Abstract TP79: Inhibition of Toll Like Receptor-4 (tlr4) Improves Neurobehavioral Outcomes After Acute Ischemic Stroke in Diabetic Rats

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Yasir Abdul ◽  
Mohammed Abdelsaid ◽  
Wieguo Li ◽  
Guangkuo Dong ◽  
Adviye Ergul
Keyword(s):  
Ischemic Stroke ◽  
Immune System ◽  
Functional Outcomes ◽  
Therapeutic Potential ◽  
Adaptive Immune System ◽  
Artery Occlusion ◽  
Stroke Recovery ◽  
Microvascular Endothelial Cell ◽  
Poor Recovery ◽  
Tlr4 Receptor

Introduction: Diabetes increases the risk of occurrence and poor recovery of ischemic stroke injury. Activation of adaptive immune system and resulting inflammation contributes to neurovascular injury and deterioration of neurological functions post stroke in diabetes. We have shown that activation of TLR4, a key player in the innate immune system, decreases brain microvascular endothelial cell survival after hypoxic injury in diabetic conditions. Our previous work also demonstrated greater bleeding/edema and poor recovery after stroke in diabetes. Current study tested the hypothesis that activation of TLR4 contributes to worsened stroke injury in diabetes and its inhibition can improve functional outcomes. Methods: Low dose of Streptozotocin (30mg/kg) and high fat diet were used to induce type 2 diabetes in male Wistar rats. Middle cerebral artery occlusion for 60 mins was performed in 13 weeks old animals. Expression of TLR4 receptor in brain homogenates and cerebral microvasculature were assessed by immunoblotting (relative density). Another set of animals was treated with TLR4 inhibitor TAK242 (3mg/kg; i.p. after reperfusion, 24 and 48 hours). Neurobehavioral deficits were measured by composite score and adhesive removal test at baseline, day 1 and 3 post ischemic stroke. Results: Ischemic stroke increased the expression of TLR4 receptor in ischemic hemisphere (0.50±0.06 sham, 0.68±0.02 control and 1.24±2.0* diabetic; *p<0.05 vs sham) as well as in microvasculature (0.55±035 sham, 1.34±0.24 control and 9.49±2.5* diabetic; *p<0.05 vs sham) and this was significantly higher in diabetic animals. Diabetes worsened functional outcomes and inhibition of TLR4 significantly improved the deficits (Table). Conclusions: Our findings that TLR4 is highly upregulated in the microvasculature and that beneficial effects of TLR4 inhibition are more profound in diabetes suggest that vascular TLR4 holds a therapeutic potential for stroke recovery in diabetes.

Natural Products: Experimental Efficient Agents for Inflammatory Bowel Disease Therapy

2020 ◽  
Vol 25 (46) ◽  
pp. 4893-4913 ◽  
Author(s):  
Fan Cao ◽  
Jie Liu ◽  
Bing-Xian Sha ◽  
Hai-Feng Pan
Keyword(s):  
Inflammatory Bowel Disease ◽  
Natural Products ◽  
Immune System ◽  
Bowel Disease ◽  
Therapeutic Potential ◽  
Adaptive Immune System ◽  
Receptor Protein ◽  
Intestinal Epithelia ◽  
Inflammatory Bowel ◽  
The Individual

: Inflammatory bowel disease (IBD) is a chronic, elusive disorder resulting in relapsing inflammation of intestine with incompletely elucidated etiology, whose two representative forms are ulcerative colitis (UC) and Crohn’s disease (CD). Accumulating researches have revealed that the individual genetic susceptibility, environmental risk elements, intestinal microbial flora, as well as innate and adaptive immune system are implicated in the pathogenesis and development of IBD. Despite remarkable progression of IBD therapy has been achieved by chemical drugs and biological therapies such as aminosalicylates, corticosteroids, antibiotics, anti-tumor necrosis factor (TNF)-α, anti-integrin agents, etc., healing outcome still cannot be obtained, along with inevitable side effects. Consequently, a variety of researches have focused on exploring new therapies, and found that natural products (NPs) isolated from herbs or plants may serve as promising therapeutic agents for IBD through antiinflammatory, anti-oxidant, anti-fibrotic and anti-apoptotic effects, which implicates the modulation on nucleotide- binding domain (NOD) like receptor protein (NLRP) 3 inflammasome, gut microbiota, intestinal microvascular endothelial cells, intestinal epithelia, immune system, etc. In the present review, we will summarize the research development of IBD pathogenesis and current mainstream therapy, as well as the therapeutic potential and intrinsic mechanisms of NPs in IBD.

Abstract MP16: Excessive White Matter Hyperintensity Burden and Functional Outcomes After Acute Ischemic Stroke

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Sungmin Hong ◽  
Anne-katrin Giese ◽  
Markus D Schirmer ◽  
Adrian V Dalca ◽  
Anna Bonkhoff ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
White Matter ◽  
Acute Ischemic Stroke ◽  
Functional Outcomes ◽  
Life Time ◽  
Stroke Recovery ◽  
White Matter Hyperintensity ◽  
Brain Health ◽  
Stroke Outcomes ◽  
The Brain

Objective: Ability of the brain to recover after an acute ischemic stroke (AIS) is linked to the pre-stroke burden of white matter hyperintensity (WMH), a radiographic marker of brain health. We sought to determine the excessive WMH burden in an AIS population and investigate its association with 3-month stroke outcomes. Data: We used 2,435 subjects from the MRI-GENIE study. Three-month functional outcomes of 872 subjects among those subjects were measured by 90-day modified Ranking Scale (mRS). Methods: We automatically quantified WMH volume (WMHv) on FLAIR images and adjusted for a brain volume. We modeled a trend using the factor analysis (FA) log-linear regression using age, sex, atrial fibrillation, diabetes, hypertension, coronary artery disease and smoking as input variables. We categorized three WMH burden groups based on the conditional probability given by the model (LOW: lower 33%, MED: middle 34%, and HIGH: upper 33%). The subgroups were compared with respect to mRS (median and dichotomized odds ratio (OR) (good/poor: mRS 0-2/3-6)). Results: Five FA components out of seven with significant relationship to WMHv (p<0.001) were used for the regression modeling (R 2 =0.359). The HIGH group showed higher median (median=2, IQR=2) mRS score than LOW (median=1, IQR=1) and MED (median=1, IQR=1). The odds (OR) of good AIS outcome for LOW and MED were 1.8 (p=0.0001) and 1.6 (p=0.006) times higher than HIGH, respectively. Conclusion: Once accounted for clinical covariates, the excessive WMHv was associated with worse 3-month stroke outcomes. These data suggest that a life-time of injury to the white matter reflected in WMH is an important factor for stroke recovery and an indicator of the brain health.

scholarly journals Inflammatory arthritis can be reined in by CpG-induced DC–NK cell cross talk

2007 ◽  
Vol 204 (8) ◽  
pp. 1911-1922 ◽  
Author(s):  
Hsin-Jung Wu ◽  
Heloisa Sawaya ◽  
Bryce Binstadt ◽  
Margot Brickelmaier ◽  
Amanda Blasius ◽  
...  
Keyword(s):  
Immune System ◽  
Cross Talk ◽  
Inflammatory Arthritis ◽  
Nk Cell ◽  
Therapeutic Potential ◽  
Adaptive Immune System ◽  
Interleukin 12 ◽  
Inhibitory Influence ◽  
Cpg Oligodeoxynucleotides ◽  
Cpg Odns

Unmethylated CpG-oligodeoxynucleotides (ODNs) are generally thought of as potent adjuvants with considerable therapeutic potential to enhance immune responses against microbes and tumors. Surprisingly, certain so-called stimulatory CpG-ODNs strongly inhibited the effector phase of inflammatory arthritis in the K/BxN serum transfer system, either preventively or therapeutically. Also unexpected was that the inhibitory influence did not depend on the adaptive immune system cells mobilized in an immunostimulatory context. Instead, they relied on cells of the innate immune system, specifically on cross talk between CD8α+ dendritic cells and natural killer cells, resulting in suppression of neutrophil recruitment to the joint, orchestrated through interleukin-12 and interferon-γ. These findings highlight potential applications of CpG-ODNs and downstream molecules as antiinflammatory agents.

scholarly journals Infarct topography and functional outcomes

2017 ◽  
Vol 38 (9) ◽  
pp. 1517-1532 ◽  
Author(s):  
Mark R Etherton ◽  
Natalia S Rost ◽  
Ona Wu
Keyword(s):  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Functional Outcomes ◽  
Brain Regions ◽  
Stroke Recovery ◽  
Acute Ischemia ◽  
Post Stroke ◽  
Neurologic Outcomes ◽  
Recovery Potential

Acute ischemic stroke represents a major cause of long-term adult disability. Accurate prognostication of post-stroke functional outcomes is invaluable in guiding patient care, targeting early rehabilitation efforts, selecting patients for clinical research, and conveying realistic expectations to families. The involvement of specific brain regions by acute ischemia can alter post-stroke recovery potential. Understanding the influences of infarct topography on neurologic outcomes holds significant promise in prognosis of functional recovery. In this review, we discuss the recent evidence of the contribution of infarct location to patient management decisions and functional outcomes after acute ischemic stroke.

scholarly journals Ischemia-induced stimulation of cerebral microvascular endothelial cell Na-K-Cl cotransport involves p38 and JNK MAP kinases

2012 ◽  
Vol 302 (3) ◽  
pp. C505-C517 ◽  
Author(s):  
Breanna K. Wallace ◽  
Karen A. Jelks ◽  
Martha E. O'Donnell
Keyword(s):  
Endothelial Cells ◽  
Ischemic Stroke ◽  
Endothelial Cell ◽  
Map Kinases ◽  
Artery Occlusion ◽  
Microvascular Endothelial Cell ◽  
Microvascular Endothelial ◽  
Cerebral Artery Occlusion ◽  
Sb 239063 ◽  
Stimulation Of

Previous studies have provided evidence that, in the early hours of ischemic stroke, a luminal membrane blood-brain barrier (BBB) Na-K-Cl cotransporter (NKCC) participates in ischemia-induced cerebral edema formation. Inhibition of BBB NKCC activity by intravenous bumetanide significantly reduces edema and infarct in the rat permanent middle cerebral artery occlusion model of ischemic stroke. We demonstrated previously that the BBB cotransporter is stimulated by hypoxia, aglycemia, and AVP, factors present during cerebral ischemia. However, the underlying mechanisms have not been known. Ischemic conditions have been shown to activate p38 and JNK MAP kinases (MAPKs) in brain, and the p38 and JNK inhibitors SB-239063 and SP-600125, respectively, have been found to reduce brain damage following middle cerebral artery occlusion and subarachnoid hemorrhage, respectively. The present study was conducted to determine whether one or both of these MAPKs participates in ischemic factor stimulation of BBB NKCC activity. Cultured cerebral microvascular endothelial cell NKCC activity was evaluated as bumetanide-sensitive86Rb influx. Activities of p38 and JNK were assessed by Western blot and immunofluorescence methods using antibodies that detect total vs. phosphorylated (activated) p38 or JNK. We report that p38 and JNK are present in cultured cerebral microvascular endothelial cells and in BBB endothelial cells in situ and that hypoxia (7% O2and 2% O2), aglycemia, AVP, and O2-glucose deprivation (5- to 120-min exposures) all rapidly activate p38 and JNK in the cells. We also provide evidence that SB-239063 and SP-600125 reduce or abolish ischemic factor stimulation of BBB NKCC activity. These findings support the hypothesis that ischemic factor stimulation of the BBB NKCC involves activation of p38 and JNK MAPKs.

scholarly journals CRISPR as a Versatile Technology for Gene Activation and Genome Editing

2018 ◽  
Vol 4 ◽  
pp. 5
Author(s):  
Habib Rezanejadbardeji ◽  
Bahareh Behroozi-Asl ◽  
Raheleh Amirkhah
Keyword(s):  
Immune System ◽  
Therapeutic Potential ◽  
Genetic Disorders ◽  
Gene Activation ◽  
Adaptive Immune System ◽  
Stem Cell Differentiation ◽  
Zinc Finger Nucleases ◽  
Viral Gene ◽  
Transcription Activator ◽  
Adaptive Immune

CRISPR/Cas system, a microbial adaptive immune system, has rapidly transformed the ways researchers can interrogate the genome. CRISPR has many advantages over traditional methods such as Transcription activator-like effector nucleases (TALEN) and Zinc-finger nucleases (ZFN). Since CRISPR discovery as an adaptive immune system used by bacterial against viruses, it has been repurposed to help in many different genome-related studies such as gene knocking in and out, gene expression upregulation and downregulation. Also CRISPR holds vast therapeutic potential for the management of genetic disorders by straight modifying disease-causing mutations. Although the Cas9 protein has been revealed to attach and cleave DNA at off-target sites, the field of Cas9 specificity is quickly progressing, with marked modifying in guide RNA choice, protein and guide engineering, innovative enzymes, and off-target recognition methods. In current review we mostly focus on CRISPR unique ability in gene activation/ upregulation, which has wide applications in different aspects such as gene studies, stem cell differentiation, and trans-differentiation. Compared to other gene activation methods such as viral gene overexpression, TALEN and ZFN, CRISPR offers many benefits such as easy designing and high precision.

scholarly journals Monocyte-lymphocyte cross-communication via soluble CD163 directly links innate immune system activation and adaptive immune system suppression following ischemic stroke

2017 ◽  
Author(s):  
Grant C. O’Connell ◽  
Connie S. Tennant ◽  
Noelle Lucke-Wold ◽  
Yasser Kabbani ◽  
Abdul R. Tarabishy ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Immune System ◽  
Innate Immune System ◽  
Healthy Donor ◽  
Adaptive Immune System ◽  
Innate Immune ◽  
Stroke Patients ◽  
Adaptive Immune ◽  
Soluble Cd163

AbstractCD163 is a scavenger receptor expressed on innate immune cell populations which can be shed from the plasma membrane via the metalloprotease ADAM17 to generate a soluble peptide with lympho-inhibitory properties. The purpose of this study was to investigate CD163 as a possible effector of stroke-induced adaptive immune system suppression. Liquid biopsies were collected from ischemic stroke patients (n=39), neurologically asymptomatic controls (n=20), and stroke mimics (n=20) within 24 hours of symptom onset. Peripheral blood ADAM17 activity and soluble CD163 levels were elevated in stroke patients relative to non-stroke control groups, and negatively associated with post-stroke lymphocyte counts. Subsequent in vitro experiments suggested that this stroke-induced elevation in circulating soluble CD163 likely originates from activated monocytic cells, as serum from stroke patients stimulated ADAM17-dependant CD163 shedding from healthy donor-derived monocytes. Additional in vitro experiments demonstrated that stroke-induced elevations in circulating soluble CD163 can elicit direct suppressive effects on the adaptive immune system, as serum from stroke patients inhibited the proliferation of healthy donor-derived lymphocytes, an effect which was attenuated following serum CD163 depletion. Collectively, these observations provide novel evidence that the innate immune system employs protective mechanisms aimed at mitigating the risk of post-stroke autoimmune complications driven by adaptive immune system overactivation, and that CD163 is key mediator of this phenomenon.

scholarly journals Glia–immune interactions post-ischemic stroke and potential therapies

2018 ◽  
Vol 243 (17-18) ◽  
pp. 1302-1312 ◽  
Author(s):  
Jessica Hersh ◽  
Shao-Hua Yang
Keyword(s):  
Ischemic Stroke ◽  
Immune System ◽  
Glial Cell ◽  
Glial Cells ◽  
Immune Cell ◽  
Immune Surveillance ◽  
Vital Role ◽  
Stroke Recovery ◽  
Therapeutic Window ◽  
Cns Injury

Although the primary responsibility of the immune system has for over a century been perceived as the protector of the host against infection in the peripheral organs, we now know the immune system also plays a vital role in recovery pathways associated with central nervous system (CNS) injury. There is mounting evidence that the blood–brain barrier does not preclude the CNS from immune surveillance. Of particular interest for this review is how microglia and astrocytes interact with the cells of the immune system to modulate repair and recovery mechanisms in ischemic stroke. Our review argues that by deepening our understanding of neuroimmunity, specifically the bidirectional glial–immune cell communications, a plethora of new therapeutic targets and mechanisms may be revealed. Consequently, this review instigates novel experimental approaches to neuroimmunology and fosters a more rapid discovery process for the treatment of stroke. Impact statement This article reviews glial cell interactions with the immune system post-ischemic stroke. Research has shown that glial cells in the brain play a role in altering phenotypes of other glial cells and have downstream immune cell targets ultimately regulating a neuroinflammatory response. These interactions may play a deleterious as well as beneficial role in stroke recovery. Furthermore, they may provide a novel way to approach potential therapies, since current stroke drug therapy is limited to only one Food and Drug Administration-approved drug complicated by a narrow therapeutic window. Until this point, most research has emphasized neuroimmune interactions, but little focus has been on bidirectional communication of glial–immune interactions in the ischemic brain. By expanding our understanding of these interactions through a compilation of glial cell effects, we may be able to pinpoint major modulating factors in brain homeostasis to maintain or discover ways to suppress irreversible ischemic damage and improve brain repair.

scholarly journals The Yin and Yang of Innate Immunity in Stroke

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Xiaomeng Xu ◽  
Yongjun Jiang
Keyword(s):  
Immune Response ◽  
Innate Immunity ◽  
Ischemic Stroke ◽  
Immune System ◽  
Innate Immune Response ◽  
Time Window ◽  
Adaptive Immune System ◽  
Innate Immune ◽  
Yin And Yang ◽  
Molecular Patterns

Immune system plays an elementary role in the pathophysiological progress of ischemic stroke. It consists of innate and adaptive immune system. Activated within minutes after ischemic onset, innate immunity is responsible for the elimination of necrotic cells and tissue repair, while it is critically involved in the initiation and amplification of poststroke inflammation that amplifies ischemic damage to the brain tissue. Innate immune response requires days to be fully developed, providing a considerable time window for therapeutic intervention, suggesting prospect of novel immunomodulatory therapies against poststroke inflammation-induced brain injury. However, obstacles still exist and a comprehensive understanding of ischemic stroke and innate immune reaction is essential. In this review, we highlighted the current experimental and clinical data depicting the innate immune response following ischemic stroke, mainly focusing on the recognition of damage-associated molecular patterns, activation and recruitment of innate immune cells, and involvement of various cytokines. In addition, clinical trials targeting innate immunity were also documented regardless of the outcome, stressing the requirements for further investigation.

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