Neflamapimod inhibits endothelial cell activation, adhesion molecule expression, leukocyte attachment and vascular inflammation by inhibiting p38 MAPKα and NF-κB signaling.

Neflamapimod, a selective inhibitor of the alpha isoform of p38 mitogen-activated protein kinase (MAPKα), was investigated for its potential to inhibit lipopolysaccharide (LPS)-induced activation of endothelial cells (ECs), adhesion molecule induction, and subsequent leukocyte attachment to EC monolayers. These events are known to contribute to vascular inflammation and cardiovascular dysfunction. Our results demonstrate that LPS treatment of cultured ECs and rats leads to significant upregulation of adhesion molecules, both in vitro and in vivo, which can be effectively inhibited by neflamapimod treatment.

Detection and Diagnosis of Cardiac Amyloidosis in Egypt.

Cardiac amyloidosis is a life-threatening disease that occurs when amyloid proteins, most commonly immunoglobulin light chain or transthyretin, mutate or become unstable, misfold, deposit as amyloid fibrils, and accumulate in the myocardium. Early diagnosis of cardiac amyloidosis is hindered by insufficient awareness, specifically regarding clinical red flags and diagnostic pathways. Cardiac amyloidosis diagnosis comprises two important phases, clinical suspicion (phase one) followed by definitive diagnosis (phase two).

Neflamapimod induces vasodilation in resistance mesenteric arteries by inhibiting p38 MAPKα and downstream Hsp27 phosphorylation.

Neflamapimod, a selective inhibitor of p38 mitogen activated protein kinase alpha (MAPKα), is under clinical investigation for its efficacy in Alzheimer's disease (AD) and dementia with Lewy Bodies (DLB). Here, we investigated if neflamapimod-mediated acute inhibition of p38 MAPKα could induce vasodilation in resistance-size rat mesenteric arteries. Our pressure myography data demonstrated that neflamapimod produced a dose-dependent vasodilation in mesenteric arteries.

Mechanisms of Preconditioning Exercise-Induced Neurovascular Protection in Stroke.

Ischemic stroke is a leading cause of death and disability. Tissue plasminogen activator is the only U.S.

Deferoxamine Treatment Prevents Post-Stroke Vasoregression and Neurovascular Unit Remodeling Leading to Improved Functional Outcomes in Type 2 Male Diabetic Rats: Role of Endothelial Ferroptosis.

It is a clinically well-established fact that patients with diabetes have very poor stroke outcomes. Yet, the underlying mechanisms remain largely unknown. Our previous studies showed that male diabetic animals show greater hemorrhagic transformation (HT), profound loss of cerebral vasculature in the recovery period, and poor sensorimotor and cognitive outcomes after ischemic stroke.

Short-Term Acute Exercise Preconditioning Reduces Neurovascular Injury After Stroke Through Induced eNOS Activation.

Physical exercise is known to reduce cardiovascular risk but its role in ischemic stroke is not clear. It was previously shown that an acute single bout of exercise reduced increased eNOS activation in the heart and reduced myocardial infarction. However, the impact of a single bout or short-term exercise on eNOS-induced neuroprotection after stroke was not previously studied.

Review of Diabetic Polyneuropathy: Pathogenesis, Diagnosis and Management According to the Consensus of Egyptian Experts.

Diabetic polyneuropathy (DPN) is a complex and multifactorial entity in which various factors besides hyperglycemia play an important role. Symptoms of DPN are sensory, motor or autonomic. Intensive research proved that oxidative stress is the common denominator for the four major destructive pathways of hyperglycemia including increased hexosamine pathway flux, activation of Protein kinase-C (PKC) pathway, increased Advanced Glycated End-products (AGEs) formation, and increased Polyol Pathway flux.

Endothelial stromelysin1 regulation by the forkhead box-O transcription factors is crucial in the exudative phase of acute lung injury.

Enhanced vascular permeability is associated with inflammation and edema in alveoli during the exudative phase of acute respiratory distress syndrome (ARDS). Mechanisms leading to the endothelial contribution on the early exudative stage of ARDS are not precise. We hypothesized that modulation of endothelial stromelysin1 expression and activity by Akt1-forkhead box-O transcription factors 1/3a (FoxO1/3a) pathway could play a significant role in regulating pulmonary edema during the initial stages of acute lung injury (ALI).

Peroxynitrite-Induced Tyrosine Nitration Contributes to Matrix Metalloprotease-3 Activation: Relevance to Hyperglycemic Ischemic Brain Injury and Tissue Plasminogen Activator.

Matrix metalloprotease-3 (MMP3) activation mediates the tissue plasminogen activator (tPA)-induced hemorrhagic transformation after stroke. Hyperglycemia (HG) further exacerbates this outcome. We have recently shown that HG increases MMP3 activity in the brain after stroke.

Chronic Remote Ischemic Conditioning Is Cerebroprotective and Induces Vascular Remodeling in a VCID Model.

Vascular contributions to cognitive impairment and dementia (VCID) make up 50% of the cases of dementia. The purpose of this study was to determine the effect of chronic remote ischemic conditioning (C-RIC) on improving long-term (6 months) outcomes and cerebral blood flow (CBF) and collateral formation in a mouse model of VCID. Adult C57BL/6J male mice (10 weeks) were randomly assigned to four different groups: (1) sham-bilateral carotid artery stenosis (BCAS), (2) BCAS + sham RIC, (3) BCAS+C-RIC for 1 month (1MO), and (4) BCAS+C-RIC-4 months (4MO).

Enhanced VEGF signalling mediates cerebral neovascularisation via downregulation of guidance protein ROBO4 in a rat model of diabetes.

Aims/hypothesis: Diabetes promotes cerebral neovascularisation via increased vascular endothelial growth factor (VEGF) angiogenic signalling. Roundabout-4 (ROBO4) protein is an endogenous inhibitor of VEGF signalling that stabilises the vasculature. Yet, how diabetes affects ROBO4 function remains unknown.

Impact of Comorbidities on Acute Injury and Recovery in Preclinical Stroke Research: Focus on Hypertension and Diabetes.

Human ischemic stroke is very complex, and no single preclinical model can comprise all the variables known to contribute to stroke injury and recovery. Hypertension, diabetes, and hyperlipidemia are leading comorbidities in stroke patients. The use of predominantly young adult and healthy animals in experimental stroke research has created a barrier for translation of findings to patients.

Matrix Metalloprotease 3 Exacerbates Hemorrhagic Transformation and Worsens Functional Outcomes in Hyperglycemic Stroke.

Background And Purpose: Acute hyperglycemia worsens the clinical outcomes and exacerbates cerebral hemorrhage after stroke. The mediators of hemorrhagic transformation (HT) in hyperglycemic stroke are not fully understood. Matrix metalloproteinase 3 (MMP3) plays a critical role in the tissue-type plasminogen activator-induced HT.

Comparative Analysis of Different Methods of Ischemia/Reperfusion in Hyperglycemic Stroke Outcomes: Interaction with tPA.

Acute hyperglycemia (HG) exacerbates reperfusion injury and aggravates tissue plasminogen activator (tPA)-induced hemorrhagic transformation (HT). Previous experimental hyperglycemic stroke studies employed very high blood glucose levels and exclusively used suture occlusion model to induce ischemia. Only few studies evaluated HG in embolic stroke and mostly involving the use of 10-fold higher dose of tPA than that is used in patients.

SOD1 overexpression prevents acute hyperglycemia-induced cerebral myogenic dysfunction: relevance to contralateral hemisphere and stroke outcomes.

Admission hyperglycemia (HG) amplifies vascular injury and neurological deficits in acute ischemic stroke, but the mechanisms remain controversial. We recently reported that ischemia-reperfusion (I/R) injury impairs the myogenic response in both hemispheres via increased nitration. However, whether HG amplifies contralateral myogenic dysfunction and whether loss of tone in the contralateral hemisphere contributes to stroke outcomes remain to be determined.

Metformin treatment in the period after stroke prevents nitrative stress and restores angiogenic signaling in the brain in diabetes.

Diabetes impedes vascular repair and causes vasoregression in the brain after stroke, but mechanisms underlying this response are still unclear. We hypothesized that excess peroxynitrite formation in diabetic ischemia/reperfusion (I/R) injury inactivates the p85 subunit of phosphoinositide 3-kinase (PI3K) by nitration and diverts the PI3K-Akt survival signal to the p38-mitogen-activated protein kinase apoptosis pathway. Nitrotyrosine (NY), Akt and p38 activity, p85 nitration, and caspase-3 cleavage were measured in brains from control, diabetic (GK), or metformin-treated GK rats subjected to sham or stroke surgery and in brain microvascular endothelial cells (BMVECs) from Wistar and GK rats subjected to hypoxia/reoxygenation injury.

Hyperglycemia, acute ischemic stroke, and thrombolytic therapy.

Ischemic stroke is a leading cause of disability and is considered now the fourth leading cause of death. Many clinical trials have shown that stroke patients with acute elevation in blood glucose at onset of stroke suffer worse functional outcomes, longer in-hospital stay, and higher mortality rates. The only therapeutic hope for these patients is the rapid restoration of blood flow to the ischemic tissue through intravenous administration of the only currently proven effective therapy, tissue plasminogen activator (tPA).

Remote ischemic perconditioning is effective after embolic stroke in ovariectomized female mice.

Remote ischemic conditioning is neuroprotective in young male rodents after experimental stroke. However, it has never been tested in females whom remain at higher risk of stroke injury after menopause. We tested remote ischemic perconditioning therapy (RIPerC) at 2 h after embolic stroke in ovariectomized (OVX) female mice with and without intravenous tissue plasminogen activator (IV-tPA) treatment.

Thioredoxin-interacting protein is required for endothelial NLRP3 inflammasome activation and cell death in a rat model of high-fat diet.

Aims/hypothesis: Obesity and hypertension, known pro-inflammatory states, are identified determinants for increased retinal microvascular abnormalities. However, the molecular link between inflammation and microvascular degeneration remains elusive. Thioredoxin-interacting protein (TXNIP) is recognised as an activator of the NOD-like receptor pyrin domain containing-3 (NLRP3) inflammasome.

Candesartan reduces the hemorrhage associated with delayed tissue plasminogen activator treatment in rat embolic stroke.

We have previously reported that angiotensin receptor blockade reduces reperfusion hemorrhage in a suture occlusion model of stroke, despite increasing matrix metalloproteinase (MMP-9) activity. We hypothesized that candesartan will also decrease hemorrhage associated with delayed (6 h) tissue plasminogen activator (tPA) administration after embolic stroke, widening the therapeutic time window of tPA. Adult male Wistar rats were subjected to embolic middle cerebral artery occlusion (eMCAO) and treated with either candesartan (1 mg/kg) alone early at 3 h, delayed tPA (10 mg/kg) alone at 6 h, the combination of candesartan and tPA, or vehicle control.

Experimental evaluation of Candonocypris novaezelandiae (Crustacea: Ostracoda) in the biocontrol of Schistosomiasis mansoni transmission.

Objective: To test Candonocypris novaezelandiae (Baird) (C. novaezelandiae), sub-class Ostracoda, obtained from the Nile, Egypt for its predatory activity on snail, Biomphalaria alexandrina (B. alexandrina), intermediate host of Schistosoma mansoni (S.

Targets of vascular protection in acute ischemic stroke differ in type 2 diabetes.

Hemorrhagic transformation is an important complication of acute ischemic stroke, particularly in diabetic patients receiving thrombolytic treatment with tissue plasminogen activator, the only approved drug for the treatment of acute ischemic stroke. The objective of the present study was to determine the effects of acute manipulation of potential targets for vascular protection [i.e.

Remote ischemic perconditioning is effective alone and in combination with intravenous tissue-type plasminogen activator in murine model of embolic stroke.

Background And Purpose: Remote ischemic conditioning is cardioprotective in myocardial infarction and neuroprotective in mechanical occlusion models of stroke. However, there is no report on its therapeutic potential in a physiologically relevant embolic stroke model (embolic middle cerebral artery occlusion) in combination with intravenous tissue-type plasminogen activator (tPA).

Methods: We tested remote ischemic perconditioning therapy (RIPerC) at 2 hours after embolic middle cerebral artery occlusion in the mouse with and without intravenous tPA at 4 hours.