scholarly journals Investigation of the mechanism of the neuroprotective effect of the peptide preparation Semax in rat brain under conditions of ischemia-reperfusion

2020 ◽  
pp. 76-78
Author(s):  
О.Ю. Сударкина ◽  
В.Г. Дмитриева ◽  
И.Б. Филиппенков ◽  
В.В. Ставчанский ◽  
А.Е. Денисова ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Molecular Mechanisms ◽  
Neuroprotective Effect ◽  
Ischemia Reperfusion ◽  
Cytokines And Chemokines ◽  
Tnf Α ◽  
Ischemic Brain Tissue ◽  
Active Transcription ◽  
Factor C ◽  
Peptide Preparation

Синтетический пептид АКТГ(4-7)PGP ускоряет регресс неврологических нарушений при ишемическом инсульте, однако молекулярные механизмы его действия полностью не известны. На модели полуторачасовой окклюзии средней мозговой артерии крыс был проведен анализ влияния пептида на экспрессию ряда генов и белков, вовлеченных в сигнальные пути, приводящие к воспалению и гибели клеток в условиях ишемии-реперфузии. Показано, что пептид через 24 ч от начала окклюзии снижает повышенный при ишемии уровень экспрессии в ишемизированной ткани мозга крыс мРНК провоспалительных цитокинов и хемокинов IL-1α, IL-1β, IL-6, TNF-α, Cxcl2 и Ccl3. Пептид снижал повышенные при ишемии уровни экспрессии белков металлопротеиназы ММР-9, транскрипционного фактора c-Fos, активных JNK киназ и предотвращал ишемическое снижение уровня активного транскрипционного фактора CREB. The synthetic peptide ACTH (4-7) PGP accelerates the regression of neurological disorders in ischemic stroke, but the molecular mechanisms of its action are not completely known. On the model of an hour and a half occlusion of the rat middle cerebral artery, an analysis was made of the effect of the peptide on the expression of a number of genes and proteins involved in signaling pathways leading to inflammation and cell death under conditions of ischemia-reperfusion. It was shown that the peptide 24 hours after the onset of occlusion reduces the level of expression of mRNA of pro-inflammatory cytokines and chemokines IL-1α, IL-1β, IL-6, TNF-α, Cxcl2 and Ccl3 in ischemic brain tissue. The peptide decreased the levels of expression of proteins metalloproteinase MMP-9, transcription factor c-Fos, active JNK kinases wich were increased under ischemia, and prevented ischemic decrease in the level of active transcription factor CREB.

scholarly journals Nucleolar AATF regulates c-Jun–mediated apoptosis

2012 ◽  
Vol 23 (21) ◽  
pp. 4323-4332 ◽  
Author(s):  
Saima E. Ferraris ◽  
Kimmo Isoniemi ◽  
Elin Torvaldson ◽  
Julius Anckar ◽  
Jukka Westermarck ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Wild Type ◽  
Embryonic Fibroblasts ◽  
Expression Levels ◽  
Nucleolar Stress ◽  
Tnf Α ◽  
Induced Apoptosis ◽  
Factor C

The AP-1 transcription factor c-Jun has been shown to be essential for stress-induced apoptosis in several models. However, the molecular mechanisms underlying the proapoptotic activity of c-Jun are poorly understood. We identify the apoptosis-antagonizing transcription factor (AATF) as a novel nucleolar stress sensor, which is required as a cofactor for c-Jun–mediated apoptosis. Overexpression or down-regulation of AATF expression levels led to a respective increase or decrease in the amount of activated and phosphorylated c-Jun with a proportional alteration in the induction levels of the proapoptotic c-Jun target genes FasL and TNF-α. Accordingly, AATF promoted commitment of ultraviolet (UV)-irradiated cells to c-Jun-dependent apoptosis. Whereas AATF overexpression potentiated UV-induced apoptosis in wild-type cells, c-Jun–deficient mouse embryonic fibroblasts were resistant to AATF-mediated apoptosis induction. Furthermore, AATF mutants defective in c-Jun binding were also defective in inducing AP-1 activity and c-Jun–mediated apoptosis. UV irradiation induced a translocation of AATF from the nucleolus to the nucleus, thereby enabling its physical association to c-Jun. Analysis of AATF deletion mutants revealed that the AATF domains required for compartmentalization, c-Jun binding, and enhancement of c-Jun transcriptional activity were all also required to induce c-Jun–dependent apoptosis. These results identify AATF as a nucleolar-confined c-Jun cofactor whose expression levels and spatial distribution determine the stress-induced activity of c-Jun and the levels of c-Jun–mediated apoptosis.

scholarly journals Pharmacological Inhibition of Caspase-8 Suppresses Inflammation-Induced Angiogenesis in the Cornea

Biomolecules ◽  
2020 ◽  
Vol 10 (2) ◽  
pp. 210
Author(s):  
Yunzhe Tian ◽  
He Li ◽  
Xiuxing Liu ◽  
Lihui Xie ◽  
Zhaohao Huang ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Corneal Neovascularization ◽  
Caspase 8 ◽  
Inhibitory Effects ◽  
Toll Like Receptor 4 ◽  
Pharmacological Inhibition ◽  
Cytokines And Chemokines ◽  
Tnf Α

Inflammation-induced angiogenesis is closely related to many diseases and has been regarded as a therapeutic target. Caspase-8 has attracted increasing attention for its immune properties and therapeutic potential in inflammatory disorders. The aim of our study is to investigate the clinical application of pharmacological inhibition of caspase-8 and the underlying molecular mechanisms in inflammation-induced angiogenesis in the cornea. A model of alkali burn (AB)-induced corneal neovascularization (CNV) in C57BL/6 wild-type (WT) mice and toll-like receptor 4 knockout (Tlr4-/-) mice was used. We found that AB increased caspase-8 activity and the pharmacological inhibition of caspase-8 exerted substantial inhibitory effects on CNV, with consistent decreases in caspase-8 activity, inflammatory cell infiltration, macrophage recruitment and activation, VEGF-A, TNF-α, IL-1β, MIP-1, and MCP-1 expression in the cornea. In vitro, caspase-8 mediated TLR4–dependent chemokines and VEGF-A production by macrophages. The TLR4 knockout significantly alleviated CNV, suppressed caspase-8 activity and downregulated expression of inflammatory cytokines and chemokines after AB. Taken together, these findings provide the first demonstration that the pharmacological inhibition of caspase-8 suppresses inflammation-induced angiogenesis and support the use of a pharmacological caspase-8 inhibitor as a novel clinical treatment for CNV and other angiogenic disorders.

scholarly journals The neuroprotective effect of pretreatment with carbon dots from Crinis Carbonisatus (carbonized human hair) against cerebral ischemia reperfusion injury

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Yue Zhang ◽  
Suna Wang ◽  
Fang Lu ◽  
Meiling Zhang ◽  
Hui Kong ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Reperfusion Injury ◽  
Carbon Dots ◽  
Ischemia Reperfusion Injury ◽  
Neuroprotective Effect ◽  
Ischemia Reperfusion ◽  
Inflammatory Factors ◽  
Lesion Volume ◽  
Ischemic Lesion ◽  
Tnf Α

Abstract Background Cerebral infarction and cerebral hemorrhage, also known as “stroke”, is one of the leading cause of death. At present, there is no real specific medicine for stroke. Crinis Carbonisatus (named Xue-yu-tan in Chinese), produced from carbonized hair of healthy human, and has been widely applied to relieve pain and treat epilepsy, stroke and other diseases in China for thousands of years. Results In this work, a new species of carbon dots derived from Crinis Carbonisatus (CrCi-CDs) were separated and identified. And the neuroprotective effect of carbon dots from CrCi were evaluated using the middle cerebral artery occlusion (MCAO) model. Neurological deficit score and infarction volume was assessed, evans blue content of ischemic hemispheres was measured, the concentrations of inflammatory factors, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) in the cortex were measured, and the levels of neurotransmitters in the brain were determined. Preconditioning of CrCi-CDs significantly reduced ischemic lesion volume and blood–brain-barrier (BBB) permeability, improved neurologic deficits, decreased the level of TNF-α and IL-6 in MCAO rats, inhibited excitatory neurotransmitters aspartate (Asp) and glutamate (Glu), and increased the level of 5-hydroxytryptamine (5-HT). The RNA-Sequencing results reveal that further potential mechanisms behind the activities may be related to the anti-inflammation effects and inhibition of neuroexcitatory toxicity. Conclusion CrCi-CDs performs neuroprotective effect on cerebral ischemia and reperfusion injury, and the mechanisms may correlate with its anti-inflammatory action, which suggested that CrCi-CDs have potential value in clinical therapy on the acute apoplexy cases in combination with thrombolytic drugs. Graphic abstract

Alveolar macrophage activation is a key initiation signal for acute lung ischemia-reperfusion injury

2006 ◽  
Vol 291 (5) ◽  
pp. L1018-L1026 ◽  
Author(s):  
Minqing Zhao ◽  
Lucas G. Fernandez ◽  
Allan Doctor ◽  
Ashish K. Sharma ◽  
Alexander Zarbock ◽  
...  
Keyword(s):  
Lung Injury ◽  
Ischemia Reperfusion ◽  
Weight Ratio ◽  
Lung Model ◽  
Mouse Lung ◽  
Chemokine Production ◽  
Cytokines And Chemokines ◽  
Tnf Α ◽  
Lung Dysfunction ◽  
The Impact

Lung ischemia-reperfusion (I/R) injury is a biphasic inflammatory process. Previous studies indicate that the later phase is neutrophil-dependent and that alveolar macrophages (AMs) likely contribute to the acute phase of lung I/R injury. However, the mechanism is unclear. AMs become activated and produce various cytokines and chemokines in many inflammatory responses, including transplantation. We hypothesize that AMs respond to I/R by producing key cytokines and chemokines and that depletion of AMs would reduce cytokine/chemokine expression and lung injury after I/R. To test this, using a buffer-perfused, isolated mouse lung model, we studied the impact of AM depletion by liposome-clodronate on I/R-induced lung dysfunction/injury and expression of cytokines/chemokines. I/R caused a significant increase in pulmonary artery pressure, wet-to-dry weight ratio, vascular permeability, tumor necrosis factor (TNF)-α, monocyte chemoattractant protein (MCP)-1, and macrophage inflammatory protein (MIP)-2 expression, as well as decreased pulmonary compliance, when compared with sham lungs. After AM depletion, the changes in each of these parameters between I/R and sham groups were significantly attenuated. Thus AM depletion protects the lungs from I/R-induced dysfunction and injury and significantly reduces cytokine/chemokine production. Protein expression of TNF-α and MCP-1 are positively correlated to I/R-induced lung injury, and AMs are a major producer/initiator of TNF-α, MCP-1, and MIP-2. We conclude that AMs are an essential player in the initiation of acute lung I/R injury.

Critical role of glass fiber length in TNF-α production and transcription factor activation in macrophages

1999 ◽  
Vol 276 (3) ◽  
pp. L426-L434 ◽  
Author(s):  
Jianping Ye ◽  
Xianglin Shi ◽  
William Jones ◽  
Yon Rojanasakul ◽  
Ningli Cheng ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Fiber Length ◽  
Promoter Activity ◽  
Molecular Mechanisms ◽  
Glass Fibers ◽  
Critical Role ◽  
Gene Promoter ◽  
Tnf Α ◽  
Gene Transcription Level ◽  
Cytokine Tumor Necrosis Factor

Recent studies have demonstrated that dielectrophoresis is an efficient method for the separation of fibers according to fiber length. This method allows the investigation of fiber-cell interactions with fiber samples of the same composition but of different lengths. In the present study, we analyzed the effects of length on the interaction between glass fibers and macrophages by focusing on production of the inflammatory cytokine tumor necrosis factor (TNF)-α in a mouse macrophage cell line (RAW 264.7). The underlying molecular mechanisms controlling TNF-α production were investigated at the gene transcription level. The results show that glass fibers induced TNF-α production in macrophages and that this induction was associated with activation of the gene promoter. Activation of the transcription factor nuclear factor (NF)-κB was responsible for this induced promoter activity. The inhibition of both TNF-α production and NF-κB activation by N-acetyl-l-cysteine, an antioxidant, indicates that generation of oxidants may contribute to the induction of this cytokine and activation of this transcription factor by glass fibers. Long fibers (17 μm) were significantly more potent than short fibers (7 μm) in inducing NF-κB activation, the gene promoter activity, and the production of TNF-α. This fiber length-dependent difference in the stimulatory potency correlated with the fact that macrophages were able to completely engulf short glass fibers, whereas phagocytosis of long glass fibers was incomplete. These results suggest that fiber length plays a critical role in the potential pathogenicity of glass fibers.

Neuroprotective effect of hydroxy safflor yellow A against cerebral ischemia-reperfusion injury in rats: putative role of mPTP

2016 ◽  
Vol 27 (1) ◽  
pp. 1-8 ◽  
Author(s):  
Sruthi Ramagiri ◽  
Rajeev Taliyan
Keyword(s):  
Oxidative Damage ◽  
Protective Effect ◽  
Mitochondrial Permeability Transition ◽  
Ischemia Reperfusion Injury ◽  
Neuroprotective Effect ◽  
Ischemia Reperfusion ◽  
Radical Scavenger ◽  
Neuroprotective Effects ◽  
Y Maze ◽  
Tnf Α

AbstractHydroxy safflor yellow A (HSYA) has been translated clinically for cardiovascular diseases. HSYA is also greatly acknowledged for its protective effects against cerebral ischemic-reperfusion (I/R) injury. Although the precise mechanism of cerebral I/R injury is not fully understood, oxygen-derived free radicals and mitochondrial permeability transition pore (mPTP) opening during I/R injury are widely recognized as an important contributor to neuronal injury. Thus, we speculated that the neuroprotective effects of HSYA against cerebral I/R injury may be associated with mPTP modulation.Induction of I/R injury was achieved by 60 min of middle cerebral artery occlusion, followed by reperfusion for 24 h. For behavior and cognitive assessment, neurological scoring (NSS), rotarod, and Y-maze task were performed. Oxidative damage was measured in terms of markers such as malondialdehyde, reduced glutathione, and catalase levels and cerebral infarct volumes were quantified using 2,3,5-triphenyl tetrazolinium chloride staining. I/R injury-induced inflammation was determined using tumor necrosis factor-α (TNF-α) levels.Animals exposed to I/R injury showed neurological severity, functional and cognitive disability, elevated oxidative markers, and TNF-α levels along with large infarct volumes. HSYA treatment during onset of reperfusion ameliorated performance in NSS, rotarod and Y-maze attenuated oxidative damage, TNF-α levels, and infarction rate. However, treatment with carboxyatractyloside, an mPTP opener, 20 min before HSYA, attenuated the protective effect of HSYA.Our study confirmed that protective effect of HSYA may be conferred through its free radical scavenger action followed by inhibiting the opening of mPTP during reperfusion and HSYA might act as a promising therapeutic agent against cerebral I/R injury.

scholarly journals Genes Induced by Panax Notoginseng in a Rodent Model of Ischemia-Reperfusion Injury

2020 ◽  
Vol 2020 ◽  
pp. 1-13
Author(s):  
Lanqing Meng ◽  
Qing Huang ◽  
Xuebin Li ◽  
Ping Liang ◽  
Yueyong Li ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Ischemia Reperfusion Injury ◽  
Neuroprotective Effect ◽  
Ischemia Reperfusion ◽  
Neurovascular Unit ◽  
Panax Notoginseng ◽  
Artery Occlusion ◽  
Stroke Recovery ◽  
Ultrastructural Changes ◽  
Triphenyltetrazolium Chloride

Stroke is a cerebrovascular disease that results in decreased blood flow. Although Panax notoginseng (PN), a Chinese herbal medicine, has been proven to promote stroke recovery, its molecular mechanism remains unclear. In this study, middle cerebral artery occlusion (MCAO) was induced in rats with thrombi generated by thread and subsequently treated with PN. After that, staining with 2,3,5-triphenyltetrazolium chloride was employed to evaluate the infarcted area, and electron microscopy was used to assess ultrastructural changes of the neurovascular unit. RNA-Seq was performed to determine the differential expressed genes (DEGs) which were then verified by qPCR. In total, 817 DEGs were identified to be related to the therapeutic effect of PN on stroke recovery. Further analysis by Gene Oncology analysis and Kyoto Encyclopedia of Genes and Genomes revealed that most of these genes were involved in the biological function of nerves and blood vessels through the regulation of neuroactive live receptor interactions of PI3K-Akt, Rap1, cAMP, and cGMP-PKG signaling, which included in the 18 pathways identified in our research, of which, 9 were reported firstly that related to PN’s neuroprotective effect. This research sheds light on the potential molecular mechanisms underlying the effects of PN on stroke recovery.

Inhibitory Effect of Dauricine on Inflammatory Process Following Focal Cerebral Ischemia/Reperfusion in Rats

2007 ◽  
Vol 35 (03) ◽  
pp. 477-486 ◽  
Author(s):  
Xiao-Yan Yang ◽  
Shi-Qin Jiang ◽  
Li Zhang ◽  
Qiang-Ni Liu ◽  
Pei-Li Gong
Keyword(s):  
Inflammatory Process ◽  
Acute Inflammation ◽  
Focal Cerebral Ischemia ◽  
Neuroprotective Effect ◽  
Ischemia Reperfusion ◽  
Experimental Studies ◽  
Inhibitory Effect ◽  
Tnf Α ◽  
Underlying Mechanisms ◽  
The Brain

Our previous experimental studies showed that dauricine could protect the brain from ischemic damage, but the underlying mechanisms were unknown. In this study, we investigated the effect of dauricine on the changes of the inflammation process induced by ischemia/reperfusion (I/R). After I/R, the enzyme activity of MPO, the expression of ICAM-1 and the transcription of IL-1β and TNF-α mRNA were all significantly increased (p < 0.01). And after treatment with dauricine, they were all significantly reduced compared to the vehicle-treated I/R group (p < 0.05 or p < 0.01). These results suggest that dauricin attenuates the inflammation process induced by I/R. The neuroprotective effect of dauricine may partly due to the inhibition acute inflammation induced by I/R.

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