Cerebroprotective Effects of the TLR4-Binding DNA Aptamer ApTOLL in a Rat Model of Ischemic Stroke and Thrombectomy Recanalization.

ApTOLL, a TLR4 modulator aptamer, has demonstrated cerebroprotective effects in a permanent ischemic stroke mouse model, as well as safety and efficacy in early phase clinical trials. We carried out reverse translation research according to STAIR recommendations to further characterize the effects and mechanisms of ApTOLL after transient ischemic stroke in rats and to better inform the design of pivotal clinical trials. Adult male rats subjected to transient middle cerebral artery occlusion were treated either with ApTOLL or the vehicle intravenously at different doses and time-points.

Cerebroprotective Effect of 17β-Estradiol Replacement Therapy in Ovariectomy-Induced Post-Menopausal Rats Subjected to Ischemic Stroke: Role of MAPK/ERK1/2 Pathway and PI3K-Independent Akt Activation.

Despite the overwhelming advances in the understanding of the pathogenesis of stroke, a devastating disease affecting millions of people worldwide, currently there are only a limited number of effective treatments available. Preclinical and clinical studies show that stroke is a sexually dimorphic disorder, affecting males and females differently. Strong experimental evidence indicates that estrogen may play a role in this difference and that exogenous 17β-estradiol (E2) is neuroprotective against stroke in both male and female rodents.

Brain Cell Senescence: A New Therapeutic Target for the Acute Treatment of Ischemic Stroke.

Aging is a major risk factor for cerebral infarction. Since cellular senescence is intrinsic to aging, we postulated that stroke-induced cellular senescence might contribute to neural dysfunction. Adult male Wistar rats underwent 60-minute middle cerebral artery occlusion and were grouped according to 3 reperfusion times: 24 hours, 3, and 7 days.

Preclinical Characterization of Antioxidant Quinolyl Nitrone QN23 as a New Candidate for the Treatment of Ischemic Stroke.

Nitrones are encouraging drug candidates for the treatment of oxidative stress-driven diseases such as acute ischemic stroke (AIS). In a previous study, we found a promising quinolylnitrone, QN23, which exerted a neuroprotective effect in neuronal cell cultures subjected to oxygen-glucose deprivation and in experimental models of cerebral ischemia. In this paper, we update the biological and pharmacological characterization of QN23.

Clot Composition Analysis as a Diagnostic Tool to Gain Insight into Ischemic Stroke Etiology: A Systematic Review.

Mechanical thrombectomy renders the occluding clot available for analysis. Insights into thrombus composition could help establish the stroke cause. We aimed to investigate the value of clot composition analysis as a complementary diagnostic tool in determining the etiology of large vessel occlusion (LVO) ischemic strokes (International Prospective Register of Systematic Reviews [PROSPERO] registration # CRD42020199436).

Intravenous SPION-labeled adipocyte-derived stem cells targeted to the brain by magnetic attraction in a rat stroke model: An ultrastructural insight into cell fate within the brain.

Mesenchymal stem cell therapy after stroke is a promising option investigated in animal models and clinical trials. The intravenous route is commonly used in clinical settings guaranteeing an adequate safety profile although low yields of engraftment. In this report, rats subjected to ischemic stroke were injected with adipose-derived stem cells (ADSCs) labeled with superparamagnetic iron oxide nanoparticles (SPIONs) applying an external magnetic field in the skull to retain the cells.

Comparative Proteomics Unveils LRRFIP1 as a New Player in the DAPK1 Interactome of Neurons Exposed to Oxygen and Glucose Deprivation.

Death-associated protein kinase 1 (DAPK1) is a pleiotropic hub of a number of networked distributed intracellular processes. Among them, DAPK1 is known to interact with the excitotoxicity driver NMDA receptor (NMDAR), and in sudden pathophysiological conditions of the brain, e.g.

Effect of uric acid in animal models of ischemic stroke: A systematic review and meta-analysis.

Addition of uric acid (UA) to thrombolytic therapy, although safe, showed limited efficacy in improving patients' stroke outcome, despite alleged neuroprotective effects of UA in preclinical research. This systematic review assessed the effects of UA on brain structural and functional outcomes in animal models of ischemic stroke. We searched Medline, Embase and Web of Science to identify 16 and 14 eligible rodent studies for qualitative and quantitative synthesis, respectively.

Uric Acid Neuroprotection Associated to IL-6/STAT3 Signaling Pathway Activation in Rat Ischemic Stroke.

Despite the promising neuroprotective effects of uric acid (UA) in acute ischemic stroke, the seemingly pleiotropic underlying mechanisms are not completely understood. Recent evidence points to transcription factors as UA targets. To gain insight into the UA mechanism of action, we investigated its effects on pertinent biomarkers for the most relevant features of ischemic stroke pathophysiology: (1) oxidative stress (antioxidant enzyme mRNAs and MDA), (2) neuroinflammation (cytokine and Socs3 mRNAs, STAT3, NF-κB p65, and reactive microglia), (3) brain swelling (Vegfa, Mmp9, and Timp1 mRNAs), and (4) apoptotic cell death (Bcl-2, Bax, caspase-3, and TUNEL-positive cells).

Endothelin-1-Mediated Drug Resistance in -Mutant Non-Small Cell Lung Carcinoma.

Progression on therapy in non-small cell lung carcinoma (NSCLC) is often evaluated radiographically, however, image-based evaluation of said therapies may not distinguish disease progression due to intrinsic tumor drug resistance or inefficient tumor penetration of the drugs. Here we report that the inhibition of mutated promotes the secretion of a potent vasoconstrictor, endothelin-1 (EDN1), which continues to increase as the cells become resistant with a mesenchymal phenotype. As EDN1 and its receptor (EDNR) is linked to cancer progression, EDNR-antagonists have been evaluated in several clinical trials with disappointing results.

Insight into the molecular sex dimorphism of ischaemic stroke in rat cerebral cortex: Focus on neuroglobin, sex steroids and autophagy.

Including sex is of paramount importance in preclinical and clinical stroke researches, and molecular studies dealing in depth with sex differences in stroke pathophysiology are needed. To gain insight into the molecular sex dimorphism of ischaemic stroke in rat cerebral cortex, male and female adult rats were subjected to transient middle cerebral artery occlusion. The expression of neuroglobin (Ngb) and other functionally related molecules involved in sex steroid signalling (oestrogen and androgen receptors), steroidogenesis (StAR, TSPO and aromatase) and autophagic activity (LC3B-II/LC3B-I ratio, UCP2 and HIF-1α) was assessed in the ipsilateral ischaemic and contralateral non-ischaemic hemispheres.

Optimised lyophilisation-based method for different biomolecule single-extractions from the same rat brain sample: Suitability for RNA and protein expression analyses after ischemic stroke.

Background: Optimisation of tissue processing procedures in preclinical studies reduces the number of animals used and allows integrated multilevel study in the same sample. Multiple extraction of different biomolecules from the same sample has several limitations.

New Method: Using brain samples from rats subjected to ischemic stroke, we combined lyophilisation of flash-frozen tissue, mechanical pulverisation and cryopreservation in a method to optimise tissue handling and preservation for independent RNA or protein single-extract methods, and subsequent RT-qPCR or Western blot analyses.

The selective oestrogen receptor modulator, bazedoxifene, mimics the neuroprotective effect of 17β-oestradiol in diabetic ischaemic stroke by modulating oestrogen receptor expression and the MAPK/ERK1/2 signalling pathway.

Because neuroprotection in stroke should be revisited in the era of recanalisation, the present study analysed the potential neuroprotective effect of the selective oestrogen receptor modulator, bazedoxifene acetate (BZA), in an animal model of diabetic ischaemic stroke that mimics thrombectomy combined with adjuvant administration of a putative neuroprotectant. Four weeks after induction of diabetes (40 mg kg streptozotocin, i.p.

Potassium channels contribute to the increased sensitivity of the rabbit carotid artery to hydrogen sulfide in diabetes.

Hydrogen sulfide (HS) is a potential endothelium-derived hyperpolarizing factor (EDHF) and adventitium- or adipocyte-derived relaxing factor (ADRF) which vasorelaxant action is mediated by potassium channels. HS could also play an important role in the pathophysiology of diabetic cardiovascular complications. The present study has investigated the influence of alloxan-induced diabetes on the role of potassium channels mediating the relaxant response of the rabbit carotid artery to NaHS, a donor of HS.

Emergent Uric Acid Treatment is Synergistic with Mechanical Recanalization in Improving Stroke Outcomes in Male and Female Rats.

Preclinical and clinical studies support a promising, albeit not definitive, neuroprotective effect of emergent uric acid (UA) administration in ischemic stroke. We assessed the effects of UA in an ischemic stroke model relevant to the current treatment paradigm of mechanical thrombectomy within the STAIR/RIGOR recommendations. A cohort of male and female Wistar rats was subjected to ischemic stroke with mechanical recanalization under physiological monitoring.

Molecular mechanisms underlying the neuroprotective role of atrial natriuretic peptide in experimental acute ischemic stroke.

Along with its role in regulating blood pressure and fluid homeostasis, the natriuretic peptide system could be also part of an endogenous protective mechanism against brain damage. We aimed to assess the possibility that exogenous atrial natriuretic peptide (ANP) could protect against acute ischemic stroke, as well as the molecular mechanisms involved. Three groups of rats subjected to transient middle cerebral artery occlusion (tMCAO, intraluminal filament technique, 60 min) received intracerebroventricular vehicle, low-dose ANP (0.

Diabetes modifies the role of prostanoids and potassium channels which regulate the hypereactivity of the rabbit renal artery to BNP.

Diabetic nephropathy is associated with increased risk of cardiovascular disease. B-type natriuretic peptide (BNP) plays an important role in cardiovascular pathophysiology and therapeutics. The aim of the present study was to investigate the influence of experimental diabetes on the mechanisms that regulate the relaxant response of the rabbit renal artery to BNP.

Mechanisms involved in the increased sensitivity of the rabbit basilar artery to atrial natriuretic peptide in diabetes.

Atrial natriuretic peptide (ANP) is a vasodilator with significant regional differences and controversial effects in the cerebral circulation, a vascular bed particularly prone to diabetes-induced complications. The present study has investigated how alloxan-induced diabetes modifies the mechanisms involved in the response of the rabbit basilar artery to ANP. ANP (10-10M) relaxed precontracted basilar arteries, with higher potency in diabetic than in control rabbits.

Molecular mechanisms mediating the neuroprotective role of the selective estrogen receptor modulator, bazedoxifene, in acute ischemic stroke: A comparative study with 17β-estradiol.

As the knowledge on the estrogenic system in the brain grows, the possibilities to modulate it in order to afford further neuroprotection in brain damaging disorders so do it. We have previously demonstrated the ability of the selective estrogen receptor modulator, bazedoxifene (BZA), to reduce experimental ischemic brain damage. The present study has been designed to gain insight into the molecular mechanisms involved in such a neuroprotective action by investigating: 1) stroke-induced apoptotic cell death; 2) expression of estrogen receptors (ER) ERα, ERβ and the G-protein coupled estrogen receptor (GPER); and 3) modulation of MAPK/ERK1/2 and PI3K/Akt signaling pathways.

Use of cyanoacrylate adhesives in general surgery.

This paper presents a review of the use of cyanoacrylate adhesives (CA) in general surgery and digestive surgery, studies the mechanisms of action and interactions of CAs in adherent tissues, and compiles data on the latest experimental and clinical applications. More than seven million traumatic injuries are estimated to occur every year, and between 26 and 90 million surgical procedures using different techniques are performed to close the resulting wounds. Traditional methods not only are both useful and effective, but also have some drawbacks.

Allopurinol in renal ischemia.

Allopurinol is a xanthine oxidase inhibitor and antioxidant free radical scavenger which facilitates the protection of ischemic organs in part via this mechanism of action. The accumulation of free radicals during ischemia and reperfusion is in great manner overcome by inhibitors of xanthine oxidase and by the development of endogenous antioxidants. The ischemic lesion generates a well-established inflammatory response with the subsequent production of inflammatory molecules characteristically present at the first stages of the injury.