The role of Toll-like receptor signaling pathways in cerebrovascular disorders: the impact of spreading depolarization

Ahmadabad, Rezan Ashayeri; Ghadiri, Maryam Khaleghi; Gorji, Ali

doi:10.1186/s12974-020-01785-6

Cited by 23 publications

(15 citation statements)

References 197 publications

(248 reference statements)

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“…In rodent studies, the TLR9 connection is well defined, but few human studies have connected TLRs to CVD; moreover, to the best of our knowledge, none has associated TLR signaling with chemotoxicity [ 85 ]. All 13 mouse TLRs (TLR1 through TLR13) are recognized and have distinct roles in atherosclerosis pathological processes [ 86 ], atherothrombotic CVD [ 82 ], cerebral vascular diseases, acute ischemic stroke, intracerebral hemorrhage, cerebral venous sinus thrombosis [ 87 ], cardiac dysfunction, and HF [ 88 ].…”

Section: Inflammation and Cardiovascular Diseasementioning

confidence: 99%

Greenspace, Inflammation, Cardiovascular Health, and Cancer: A Review and Conceptual Framework for Greenspace in Cardio-Oncology Research

Bikomeye

Beyer

Kwarteng

et al. 2022

IJERPH

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Cardiovascular disease (CVD) is a leading cause of global morbidity and mortality. Cancer survivors have significantly elevated risk of poor cardiovascular (CV) health outcomes due to close co-morbid linkages and shared risk factors between CVD and cancer, as well as adverse effects of cancer treatment-related cardiotoxicity. CVD and cancer-related outcomes are exacerbated by increased risk of inflammation. Results from different pharmacological interventions aimed at reducing inflammation and risk of major adverse cardiovascular events (MACEs) have been largely mixed to date. Greenspaces have been shown to reduce inflammation and have been associated with CV health benefits, including reduced CVD behavioral risk factors and overall improvement in CV outcomes. Greenspace may, thus, serve to alleviate the CVD burden among cancer survivors. To understand pathways through which greenspace can prevent or reduce adverse CV outcomes among cancer survivors, we review the state of knowledge on associations among inflammation, CVD, cancer, and existing pharmacological interventions. We then discuss greenspace benefits for CV health from ecological to multilevel studies and a few existing experimental studies. Furthermore, we review the relationship between greenspace and inflammation, and we highlight forest bathing in Asian-based studies while presenting existing research gaps in the US literature. Then, we use the socioecological model of health to present an expanded conceptual framework to help fill this US literature gap. Lastly, we present a way forward, including implications for translational science and a brief discussion on necessities for virtual nature and/or exposure to nature images due to the increasing human–nature disconnect; we also offer guidance for greenspace research in cardio-oncology to improve CV health outcomes among cancer survivors.

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Section: Inflammation and Cardiovascular Diseasementioning

confidence: 99%

Greenspace, Inflammation, Cardiovascular Health, and Cancer: A Review and Conceptual Framework for Greenspace in Cardio-Oncology Research

Bikomeye

Beyer

Kwarteng

et al. 2022

IJERPH

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“…TLR4 expression is low under physiological resting conditions, but it may be increased and translocated to the cell membrane upon pathological stimulation [ 27 ]. It is clearly recognized in multiple brain injury pathologies that TLR4 activation plays a crucial role in the pro-inflammatory activation of leukocytes, including TBI [ 7 ] and cerebrovascular disorders [ 28 ]. One study reports that endogenous AXNA2 can control TLR4 internalization and negatively regulates TLR4-triggered inflammatory responses in murine macrophage cell lines [ 12 ].…”

Section: Discussionmentioning

confidence: 99%

Recombinant annexin A2 inhibits peripheral leukocyte activation and brain infiltration after traumatic brain injury

Liu

Han

et al. 2021

J Neuroinflammation

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Background Traumatic brain injury (TBI) is a significant cause of death and disability worldwide. The TLR4-NFκB signaling cascade is the critical pro-inflammatory activation pathway of leukocytes after TBI, and modulating this signaling cascade may be an effective therapeutic target for treating TBI. Previous studies indicate that recombinant annexin A2 (rA2) might be an interactive molecule modulating the TLR4-NFκB signaling; however, the role of rA2 in regulating this signaling pathway in leukocytes after TBI and its subsequent effects have not been investigated. Methods C57BL/6 mice were subjected to TBI and randomly divided into groups that received intraperitoneal rA2 or vehicle at 2 h after TBI. The peripheral leukocyte activation and infiltrating immune cells were examined by flow cytometry, RT-qPCR, and immunostaining. The neutrophilic TLR4 expression on the cell membrane was examined by flow cytometry and confocal microscope, and the interaction of annexin A2 with TLR4 was assessed by co-immunoprecipitation coupled with Western blotting. Neuroinflammation was measured via cytokine proteome profiler array and RT-qPCR. Neurodegeneration was determined by Western blotting and immunostaining. Neurobehavioral assessments were used to monitor motor and cognitive function. Brain tissue loss was assessed via MAP2 staining. Results rA2 administration given at 2 h after TBI significantly attenuates neutrophil activation and brain infiltration at 24 h of TBI. In vivo and in vitro data show that rA2 binds to and reduces TLR4 expression on the neutrophil surface and suppresses TLR4/NFκB signaling pathway in neutrophils at 12 h after TBI. Furthermore, rA2 administration also reduces pro-inflammation of brain tissues within 24 h and neurodegeneration at 48 h after TBI. Lastly, rA2 improves long-term sensorimotor ability and cognitive function, and reduces brain tissue loss at 28 days after TBI. Conclusions Systematic rA2 administration at 2 h after TBI significantly inhibits activation and brain infiltration of peripheral leukocytes, especially neutrophils at the acute phase. Consequently, rA2 reduces the detrimental brain pro-inflammation-associated neurodegeneration and ultimately ameliorates neurological deficits after TBI. The underlying molecular mechanism might be at least in part attributed to rA2 bindings to pro-inflammatory receptor TLR4 in peripheral leukocytes, thereby blocking NFκB signaling activation pathways following TBI.

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“…Another significant aspect of neuroinflammation is microglia that mainly produce pro-inflammatory cytokines, such as TNF and IL-6, which activate glial cells and induce further cytokine production and astrogliosis (Ziebell and Morganti-Kossmann 2010;Konsman et al 2007). Pro-inflammatory cytokines are also regulated by TLR4 as a key host molecule in the regulation of the innate immune response (Ahmad et al 2013;Ashayeri Ahmadabad et al 2020). Thus, inhibition of activated microglia and TLR4 can decrease inflammation and increase histological and functional outcomes after TBI (d' Avila et al 2012;Feng et al 2017).…”

Section: Discussionmentioning

confidence: 99%

Transplantation of R-GSIK scaffold with mesenchymal stem cells improves neuroinflammation in a traumatic brain injury model

et al. 2020

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Neural tissue engineering has been introduced as a novel therapeutic strategy for traumatic brain injury (TBI). Transplantation of mesenchymal stem cells (MSCs) has been demonstrated to improve functional outcome of brain injury, and RADA4GGSIKVAV (R-GSIK), a self-assembling nano-peptide scaffold, has been suggested to promote the behavior of stem cells. This study was designed to determine the ability of the R-GSIK scaffold in supporting the effects of MSCs on motor function activity and inflammatory responses in an experimental TBI model. A significant recovery of motor function was observed in rats that received MSCs+R-GSIK compared with the control groups. Further analysis showed a reduction in the number of reactive astrocytes and microglial cells in the MSCs and MSCs+R-GSIK groups compared with the control groups. Furthermore, western blot analysis indicated a significant reduction in pro-inflammatory cytokines, such as TLR4, TNF, and IL6, in the MSCs and MSCs+R-GSIK groups compared with the TBI, vehicle, and R-GSIK groups. Overall, this study strengthens the idea that the co-transplantation of MSCs with R-GSIK can increase functional outcomes by preparing a beneficial environment. This improvement may be explained by the immunomodulatory effects of MSCs and the self-assembling nano-scaffold peptide.

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The role of Toll-like receptor signaling pathways in cerebrovascular disorders: the impact of spreading depolarization

Cited by 23 publications

References 197 publications

Greenspace, Inflammation, Cardiovascular Health, and Cancer: A Review and Conceptual Framework for Greenspace in Cardio-Oncology Research

Greenspace, Inflammation, Cardiovascular Health, and Cancer: A Review and Conceptual Framework for Greenspace in Cardio-Oncology Research

Recombinant annexin A2 inhibits peripheral leukocyte activation and brain infiltration after traumatic brain injury

Transplantation of R-GSIK scaffold with mesenchymal stem cells improves neuroinflammation in a traumatic brain injury model

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