain hypothermia/body normothermia and CA were similar to those in the rats subjected to whole-body normothermia and CA. In brief, only brain hypothermia during CA was not associated with effective survival rate, neurological function or neuronal protection compared with those under body (but not brain) hypothermia during CA. Our present study suggests that regional temperature in patients during CA significantly affects the outcomes associated with survival rate and neurological recovery.

2.
Mar Drugs ; 18(1)2020 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-31940961

RESUMO

Transient brain ischemia triggers selective neuronal death/loss, especially in vulnerable regions of the brain including the hippocampus. Laminarin, a polysaccharide originating from brown seaweed, has various pharmaceutical properties including an antioxidant function. To the best of our knowledge, few studies have been conducted on the protective effects of laminarin against ischemic injury induced by ischemic insults. In this study, we histopathologically investigated the neuroprotective effects of laminarin in the Cornu Ammonis 1 (CA1) field of the hippocampus, which is very vulnerable to ischemia-reperfusion injury, following transient forebrain ischemia (TFI) for five minutes in gerbils. The neuroprotective effect was examined by cresyl violet staining, Fluoro-Jade B histofluorescence staining and immunohistochemistry for neuronal-specific nuclear protein. Additionally, to study gliosis (glial changes), we performed immunohistochemistry for glial fibrillary acidic protein to examine astrocytes, and ionized calcium-binding adaptor molecule 1 to examine microglia. Furthermore, we examined alterations in pro-inflammatory M1 microglia by using double immunofluorescence. Pretreatment with 10 mg/kg laminarin failed to protect neurons in the hippocampal CA1 field and did not attenuate reactive gliosis in the field following TFI. In contrast, pretreatment with 50 or 100 mg/kg laminarin protected neurons, attenuated reactive gliosis and reduced pro-inflammatory M1 microglia in the CA1 field following TFI. Based on these results, we firmly propose that 50 mg/kg laminarin can be strategically applied to develop a preventative against injuries following cerebral ischemic insults.

3.
Biomed Pharmacother ; 124: 109850, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31981945

RESUMO

Oxcarbazepine (OXC), a voltage-gated sodium channel blocker, is an antiepileptic medication and used for the bipolar disorders treatment. Some voltage-gated sodium channel blockers have been demonstrated to display strong neuroprotective properties in models of cerebral ischemia. However, neuroprotective effects and mechanisms of OXC have not yet been reported. Here, we investigated the protective effect of OXC and its mechanisms in the cornu ammonis 1 subfield (CA1) of gerbils subjected to 5 min of transient global cerebral ischemia (tGCI). tGCI led to death of most pyramidal neurons in CA1 at 5 days after ischemia. OXC (100 and 200 mg/kg) was intraperitoneally administered once at 30 min after tGCI. Treatment with 200 mg/kg, not 100 mg/kg OXC, significantly protected CA1 pyramidal neurons from tGCI-induced injury. OXC treatment significantly decreased superoxide anion production, 4-hydroxy-2-nonenal and 8-hydroxyguanine levels in ischemic CA1 pyramidal neurons. In addition, the treatment restored levels of superoxide dismutases, catalase, and glutathione peroxidase. Furthermore, the treatment distinctly inhibited tGCI-induced microglia activation and significantly reduced levels of pro-inflammatory cytokines (interleukin-1ß and tumor necrosis factor-α). In particular, OXC treatment significantly enhanced expressions of nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream protein heme oxygenase-1 in ischemic CA1. The neuroprotective effects of OXC were abolished by brusatol (an inhibitor of Nrf2). Taken together, these results indicate that post-treatment of OXC can display neuroprotection against brain injuries following ischemic insults. This neuroprotection may be displayed by attenuation of oxidative stress and neuroinflammation, which can be mediated by activation of Nrf2 pathway.

4.
Mol Med Rep ; 21(1): 107-114, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31746417

RESUMO

Nuclear receptor related 1 protein (Nurr1), a member of the nuclear receptor 4 family of orphan nuclear receptors, has been reported to display anti­inflammatory properties. The present study investigated the alteration of Nurr1 immunoreactivity in the gerbil hippocampus proper following 5 min of transient global cerebral ischemia. In sham operated gerbils, Nurr1 immunoreactivity was observed in pyramidal neurons in all cornu ammonis 1­3 (CA1­3) subfields of the hippocampus proper. In ischemia­operated gerbils, Nurr1 immunoreactivity was altered in the CA1 subfield. Nurr1 immunoreactivity in CA1 pyramidal neurons gradually decreased until 2 days post­ischemia, and, at 4 days post­ischemia, Nurr1 immunoreactivity was concentrated in CA1 pyramidal neurons. Additionally, Nurr1 immunoreactivity was newly expressed in microglia in the CA1 subfield at 4 days post­ischemia. Conversely, in the CA2/3 subfield, time­dependent alteration of Nurr1 immunoreactivity was not identified at any time following ischemia. These results indicated that the alteration of Nurr1 expression in the CA1 subfield in the hippocampus may be associated with the death of CA1 pyramidal neurons.

5.
Int J Mol Med ; 44(5): 1801-1810, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31573045

RESUMO

Hyperpolarization­activated cyclic nucleotide­gated (HCN) channels have been known to participate in the regulation of neuronal excitability, synaptic transmission and long­term potentiation in the hippocampus. The present study investigated transient ischemia­induced changes of HCN1 and HCN2 expressions in the Cornu Ammonis 1 (CA1) subfield of the hippocampus in gerbils subjected to 5 min transient global cerebral ischemia (tgCI). Neuronal death was exhibited in pyramidal neurons of the striatum pyramidale in the CA1 subfield 4 days after tgCI. HCN1 and HCN2 immunoreactivities were demonstrated in intact CA1 pyramidal neurons, and were transiently and markedly increased in the CA pyramidal neurons at 6 h after ischemia. Thereafter, they gradually decreased in a time­dependent manner. A total of 4 days after ischemia, HCN1 and HCN2 immunoreactivities were barely detected in the CA1 pyramidal neurons; however, HCN1 and HCN2 were began to be expressed in pericytes and astrocytes at 4 days after ischemia. The results indicated that HCN1 and HCN2 expression levels were apparently changed in the gerbil hippocampal CA1 subfield following tgCI and suggested that ischemia­induced alterations in HCN1 and HCN2 expression levels may be closely associated with the death of CA1 pyramidal neurons following 5 min of tgCI.

6.
Brain Sci ; 9(10)2019 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-31627311

RESUMO

Oxcarbazepine, an antiepileptic drug, has been reported to modulate voltage-dependent sodium channels, and it is commonly used in epilepsy treatment. In this study, we investigated the neuroprotective effect of oxcarbazepine in the hippocampus after transient ischemia in gerbils. Gerbils randomly received oxcarbazepine 100 or 200 mg/kg before and after transient ischemia. We examined its neuroprotective effect in the cornu ammonis 1 subfield of the gerbil hippocampus at 5 days after transient ischemia by using cresyl violet staining, neuronal nuclei immunohistochemistry and Fluoro-Jade B histofluorescence staining for neuroprotection, and by using glial fibrillary protein and ionized calcium-binding adapter molecule 1 immunohistochemistry for reaction of astrocytes and microglia, respectively. Pre- and post-treatment with 200 mg/kg of oxcarbazepine, but not 100 mg/kg of oxcarbazepine, protected pyramidal neurons of the cornu ammonis 1 subfield from transient ischemic damage. In addition, pre- and post-treatment with oxcarbazepine (200 mg/kg) significantly ameliorated astrocytes and microglia activation in the ischemic cornu ammonis 1 subfield. In brief, our current results indicate that post-treatment as well as pre-treatment with 200 mg/kg of oxcarbazepine can protect neurons from ischemic insults via attenuation of the glia reaction.

7.
Cells ; 8(10)2019 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-31546722

RESUMO

A brief episode of transient ischemia (TI) can confer cerebral ischemic tolerance against a subsequent severer TI under standard condition. The brain under obesity's conditions is more sensitive to ischemic injury. However, the impact of a brief episode of TI under obesity's conditions has not been fully addressed yet. Thus, the objective of this study was to determine the effect of a brief TI in the hippocampus of high-fat diet (HFD)-induced obese gerbils and related mechanisms. Gerbils were maintained on HFD or normal diet (ND) for 12 weeks and subjected to 2 min TI. HFD gerbils were heavier, with higher blood glucose, serum total cholesterol, triglycerides, and leptin levels. Massive loss of pyramidal neurons occurred in the hippocampal cornu ammonis 1 (CA1) field of HFD animals at 5 days after 2 min of TI, but 2 min of TI did not elicit death of pyramidal neurons in ND gerbils. The HFD group showed significantly increased levels of oxidative stress indicators (dihydroethidium and 4-hydroxynonenal) and proinflammatory cytokines (tumor necrosis factor-α and interleukin-1ß) and microglial activation in pre- and/or post-ischemic phases compared to the ND group. Levels of mammalian target of rapamycin (mTOR) and phosphorylated-mTOR in the CA1 field of the HFD group were also significantly higher than the ND group. On the other hand, inhibition of mTOR activation by rapamycin (an allosteric mTOR inhibitor) significantly attenuated neuronal death induced by HFD, showing reduction of HFD-induced increases of oxidative stress indicators and proinflammatory cytokines, and microglia activation. Taken together, a brief episode of TI can evoke neuronal death under obesity's conditions. It might be closely associated with an abnormal increase of mTOR activation-mediated, severe oxidative stress and neuroinflammation in pre- and/or post-ischemic phases.

8.
Int J Mol Sci ; 20(18)2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31540405

RESUMO

Compelling evidence from preclinical and clinical studies has shown that mild hypothermia is neuroprotective against ischemic stroke. We investigated the neuroprotective effect of post-risperidone (RIS) treatment against transient ischemic injury and its mechanisms in the gerbil brain. Transient ischemia (TI) was induced in the telencephalon by bilateral common carotid artery occlusion (BCCAO) for 5 min under normothermic condition (37 ± 0.2 °C). Treatment of RIS induced hypothermia until 12 h after TI in the TI-induced animals under uncontrolled body temperature (UBT) compared to that under controlled body temperature (CBT) (about 37 °C). Neuroprotective effect was statistically significant when we used 5 and 10 mg/kg doses (p < 0.05, respectively). In the RIS-treated TI group, many CA1 pyramidal neurons of the hippocampus survived under UBT compared to those under CBT. In this group under UBT, post-treatment with RIS to TI-induced animals markedly attenuated the activation of glial cells, an increase of oxidative stress markers [dihydroethidium, 8-hydroxy-2' -deoxyguanosine (8-OHdG), and 4-Hydroxynonenal (4-HNE)], and a decrease of superoxide dismutase 2 (SOD2) in their CA1 pyramidal neurons. Furthermore, RIS-induced hypothermia was significantly interrupted by NBOH-2C-CN hydrochloride (a selective 5-HT2A receptor agonist), but not bromocriptine mesylate (a D2 receptor agonist). Our findings indicate that RIS-induced hypothermia can effectively protect neuronal cell death from TI injury through attenuation of glial activation and maintenance of antioxidants, showing that 5-HT2A receptor is involved in RIS-induced hypothermia. Therefore, RIS could be introduced to reduce body temperature rapidly and might be applied to patients for hypothermic therapy following ischemic stroke.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Hipocampo/efeitos dos fármacos , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Risperidona/uso terapêutico , Animais , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Gerbillinae , Hipocampo/metabolismo , Hipocampo/patologia , Hipotermia/induzido quimicamente , Hipotermia Induzida/métodos , Masculino , Estresse Oxidativo/efeitos dos fármacos
9.
J Clin Neurol ; 15(3): 275-284, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31286697

RESUMO

BACKGROUND AND PURPOSE: GNE myopathy is a rare progressive myopathy caused by biallelic mutations in the GNE gene, and frequently accompanied by rimmed vacuoles in muscle pathology. The initial symptom of foot drop or hip-girdle weakness eventually spreads to all limbs over a period of decades. Recent advances in pathophysiologic research have facilitated therapeutic trials aimed at resolving the core biochemical defect. However, there remains unsettled heterogeneity in its natural course, which confounds the analysis of therapeutic outcomes. We performed the first large-scale study of Korean patients with GNE myopathy. METHODS: We gathered the genetic and clinical profiles of 44 Korean patients with genetically confirmed GNE myopathy. The clinical progression was estimated retrospectively based on a patient-reported questionnaire on the status of the functional joint sets and daily activities. RESULTS: The wrist and neck were the last joints to lose antigravity functionality irrespective of whether the weakness started from the ankle or hip. Two-thirds of the patients could walk either independently or with an aid. The order of losing daily activities could be sorted from standing to eating. Patients with limb-girdle phenotype showed an earlier age at onset than those with foot-drop onset. Patients with biallelic kinase domain mutations tended to progress more rapidly than those with epimerase and kinase domain mutations. CONCLUSIONS: The reported data can guide the clinical management of GNE myopathy, as well as provide perspective to help the development of clinical trials.

10.
J Therm Biol ; 83: 1-7, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31331507

RESUMO

Spinal cord ischemia can result from cardiac arrest. It is an important cause of severe spinal cord injury that can lead to serious spinal cord disorders such as paraplegia. Hypothermia is widely acknowledged as an effective neuroprotective intervention following cardiac arrest injury. However, studies on effects of hypothermia on spinal cord injury following asphyxial cardiac arrest and cardiopulmonary resuscitation (CA/CPR) are insufficient. The objective of this study was to examine effects of hypothermia on motor deficit of hind limbs of rats and vulnerability of their spinal cords following asphyxial CA/CPR. Experimental groups included a sham group, a group subjected to CA/CPR, and a therapeutic hypothermia group. Severe motor deficit of hind limbs was observed in the control group at 1 day after asphyxial CA/CPR. In the hypothermia group, motor deficit of hind limbs was significantly attenuated compared to that in the control group. Damage/death of motor neurons in the lumbar spinal cord was detected in the ventral horn at 1 day after asphyxial CA/CPR. Neuronal damage was significantly attenuated in the hypothermia group compared to that in the control group. These results indicated that therapeutic hypothermia after asphyxial CA/CPR significantly reduced hind limb motor dysfunction and motoneuronal damage/death in the ventral horn of the lumbar spinal cord following asphyxial CA/CPR. Thus, hypothermia might be a therapeutic strategy to decrease motor dysfunction by attenuating damage/death of spinal motor neurons following asphyxial CA/CPR.


Assuntos
Parada Cardíaca/complicações , Hipotermia Induzida/métodos , Isquemia/terapia , Neurônios Motores/fisiologia , Paraplegia/terapia , Animais , Reanimação Cardiopulmonar/efeitos adversos , Parada Cardíaca/terapia , Isquemia/etiologia , Região Lombossacral/irrigação sanguínea , Região Lombossacral/fisiopatologia , Masculino , Paraplegia/etiologia , Ratos , Ratos Sprague-Dawley
11.
Calcif Tissue Int ; 105(5): 497-505, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31324954

RESUMO

Bisphosphonates are used in treating patients with breast cancer. In vitro studies have shown that bisphosphonates act directly on tumour cells, inhibiting cell proliferation and inducing apoptosis. In most such studies, drugs were added to culture media exposing cells to high bisphosphonate concentrations in solution. However, since bisphosphonates bind to bone hydroxyapatite with high affinity and remain bound for very long periods of time, these experimental systems are not an optimal model for the action of the drugs in vivo. The aim of this study was to determine whether bone-bound zoledronate has direct effects on adjacent breast cancer cells. Bone slices were pre-incubated with bisphosphonate solutions, washed, and seeded with cells of the breast cancer cell lines, MCF7 or MDA-MB-231. Proliferation was assessed by cell counts and thymidine incorporation for up to 72 h. Inhibition of the mevalonate pathway was tested by measuring the levels of unprenylated Rap1A, and apoptosis was examined by the presence of cleaved caspase-8 on western blots. The proliferation rate of breast cancer cells on zoledronate-treated bone was significantly lower compared to cells on control bone. Other bisphosphonates showed a similar inhibitory effect, with an order of potency similar to their clinical potencies. Unprenylated Rap1A accumulated in MCF7 cells on zoledronate-treated bone, suggesting zoledronate acted through the inhibition of the mevalonate pathway. Accumulation of cleaved caspase-8 in MDA-MB-231 cells on bisphosphonate-treated bone indicated increased apoptosis in the cells. In conclusion, bone-bound zoledronate inhibits breast cancer cell proliferation, an activity that may contribute to its clinical anti-tumour effects.

12.
Clin Neurol Neurosurg ; 180: 48-51, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30928807

RESUMO

FHL1-related myopathies are clinically heterogeneous, involving skeletal and cardiac muscles. Overlapping clinical features include joint contractures, rigid spine, scapuloperoneal weakness and cardiac diseases. Histopathologically, reducing bodies are the most characteristic finding, but not present in all FHL1-related cases. Non-specific dystrophic pathology without reducing body is usual in the forms of X-linked myopathy with postural muscle atrophy, Emery-Dreifuss muscular dystrophy and isolated hypertrophic cardiomyopathy. Here, we describe a patient with mild weakness with ankle contracture. We finally concluded he has a FHL1-related myopathy at an extreme end of phenotypic spectrum of FHL1 myopathy, which one might miss to recognize as a form of myopathy. The genetic variant was detected by whole exome sequencing, and its pathogenicity was clearly confirmed with pathological and biochemical studies. This is the first FHL1 case with a mildest phenotype backed by biochemical/genetic evidence. This report will help clinicians hesitating to further evaluate mild cases to better correlate the genotype to the phenotype.

13.
Anat Histol Embryol ; 48(4): 334-339, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31016783

RESUMO

The olfactory bulb (OB) shows special characteristics in its phylogenetic cortical structure and synaptic pattern. In the OB, gamma-aminobutyric acid (GABA), as an inhibitory neurotransmitter, is secreted from GABAergic neurons which contain parvalbumin (a calcium-binding protein). Many studies on the distribution of parvalbumin-immunoreactive neurons in the rodent OB have been published but poorly reported in the avian OB. Therefore, in this study, we compared the structure of the OB and distribution of parvalbumin-immunoreactive neurons in the OB between the rat and pigeon using cresyl violet staining and immunohistochemistry for parvalbumin, respectively. Fundamentally, the pigeon OB showed layers like those of the rat OB; however, some layers were not clear like in the rat OB. Parvalbumin-immunoreactive neurons in the pigeon OB were predominantly distributed in the external plexiform layer like that in the rat OB; however, the neurons did not have long processes like those in the rat. Furthermore, parvalbumin-immunoreactive fibres were abundant in some layers; this finding was not shown in the rat OB. In brief, parvalbumin-immunoreactive neurons were found like those in the rat OB; however, parvalbumin-immunoreactive fibres were significantly abundant in the pigeon OB compared to those in the rat OB.


Assuntos
Columbidae/anatomia & histologia , Bulbo Olfatório/citologia , Parvalbuminas/análise , Ratos Sprague-Dawley/anatomia & histologia , Animais , Benzoxazinas , Corantes , Columbidae/metabolismo , Imuno-Histoquímica/veterinária , Masculino , Bulbo Olfatório/química , Parvalbuminas/imunologia , Ratos , Ratos Sprague-Dawley/metabolismo , Coloração e Rotulagem/veterinária
14.
Int J Mol Sci ; 20(4)2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30781368

RESUMO

Neuronal death and reactive gliosis are major features of brain tissue damage following transient global cerebral ischemia (tgCI). This study investigated long-term changes in neuronal death and astrogliosis in the gerbil hippocampus for 180 days after 5 min of tgCI. A massive loss of pyramidal neurons was found in the hippocampal CA1 area (CA1) area between 5 and 30 days after tgCI by Fluoro-Jade B (FJB, a marker for neuronal degeneration) histofluorescence staining, but pyramidal neurons in the CA2/3 area did not die. The reaction of astrocytes (astrogliosis) was examined by glial fibrillary acidic protein (GFAP) immunohistochemistry. Morphological change or degeneration (death) of the astrocytes was found in the CA1 area after tgCI, but, in the CA2/3 area, astrogliosis was hardly shown. GFAP immunoreactive astrocytes in the CA1 area was significantly increased in number with time and peaked at 30 days after tgCI, and they began to be degenerated or dead from 40 days after tgCI. The effect was examined by double immunofluorescence staining for FJB and GFAP. The number of FJB/GFAP⁺ cells (degenerating astrocytes) was gradually increased with time after tgCI. At 180 days after tgCI, FJB/GFAP⁺ cells were significantly decreased, but FJB⁺ cells (dead astrocytes) were significantly increased. In brief, 5 min of tgCI induced a progressive degeneration of CA1 pyramidal neurons from 5 until 30 days with an increase of reactive astrocytes, and, thereafter, astrocytes were degenerated with time and dead at later times. This phenomenon might be shown due to the death of neurons.


Assuntos
Astrócitos/patologia , Linhagem da Célula , Gerbillinae/fisiologia , Hipocampo/patologia , Ataque Isquêmico Transitório/patologia , Animais , Astrócitos/metabolismo , Proteína Glial Fibrilar Ácida/metabolismo , Ataque Isquêmico Transitório/metabolismo , Masculino , Coloração e Rotulagem
15.
J Orthop Surg Res ; 14(1): 60, 2019 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-30786911

RESUMO

BACKGROUND: Alternative grafts are needed to improve the healing of bone non-union. Here, we assessed a bovine bone product which retains the inorganic and organic components of bone, as an alternative bone graft. METHODS: Bovine bone matrix proteins (BBMPs) were isolated from bovine bone particulates (BBPs) and tested in vitro. Primary rat osteoblast viability, differentiation, and mineralisation were assessed with alamarBlue®, real-time PCR, and von Kossa staining assays, respectively. Osteoclast formation was assessed in primary murine bone marrow cultures with TRAP staining. Human osteoblast growth and differentiation in the presence of BBPs was evaluated in 3D collagen gels in vitro using alamarBlue® and real-time PCR, respectively. The efficacy of BBPs as an alternative bone graft was tested in a rat critical-size calvarial defect model, with histology scored at 4 and 12 weeks post-surgery. RESULTS: In vitro, the highest concentration of BBMPs increased mineral deposition five-fold compared to the untreated control group (P < 0.05); enhanced the expression of key osteoblast genes encoding for RUNX2, alkaline phosphatase, and osteocalcin (P < 0.05); and decreased osteoclast formation three-fold, compared to the untreated control group (P < 0.05). However, the BBPs had no effect on primary human osteoblasts in vitro, and in vivo, no difference was found in healing between the BBP-treated group and the untreated control group. CONCLUSIONS: Overall, despite the positive effects of the BBMPs on the cells of the bone, the bovine bone product as a whole did not enhance bone healing. Finding a way to harness the positive effect of these BBMPs would provide a clear benefit for healing bone non-union.


Assuntos
Matriz Óssea , Substitutos Ósseos/administração & dosagem , Transplante Ósseo/métodos , Osteogênese/efeitos dos fármacos , Congêneres da Testosterona/administração & dosagem , Animais , Matriz Óssea/metabolismo , Substitutos Ósseos/metabolismo , Transplante Ósseo/tendências , Bovinos , Células Cultivadas , Humanos , Masculino , Camundongos , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Osteogênese/fisiologia , Ratos , Ratos Sprague-Dawley , Congêneres da Testosterona/metabolismo
16.
Mol Med Rep ; 19(3): 1721-1727, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30628688

RESUMO

Intermittent fasting (ImF) is known to reduce oxidative stress and affects adult neurogenesis in the hippocampal dentate gyrus. However, it is unknown how ImF affects endogenous antioxidants expressions, cell proliferation, and neuroblast differentiation and their dendrite remodeling over 3 months in the dentate gyrus of adult gerbils. The present study subjected 6­month old male gerbils to a normal diet or alternate­day ImF for 1, 2 and 3 months. Changes in body weight were not significantly different between gerbils fed a normal diet and on ImF. The present study also investigated the effects of ImF on antioxidant enzymes [superoxide dismutase (SOD)­1, SOD2 and catalase] using immunohistochemistry, and endogenous cell proliferation, neuroblast differentiation and neuroblast dendrite complexity by using Ki67 (a cell proliferation marker) and doublecortin (neuroblast differentiation marker) immunohistochemistry in the dentate gyrus. SOD1, SOD2 and CAT immunoreactivities were shown in cells in the granule cell and polymorphic layers. SOD1, SOD2 and catalase immunoreactivity in the cells peaked at 2, 1 and 1 month, respectively, following ImF. Cell proliferation was ~250, 129 and 186% of the control, at 1, 2 and 3 months of ImF, respectively. Neuroblast differentiation was ~41, 32 and 12% of the control, at 1, 2 and 3 months of ImF, respectively, indicating that dendrites of neuroblasts were more arborized and developed at 3 months of ImF. Taken together, these results indicate that ImF for 3 months improves endogenous SOD1, SOD2 and catalase expressions and enhances cell proliferation, and neuroblast dendrites complexity and maturation in the adult gerbil dentate gyrus.


Assuntos
Diferenciação Celular/genética , Dendritos/genética , Gerbillinae/genética , Neurogênese/genética , Animais , Antioxidantes/metabolismo , Catalase/genética , Proliferação de Células/genética , Dendritos/metabolismo , Giro Denteado/crescimento & desenvolvimento , Jejum/metabolismo , Gerbillinae/crescimento & desenvolvimento , Hipocampo/crescimento & desenvolvimento , Hipocampo/metabolismo , Humanos , Células-Tronco Neurais/metabolismo , Neurônios/metabolismo , Estresse Oxidativo/genética , Superóxido Dismutase/genética , Superóxido Dismutase-1/genética
17.
Metab Brain Dis ; 34(1): 223-233, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30443768

RESUMO

The degree of transient ischemic damage in the cerebral hemisphere is different according to duration of transient ischemia and cerebral regions. Mongolian gerbils show various lesions in the hemisphere after transient unilateral occlusion of the common carotid artery (UOCCA) because they have different types of patterns of anterior and posterior communicating arteries. We examined differential regional damage in the ipsilateral hemisphere of the gerbil after 30 min of UOCCA by using 2,3,5-triphenyltetrazolium chloride (TTC) staining, cresyl violet (CV) Nissl staining, Fluoro-Jade B (F-J B) fluorescence staining, and NeuN immunohistochemistry 5 days after UOCCA. In addition, regional differences in reactions of astrocytes and microglia were examined using GFAP and Iba-1 immunohistochemistry. After right UOCCA, neurological signs were assessed to define ischemic symptomatic animals. Moderate symptomatic gerbils showed several infarcts, while mild symptomatic gerbils showed selective neuronal death/loss in the primary motor and sensory cortex, striatum, thalamus, and hippocampus 5 days after UOCCA. In the areas, morphologically changed GFAP immunoreactive astrocytes and Iba-1 immunoreactive microglia were found, and their numbers were increased or decreased according to the damaged areas. In brief, our results demonstrate that 30 min of UOCCA in gerbils produced infarcts or selective neuronal death depending on ischemic severity in the ipsilateral cerebral cortex, striatum, thalamus and hippocampus, showing that astrocytes and microglia were differently reacted 5 days after UOCCA. Taken together, a gerbil model of 30 min of UOCCA can be used to study mechanisms of infarction and/or regional selective neuronal death/loss as well as neurological dysfunction following UOCCA.


Assuntos
Infarto Encefálico/patologia , Estenose das Carótidas/patologia , Morte Celular/fisiologia , Gliose/patologia , Neurônios/patologia , Animais , Astrócitos/metabolismo , Astrócitos/patologia , Infarto Encefálico/etiologia , Infarto Encefálico/metabolismo , Proteínas de Ligação ao Cálcio , Artéria Carótida Primitiva , Estenose das Carótidas/complicações , Estenose das Carótidas/metabolismo , Proteínas de Ligação a DNA/metabolismo , Gerbillinae , Proteína Glial Fibrilar Ácida/metabolismo , Gliose/etiologia , Gliose/metabolismo , Masculino , Proteínas dos Microfilamentos , Microglia/metabolismo , Microglia/patologia , Neurônios/metabolismo
18.
Korean J Intern Med ; 34(4): 917-931, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29334721

RESUMO

BACKGROUND/AIMS: To investigate the efficacy and safety of tocilizumab (TCZ) humanized anti-interleukin-6 receptor monoclonal antibody, in Korean patients with active rheumatoid arthritis (RA) refractory to conventional disease modifying anti-rheumatic drugs (DMARDs) including methotrexate (MTX). METHODS: The main study was a 24-week, randomized, double-blind, controlled trial that was followed by a 48-week, open-labeled, extension phase. TCZ (8 mg/kg) or placebo was intravenously administered every 4 weeks. RESULTS: Those treated with TCZ showed more favorable outcomes in terms of 20% according to the American College of Rheumatology response criteria (ACR20) and ACR50 responses, individual parameters of ACR core set, disease activity score in 28 joints (DAS28) remission, and European League Against Rheumatism (EULAR) response at week 24. These improvements were maintained or increased during the extension period. DAS28 remission at week 72 was associated with EULAR good response at week 12. The patients who experienced any adverse event (AE) were more frequent in the TCZ group compared to the placebo group. Most AEs were mild or moderate in intensity, although TCZ therapy had possible AEs including serious infection, abnormal liver function, and atherogenic lipid profile. CONCLUSION: TCZ infusion add-on is highly efficacious and well-tolerated in Korean patients with active RA refractory to conventional DMARDs including MTX. EULAR good response at week 12 could predict DAS28 remission at week 72.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Articulações/efeitos dos fármacos , Adulto , Anticorpos Monoclonais Humanizados/efeitos adversos , Antirreumáticos/efeitos adversos , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/imunologia , Artrite Reumatoide/fisiopatologia , Método Duplo-Cego , Feminino , Humanos , Articulações/imunologia , Articulações/fisiopatologia , Masculino , Pessoa de Meia-Idade , Recuperação de Função Fisiológica , Indução de Remissão , República da Coreia , Fatores de Tempo , Resultado do Tratamento
19.
Muscle Nerve ; 58(2): 235-244, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29669168

RESUMO

INTRODUCTION: Congenital myopathies are muscle diseases characterized by specific histopathologic features, generalized hypotonia from birth, and perinatal complications, although some cases develop during childhood or, rarely, in adulthood. We undertook this study to characterize congenital myopathies among patients registered at our institution. METHODS: Clinical, histopathologic, and genetic features were evaluated in 34 patients recruited for this study. RESULTS: The majority of patients experienced a childhood onset, and no disease-related mortality was recorded during follow-up. Functional outcomes were no better for those with late-onset disease, indicating later disease progression can be significant. Nemaline myopathy was the most frequent pathology, followed by central core disease and centronuclear myopathy. Among the 18 (54.5%) genetically confirmed patients, NEB and RYR1 mutations were the most common, followed by DNM2 mutations. DISCUSSION: This study shows features not previously reported and suggests that congenital myopathy should be considered an important issue among adult patients. Muscle Nerve 58: 235-244, 2018.


Assuntos
Miotonia Congênita/patologia , Adolescente , Adulto , Idade de Início , Criança , Pré-Escolar , Dinaminas/genética , Feminino , Humanos , Lactente , Masculino , Fibras Musculares Esqueléticas/patologia , Proteínas Musculares/genética , Mutação , Miopatias da Nemalina/genética , Miopatias da Nemalina/patologia , Miopatias Congênitas Estruturais/congênito , Miopatias Congênitas Estruturais/genética , Miopatias Congênitas Estruturais/patologia , Miopatia da Parte Central/congênito , Miopatia da Parte Central/genética , Miopatia da Parte Central/patologia , Miotonia Congênita/genética , República da Coreia , Estudos Retrospectivos , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Resultado do Tratamento , Adulto Jovem
20.
J Exp Psychol Hum Percept Perform ; 44(6): 925-940, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29494191

RESUMO

Previous studies have suggested that people can maintain prioritized items in visual working memory for many seconds, with negligible loss of information over time. Such findings imply that working memory representations are robust to the potential contaminating effects of internal noise. However, once visual information is encoded into working memory, one might expect it to inevitably begin degrading over time, as this actively maintained information is no longer tethered to the original perceptual input. Here, we examined this issue by evaluating working memory for single central presentations of an oriented grating, color patch, or face stimulus, across a range of delay periods (1, 3, 6, or 12 s). We applied a mixture-model analysis to distinguish changes in memory precision over time from changes in the frequency of outlier responses that resemble random guesses. For all 3 types of stimuli, participants exhibited a clear and consistent decline in the precision of working memory as a function of temporal delay, as well as a modest increase in guessing-related responses for colored patches and face stimuli. We observed a similar loss of precision over time while controlling for temporal distinctiveness. Our results demonstrate that visual working memory is far from lossless: while basic visual features and complex objects can be maintained in a quite stable manner over time, these representations are still subject to noise accumulation and complete termination. (PsycINFO Database Record


Assuntos
Percepção de Cores/fisiologia , Memória de Curto Prazo/fisiologia , Reconhecimento Visual de Modelos/fisiologia , Percepção Espacial/fisiologia , Adulto , Reconhecimento Facial/fisiologia , Feminino , Humanos , Masculino , Fatores de Tempo , Adulto Jovem
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