Matrix-derived inflammatory mediator N-acetyl proline-glycine-proline is neurotoxic and upregulated in brain after ischemic stroke

Hill, Jeff W.; Nemoto, Edwin M.

doi:10.1186/s12974-015-0428-z

Cited by 14 publications

(12 citation statements)

References 23 publications

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“…That I/R could trigger activation of the complement cascade was first described by Hill and Ward (340) almost 50 years ago. Subsequent studies demonstrated increased expression for all of the classical complement cascade proteins in ischemic tissues (804, 876).…”

Section: Inflammation Plays a Prominent Role In The Reperfusion Compomentioning

confidence: 94%

Ischemia/Reperfusion

Kalogeris

Baines

Krenz

et al. 2016

Comprehensive Physiology

619

565

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Ischemic disorders, such as myocardial infarction, stroke, and peripheral vascular disease, are the most common causes of debilitating disease and death in westernized cultures. The extent of tissue injury relates directly to the extent of blood flow reduction and to the length of the ischemic period, which influence the levels to which cellular ATP and intracellular pH are reduced. By impairing ATPase-dependent ion transport, ischemia causes intracellular and mitochondrial calcium levels to increase (calcium overload). Cell volume regulatory mechanisms are also disrupted by the lack of ATP, which can induce lysis of organelle and plasma membranes. Reperfusion, although required to salvage oxygen-starved tissues, produces paradoxical tissue responses that fuel the production of reactive oxygen species (oxygen paradox), sequestration of proinflammatory immunocytes in ischemic tissues, endoplasmic reticulum stress, and development of postischemic capillary no-reflow, which amplify tissue injury. These pathologic events culminate in opening of mitochondrial permeability transition pores as a common end-effector of ischemia/reperfusion (I/R)-induced cell lysis and death. Emerging concepts include the influence of the intestinal microbiome, fetal programming, epigenetic changes, and microparticles in the pathogenesis of I/R. The overall goal of this review is to describe these and other mechanisms that contribute to I/R injury. Because so many different deleterious events participate in I/R, it is clear that therapeutic approaches will be effective only when multiple pathologic processes are targeted. In addition, the translational significance of I/R research will be enhanced by much wider use of animal models that incorporate the complicating effects of risk factors for cardiovascular disease.

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Section: Inflammation Plays a Prominent Role In The Reperfusion Compomentioning

confidence: 94%

Ischemia/Reperfusion

Kalogeris

Baines

Krenz

et al. 2016

Comprehensive Physiology

619

565

View full text Add to dashboard Cite

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“…MMPs induce the production of inflammatory cytokine N-acetyl proline-glycine-proline (ac-PGP) by the degradation of the extracellular matrix. ac-PGP is a neurotoxic mediator and causes sustain inflammation in the brain [234]. Gelatinase A (MMP-2) and gelatinase B (MMP-9) are reported to be active in hypoxic/ischemic injury.…”

Section: Mmps Expressionmentioning

confidence: 99%

Heavy Metal-Induced Cerebral Small Vessel Disease: Insights into Molecular Mechanisms and Possible Reversal Strategies

Patwa

Flora

2020

IJMS

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Heavy metals are considered a continuous threat to humanity, as they cannot be eradicated. Prolonged exposure to heavy metals/metalloids in humans has been associated with several health risks, including neurodegeneration, vascular dysfunction, metabolic disorders, cancer, etc. Small blood vessels are highly vulnerable to heavy metals as they are directly exposed to the blood circulatory system, which has comparatively higher concentration of heavy metals than other organs. Cerebral small vessel disease (CSVD) is an umbrella term used to describe various pathological processes that affect the cerebral small blood vessels and is accepted as a primary contributor in associated disorders, such as dementia, cognitive disabilities, mood disorder, and ischemic, as well as a hemorrhagic stroke. In this review, we discuss the possible implication of heavy metals/metalloid exposure in CSVD and its associated disorders based on in-vitro, preclinical, and clinical evidences. We briefly discuss the CSVD, prevalence, epidemiology, and risk factors for development such as genetic, traditional, and environmental factors. Toxic effects of specific heavy metal/metalloid intoxication (As, Cd, Pb, Hg, and Cu) in the small vessel associated endothelium and vascular dysfunction too have been reviewed. An attempt has been made to highlight the possible molecular mechanism involved in the pathophysiology, such as oxidative stress, inflammatory pathway, matrix metalloproteinases (MMPs) expression, and amyloid angiopathy in the CSVD and related disorders. Finally, we discussed the role of cellular antioxidant defense enzymes to neutralize the toxic effect, and also highlighted the potential reversal strategies to combat heavy metal-induced vascular changes. In conclusion, heavy metals in small vessels are strongly associated with the development as well as the progression of CSVD. Chelation therapy may be an effective strategy to reduce the toxic metal load and the associated complications.

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“…Recent scientific reports provide information on the role of glyprolines in chronic inflammation. N‐acetylated PGP participates in the immune response as a neutrophil chemoattractant in lung diseases (COPD and cystic fibrosis), IBD, ischemic brain stroke as well as chorioamnionitis. Apart from proinflammatory activity, numerous beneficial effects of proline‐containing short sequences were observed.…”

Section: Biological Activity Of the Collagen‐derived Glyprolinesmentioning

confidence: 99%

“…PCPs exhibit various biological effects. They can act as a neutrophil chemoattractants in lung diseases, inflammatory bowel diseases (IBDs) or ischemic stroke. Glyprolines have been postulated to play an important role as atheroprotective and anticoagulant agents, neuroprotective agents in Parkinson's disease, and glutamate neurotoxicity as well as regulators of the insulin‐like growth factor (IGF) availability.…”

Section: Introductionmentioning

confidence: 99%

Proline‐containing peptides—New insight and implications: A Review

Misiura

Miltyk

2019

BioFactors

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The family of regulatory proline‐containing peptides (PCPs), also known as glyprolines, exhibit significant biological activity. The group of glyprolines includes Gly‐Pro (GP), Pro‐Gly‐Pro (PGP), cyclic Gly‐Pro (cGP), as well as PGP derivatives, for example, N‐acetylated PGP (N‐a‐PGP) and N‐methylated PGP (N‐m‐PGP). PCPs are engaged in various biological processes including the proinflammatory neutrophil chemoattraction in lung diseases, inflammatory bowel diseases or ischemic stroke. Glyprolines have been also postulated to play an important role as atheroprotective and anticoagulant agents, exhibit neuroprotective effects in Parkinson's disease, as well as regulate insulin‐like growth factor (IGF) homeostasis. It was also noticed that PCPs inhibit proliferation and migration of keratinocytes in wound healing, protection of the gastric mucosa and stimulation of its regeneration. The regulatory glyprolines are derived from endogenous and exogenous sources. Most PCPs are derived from collagen or diet protein degradation. Recently, great interest is concentrated on short proline‐rich oligopeptides derived from IGF‐1 degradation. The mechanism of PCPs biological activity is not fully explained. It involves receptor‐mediated mechanisms, for example, N‐a‐PGP acts as CXCR1/2 receptor ligand, whereas cGP regulates IGF‐1 bioavailability by modifying the IGF‐1 binding to the IGF‐1 binding protein‐3. PGP has been observed to interact with collagen‐specific receptors. The data suggest a promising role of PGP as a target of various diseases therapy. This review is focused on the effect of PCPs on metabolic processes in different tissues and the molecular mechanism of their action as an approach to pharmacotherapy of PCPs‐dependent diseases.

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Matrix-derived inflammatory mediator N-acetyl proline-glycine-proline is neurotoxic and upregulated in brain after ischemic stroke

Cited by 14 publications

References 23 publications

Ischemia/Reperfusion

Ischemia/Reperfusion

Heavy Metal-Induced Cerebral Small Vessel Disease: Insights into Molecular Mechanisms and Possible Reversal Strategies

Proline‐containing peptides—New insight and implications: A Review

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