- Urokinase-type Plasminogen Activator Induces Neurorepair in the Ischemic Brain. [Journal Article]
- JNJ Neurol Exp Neurosci 2018; 4(2):24-29
- Urokinase-type plasminogen activator (uPA) is a serine proteinase that upon binding to its receptor (uPAR) catalyzes the conversion of plasminogen into plasmin on the cell surface. Recent studies ind...
Urokinase-type plasminogen activator (uPA) is a serine proteinase that upon binding to its receptor (uPAR) catalyzes the conversion of plasminogen into plasmin on the cell surface. Recent studies indicate that neurons but not astrocytes release uPA during the recovery phase from an ischemic injury, and that binding of uPA to uPAR promotes neurorepair in the ischemic brain by a mechanism that does not require plasmin generation. A combined approach of in vitro and in vivo studies has shown that uPA binding to uPAR induces the reorganization of the actin cytoskeleton in dendritic spines and axons that have suffered an ischemic injury. Furthermore, recent data indicate that uPA-uPAR binding induces astrocytic activation and a crosstalk between activated astrocytes and the injured neuron that triggers a sequence of biochemical events that promote the repair of synapses injured by the ischemic insult. The translational relevance of these observations is noteworthy because following its intravenous administrations recombinant uPA (ruPA) reaches the ischemic tissue, thus raising the question of whether treatment with ruPA is an effective therapeutic strategy to promote neurorepair functional recovery among ischemic stroke survivors.
- Molecular biomarkers of Graves' ophthalmopathy. [Review]
- EMExp Mol Pathol 2018 Nov 08
- Graves' ophthalmopathy (GO), a complication of Graves' disease (GD), is typified by orbital inflammation, ocular tissue expansion and remodeling and, ultimately, fibrosis. Orbital fibroblasts are key...
Graves' ophthalmopathy (GO), a complication of Graves' disease (GD), is typified by orbital inflammation, ocular tissue expansion and remodeling and, ultimately, fibrosis. Orbital fibroblasts are key effectors of GO pathogenesis exhibiting exaggerated inflammatory and fibroproliferative responses to cytokines released by infiltrating immune cells. Activated orbital fibroblasts also produce inflammatory mediators that contribute to disease progression, facilitate the orbital trafficking of monocytes and macrophages, promote differentiation of matrix-producing myofibroblasts and stimulate accumulation of a hyaluronan-rich stroma, which leads to orbital tissue edema and fibrosis. Proteomic and transcriptome profiling of the genomic response of ocular and non-ocular fibroblasts to INF-γ and TGF-β1 focused on identification of translationally-relevant therapeutic candidates. Induction of plasminogen activator inhibitor-1 (PAI-1, SERPINE1), a clade E member of the serine protease inhibitor (SERPIN) gene family and a prominent regulator of the pericellular proteolytic microenvironment, was one of the most highly up-regulated proteins in INF-γ- or TGF-β1-stimulated GO fibroblasts as well as in severe active GD compared to patients without thyroid disease. PAI-1 has multifunctional roles in inflammatory and fibrotic processes that impact tissue remodeling, immune cell trafficking and survival as well as signaling through several receptor systems. This review focuses on the pathophysiology of the GO fibroblast and possible targets for effective drug therapy.
- Achyranthes bidentata polypeptide k improves long-term neurological outcomes through reducing downstream microvascular thrombosis in experimental ischemic stroke. [Journal Article]
- BRBrain Res 2018 Nov 08
- Achyranthes bidentata Bl. (A. bidentata) occupies an important position in traditional Chinese medicine owing to the property of promoting the circulation of blood and removing stasis. Achyranthes bi...
Achyranthes bidentata Bl. (A. bidentata) occupies an important position in traditional Chinese medicine owing to the property of promoting the circulation of blood and removing stasis. Achyranthes bidentata polypeptide k (ABPPk) is one of the active components isolated from A. bidentata.We previously demonstrated that ABPPk has potent neuroprotective effects against neuronal apoptosis both in vitro and in vivo, but the roles and mechanisms of ABPPk on long-term functional recovery after ischemic stroke remain unknown. In the current study, we investigated the neuroprotective effects of ABPPk on filament transient middle cerebral artery occlusion (tMCAO) rats and found that ABPPk reduced the infarct volume and maintained the neuronal integrity in the ischemic penumbra. Moreover, we found that ABPPk might reduce the formation of downstream microthrombus through preventing ischemic-induced oxidative damage of brain endothelial cells and activation of tissue factor (TF), plasminogen activator inhibitor-1 (PAI-1), and NF-κB. ABPPk also inhibited polymorphonuclearleukocytes(PMNs) infiltration and matrix metalloproteinase-2/-9 (MMP-2/-9) activation in the ischemic penumbra. Morris water maze, foot fault test, and modified neurological severity score were assessed for a period of 6 weeks following tMCAO. ABPPk improved long-term recognition abilities and neurological outcomes after stroke compared with saline-treated rats. Taken together, these results suggested that ABPPk is beneficial to the improvement of long-term outcomes after transient cerebral ischemia injury and can be used as a potential neuroprotective agent.
- Systematic Review and Meta-Analysis on the Impact of Thrombolytic Therapy in Liver Transplantation Following Donation after Circulatory Death. [Review]
- JCJ Clin Med 2018 Nov 08; 7(11)
- CONCLUSIONS: To recapitulate, tPA in DCD liver transplantation decreased the incidence of ITBLs, re-transplantation and markedly improved 1-year graft survival, without any increased risk for blood transfusion, hence it has potential to expand the boundaries of DCD liver transplantation.
- Successful low-dosage thrombolysis of massive pulmonary embolism in primigravida: A case report. [Journal Article]
- MMedicine (Baltimore) 2018; 97(43):e12985
- CONCLUSIONS: Administration of low-dosage alteplase in primigravida with hemodynamic instability is extremely rare and controversial; however, our case suggests that this treatment strategy is relatively safe and feasible. In addition, nonradiometric examination played a major role in the diagnosis of PE in this patient. Because radiation use is contraindicated during pregnancy, these examinations could be the first choice for pregnant patients with suspected PE.
- Review of the Mobile Stroke Unit Experience Worldwide. [Review]
- INInterv Neurol 2018; 7(6):347-358
- The treatment of stroke is dependent on a narrow therapeutic time window that requires interventions to be emergently pursued. Despite recent "FAST" initiatives that have underscored "time is brain,"...
The treatment of stroke is dependent on a narrow therapeutic time window that requires interventions to be emergently pursued. Despite recent "FAST" initiatives that have underscored "time is brain," many patients still fail to present within the narrow time window to receive maximum treatment benefit from advanced stroke therapies, including recombinant tissue plasminogen activator (tPA) and mechanical thrombectomy. The convergence of emergency medical services, telemedicine, and mobile technology, including transportable computed tomography scanners, has presented a unique opportunity to advance patient stroke care in the prehospital field by shortening time to hyperacute stroke treatment with a mobile stroke unit (MSU).
- Repurposing of approved cardiovascular drugs against ischemic cerebrovascular disease by disease-disease associated network-assisted prediction. [Journal Article]
- CPChem Pharm Bull (Tokyo) 2018 Nov 08
- Stroke is one of the leading causes of death and disability globally, while intravenous thrombolysis with recombinant tissue plasminogen activator remains the only FDA-approved therapy for ischemic s...
Stroke is one of the leading causes of death and disability globally, while intravenous thrombolysis with recombinant tissue plasminogen activator remains the only FDA-approved therapy for ischemic stroke. The attempts to develop new treatments for acute ischemic stroke meet costly and spectacularly disappointing results, which requires both long time and high costs, whereas repurposing of safe existing drugs to new indications provides a cost-effective and not time-consuming alternative. Vascular protection is a promising strategy for improving stroke outcome, as vascular function is critical to both cardiovascular diseases (CVD) and ischemic cerebrovascular disease (ICD). Vascular function related biological processes and pathways maybe the critical associations between CVD and ICD. In this study, a multi-database, in silico target identification, gene function enrichment, and network pharmacology analysis integration approach was proposed and applied to investigate the FDA-approved CVD drugs repurposing for ICD. A list of 119 candidate drugs can be obtained for further investigation of their potential in ICD treatment. As a pleiotropic drug with multi-target, carvedilol was set an example to investigate its promising potential for ICD therapy. Our results indicated that the mode of action of carvedilol for ICD treatment may tightly associated with vascular function regulation and the mechanism is multi-target and multi-signaling pathway related. The disease-disease association network-assisted prediction needs further investigations. In summary, the proposed methods herein may provide a promising alternative to inferring novel disease indications for known drugs.
- Amyloid beta soluble forms and plasminogen activation system in Alzheimer's disease: Consequences on extracellular maturation of brain-derived neurotrophic factor and therapeutic implications. [Review]
- CNCNS Neurosci Ther 2018 Nov 06
- Soluble oligomeric forms of amyloid beta (Aβ) play an important role in causing the cognitive deficits in Alzheimer's disease (AD) by targeting and disrupting synaptic pathways. Thus, the present res...
Soluble oligomeric forms of amyloid beta (Aβ) play an important role in causing the cognitive deficits in Alzheimer's disease (AD) by targeting and disrupting synaptic pathways. Thus, the present research is directed toward identifying the neuronal pathways targeted by soluble forms and, accordingly, develops alternative therapeutic strategies. The neurotrophin brain-derived neurotrophic factor (BDNF) is synthesized as a precursor (pro-BDNF) which is cleaved extracellularly by plasmin to release the mature form. The conversion from pro-BDNF to BDNF is an important process that regulates neuronal activity and memory processes. Plasmin-dependent maturation of BDNF in the brain is regulated by plasminogen activator inhibitor-1 (PAI-1), the natural inhibitor of tissue-type plasminogen activator (tPA). Therefore, tPA/PAI-1 system represents an important regulator of extracellular BDNF/pro-BDNF ratio. In this review, we summarize the data on the components of the plasminogen activation system and on BDNF in AD. Moreover, we will hypothesize a possible pathogenic mechanism caused by soluble Aβ forms based on the effects on tPA/PAI-1 system and on the consequence of an altered conversion from pro-BDNF to the mature BDNF in the brain of AD patients. Translation into clinic may include a better characterization of the disease stage and future direction on therapeutic targets.
- Upregulation of Plasminogen Activator Inhibitor-1 in Irradiated Recipient Arteries and Veins from Free Tissue Transfer Reconstruction in Cancer Patients. [Journal Article]
- MIMediators Inflamm 2018; 2018:4058986
- CONCLUSIONS: The current study shows a sustained upregulation of PAI-1 in both arteries and veins after exposure to ionizing radiation, indicating a chronic inflammation mainly in the adventitia. We believe that the results contribute to further understanding of radiation-induced vascular disease, where targeting PAI-1 may be a potential treatment.
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- Dual mechanisms for the regulation of brain-derived neurotrophic factor by valproic acid in neural progenitor cells. [Journal Article]
- KJKorean J Physiol Pharmacol 2018; 22(6):679-688
- Autism spectrum disorders (ASDs) are neurodevelopmental disorders that share behavioral features, the results of numerous studies have suggested that the underlying causes of ASDs are multifactorial....
Autism spectrum disorders (ASDs) are neurodevelopmental disorders that share behavioral features, the results of numerous studies have suggested that the underlying causes of ASDs are multifactorial. Behavioral and/or neurobiological analyses of ASDs have been performed extensively using a valid model of prenatal exposure to valproic acid (VPA). Abnormal synapse formation resulting from altered neurite outgrowth in neural progenitor cells (NPCs) during embryonic brain development has been observed in both the VPA model and ASD subjects. Although several mechanisms have been suggested, the actual mechanism underlying enhanced neurite outgrowth remains unclear. In this study, we found that VPA enhanced the expression of brain-derived neurotrophic factor (BDNF), particularly mature BDNF (mBDNF), through dual mechanisms. VPA increased the mRNA and protein expression of BDNF by suppressing the nuclear expression of methyl-CpG-binding protein 2 (MeCP2), which is a transcriptional repressor of BDNF. In addition, VPA promoted the expression and activity of the tissue plasminogen activator (tPA), which induces BDNF maturation through proteolytic cleavage. Trichostatin A and sodium butyrate also enhanced tPA activity, but tPA activity was not induced by valpromide, which is a VPA analog that does not induce histone acetylation, indicating that histone acetylation activity was required for tPA regulation. VPA-mediated regulation of BDNF, MeCP2, and tPA was not observed in astrocytes or neurons. Therefore, these results suggested that VPA-induced mBDNF upregulation was associated with the dysregulation of MeCP2 and tPA in developing cortical NPCs.