Metal Organic Frameworks in Biomedicine Patricia Horcajada,* Ruxandra Gref, Tarek Baati, Phoebe K. Allan, Guillaume Maurin, Patrick Couvreur, G erard F erey, Russell E. Morris, and Christian Serre* Institut Lavoisier, UMR CNRS 8180, Universit e de Versailles St-Quentin en Yvelines, 45 Avenue des Etats-Unis, 78035 Versailles Cedex, France Facult e de Pharmacie, UMR CNRS 8612, Universit e Paris-Sud, 92296 Châtenay-Malabry Cedex, France Institut Charles Gerhardt Montpellier, UMR CNRS 5253, Universit e Montpellier 2, 34095 Montpellier cedex 05, France EaStChem School of Chemistry, University of St. Andrews Purdie Building, St Andrews, KY16 9ST U.K.

Metal-organic frameworks in biomedicine.

Immunity and inflammation are key elements of the pathobiology of stroke, a devastating illness second only to cardiac ischemia as a cause of death worldwide. The immune system participates in the brain damage produced by ischemia, and the damaged brain, in turn, exerts an immunosuppressive effect that promotes fatal infections that threaten the survival of people after stroke. Inflammatory signaling is involved in all stages of the ischemic cascade, from the early damaging events triggered by arterial occlusion to the late regenerative processes underlying post-ischemic tissue repair. Recent developments have revealed that stroke engages both innate and adaptive immunity. But adaptive immunity triggered by newly exposed brain antigens does not have an impact on the acute phase of the damage. Nevertheless, modulation of adaptive immunity exerts a remarkable protective effect on the ischemic brain and offers the prospect of new stroke therapies. As immunomodulation is not devoid of deleterious side effects, a better understanding of the reciprocal interaction between the immune system and the ischemic brain is essential to harness the full therapeutic potential of the immunology of stroke.

/pdf/the-immunology-of-stroke-from-mechanisms-to-translation-2fmsgo5pr1.pdf

The immunology of stroke: from mechanisms to translation

EVOLUTION: Of Mice . . .

The journal of neuroscience : the official journal of the Society for Neuroscience.

Inflammation plays an important role in the pathogenesis of ischemic stroke and other forms of ischemic brain injury. Experimentally and clinically, the brain responds to ischemic injury with an acute and prolonged inflammatory process, characterized by rapid activation of resident cells (mainly microglia), production of proinflammatory mediators, and infiltration of various types of inflammatory cells (including neutrophils, different subtypes of T cells, monocyte/macrophages, and other cells) into the ischemic brain tissue. These cellular events collaboratively contribute to ischemic brain injury. Despite intense investigation, there are still numerous controversies concerning the time course of the recruitment of inflammatory cells in the brain and their pathogenic roles in ischemic brain injury. In this review, we provide an overview of the time-dependent recruitment of different inflammatory cells following focal cerebral I/R. We discuss how these cells contribute to ischemic brain injury and highlight certain recent findings and currently unanswered questions about inflammatory cells in the pathophysiology of ischemic stroke.

https://jlb.onlinelibrary.wiley.com/doi/epdf/10.1189/jlb.1109766

Inflammatory mechanisms in ischemic stroke: role of inflammatory cells.

Background: Others and we reported that RIC-therapy is safe in humans, and protective in rodents that can be repeatedly used under both, hemorrhagic and ischemic stroke. Since TBI shares some common features of ischemic and hemorrhagic injury as in stroke, we hypothesized that RIC-therapy will remain protective in TBI, too. Methods: We tested RIC-therapy in a closed-head injury model of pediatric TBI in male mice (28 days old). Mice were later randomized for either RIC-therapy or its sham-procedure once daily starting 1-hour post-TBI until sacrifice. Cerebral blood flow (CBF) was measured by laser speckle imager (LSCI), and MRI was used to estimate edema and cerebral perfusion. Mice were also tested for functional outcomes. Statistical significance was determined at p Results: Micro-CT showed a shallow dent along the median suture of skull. Closed-head TBI led to progressive acute ischemia, which was attenuated with time. However, reduced CBF and significant edema was observed at 48-hours post-TBI, which was attenuated by RIC-therapy. Open-field test showed no significant difference at 3 days post-TBI but in the narrow beam-walk challenge, TBI mice showed significantly impaired activity, which was improved by RIC-therapy. Flowcytometry in brain tissue confirmed significantly increased opening of mitochondrial permeability transition pore and necro-apoptotic cell death at 3 days post-TBI that was blocked by RIC-therapy. In a 3-weeks follow up, the mice with TBI were apparently normal but showed depressive phenotype in challenged environments, such as lesser mobility during forced swim test, and reduced cerebrovascular reserve capacity (CVRC). Flowcytometric analysis of the brain tissue at 3-weeks post-TBI showed reduced neuronal activity as detected by the poor population of cFOS positive neurons. RIC-therapy after TBI significantly attenuated the depressive phenotype, improved CVRC and cFOS positive neurons, collectively indicating improved neurovascular coupling and function. Conclusion: Post-TBI RIC-therapy is safe and beneficial, and can be translated to prevent ischemic injury.

Abstract T P92: Remote Ischemic Conditioning (RIC) Attenuates Post-TBI Ischemic Injury and Improves Behavioral Outcomes

Introduction: Diet-induced metabolic syndrome (MetS) is an increasing risk factor for stroke. We have previously shown that high fat diet 1) increases infarct size and hemorrhagic transformation and worsens functional outcome after stroke and 2) impairs neurovascular function even before stroke. However, the impact of MetS on cerebrovascular architecture remained unknown. Hypotheses: 1) Diet-induced MetS causes pathological neovascularization; and 2) these changes lead to cognitive deficits at baseline and poor recovery after stroke. Methods: Male Wistar rats were given a control diet or low dose streptozotocin (30mg/kg) plus high fat (45%) diet for a period of eight weeks (n=4-8/group). Animals were then subjected to sham or middle cerebral artery occlusion (MCAO) surgery. Motor and cognitive functions were assessed by at Days 1, 3, 10 and 14 after stroke using Bederson’s Score, Beam Walking Test, and Novel Object Recognition. Vascular indices (branch density, tortuosity, vascular volume and surface area) were then measured in cortex and striatum using confocal imaging of FITC-filled vasculature. Results: Branch density was higher and recognition index was lower in the sham MetS group compared to sham control group. Stroke significantly reduced vascular volume and surface area in both groups, which was more prominent in the MetS group. Branch density was increased after stroke in the control group only. At Day 14, motor and cognitive scores in the sham MetS group were lower than control. Conclusion: Cerebrovascular structure, function, and cognition are impaired from diet-induced MetS alone . Collectively, these data suggest that cerebrovasculature is an early target in MetS and vasculoprotective strategies are needed to prevent cerebral complications.

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Abstract W P412: Metabolic Syndrome Alters Cerebrovascular Architecture: Relevance to Cognitive Deficits and Stroke Outcomes

Response:

We thank Dr Michel Hanss1 for his interest in our article and his valuable suggestion in this direction. It requires further attention. The embolic clot model (eMCAO) is best suited to study in vivo clot lysis. Most of the previous reports are the studies of PRE and POST conditioning in mechanical occlusion models (mMCAO). Ours is the first report in any kind of clot model showing that remote ischemic PER conditioning (RIPerC) upregulates cerebral blood flow and provides neuroprotection.2 Therefore, our report is not the confirmation of any previous finding but a novel result.

We agree with the speculation that RIPerC, similar to venous occlusion, may increase the endogenous …

Response to letter regarding article, "Remote ischemic perconditioning is effective alone and in combination with intravenous tissue-type".

Deletion of Thioredoxin Interacting Protein (TXNIP) Augments Hyperoxia-induced Vaso-obliteration in Ischemic Retinopathy.

Admission hyperglycemia worsens clinical outcomes in acute ischemic stroke (AIS) but the mechanism remains controversial. Our previous studies showing that even a modest acute elevation in blood glucose amplifies vascular injury and neurological deficit emphasize the importance of an intact cerebrovasculature in functional outcomes. Given that stroke lowers perfusion even in the nonischemic hemisphere, the impact of hyperglycemic AIS on cerebrovascular reactivity in the contralateral hemispheres needs to be determined.

Hypothesis: Acute hyperglycemia exacerbates cerebrovascular myogenic dysfunction in the contralateral hemisphere causing cerebral blood flow (CBF) impairment and worsening stroke outcomes.

Methods: Weight-matched male Wistar rats (n=6-8) were subjected to 30 min middle cerebral artery occlusion (MCAO)/45 min reperfusion after administration of saline or 40 % glucose solution 10 min before procedure. Myogenic tone of isolated MCAs was determined across the pressure range. In another set of animals (n=5), infarct size, edema and neurologic deficit were measured in rats exposed to 30 min hyperglycemic MCAO/24 h reperfusion. Cerebral perfusion was evaluated with laser Doppler flowmetry.

Results: The myogenic tone was decreased in both ischemic and nonischemic sides albeit to a different degree (at 80mmHg 5±0.85† and 7.8±0.7*, respectively vs sham 9.4±0.9). Interestingly acute hyperglycemia exacerbated myogenic dysfunction (at 80mmHg 4.8±0.3\***|) and amplified CBF reduction in the nonischemic hemisphere (MCAO 4.5±3.1% vs hyperglycemic MCAO 22.3±7.1% *p<0.05). When ischemic injury was superimposed with acute hyperglycemia, this led to infarct size expansion (35.6±6.1% vs 15.7±1.6 % *p<0.05), increased edema (15±2.7% vs 7.2±1% *p<0.05) and more pronounced neurological deficit (#p<0.001).

Conclusion: Our results provide evidence that there is early loss of tone in the contralateral hemisphere, augmented myogenic dysfunction in hyperglycemia is associated with poor stroke outcomes, and that the nonischemic hemisphere may be a novel target for the management of AIS. (†P<0.001, *P<0.05 vs sham, \***|p<0.001 vs nonischemic hemisphere)

Adviye Ergul

Papers

Abstract T P92: Remote Ischemic Conditioning (RIC) Attenuates Post-TBI Ischemic Injury and Improves Behavioral Outcomes

Abstract W P412: Metabolic Syndrome Alters Cerebrovascular Architecture: Relevance to Cognitive Deficits and Stroke Outcomes

Response to letter regarding article, "Remote ischemic perconditioning is effective alone and in combination with intravenous tissue-type".

Deletion of Thioredoxin Interacting Protein (TXNIP) Augments Hyperoxia-induced Vaso-obliteration in Ischemic Retinopathy.

Abstract 153: The Role of Contralateral Cerebrovascular Myogenic Dysfunction in Hyperglycemic Stroke