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N-Acetyl-Seryl-Aspartyl-Lysyl-Proline Mitigates Experimental Colitis Through Inhibition of Intestinal Mucosal Inflammatory Responses via MEK-ERK Signaling.

ABSTRACT: N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) is an endogenous immunomodulatory peptide that is generated from thymosin β4 (Tβ4) through stepwise hydrolysis, involving meprin-α and prolyl endopeptidase (PREP). It is well acknowledged that AcSDKP exerts beneficial effects on multiple cardiovascular and renal diseases. However, the functional role of AcSDKP in inflammatory bowel disease (IBD) remains poorly understood. Here, we aimed to assess the content of AcSDKP in patients with IBD and investigate the impact of AcSDKP on intestinal inflammation in IBD. We found that in the inflamed mucosal specimens of patients with ulcerative colitis, the expression levels of Tβ4 and meprin-α were decreased, while PREP was expressed at similar levels to non-inflamed mucosa. In vitro, AcSDKP inhibited the expression of proinflammatory factors in intestinal epithelial cells partially by reducing the activation of MEK-ERK signaling. In vivo studies showed that transgenic mice, with lower levels of AcSDKP, were more vulnerable to dextran sulfate sodium (DSS)-induced colitis and exhibited more severe intestinal inflammatory responses. On the other hand, exogenous AcSDKP infusion significantly attenuated the clinical symptoms and intestinal mucosal inflammation in DSS-induced mice. In conclusion, results from this study demonstrated the anti-inflammatory function of AcSDKP within the intestine and suggest that AcSDKP has a promising therapeutic potential for IBD treatment.

SUBMITTER: Shi Y

PROVIDER: S-EPMC7218092 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background and Purpose- Stroke is a leading cause of disability worldwide, mainly affecting the elderly. However, preclinical studies in aged ischemic animals are limited. N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) is a naturally occurring tetrapeptide with vascular-protective properties. The present study investigated the effect of AcSDKP on tPA (tissue-type plasminogen activator)-induced thrombolysis in aged rats after ischemic stroke. Methods- Aged male rats (18 months) were subjected to embolic middle cerebral artery occlusion. Rats subjected to 4 hours of middle cerebral artery occlusion were randomized into the following groups: (1) AcSDKP; (2) tPA; (3) AcSDKP in combination with tPA; and (4) saline. Neurological deficits, cerebral microvascular patency and integrity, and infarction were examined at 1 day and 7 days after middle cerebral artery occlusion. In vitro experiments were performed to examine the effect of AcSDKP on aged cerebral endothelial cell permeability. Results- Compared with saline, AcSDKP, or tPA as monotherapy did not have any therapeutic effects, whereas AcSDKP in combination with tPA significantly reduced cerebral tissue infarction and improved neurological outcome without increasing cerebral hemorrhage. Concurrently, the combination treatment significantly augmented microvascular perfusion and reduced thrombosis and blood-brain barrier leakage. In vitro, compared with cerebral endothelial cells from ischemic adult rats, the endothelial cells from ischemic aged rats exhibited significantly increased leakage. AcSDKP suppressed tPA-induced aged endothelial cell leakage and reduced expression of ICAM-1 (intercellular adhesion molecule 1) and NF (nuclear factor)-κB. Conclusions- The present study provides evidence for the therapeutic efficacy of AcSDKP in combination tPA for the treatment of embolic stroke in aged rats at 4 hours after stroke onset. AcSDKP likely acts on cerebral endothelial cells to enhance the benefits of tPA by increasing tissue perfusion and augmenting the integrity of the blood-brain barrier. Visual Overview- An online visual overview is available for this article.

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N-Acetyl-Seryl-Aspartyl-Lysyl-Proline Mitigates Experimental Colitis Through Inhibition of Intestinal Mucosal Inflammatory Responses via MEK-ERK Signaling.

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