scholarly journals Plasticity-Enhancing Effects of Levodopa Treatment after Stroke

2021 ◽  
Vol 22 (19) ◽  
pp. 10226
Author(s):  
Daniela Talhada ◽  
Niklas Marklund ◽  
Tadeusz Wieloch ◽  
Enida Kuric ◽  
Karsten Ruscher
Keyword(s):  
Transcription Factor ◽  
Wistar Rats ◽  
Focal Ischemia ◽  
Infarct Core ◽  
Protein Levels ◽  
Infarct Area ◽  
Lower Protein ◽  
Stroke Models ◽  
Underlying Mechanisms

Dopaminergic treatment in combination with rehabilitative training enhances long-term recovery after stroke. However, the underlying mechanisms on structural plasticity are unknown. Here, we show an increased dopaminergic innervation of the ischemic territory during the first week after stroke induced in Wistar rats subjected to transient occlusion of the middle cerebral artery (tMCAO) for 120 min. This response was also found in rats subjected to permanent focal ischemia induced by photothrombosis (PT) and mice subjected to PT or tMCAO. Dopaminergic branches were detected in the infarct core of mice and rats in both stroke models. In addition, the Nogo A pathway was significantly downregulated in rats treated with levodopa (LD) compared to vehicle-treated animals subjected to tMCAO. Specifically, the number of Nogo A positive oligodendrocytes as well as the levels of Nogo A and the Nogo A receptor were significantly downregulated in the peri-infarct area of LD-treated animals, while the number of Oligodendrocyte transcription factor 2 positive cells increased in this region after treatment. In addition, we observed lower protein levels of Growth Associated Protein 43 in the peri-infarct area compared to sham-operated animals without treatment effect. The results provide the first evidence of the plasticity-promoting actions of dopaminergic treatment following stroke.

scholarly journals Long-term physical inactivity exacerbates hindlimb unloading-induced muscle atrophy in young rat soleus muscle

2021 ◽  
Author(s):  
Toshinori Yoshihara ◽  
Toshiharu Natsume ◽  
Takamasa Tsuzuki ◽  
Shuo-wen Chang ◽  
Ryo Kakigi ◽  
...  
Keyword(s):  
Muscle Atrophy ◽  
Soleus Muscle ◽  
Physical Inactivity ◽  
Wistar Rats ◽  
Hindlimb Unloading ◽  
Whole Body ◽  
Protein Levels ◽  
Male Wistar Rats ◽  
Rat Soleus Muscle

This study investigated the effects of long-term physical inactivity in adolescent on subsequent hindlimb unloading-induced muscle atrophy in rat soleus muscle. First, 3-week-old male Wistar rats were assigned to an age-matched control (n=6) or a physical inactivity (n=8) group. Rats in the physical inactivity group were housed in narrow cages with approximately half the usual floor space for 8 weeks to limit range of movement. Whole body energy consumption was measured and the blood, organs, femoral bone, and hindlimb muscles were removed. We found that long-term physical inactivity did not affect the metabolic and physiological characteristics of growing rats. Then, fifty-six 3-week-old male Wistar rats were assigned randomly into control (n=28) and physical inactivity (n=28) groups. After 8 weeks, the rats in both groups underwent hindlimb unloading. The soleus muscles were removed before unloading (0-day), and 1, 3, and 7 days after unloading (n=7 for each). Although the soleus muscle weight was significantly decreased after 7 days of hindlimb unloading in both groups, the decrease was drastic in the inactive group. A significant interaction between inactivity and unloading (p<0.01) was observed according to the 4-hydroxynonenal-conjugated protein levels and the histone deacetylase 4 (HDAC4) and NF-kB protein levels. HDAC4 and NF-kB p65 protein levels in the physical inactivity group increased significantly 1 day after hindlimb unloading, along with the mRNA levels of their downstream targets myogenin and muscle RING finger protein 1 (MuRF1). Subsequent protein ubiquitination was upregulated by long-term physical inactivity (p<0.05).

Abstract 96: Ischemic Postconditioning Did Not Attenuate Acute Infarction But Improved Long-term Outcomes By Promoting mTOR Activity In Nude rats

Stroke ◽  
2013 ◽  
Vol 44 (suppl_1) ◽  
Author(s):  
Rong Xie ◽  
Peng Wang ◽  
Xunming Ji ◽  
Heng Zhao
Keyword(s):  
T Cell ◽  
Mtor Inhibitor ◽  
Focal Ischemia ◽  
Ischemic Postconditioning ◽  
Protective Effects ◽  
Protein Levels ◽  
Acute Infarction ◽  
Nude Rats ◽  
Mtor Activity

Introduction: Ischemic postconditioning provides protective effects against focal ischemia and improves neurological deficits. Recent studies have shown that T cells play important roles in stroke. In this study, we investigated whether postconditioning protects against stroke in nude rats with T-cell deficiency, and examined the potential role of mTOR pathway in the protective effects of postconditioning. Methods: Focal ischemia was induced by 30min of transient bilateral CCA occlusion and permanent distal MCA occlusion in nude rats with T-cell deficiency (RNU rats, Charles River). Ischemic postconditioning was conducted immediately after reperfusion by 3 cycles of 30 sec reperfusion and 10 sec occlusion of the bilateral CCAs. Rapamycin, an mTOR inhibitor, was injected into the left lateral ventricle 1h before stroke. For the behavior test, home cage, vibrissa-elicited limb use and postural reflex tests were performed until 30d after stroke. Peri-infarct and ischemic core tissues were collected 1, 5, 9 and 24h after stroke for Western blotting. Protein levels of p-mTOR, S6K, 4EBP -1, Akt and its isoforms (Akt1-3) were also measured. Results: Different from wild type rats, the cortical infarction induced by stroke was not significantly reduced by postconditioning in nude rats when measured 2d post-stroke (27.1±4.3% in control ischemia vs 23.7±4.2% in postconditioning, n=6). Despite the unaltered infarct size, Western blot showed that postconditioning significantly increased the protein levels of p-Akt, Akt isoforms, p-mTOR, p-S6K and p-4EBP1, both in the peri-infarct area and core 24h after stroke (p<0.05). In addition, postconditioning improved neurological function when measured 30d after stroke (n=6, p<0.05), and reduced brain damage size from 10.2±1.4% to 4.9±1.6% (n=6, p<0.05). The mTOR inhibitor, rapamycin, significantly attenuated p-mTOR and p-S6K levels both in the peri-infart area and core at 1, 5, 9 and 24h after stroke (p<0.05), and abolished the long-term protective effects of postconditioning. Conclusions: Ischemic postconditioning did not inhibit acute infarction but provided long-term protection by enhancing Akt and mTOR activity in the acute phase after stroke in nude rats.

scholarly journals Neurofilament Proteolysis after Focal Ischemia; When Do Cells Die after Experimental Stroke?

1999 ◽  
Vol 19 (6) ◽  
pp. 652-660 ◽  
Author(s):  
Jaroslaw Aronowski ◽  
Ki-Hyun Cho ◽  
Roger Strong ◽  
James C. Grotta
Keyword(s):  
Time Course ◽  
Infarct Volume ◽  
Focal Ischemia ◽  
Cellular Damage ◽  
Experimental Stroke ◽  
Infarct Core ◽  
Similar Time ◽  
The Core ◽  
Tetrazolium Staining ◽  
Previous Demonstration

To determine the occurrence and time-course of presumably irreversible subcellular damage after moderate focal ischemia, rats were subjected to 1, 3, 6, 9, or 24 hours of permanent unilateral middle cerebral and common carotid occlusion or 3 hours of reversible occlusion followed by 3, 6, or 21 hours of reperfusion. The topography and the extent of damage were analyzed with tetrazolium staining and immunoblot using an antibody capable of detecting breakdown of neurofilament. Neurofilament proteolysis began after 3 hours in the infarct core but was still incomplete in penumbral regions up to 9 hours. Similarly, tetrazolium-staining abnormalities were observed in the core of 50% of animals after 3 hours of ischemia. At 6 hours of permanent ischemia, infarct volume was maximal, and further prolongation of occlusion to 9 or 24 hours did not increase abnormal tetrazolium staining. In contrast to permanent ischemia and in agreement with the authors' previous demonstration of “reperfusion injury” in this model, prolongation of reperfusion from 3 hours to 6 and 21 hours after 3 hours of reversible occlusion gradually augmented infarct volume by 203% and 324%, respectively. Neurofilament proteolysis initiated approximately 3 hours after ischemia was quantitatively greatest in the core and extended during reperfusion to incorporate penumbra with a similar time course to that of tetrazolium abnormalities. These data demonstrate that, at least as measured by neurofilament breakdown and mitochondrial failure, extensive cellular damage is not present in penumbral regions for up to 9 hours, suggesting the potential for rescuing these regions by appropriate and timely neuroprotective strategies.

Enhanced Seasonal Exchange of CO2 by Northern Ecosystems Since 1960

Science ◽  
2013 ◽  
Vol 341 (6150) ◽  
pp. 1085-1089 ◽  
Author(s):  
H. D. Graven ◽  
R. F. Keeling ◽  
S. C. Piper ◽  
P. K. Patra ◽  
B. B. Stephens ◽  
...  
Keyword(s):  
Boreal Forests ◽  
Atmospheric Carbon Dioxide ◽  
Ecosystem Models ◽  
The North ◽  
Ecological Changes ◽  
Term Change ◽  
Major Shift ◽  
Underlying Mechanisms ◽  
Global Carbon

Seasonal variations of atmospheric carbon dioxide (CO2) in the Northern Hemisphere have increased since the 1950s, but sparse observations have prevented a clear assessment of the patterns of long-term change and the underlying mechanisms. We compare recent aircraft-based observations of CO2 above the North Pacific and Arctic Oceans to earlier data from 1958 to 1961 and find that the seasonal amplitude at altitudes of 3 to 6 km increased by 50% for 45° to 90°N but by less than 25% for 10° to 45°N. An increase of 30 to 60% in the seasonal exchange of CO2 by northern extratropical land ecosystems, focused on boreal forests, is implicated, substantially more than simulated by current land ecosystem models. The observations appear to signal large ecological changes in northern forests and a major shift in the global carbon cycle.

scholarly journals Safety profile of the transcription factor EB (TFEB)-based gene therapy through intracranial injection in mice

2020 ◽  
Vol 11 (1) ◽  
pp. 241-250
Author(s):  
Zhenyu Li ◽  
Guangqian Ding ◽  
Yudi Wang ◽  
Zelong Zheng ◽  
Jianping Lv
Keyword(s):  
Gene Therapy ◽  
Transcription Factor ◽  
Neurodegenerative Diseases ◽  
Brain Tissue ◽  
Inflammatory Responses ◽  
Tissue Samples ◽  
Protein Levels ◽  
Virus Serotype ◽  
Transcription Factor Eb ◽  
The Brain

AbstractTranscription factor EB (TFEB)-based gene therapy is a promising therapeutic strategy in treating neurodegenerative diseases by promoting autophagy/lysosome-mediated degradation and clearance of misfolded proteins that contribute to the pathogenesis of these diseases. However, recent findings have shown that TFEB has proinflammatory properties, raising the safety concerns about its clinical application. To investigate whether TFEB induces significant inflammatory responses in the brain, male C57BL/6 mice were injected with phosphate-buffered saline (PBS), adeno-associated virus serotype 8 (AAV8) vectors overexpressing mouse TFEB (pAAV8-CMV-mTFEB), or AAV8 vectors expressing green fluorescent proteins (GFPs) in the barrel cortex. The brain tissue samples were collected at 2 months after injection. Western blotting and immunofluorescence staining showed that mTFEB protein levels were significantly increased in the brain tissue samples of mice injected with mTFEB-overexpressing vectors compared with those injected with PBS or GFP-overexpressing vectors. pAAV8-CMV-mTFEB injection resulted in significant elevations in the mRNA and protein levels of lysosomal biogenesis indicators in the brain tissue samples. No significant changes were observed in the expressions of GFAP, Iba1, and proinflammation mediators in the pAAV8-CMV-mTFEB-injected brain compared with those in the control groups. Collectively, our results suggest that AAV8 successfully mediates mTFEB overexpression in the mouse brain without inducing apparent local inflammation, supporting the safety of TFEB-based gene therapy in treating neurodegenerative diseases.

scholarly journals Brassinosteroids repress the seed maturation program during the seed-to-seedling transition

2021 ◽  
Author(s):  
Jiuxiao Ruan ◽  
Huhui Chen ◽  
Tao Zhu ◽  
Yaoguang Yu ◽  
Yawen Lei ◽  
...  
Keyword(s):  
Arabidopsis Thaliana ◽  
Transcription Factor ◽  
Abscisic Acid ◽  
Plant Hormone ◽  
Flowering Plants ◽  
Seed Maturation ◽  
Domain Protein ◽  
Abscisic Acid Insensitive3 ◽  
Underlying Mechanisms ◽  
Embryonic Structure

Abstract In flowering plants, repression of the seed maturation program is essential for the transition from the seed to the vegetative phase, but the underlying mechanisms remain poorly understood. The B3-domain protein VIVIPAROUS1/ABSCISIC ACID-INSENSITIVE3-LIKE 1 (VAL1) is involved in repressing the seed maturation program. Here we uncovered a molecular network triggered by the plant hormone brassinosteroid (BR) that inhibits the seed maturation program during the seed-to-seedling transition in Arabidopsis (Arabidopsis thaliana). val1-2 mutant seedlings treated with a BR biosynthesis inhibitor form embryonic structures, whereas BR signaling gain-of-function mutations rescue the embryonic structure trait. Furthermore, the BR-activated transcription factors BRI1-EMS-SUPPRESSOR 1 and BRASSINAZOLE-RESISTANT 1 bind directly to the promoter of AGAMOUS-LIKE15 (AGL15), which encodes a transcription factor involved in activating the seed maturation program, and suppress its expression. Genetic analysis indicated that BR signaling is epistatic to AGL15 and represses the seed maturation program by downregulating AGL15. Finally, we showed that the BR-mediated pathway functions synergistically with the VAL1/2-mediated pathway to ensure the full repression of the seed maturation program. Together, our work uncovered a mechanism underlying the suppression of the seed maturation program, shedding light on how BR promotes seedling growth.

scholarly journals Blood–brain barrier disruption and ventricular enlargement are the earliest neuropathological changes in rats with repeated sub-concussive impacts over 2 weeks

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Bailey Hiles-Murison ◽  
Andrew P. Lavender ◽  
Mark J. Hackett ◽  
Joshua J. Armstrong ◽  
Michael Nesbit ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Blood Brain Barrier ◽  
Hippocampal Formation ◽  
Brain Barrier ◽  
Lateral Ventricles ◽  
Blood Brain Barrier Disruption ◽  
Blood Brain ◽  
Brain Barrier Disruption ◽  
Underlying Mechanisms

AbstractRepeated sub-concussive impact (e.g. soccer ball heading), a significantly lighter form of mild traumatic brain injury, is increasingly suggested to cumulatively alter brain structure and compromise neurobehavioural function in the long-term. However, the underlying mechanisms whereby repeated long-term sub-concussion induces cerebral structural and neurobehavioural changes are currently unknown. Here, we utilised an established rat model to investigate the effects of repeated sub-concussion on size of lateral ventricles, cerebrovascular blood–brain barrier (BBB) integrity, neuroinflammation, oxidative stress, and biochemical distribution. Following repeated sub-concussion 3 days per week for 2 weeks, the rats showed significantly enlarged lateral ventricles compared with the rats receiving sham-only procedure. The sub-concussive rats also presented significant BBB dysfunction in the cerebral cortex and hippocampal formation, whilst neuromotor function assessed by beamwalk and rotarod tests were comparable to the sham rats. Immunofluorescent and spectroscopic microscopy analyses revealed no significant changes in neuroinflammation, oxidative stress, lipid distribution or protein aggregation, within the hippocampus and cortex. These data collectively indicate that repeated sub-concussion for 2 weeks induce significant ventriculomegaly and BBB disruption, preceding neuromotor deficits.

scholarly journals Remediation of mercury-contaminated soils and sediments using biochar: a critical review

Biochar ◽  
2021 ◽  
Author(s):  
Qian Yang ◽  
Yongjie Wang ◽  
Huan Zhong
Keyword(s):  
Health Risks ◽  
Contaminated Soils ◽  
Functional Materials ◽  
Redox Conditions ◽  
Existing Problems ◽  
Soils And Sediments ◽  
Underlying Mechanisms ◽  
Biochar Amendment

AbstractThe transformation of mercury (Hg) into the more toxic and bioaccumulative form methylmercury (MeHg) in soils and sediments can lead to the biomagnification of MeHg through the food chain, which poses ecological and health risks. In the last decade, biochar application, an in situ remediation technique, has been shown to be effective in mitigating the risks from Hg in soils and sediments. However, uncertainties associated with biochar use and its underlying mechanisms remain. Here, we summarize recent studies on the effects and advantages of biochar amendment related to Hg biogeochemistry and its bioavailability in soils and sediments and systematically analyze the progress made in understanding the underlying mechanisms responsible for reductions in Hg bioaccumulation. The existing literature indicates (1) that biochar application decreases the mobility of inorganic Hg in soils and sediments and (2) that biochar can reduce the bioavailability of MeHg and its accumulation in crops but has a complex effect on net MeHg production. In this review, two main mechanisms, a direct mechanism (e.g., Hg-biochar binding) and an indirect mechanism (e.g., biochar-impacted sulfur cycling and thus Hg-soil binding), that explain the reduction in Hg bioavailability by biochar amendment based on the interactions among biochar, soil and Hg under redox conditions are highlighted. Furthermore, the existing problems with the use of biochar to treat Hg-contaminated soils and sediments, such as the appropriate dose and the long-term effectiveness of biochar, are discussed. Further research involving laboratory tests and field applications is necessary to obtain a mechanistic understanding of the role of biochar in reducing Hg bioavailability in diverse soil types under varying redox conditions and to develop completely green and sustainable biochar-based functional materials for mitigating Hg-related health risks.

Targeting EZH2 Ameliorates the LPS-Inhibited PDLSC Osteogenesis via Wnt/β-Catenin Pathway

2021 ◽  
pp. 1-9
Author(s):  
Mosha Cheng ◽  
Qing Zhou
Keyword(s):  
Bone Morphogenetic Protein 2 ◽  
Periodontal Ligament Stem Cells ◽  
Alizarin Red ◽  
Protein Levels ◽  
Inflammatory Conditions ◽  
Morphogenetic Protein ◽  
Related Transcription Factor ◽  
Underlying Mechanisms ◽  
Factor Α ◽  
Osteoblast Maturation

As a histone methyltransferase, enhancer of zeste homolog 2 (EZH2), suppresses osteoblast maturation and is involved in inflammation. However, the role of EZH2 in human periodontal ligament stem cells (PDLSCs) under inflammation still needs to be further investigated. This study aimed to identify the underlying mechanisms and explore the function of EZH2 in PDLSC osteogenesis under inflammation. PDLSCs were treated with sh-EZH2, DZNep or DKK1 under inflammation. The alkaline phosphatase (ALP) activity, alizarin red staining, and osteogenesis-related protein levels were analyzed. Lipopolysaccharide (LPS)-induced inflammation restrained osteogenic differentiation. Under inflammation, the upregulation of EZH2 suppressed the expression of osteogenic markers, including osteocalcin, runt-related transcription factor 2, and bone morphogenetic protein-2, the activity of ALP, and the accumulation of mineralization through the Wnt/β-catenin pathway. EZH2 knockdown inhibited the levels of proinflammatory cytokines such as interleukin-6 and tumor necrosis factor-α. These results suggested that LPS-induced overexpression of EZH2 suppressed PDLSC osteogenesis under inflammatory conditions through the Wnt/β-catenin pathway. These findings give new insights into the physiological differentiation and pathological inflammation of PDLSC osteogenesis, and provide an underlying therapeutic target for periodontitis.

scholarly journals The hypoxia sensitive metal transcription factor MTF-1 activates NCX1 brain promoter and participates in remote postconditioning neuroprotection in stroke

2021 ◽  
Vol 12 (5) ◽  
Author(s):  
Valeria Valsecchi ◽  
Giusy Laudati ◽  
Ornella Cuomo ◽  
Rossana Sirabella ◽  
Lucio Annunziato ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Brain Ischemia ◽  
Femoral Artery ◽  
Infarct Volume ◽  
Neuroprotective Effect ◽  
Artery Occlusion ◽  
Sodium Calcium Exchanger ◽  
Protein Levels ◽  
Relevant Role ◽  
Remote Postconditioning

AbstractRemote limb ischemic postconditioning (RLIP) is an experimental strategy in which short femoral artery ischemia reduces brain damage induced by a previous harmful ischemic insult. Ionic homeostasis maintenance in the CNS seems to play a relevant role in mediating RLIP neuroprotection and among the effectors, the sodium-calcium exchanger 1 (NCX1) may give an important contribution, being expressed in all CNS cells involved in brain ischemic pathophysiology. The aim of this work was to investigate whether the metal responsive transcription factor 1 (MTF-1), an important hypoxia sensitive transcription factor, may (i) interact and regulate NCX1, and (ii) play a role in the neuroprotective effect mediated by RLIP through NCX1 activation. Here we demonstrated that in brain ischemia induced by transient middle cerebral occlusion (tMCAO), MTF-1 is triggered by a subsequent temporary femoral artery occlusion (FAO) and represents a mediator of endogenous neuroprotection. More importantly, we showed that MTF-1 translocates to the nucleus where it binds the metal responsive element (MRE) located at −23/−17 bp of Ncx1 brain promoter thus activating its transcription and inducing an upregulation of NCX1 that has been demonstrated to be neuroprotective. Furthermore, RLIP restored MTF-1 and NCX1 protein levels in the ischemic rat brain cortex and the silencing of MTF-1 prevented the increase of NCX1 observed in RLIP protected rats, thus demonstrating a direct regulation of NCX1 by MTF-1 in the ischemic cortex of rat exposed to tMCAO followed by FAO. Moreover, silencing of MTF-1 significantly reduced the neuroprotective effect elicited by RLIP as demonstrated by the enlargement of brain infarct volume observed in rats subjected to RLIP and treated with MTF-1 silencing. Overall, MTF-dependent activation of NCX1 and their upregulation elicited by RLIP, besides unraveling a new molecular pathway of neuroprotection during brain ischemia, might represent an additional mechanism to intervene in stroke pathophysiology.

Sign in / Sign up

Export Citation Format

Share Document