共查询到20条相似文献,搜索用时 31 毫秒
1.
Cilia R Rossi C Frosini D Volterrani D Siri C Pagni C Benti R Pezzoli G Bonuccelli U Antonini A Ceravolo R 《PloS one》2011,6(5):e18301
Objective
To investigate dopaminergic function in a large cohort of patients with corticobasal syndrome (CBS) and describe its relationship with clinical features in comparison to Parkinson''s disease and healthy control subjects. In addition, we assessed prevalence and features of individuals with CBS and in vivo evidence of preserved nigral neuronal density.Background
Substantia nigra pars compacta (SNc) neuronal degeneration is a mandatory pathological criterion for definite corticobasal degeneration, though sporadic autopsy-proven cases with ante-mortem imaging evidence of preserved nigral terminals have been recently described.Methods
In this multicenter study, we investigated presynaptic nigrostriatal function in 36 outpatients fulfilling clinical criteria for “probable corticobasal degeneration” (age 71±7.3 years; disease duration 3.9±1.6 years), 37 PD and 24 healthy control subjects using FP-CIT single photon emission computed tomography. Clinical, neuropsychological, and magnetic resonance imaging assessment was performed to characterize CBS patients. Linear discriminant analysis was used to categorize normal vs. pathological scans.Results
FP-CIT binding reduction in patients with CBS was characterized by larger variability, more uniform reduction throughout the striatum and greater hemispheric asymmetry compared to PD. Moreover, there was no significant correlation between tracer uptake values and clinical features such as disease duration and severity. Despite all CBS subjects showed obvious bilateral extrapyramidal signs, FP-CIT uptake was found to be normal bilaterally in four CBS patients and only unilaterally in other four cases. Extensive clinical, neuropsychological and imaging assessment did not reveal remarkable differences between CBS subjects with normal vs. pathological FP-CIT uptake.Conclusions
Our findings support the hypothesis that extrapyramidal motor symptoms in CBS are not invariably associated with SNc neuronal degeneration and that supranigral factors may play a major role in several cases. CBS individuals with normal FP-CIT uptake do not show any clinical or cognitive feature suggesting a different pathology than CBD. 相似文献2.
Sarah J Bolton Kate Pinnion Victor Oreffo Martyn Foster Kent E Pinkerton 《Respiratory research》2009,10(1):118
Background
Continuous exposure to tobacco smoke (TS) is a key cause of chronic obstructive pulmonary disease (COPD), a complex multifactorial disease that is difficult to model in rodents. The spontaneously hypertensive (SH) rat exhibits several COPD-associated co-morbidities such as hypertension and increased coagulation. We have investigated whether SH rats are a more appropriate animal paradigm of COPD.Methods
SH rats were exposed to TS for 6 hours/day, 3 days/week for 14 weeks, and the lung tissues examined by immunohistochemistry.Results
TS induced a CK13-positive squamous metaplasia in proximal airways, which also stained for Ki67 and p63. We hypothesise that this lesion arises by basal cell proliferation, which differentiates to a squamous cell phenotype. Differences in staining profiles for the functional markers CC10 and surfactant D, but not phospho-p38, indicated loss of ability to function appropriately as secretory cells. Within the parenchyma, there were also differences in the staining profiles for CC10 and surfactant D, indicating a possible attempt to compensate for losses in proximal airways. In human COPD sections, areas of CK13-positive squamous metaplasia showed sporadic p63 staining, suggesting that unlike the rat, this is not a basal cell-driven lesion.Conclusion
This study demonstrates that although proximal airway metaplasia in rat and human are both CK13+ and therefore squamous, they potentially arise by different mechanisms. 相似文献3.
Mahar I Tan S Davoli MA Dominguez-Lopez S Qiang C Rachalski A Turecki G Mechawar N 《PloS one》2011,6(10):e26610
Background
Adult hippocampal neurogenesis has been implicated in the mechanism of antidepressant action, and neurotrophic factors can mediate the neurogenic changes underlying these effects. The neurotrophic factor neuregulin-1 (NRG1) is involved in many aspects of brain development, from cell fate determination to neuronal maturation. However, nothing is known about the influence of NRG1 on neurodevelopmental processes occurring in the mature hippocampus.Methods
Adult male mice were given subcutaneous NRG1 or saline to assess dentate gyrus proliferation and neurogenesis, as well as cell fate determination. Mice also underwent behavioral testing. Expression of ErbB3 and ErbB4 NRG1 receptors in newborn dentate gyrus cells was assessed at various time points between birth and maturity. The phenotype of ErbB-expressing progenitor cells was also characterized with cell type-specific markers.Results
The current study shows that subchronic peripheral NRG1β administration selectively increased cell proliferation (by 71%) and neurogenesis (by 50%) in the caudal dentate gyrus within the ventral hippocampus. This pro-proliferative effect did not alter neuronal fate, and may have been mediated by ErbB3 receptors, which were expressed by newborn dentate gyrus cells from cell division to maturity and colocalized with SOX2 in the subgranular zone. Furthermore, four weeks after cessation of subchronic treatment, animals displayed robust antidepressant-like behavior in the absence of changes in locomotor activity, whereas acute treatment did not produce antidepressant effects.Conclusions
These results show that neuregulin-1β has pro-proliferative, neurogenic and antidepressant properties, further highlight the importance of peripheral neurotrophic factors in neurogenesis and mood, and support the role of hippocampal neurogenesis in mediating antidepressant effects. 相似文献4.
Poya Tababat-Khani Lisa M. Berglund Carl-David Agardh Maria F. Gomez Elisabet Agardh 《PloS one》2013,8(8)
Aims
Sight-threatening diabetic retinopathy has been treated with photocoagulation for decades but the mechanisms behind the beneficial clinical effects are poorly understood. One target of irradiation and a potential player in this process is the retinal pigment epithelium (RPE). Here we establish an in vitro model for photocoagulation of human RPE cells.Methods
ARPE-19 cells were exposed to photocoagulation and studied at various time points up to 168h. Lesion morphology, necrosis and apoptosis were investigated by light microscopy; LIVE/DEAD staining and measurements of lactate dehydrogenase activity; and TUNEL- and ELISA-based quantification of DNA fragments, respectively. Cell migration and proliferation were explored using docetaxel and mitomycin C; temporal and spatial changes in proliferation were assessed by confocal immunofluorescence of proliferating cell nuclear antigen. Gene expression was measured by qPCR.Results
Photocoagulation of ARPE-19 resulted in denaturation of proteins and reproducible lesion formation. A transient peak in necrosis, followed by a peak in apoptosis was observed in cells within the lesions at 6h and 24h, respectively after photocoagulation. Cell proliferation was depressed during the first hours after photocoagulation, back to control levels at 24h and augmented in the following days. These effects were not limited to cells in the lesions, but also evident in neighbouring cells. Changes in cell proliferation during lesion repair were preceded by changes in cell migration. Altered mRNA expression of genes previously implicated in the regulation of cell proliferation (FOS, IL-1β, IL-8, HMGA2), migration and tissue repairing (TGFBR2, ADAMTS6, TIMP3, CTGF) was observed, as well as increased expression of the alarmin IL33 and the cytoprotective gene HSPA6.Conclusions
Using a laser system and experimental settings that comply with standards used in clinical practice, we have established a suitable model for in vitro photocoagulation of human RPE cells to isolate their contribution to the beneficial effects of laser treatment. 相似文献5.
Sietke G. Postema Corry K. van der Sluis Kristina Waldenl?v Liselotte M. Norling Hermansson 《PloS one》2012,7(11)
Objective
To describe upper body structures associated with upper limb reduction deficiency and the development of these structures over time, to examine the presence of physical complaints in this population, and to compare body structures and complaints between groups based on prosthesis use.Design
Prospective cohort study with a follow-up period of 24 years, with matched able-bodied controls.Subjects
Twenty-eight patients with unilateral below-elbow reduction deficiency fitted with myoelectric prostheses, aged 8–18 years at inclusion.Method
Measurements of upper arm, trunk and spine were performed and study-specific questionnaires were answered at baseline and follow-up; the Brief Pain Inventory and the Quick Disability of Arm, Shoulder, and Hand questionnaires were answered at follow-up.Results
Both at baseline and follow-up, within-subjects differences in structures of the arm and trunk were shown in patients but not in controls. Spinal deviations, although small, were greater in patients compared to controls. Self-reported disability was higher in patients compared to controls. Differences in back pain and effect of prostheses use could not be shown.Conclusions
Patients with unilateral below-elbow reduction deficiency have consistent differences in upper body structures. Deviations of the spine, probably of functional origin, do not progress to clinically relevant scoliosis. 相似文献6.
Iwata Y Suzuki K Wakuda T Seki N Thanseem I Matsuzaki H Mamiya T Ueki T Mikawa S Sasaki T Suda S Yamamoto S Tsuchiya KJ Sugihara G Nakamura K Sato K Takei N Hashimoto K Mori N 《PloS one》2008,3(5):e2283
Background
Epidemiological studies suggest that radiation exposure may be a potential risk factor for schizophrenia in adult humans. Here, we investigated whether adult irradiation in rats caused behavioral abnormalities relevant to schizophrenia.Methodology/Principal Findings
A total dose of 15-Gy irradiation in six fractionations during 3 weeks was exposed to the forebrain including the subventricular zone (SVZ) and subgranular zone (SGZ) with male rats in the prone position. Behavioral, immunohistochemical, and neurochemical studies were performed three months after fractionated ionizing irradiation. Three months after fractionated ionizing irradiation, the total numbers of BrdU-positive cells in both the SVZ and SGZ zones of irradiated rats were significantly lower than those of control (sham-irradiated) rats. Hyperactivity after administration of the dopaminergic agonist methamphetamine, but not the N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine, was significantly enhanced in the irradiated rats although spontaneous locomotion in the irradiated rats was significantly lower than that of controls. Behavioral abnormalities including auditory sensory gating deficits, social interaction deficits, and working memory deficits were observed in the irradiated rats.Conclusion/Significance
The present study suggests that irradiation in adulthood caused behavioral abnormalities relevant to schizophrenia, and that reduction of adult neurogenesis by irradiation may be associated with schizophrenia-like behaviors in rats. 相似文献7.
Lilia Marinova-Mutafchieva Mona Sadeghian Lauren Broom John B. Davis† rew D. Medhurst† David T. Dexter 《Journal of neurochemistry》2009,110(3):966-975
Cellular interactions between activated microglia and degenerating neurons in in vivo models of Parkinson's disease are not well defined. This time course study assesses the dynamics of morphological and immunophenotypic properties of activated microglia in a 6-hydroxydopamine (6-OHDA) model of Parkinson's disease. Neurodegeneration in the substantia nigra pars compacta (SNc) was induced by unilateral injection of 6-OHDA into the medial forebrain bundle. Activated microglia, identified using monoclonal antibodies: clone of antibody that detects major histocompatibility complex (MHC) class II antigens (OX6) for MHC class II, clone of antibody that detects cell surface antigen-cluster of differentiation 11b – anti-complement receptor 3, a marker for complement receptor 3 and CD 68 for phagocytic activity. Activation of microglia in the lesioned SNc was rapid with cells possessing amoeboid or ramified morphology appeared on day 1, whilst antibody clone that detects macrophage-myeloid associated antigen immunoreactivity was observed at day 3 post-lesion when there was no apparent loss of tyrosine hydroxylase (TH)+ve dopaminergic (DA) SNc neurons. Thereafter, OX6 and antibody clone that detects macrophage-myeloid associated antigen activated microglia selectively adhered to degenerating axons, dendrites and apoptotic (caspase 3+ve) DA neurons in the SNc were observed at day 7. This was followed by progressive loss of TH+ve SNc neurons, with the peak of TH+ve cell loss (51%) being observed at day 9. This study suggests that activation of microglia precedes DA neuronal cell loss and neurons undergoing degeneration may be phagocytosed prematurely by phagocytic microglia. 相似文献
8.
Perera TD Dwork AJ Keegan KA Thirumangalakudi L Lipira CM Joyce N Lange C Higley JD Rosoklija G Hen R Sackeim HA Coplan JD 《PloS one》2011,6(4):e17600
Background
Rodent studies show that neurogenesis is necessary for mediating the salutary effects of antidepressants. Nonhuman primate (NHP) studies may bridge important rodent findings to the clinical realm since NHP-depression shares significant homology with human depression and kinetics of primate neurogenesis differ from those in rodents. After demonstrating that antidepressants can stimulate neurogenesis in NHPs, our present study examines whether neurogenesis is required for antidepressant efficacy in NHPs.Materials/Methodology
Adult female bonnets were randomized to three social pens (N = 6 each). Pen-1 subjects were exposed to control-conditions for 15 weeks with half receiving the antidepressant fluoxetine and the rest receiving saline-placebo. Pen-2 subjects were exposed to 15 weeks of separation-stress with half receiving fluoxetine and half receiving placebo. Pen-3 subjects 2 weeks of irradiation (N = 4) or sham-irradiation (N = 2) and then exposed to 15 weeks of stress and fluoxetine. Dependent measures were weekly behavioral observations and postmortem neurogenesis levels.Results
Exposing NHPs to repeated separation stress resulted in depression-like behaviors (anhedonia and subordinance) accompanied by reduced hippocampal neurogenesis. Treatment with fluoxetine stimulated neurogenesis and prevented the emergence of depression-like behaviors. Ablation of neurogenesis with irradiation abolished the therapeutic effects of fluoxetine. Non-stressed controls had normative behaviors although the fluoxetine-treated controls had higher neurogenesis rates. Across all groups, depression-like behaviors were associated with decreased rates of neurogenesis but this inverse correlation was only significant for new neurons in the anterior dentate gyrus that were at the threshold of completing maturation.Conclusion
We provide evidence that induction of neurogenesis is integral to the therapeutic effects of fluoxetine in NHPs. Given the similarity between monkeys and humans, hippocampal neurogenesis likely plays a similar role in the treatment of clinical depression. Future studies will examine several outstanding questions such as whether neuro-suppression is sufficient for producing depression and whether therapeutic neuroplastic effects of fluoxetine are specific to antidepressants. 相似文献9.
Background
Promotion of remyelination is a major goal in treating demyelinating diseases such as multiple sclerosis (MS). The recombinant human monoclonal IgM, rHIgM22, targets myelin and oligodendrocytes (OLs) and promotes remyelination in animal models of MS. It is unclear whether rHIgM22-mediated stimulation of lesion repair is due to promotion of oligodendrocyte progenitor cell (OPC) proliferation and survival, OPC differentiation into myelinating OLs or protection of mature OLs. It is also unknown whether astrocytes or microglia play a functional role in IgM-mediated lesion repair.Methods
We assessed the effect of rHIgM22 on cell proliferation in mixed CNS glial and OPC cultures by tritiated-thymidine uptake and by double-label immunocytochemistry using the proliferation marker, Ki-67. Antibody-mediated signaling events, OPC differentiation and OPC survival were investigated and quantified by Western blots.Results
rHIgM22 stimulates OPC proliferation in mixed glial cultures but not in purified OPCs. There is no proliferative response in astrocytes or microglia. rHIgM22 activates PDGFαR in OPCs in mixed glial cultures. Blocking PDGFR-kinase inhibits rHIgM22-mediated OPC proliferation in mixed glia. We confirm in isolated OPCs that rHIgM22-mediated anti-apoptotic signaling and inhibition of OPC differentiation requires PDGF and FGF-2. We observed no IgM-mediated effect in mature OLs in the absence of PDGF and FGF-2.Conclusion
Stimulation of OPC proliferation by rHIgM22 depends on co-stimulatory astrocytic and/or microglial factors. We demonstrate that rHIgM22-mediated activation of PDGFαR is required for stimulation of OPC proliferation. We propose that rHIgM22 lowers the PDGF threshold required for OPC proliferation and protection, which can result in remyelination of CNS lesions. 相似文献10.
José K. van den Heuvel Leslie Eggels Eric Fliers Andries Kalsbeek Roger A. H. Adan Susanne E. la Fleur 《PloS one》2014,9(1)
Objective
Leptin resistance is a common hallmark of obesity. Rats on a free-choice high-fat high-sugar (fcHFHS) diet are resistant to peripherally administered leptin. The aim of this study was to investigate feeding responses to central leptin as well as the associated changes in mRNA levels in hypothalamic and mesolimbic brain areas.Design and Methods
Rats on a CHOW or fcHFHS diet for 8 days received leptin or vehicle intracerebro(lateral)ventricularly (ICV) and food intake was measured 5 h and 24 h later. Four days later, rats were sacrificed after ICV leptin or vehicle and mRNA levels were quantified for hypothalamic pro-opiomelanocortin (POMC) and neuropeptide Y (NPY) and for preproenkephalin (ppENK) in nucleus accumbens and tyrosine hydroxylase (TH) in ventral tegmental area (VTA).Results
ICV leptin decreased caloric intake both in CHOW and fcHFHS rats. In fcHFHS, leptin preferentially decreased chow and fat intake. Leptin increased POMC and decreased NPY mRNA in CHOW, but not in fcHFHS rats. In CHOW rats, leptin had no effect on ppENK mRNA and decreased TH mRNA. In fcHFHS, leptin decreased ppENK mRNA and increased TH mRNA.Conclusion
Despite peripheral and arcuate leptin resistance, central leptin suppresses feeding in fcHFHS rats. As the VTA and nucleus accumbens are still responsive to leptin, these brain areas may therefore, at least partly, account for the leptin-induced feeding suppression in rats on a fcHFHS diet. 相似文献11.
12.
Purpose
Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a member of the epidermal growth factor family. The membrane-bound proHB-EGF is known to be a precursor of the soluble form of HB-EGF (sHB-EGF), which promotes cell proliferation and survival. While the functions of sHB-EGF have been extensively studied, it is not yet fully understood if proHB-EGF is also involved in cellular signaling events. In this study, we utilized the anti-HB-EGF monoclonal antibodies Y-142 and Y-073, which have differential specificities toward proHB-EGF, in order to elucidate proHB-EGF functions in cancer cells.Experimental Design
The biological activities of proHB-EGF were assessed in cell proliferation, caspase activation, and juxtacrine activity assays by using a 3D spheroid culture of NUGC-3 cells.Results
Y-142 and Y-073 exhibited similar binding and neutralizing activities for sHB-EGF. However, only Y-142 bound to proHB-EGF. We could detect the function of endogenously expressed proHB-EGF in a 3D spheroid culture. Blocking proHB-EGF with Y-142 reduced spheroid formation, suppressed cell proliferation, and increased caspase activation in the 3D spheroid culture of NUGC-3 cells.Conclusions
Our results show that proHB-EGF acts as a cell proliferation and cell survival factor in cancer cells. The results suggest that proHB-EGF may play an important role in tumor progression. 相似文献13.
Esther Sastre Laura Caracuel Fabiano E. Xavier Gloria Balfagón Javier Blanco-Rivero 《PloS one》2013,8(8)
Objectives
We analyzed whether mast cell stabilization by either ketotifen or tranilast could alter either sympathetic or nitrergic innervation function in rat mesenteric arteries.Methods
Electrical field stimulation (EFS)-induced contraction was analyzed in mesenteric segments from 6-month-old Wistar rats in three experimental groups: control, 3-hour ketotifen incubated (0.1 αmol/L), and 3-hour tranilast incubated (0.1 mmol/L). To assess the possible participation of nitrergic or sympathetic innervation, EFS contraction was analyzed in the presence of non-selective nitric oxide synthase (NOS) inhibitor L-NAME (0.1 mmol/L), α-adrenergic receptor antagonist phentolamine (0.1 µmol/L), or the neurotoxin 6-hydroxydopamine (6-OHDA, 1.46 mmol/L). Nitric oxide (NO) and superoxide anion (O2 .-) levels were measured, as were vasomotor responses to noradrenaline (NA) and to NO donor DEA-NO, in the presence and absence of 0.1 mmol/L tempol. Phosphorylated neuronal NOS (P-nNOS) expression was also analyzed.Results
EFS-induced contraction was increased by ketotifen and decreased by tranilast. L-NAME increased the vasoconstrictor response to EFS only in control segments. The vasodilator response to DEA-NO was higher in ketotifen- and tranilast-incubated segments, while tempol increased vasodilator response to DEA-NO only in control segments. Both NO and O2 - release, and P-nNOS expression were diminished by ketotifen and by tranilast treatment. The decrease in EFS-induced contraction produced by phentolamine was lower in tranilast-incubated segments. NA vasomotor response was decreased only by tranilast. The remnant vasoconstriction observed in control and ketotifen-incubated segments was abolished by 6-OHDA.Conclusion
While both ketotifen and tranilast diminish nitrergic innervation function, only tranilast diminishes sympathetic innnervation function, thus they alter the vasoconstrictor response to EFS in opposing manners. 相似文献14.
Eva Chinier Sylvie N’Guyen Grégoire Lignon Aram Ter Minassian Isabelle Richard Micka?l Dinomais 《PloS one》2014,9(4)
Background
Motor imagery is considered as a promising therapeutic tool for rehabilitation of motor planning problems in patients with cerebral palsy. However motor planning problems may lead to poor motor imagery ability.Aim
The aim of this functional magnetic resonance imaging study was to examine and compare brain activation following motor imagery tasks in patients with hemiplegic cerebral palsy with left or right early brain lesions. We tested also the influence of the side of imagined hand movement.Method
Twenty patients with clinical hemiplegic cerebral palsy (sixteen males, mean age 12 years and 10 months, aged 6 years 10 months to 20 years 10 months) participated in this study. Using block design, brain activations following motor imagery of a simple opening-closing hand movement performed by either the paretic or nonparetic hand was examined.Results
During motor imagery tasks, patients with early right brain damages activated bilateral fronto-parietal network that comprise most of the nodes of the network well described in healthy subjects. Inversely, in patients with left early brain lesion brain activation following motor imagery tasks was reduced, compared to patients with right brain lesions. We found also a weak influence of the side of imagined hand movement.Conclusion
Decreased activations following motor imagery in patients with right unilateral cerebral palsy highlight the dominance of the left hemisphere during motor imagery tasks. This study gives neuronal substrate to propose motor imagery tasks in unilateral cerebral palsy rehabilitation at least for patients with right brain lesions. 相似文献15.
Swee Tin Aw Michael John Todd Nadine Lehnen Grace Elizabeth Aw Konrad Peter Weber Thomas Eggert Gabor Michael Halmagyi 《PloS one》2013,8(12)
Background
Vestibular reflexes, evoked by human electrical (galvanic) vestibular stimulation (EVS), are utilized to assess vestibular function and investigate its pathways. Our study aimed to investigate the electrically-evoked vestibulo-ocular reflex (eVOR) output after bilateral and unilateral vestibular deafferentations to determine the characteristics for interpreting unilateral lesions such as vestibular schwannomas.Methods
EVOR was recorded with dual-search coils as binocular three-dimensional eye movements evoked by bipolar 100 ms-step at EVS intensities of [0.9, 2.5, 5.0, 7.5, 10.0]mA and unipolar 100 ms-step at 5 mA EVS intensity. Five bilateral vestibular deafferented (BVD), 12 unilateral vestibular deafferented (UVD), four unilateral vestibular schwannoma (UVS) patients and 17 healthy subjects were tested with bipolar EVS, and five UVDs with unipolar EVS.Results
After BVD, bipolar EVS elicited no eVOR. After UVD, bipolar EVS of one functioning ear elicited bidirectional, excitatory eVOR to cathodal EVS with 9 ms latency and inhibitory eVOR to anodal EVS, opposite in direction, at half the amplitude with 12 ms latency, exhibiting an excitatory-inhibitory asymmetry. The eVOR patterns from UVS were consistent with responses from UVD confirming the vestibular loss on the lesion side. Unexpectedly, unipolar EVS of the UVD ear, instead of absent response, evoked one-third the bipolar eVOR while unipolar EVS of the functioning ear evoked half the bipolar response.Conclusions
The bidirectional eVOR evoked by bipolar EVS from UVD with an excitatory-inhibitory asymmetry and the 3 ms latency difference between normal and lesion side may be useful for detecting vestibular lesions such as UVS. We suggest that current spread could account for the small eVOR to 5 mA unipolar EVS of the UVD ear. 相似文献16.
Tseng KY Caballero A Dec A Cass DK Simak N Sunu E Park MJ Blume SR Sammut S Park DJ West AR 《PloS one》2011,6(11):e27187
Objective
There is clearly a necessity to identify novel non-dopaminergic mechanisms as new therapeutic targets for Parkinson''s disease (PD). Among these, the soluble guanylyl cyclase (sGC)-cGMP signaling cascade is emerging as a promising candidate for second messenger-based therapies for the amelioration of PD symptoms. In the present study, we examined the utility of the selective sGC inhibitor 1H-[1], [2], [4] oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ) for reversing basal ganglia dysfunction and akinesia in animal models of PD.Methods
The utility of the selective sGC inhibitor ODQ for reversing biochemical, electrophysiological, histochemical, and behavioral correlates of experimental PD was performed in 6-OHDA-lesioned rats and mice chronically treated with MPTP.Results
We found that one systemic administration of ODQ is sufficient to reverse the characteristic elevations in striatal cGMP levels, striatal output neuron activity, and metabolic activity in the subthalamic nucleus observed in 6-OHDA-lesioned rats. The latter outcome was reproduced after intrastriatal infusion of ODQ. Systemic administration of ODQ was also effective in improving deficits in forelimb akinesia induced by 6-OHDA and MPTP.Interpretation
Pharmacological inhibition of the sGC-cGMP signaling pathway is a promising non-dopaminergic treatment strategy for restoring basal ganglia dysfunction and attenuating motor symptoms associated with PD. 相似文献17.
Background
Genetic architecture of coronary artery disease (CAD) is still to be defined. Since low density lipoprotein receptor-related protein 6 (LRP6) gene play critical roles in Wnt signal transduction which are important for vascular development and endodermis specification, we therefore resequenced it to search for mutations in CAD patients.Methods
We systemically sequenced all the exons and promoter region of LRP6 gene in a sample of 380 early onset CAD patients and 380 control subjects in Chinese.Results
In total, we identified 5 patient-specific mutations including K82N (two patients), S488Y (one patient), P1066T (two patients), P1206H (two patients) and I1264V (one patient) All these mutations located at the extracellular domain of LRP6 gene. In vitro functional analysis of patient-specific mutations demonstrated that these mutations resulted in a significant reduction in both protein level transporting to cell membrane and downstream Wnt signal activity. Furthermore, we found that LRP6 novel mutations attenuated proliferation and migration of human umbilical vein endothelial cells (HUVECs) when compared with wild type (WT) LRP6.Conclusion
Our results demonstrated that these loss-of-function variants might contribute to disease liability in a subset of CAD and defects in Wnt signal activation might be important contributing factors for the onset of CAD. 相似文献18.
Guoqing Chen Yuan Qiu Lihua Sun Min Yu Wensheng Wang Weidong Xiao Yang Yang Yong Liu Songwei Yang Daniel H. Teitelbaum Yuanhang Ma Dingsong Lu Hua Yang 《PloS one》2013,8(10)
Background
Notch signaling plays a critical role in the maintenance of intestinal crypt epithelial cell proliferation. The aim of this study was to investigate the role of Notch signaling in the proliferation and regeneration of intestinal epithelium after intestinal ischemia reperfusion (I/R) injury.Methods
Male Sprague-Dawley rats were subjected to sham operation or I/R by occlusion of the superior mesenteric artery (SMA) for 20 min. Intestinal tissue samples were collected at 0, 1, 2, 4, and 6 h after reperfusion. Proliferation of the intestinal epithelium was evaluated by immunohistochemical staining of proliferating nuclear antigen (PCNA). The mRNA and protein expression levels of Notch signaling components were examined using Real-time PCR and Western blot analyses. Immunofluorescence was also performed to detect the expression and location of Jagged-2, cleaved Notch-1, and Hes-1 in the intestine. Finally, the γ-secretase inhibitor DAPT and the siRNA for Jagged-2 and Hes-1 were applied to investigate the functional role of Notch signaling in the proliferation of intestinal epithelial cells in an in vitro IEC-6 culture system.Results
I/R injury caused increased intestinal crypt epithelial cell proliferation and increased mRNA and protein expression of Jagged-2, Notch-1, and Hes-1. The immunofluorescence results further confirmed increased protein expression of Jagged-2, cleaved Notch-1, and Hes-1 in the intestinal crypts. The inhibition of Notch signaling with DAPT and the suppression of Jagged-2 and Hes-1 expression using siRNA both significantly inhibited the proliferation of IEC-6 cells.Conclusion
The Jagged-2/Notch-1/Hes-1 signaling pathway is involved in intestinal epithelium regeneration early after I/R injury by increasing crypt epithelial cell proliferation. 相似文献19.
Kurdián M Herrero-Fresneda I Lloberas N Gimenez-Bonafe P Coria V Grande MT Boggia J Malacrida L Torras J Arévalo MA González-Martínez F López-Novoa JM Grinyó J Noboa O 《PloS one》2012,7(3):e32516
Background
The immunosuppressive mammalian target of rapamycin (mTOR) inhibitors are widely used in solid organ transplantation, but their effect on kidney disease progression is controversial. mTOR has emerged as one of the main pathways regulating cell growth, proliferation, differentiation, migration, and survival.The aim of this study was to analyze the effects of delayed inhibition of mTOR pathway with low dose of everolimus on progression of renal disease and TGFβ expression in the 5/6 nephrectomy model in Wistar rats.Methods
This study evaluated the effects of everolimus (0.3 mg/k/day) introduced 15 days after surgical procedure on renal function, proteinuria, renal histology and mechanisms of fibrosis and proliferation.Results
Everolimus treated group (EveG) showed significantly less proteinuria and albuminuria, less glomerular and tubulointerstitial damage and fibrosis, fibroblast activation cell proliferation, when compared with control group (CG), even though the EveG remained with high blood pressure. Treatment with everolimus also diminished glomerular hypertrophy.Everolimus effectively inhibited the increase of mTOR developed in 5/6 nephrectomy animals, without changes in AKT mRNA or protein abundance, but with an increase in the pAKT/AKT ratio. Associated with this inhibition, everolimus blunted the increased expression of TGFβ observed in the remnant kidney model.Conclusion
Delayed mTOR inhibition with low dose of everolimus significantly prevented progressive renal damage and protected the remnant kidney. mTOR and TGFβ mRNA reduction can partially explain this anti fibrotic effect. mTOR can be a new target to attenuate the progression of chronic kidney disease even in those nephropathies of non-immunologic origin. 相似文献20.
The interaction between regulatory T cells and NKT cells in the liver: a CD1d bridge links innate and adaptive immunity 总被引:1,自引:0,他引:1