scholarly journals ABCA1/ApoE/HDL Signaling Pathway Facilitates Myelination and Oligodendrogenesis after Stroke

2020 ◽  
Vol 21 (12) ◽  
pp. 4369 ◽  
Author(s):  
Li Li ◽  
Rongwen Li ◽  
Alex Zacharek ◽  
Fengjie Wang ◽  
Julie Landschoot-Ward ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Density Lipoprotein ◽  
Hdl Cholesterol ◽  
Artery Occlusion ◽  
Mammalian Brain ◽  
Ischemic Brain ◽  
Atp Binding Cassette Transporter ◽  
Cerebral Artery Occlusion ◽  
Apoe Expression

ATP-binding cassette transporter A1 (ABCA1) plays an important role in the regulation of apolipoprotein E (ApoE) and the biogenesis of high-density lipoprotein (HDL) cholesterol in the mammalian brain. Cholesterol is a major source for myelination. Here, we investigate whether ABCA1/ApoE/HDL contribute to myelin repair and oligodendrogenesis in the ischemic brain after stroke. Specific brain ABCA1-deficient (ABCA1-B/-B) and ABCA1-floxed (ABCA1fl/fl) control mice were subjected to permanent distal middle-cerebral-artery occlusion (dMCAo) and were intracerebrally administered (1) artificial mouse cerebrospinal fluid (CSF) as vehicle control, (2) human plasma HDL3, and (3) recombined human ApoE2 starting 24 h after dMCAo for 14 days. All stroke mice were sacrificed 21 days after dMCAo. The ABCA1-B/-B–dMCAo mice exhibit significantly reduced myelination and oligodendrogenesis in the ischemic brain as well as decreased functional outcome 21 days after stroke compared with ABCA1fl/fl mice; administration of human ApoE2 or HDL3 in the ischemic brain significantly attenuates the deficits in myelination and oligodendrogenesis in ABCA1-B/-B–dMCAo mice ( p < 0.05, n = 9/group). In vitro, ABCA1-B/-B reduces ApoE expression and decreases primary oligodendrocyte progenitor cell (OPC) migration and oligodendrocyte maturation; HDL3 and ApoE2 treatment significantly reverses ABCA1-B/-B-induced reduction in OPC migration and oligodendrocyte maturation. Our data indicate that the ABCA1/ApoE/HDL signaling pathway contributes to myelination and oligodendrogenesis in the ischemic brain after stroke.

scholarly journals Naturally occurring and bioengineered apoA-I mutations that inhibit the conversion of discoidal to spherical HDL: the abnormal HDL phenotypes can be corrected by treatment with LCAT

2007 ◽  
Vol 406 (1) ◽  
pp. 167-174 ◽  
Author(s):  
Georgios Koukos ◽  
Angeliki Chroni ◽  
Adelina Duka ◽  
Dimitris Kardassis ◽  
Vassilis I. Zannis
Keyword(s):  
Gene Transfer ◽  
Plasma Cholesterol ◽  
Density Lipoprotein ◽  
Hdl Cholesterol ◽  
Spherical Particles ◽  
Simultaneous Treatment ◽  
Cholesterol Ratio ◽  
Cholesterol Levels ◽  
Atp Binding Cassette Transporter

In the present study we have used adenovirus-mediated gene transfer of apoA-I (apolipoprotein A-I) mutants in apoA-I−/− mice to investigate how structural mutations in apoA-I affect the biogenesis and the plasma levels of HDL (high-density lipoprotein). The natural mutants apoA-I(R151C)Paris, apoA-I(R160L)Oslo and the bioengineered mutant apoA-I(R149A) were secreted efficiently from cells in culture. Their capacity to activate LCAT (lecithin:cholesterol acyltransferase) in vitro was greatly reduced, and their ability to promote ABCA1 (ATP-binding cassette transporter A1)-mediated cholesterol efflux was similar to that of WT (wild-type) apoA-I. Gene transfer of the three mutants in apoA-I−/− mice generated aberrant HDL phenotypes. The total plasma cholesterol of mice expressing the apoA-I(R160L)Oslo, apoA-I(R149A) and apoA-I(R151C)Paris mutants was reduced by 78, 59 and 61% and the apoA-I levels were reduced by 68, 64 and 55% respectively, as compared with mice expressing the WT apoA-I. The CE (cholesteryl ester)/TC (total cholesterol) ratio of HDL was decreased and the apoA-I was distributed in the HDL3 region. apoA-I(R160L)Oslo and apoA-I(R149A) promoted the formation of preβ1 and α4-HDL subpopulations and gave a mixture of discoidal and spherical particles. apoA-I(R151C)Paris generated subpopulations of different sizes that migrate between preβ and α-HDL and formed mostly spherical and a few discoidal particles. Simultaneous treatment of mice with adenovirus expressing any of the three mutants and human LCAT normalized plasma apoA-I, HDL cholesterol levels and the CE/TC ratio. It also led to the formation of spherical HDL particles consisting mostly of α-HDL subpopulations of larger size. The correction of the aberrant HDL phenotypes by treatment with LCAT suggests a potential therapeutic intervention for HDL abnormalities that result from specific mutations in apoA-I.

scholarly journals The Neuroprotective and Vasculo-Neuro-Regenerative Roles of Adrenomedullin in Ischemic Brain and Its Therapeutic Potential

Endocrinology ◽  
2006 ◽  
Vol 147 (4) ◽  
pp. 1642-1653 ◽  
Author(s):  
Kazutoshi Miyashita ◽  
Hiroshi Itoh ◽  
Hiroshi Arai ◽  
Takayasu Suganami ◽  
Naoki Sawada ◽  
...  
Keyword(s):  
Mononuclear Cells ◽  
Therapeutic Potential ◽  
Vascular Wall ◽  
Artery Occlusion ◽  
Ischemic Brain ◽  
Vascular Regeneration ◽  
Infarct Area ◽  
New Strategy ◽  
Cerebral Artery Occlusion

Adrenomedullin (AM) is a vasodilating hormone secreted mainly from vascular wall, and its expression is markedly enhanced after stroke. We have revealed that AM promotes not only vasodilation but also vascular regeneration. In this study, we focused on the roles of AM in the ischemic brain and examined its therapeutic potential. We developed novel AM-transgenic (AM-Tg) mice that overproduce AM in the liver and performed middle cerebral artery occlusion for 20 min (20m-MCAO) to examine the effects of AM on degenerative or regenerative processes in ischemic brain. The infarct area and gliosis after 20m-MCAO was reduced in AM-Tg mice in association with suppression of leukocyte infiltration, oxidative stress, and apoptosis in the ischemic core. In addition, vascular regeneration and subsequent neurogenesis were enhanced in AM-Tg mice, preceded by increase in mobilization of CD34+ mononuclear cells, which can differentiate into endothelial cells. The vasculo-neuro-regenerative actions observed in AM-Tg mice in combination with neuroprotection resulted in improved recovery of motor function. Brain edema was also significantly reduced in AM-Tg mice via suppression of vascular permeability. In vitro, AM exerted direct antiapoptotic and neurogenic actions on neuronal cells. Exogenous administration of AM in mice after 20m-MCAO also reduced the infarct area, and promoted vascular regeneration and functional recovery. In summary, this study suggests the neuroprotective and vasculo-neuro-regenerative roles of AM and provides basis for a new strategy to rescue ischemic brain through its multiple hormonal actions.

scholarly journals Neuroprotective Effect of SCM-198 through Stabilizing Endothelial Cell Function

2019 ◽  
Vol 2019 ◽  
pp. 1-13 ◽  
Author(s):  
Qiu-Yan Zhang ◽  
Zhi-Jun Wang ◽  
Lei Miao ◽  
Ying Wang ◽  
Ling-Ling Chang ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Signaling Pathway ◽  
Cell Function ◽  
Neuroprotective Effect ◽  
Glucose Deprivation ◽  
Artery Occlusion ◽  
Oxygen Glucose Deprivation ◽  
Endothelial Cell Function ◽  
Cerebral Artery Occlusion

Leonurine, also named SCM-198, which was extracted from Herba leonuri, displayed a protective effect on various cardiovascular and brain diseases, like ischemic stroke. Ischemic stroke which is the leading cause of morbidity and mortality, ultimately caused irreversible neuron damage. This study is aimed at exploring the possible therapeutic potential of SCM-198 in the protection against postischemic neuronal injury and possible underlying mechanisms. A transient middle cerebral artery occlusion (tMCAO) rat model was utilized to measure the protective effect of SCM-198 on neurons. TEM was used to determine neuron ultrastructural changes. The brain slices were stained with Nissl staining solution for Nissl bodies. Fluoro-Jade B (FJB) was used for staining the degenerating neurons. In the oxygen-glucose deprivation and re-oxygenation (OGD/R) model of bEnd.3 cells treated with SCM-198 (0.1, 1, 10 μM). Then, the bEnd.3 cells were cocultured with SH-SY5Y cells. Cell viability, MDA level, CAT activity, and apoptosis were examined to evaluate the cytotoxicity of these treatments. Western blot and immunofluorescent assays were used to examine the expression of protein related to the p-STAT3/NOX4/Bcl-2 signaling pathway. Coimmunoprecipitation was performed to determine the interaction between p-STAT3 and NOX4. In the transient middle cerebral artery occlusion (tMCAO) rat model, we found that treatment with SCM-198 could ameliorate neuron morphology and reduce the degenerating cell and neuron loss. In the in vitro model of bEnd.3 cell oxygen-glucose deprivation and reoxygenation (OGD/R), treatment with SCM-198 restored the activity of catalase (CAT), improved the expression of Cu-Zn superoxide dismutase (SOD1), and decreased the malondialdehyde (MDA) production. SCM-198 treatment prevented OGD/R-induced cell apoptosis as indicated by increased cell viability and decreased the number of TUNEL-positive cells, accompanied with upregulation of Bcl-2 and Bcl-xl protein and downregulation Bax protein. The results were consistent with SH-SY5Y cells which coculture with bEnd.3 cells. The forthcoming study revealed that SCM-198 activated the p-STAT3/NOX4/Bcl-2 signaling pathway. All the data indicated that SCM-198 protected against oxidative stress and neuronal damage in in vivo and in vitro injury models via the p-STAT3/NOX4/Bcl-2 signaling pathway. Our results suggested that SCM-198 could be the potential drug for neuroprotective effect through stabilizing endothelial cell function.

Study of Antihyperglycemic, Antihyperlipidemic and Antioxidant Activities of Tannins Extracted from Warionia saharae Benth. & Coss

2019 ◽  
Vol 19 (2) ◽  
pp. 189-198 ◽  
Author(s):  
Mohammed Ajebli ◽  
Fadwa El Ouady ◽  
Mohamed Eddouks
Keyword(s):  
Antioxidant Activity ◽  
Antioxidant Activities ◽  
Histopathological Examination ◽  
Density Lipoprotein ◽  
Hdl Cholesterol ◽  
Diabetic Rats ◽  
Lipid Lowering ◽  
Glucose Levels ◽  
Soxhlet Apparatus

Background and Objective: Warionia saharae Benth & Coss, a plant belonging to Asteraceae family, is used for its anti-diabetic properties in Morocco. The objective of this study was to evaluate the effect of tannins extracted from Warionia saharae (W. saharae) on blood glucose levels and lipid profile in normal and streptozotocin(STZ)-induced diabetic rats. Methods: Tannins (TE) were extracted from W. saharae using Soxhlet apparatus and different organic solvents. Single and once daily repeated oral administration of TE (10 mg/kg) for 15 days were used to evaluate the glucose and lipid-lowering activity in normal and diabetic rats. Furthermore, glucose test tolerance, liver histopathological examination and in vitro antioxidant activity of TE were carried out in this study. Results: The results showed that TE was able to exert antihyperglycemic and lowering total cholesterol effects as well as improvement of the high-density lipoprotein (HDL)-cholesterol serum level after 15 days of treatment. Furthermore, TE improved glucose tolerance, histopathological status of liver in diabetic rats and demonstrated interesting antioxidant activity. Conclusion: In conclusion, the present investigation revealed that TE possesses potent antidiabetic and antihyperlipidemic activities as claimed in different ethnopharmacological practices.

scholarly journals Dendritic Cells Are Present in Ischemic Brain After Permanent Middle Cerebral Artery Occlusion in the Rat

Stroke ◽  
2002 ◽  
Vol 33 (4) ◽  
pp. 1129-1134 ◽  
Author(s):  
Nikolaos Kostulas ◽  
Hu-Lun Li ◽  
Bao-Guo Xiao ◽  
Yu-Min Huang ◽  
Vasilios Kostulas ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Middle Cerebral Artery ◽  
Middle Cerebral Artery Occlusion ◽  
Cerebral Artery ◽  
Artery Occlusion ◽  
Ischemic Brain ◽  
Cerebral Artery Occlusion

scholarly journals Oncogene APOL1 promotes proliferation and inhibits apoptosis via activating NOTCH1 signaling pathway in pancreatic cancer

2021 ◽  
Vol 12 (8) ◽  
Author(s):  
Jiewei Lin ◽  
Zhiwei Xu ◽  
Junjie Xie ◽  
Xiaxing Deng ◽  
Lingxi Jiang ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Signaling Pathway ◽  
Density Lipoprotein ◽  
Human Pancreatic Cancer ◽  
Luciferase Reporter ◽  
Notch1 Signaling ◽  
In Vivo Experiments ◽  
Notch1 Signaling Pathway

AbstractAPOL1 encodes a secreted high-density lipoprotein, which has been considered as an aberrantly expressed gene in multiple cancers. Nevertheless, the role of APOL1 in the regulatory mechanisms of pancreatic cancer remains unknown and should be explored. We identified APOL1 was abnormally elevated in human pancreatic cancer tissues compared with that in adjacent tissues and was associated with poor prognosis. The effects of APOL1 in PC cell proliferation, cell cycle, and apoptosis was verified via functional in vitro and in vivo experiments. The results showed that knockdown of APOL1 significantly inhibited the proliferation and promoted apoptosis of pancreatic cancer. In addition, we identified APOL1 could be a regulator of NOTCH1 signaling pathway using bioinformatics tools, qRT-PCR, dual-luciferase reporter assay, and western blotting. In summary, APOL1 could function as an oncogene to promote proliferation and inhibit apoptosis through activating NOTCH1 signaling pathway expression in pancreatic cancer; therefore, it may act as a novel therapeutic target for pancreatic cancer.

Abstract W MP87: PDGF Contributes to BMSC Treatment Induced Neurogenesis and White Matter and Axonal Remodeling in T2DM Stroke Rats

Stroke ◽  
2015 ◽  
Vol 46 (suppl_1) ◽  
Author(s):  
Alex Zacharek ◽  
Tao Yan ◽  
Michael Chopp` ◽  
Poornima Venkat ◽  
Ruizhou Ning ◽  
...  
Keyword(s):  
Cell Migration ◽  
White Matter ◽  
Artery Occlusion ◽  
Border Zone ◽  
Axonal Outgrowth ◽  
Ischemic Brain ◽  
Neuroblast Migration ◽  
Gene And Protein Expression ◽  
Underlying Mechanisms

Objective: Our previous studies have found that bone-marrow-stromal cell (BMSC) treatment of stroke in Type two DM (T2DM) rats, initiated at 3 days after stroke, improved functional recovery. Neurogenesis and white matter (WM) remodeling play an important role in neurorestorative effects after stroke. In this study, we tested whether BMSCs regulate neurogenesis and WM remodeling and the underlying mechanisms of BMSC induced neurorestorative effects in T2DM stroke rats. Methods: T2DM was induced with streptozotocin injection in addition to a high fat diet. T2DM rats were subjected to 2h of middle cerebral artery occlusion (MCAo), then treated with human BMSCs (5X106) or vehicle control (n=8/group) initiated at 3 days after MCAo and rats were monitored for 28 days. Neuroblast migration, WM changes, and gene and protein expression were measured in the ischemic brain. Subventricular zone (SVZ) explant cell migration and primary cortical neuron (PCN) axonal outgrowth measurements were performed in vitro. Results: BMSC treatment in T2DM rats significantly improves functional outcome and increases WM remodeling identified by increased myelin and axonal density. BMSCs also increase the neuroblast migration protein doublecortin (DCX, 25.0±4.3% vs control: 4.5±1.1%), platelet-derived growth factor (PDGF)-AA, and bFGF expression in the ischemic border zone. Angiogenic ELISA array data are consistent with the immunostaining data, showing that BMSC treatment increases PDGF-AA (2.1 fold), PDGF-BB (2.5 fold) and bFGF (1.8 fold) in the ischemic brain. Using an in vitro cell culture model, we found that BMSCs secrete high levels of PDGF. PDGF treatment significantly increases SVZ explant cell migration (1.7 fold) and PCN axonal outgrowth (1.9 fold) compared to non-treatment control. Inhibition of PDGF with neutralized anti-PDGF antibody significantly attenuates BMSC conditioned medium induced SVZ cell migration and PCN axon outgrowth. Conclusion: BMSC treatment of stroke in T2DM increases WM remodeling and neurogenesis as well as increases PDGF expression. PDGF not only promotes neuronal migration, but also increases axonal outgrowth. Therefore, increasing PDGF likely contributes to BMSC induced neurogenesis and WM remodeling in T2DM stroke rats.

scholarly journals AMP-Dependent Hypothermia Affords Protection from Ischemic Brain Injury

2012 ◽  
Vol 33 (2) ◽  
pp. 171-174 ◽  
Author(s):  
Mirko Muzzi ◽  
Francesco Blasi ◽  
Alberto Chiarugi
Keyword(s):  
Brain Injury ◽  
Brain Ischemia ◽  
Adenosine Monophosphate ◽  
Artery Occlusion ◽  
Ischemic Brain Injury ◽  
Ischemic Brain ◽  
Stroke Treatment ◽  
Adenosine A1 ◽  
A1 Receptor ◽  
Cerebral Artery Occlusion

In light of the relevance of therapeutic hypothermia to stroke treatment, we investigated whether 5′-adenosine monophosphate (AMP)-dependent cooling affords protection from ischemic brain injury. We show that hypothermia by AMP is because of adenosine A1 receptor (A1R) activation and is not invariantly associated with hypotension. Inhibition of ecto-5′-nucleotidase-dependent constitutive degradation of brain extracellular AMP by methylene-ADP (AMPCP) also suffices to prompt A1R-dependent hypothermia without hypotension. Both intraischemic and postischemic hypothermia by AMP or AMPCP reduce infarct volumes and mortality of mice subjected to transient middle cerebral artery occlusion. Data disclose that AMP-dependent hypothermia is of therapeutic relevance to treatment of brain ischemia.

scholarly journals Agmatine Attenuates Brain Edema through Reducing the Expression of Aquaporin-1 after Cerebral Ischemia

2009 ◽  
Vol 30 (5) ◽  
pp. 943-949 ◽  
Author(s):  
Jae Hwan Kim ◽  
Yong Woo Lee ◽  
Kyung Ah Park ◽  
Won Taek Lee ◽  
Jong Eun Lee
Keyword(s):  
Cerebral Ischemia ◽  
Water Content ◽  
Brain Edema ◽  
Arginine Decarboxylase ◽  
Artery Occlusion ◽  
Brain Swelling ◽  
Ischemic Brain ◽  
Cerebral Artery Occlusion ◽  
Swelling Volume ◽  
Brain Water

Brain edema is frequently shown after cerebral ischemia. It is an expansion of brain volume because of increasing water content in brain. It causes to increase mortality after stroke. Agmatine, formed by the decarboxylation of L-arginine by arginine decarboxylase, has been shown to be neuroprotective in trauma and ischemia models. The purpose of this study was to investigate the effect of agmatine for brain edema in ischemic brain damage and to evaluate the expression of aquaporins (AQPs). Results showed that agmatine significantly reduced brain swelling volume 22 h after 2 h middle cerebral artery occlusion in mice. Water content in brain tissue was clearly decreased 24 h after ischemic injury by agmatine treatment. Blood–brain barrier (BBB) disruption was diminished with agmatine than without. The expressions of AQPs-1 and -9 were well correlated with brain edema as water channels, were significantly decreased by agmatine treatment. It can thus be suggested that agmatine could attenuate brain edema by limitting BBB disruption and blocking the accumulation of brain water content through lessening the expression of AQP-1 after cerebral ischemia.

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