Dataset Information

Transforming Growth Factor-? Protects against Inflammation-Related Atherosclerosis in South African CKD Patients.

ABSTRACT: Background:Transforming growth factor-? (TGF-?) may inhibit the development of atherosclerosis. We evaluated serum levels of TGF-? isoforms concurrently with serum levels of endotoxin and various inflammatory markers. In addition, we determined if any association exists between polymorphisms in the TGF-?1 gene and atherosclerosis in South African CKD patients. Methods:We studied 120 CKD patients and 40 healthy controls. Serum TGF-?1, TGF-?2, TGF-?3, endotoxin, and inflammatory markers were measured. Functional polymorphisms in the TGF-?1 genes were genotyped using a polymerase chain reaction-sequence specific primer method and carotid intima media thickness (CIMT) was assessed by B-mode ultrasonography. Results:TGF-? isoforms levels were significantly lower in the patients with atherosclerosis compared to patients without atherosclerosis (p<0.001). Overall, TGF-? isoforms had inverse relationships with CIMT. TGF-?1 and TGF-?2 levels were significantly lower in patients with carotid plaque compared to those without carotid plaque [TGF-?1: 31.9 (17.2 - 42.2) versus 45.9 (35.4 - 58.1) ng/ml, p=0.016; and TGF-?2: 1.46 (1.30 - 1.57) versus 1.70 (1.50 - 1.87) ng/ml, p=0.013]. In multiple logistic regression, age, TGF-?2, and TGF-?3 were the only independent predictors of subclinical atherosclerosis in CKD patients [age: odds ratio (OR), 1.054; 95% confidence interval (CI): 1.003 - 1.109, p=0.039; TGF-?2: OR, 0.996; 95% CI: 0.994-0.999, p=0.018; TGF-?3: OR, 0.992; 95% CI: 0.985-0.999, p=0.029). TGF-?1 genotypes did not influence serum levels of TGF-?1 and no association was found between the TGF-?1 gene polymorphisms and atherosclerosis risk. Conclusion:TGF-? isoforms seem to offer protection against the development of atherosclerosis among South African CKD patients.

SUBMITTER: Hassan MO

PROVIDER: S-EPMC6011064 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Transforming Growth Factor-<i>β</i> Protects against Inflammation-Related Atherosclerosis in South African CKD Patients.

Hassan Muzamil Olamide MO Duarte Raquel R Dix-Peek Therese T Dickens Caroline C Naidoo Sagren S Vachiat Ahmed A Grinter Sacha S Manga Pravin P Naicker Saraladevi S

International journal of nephrology 20180606

<h4>Background</h4>Transforming growth factor-<i>β</i> (TGF-<i>β</i>) may inhibit the development of atherosclerosis. We evaluated serum levels of TGF-<i>β</i> isoforms concurrently with serum levels of endotoxin and various inflammatory markers. In addition, we determined if any association exists between polymorphisms in the <i>TGF-β1</i> gene and atherosclerosis in South African CKD patients.<h4>Methods</h4>We studied 120 CKD patients and 40 healthy controls. Serum TGF-<i>β</i>1, TGF-<i>β</i> ...[more]

PMID: 29977619

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Project description:Alzheimer's disease (AD) is characterized by progressive cognitive decline, increasingly attributed to neuronal dysfunction induced by amyloid-β oligomers (AβOs). Although the impact of AβOs on neurons has been extensively studied, only recently have the possible effects of AβOs on astrocytes begun to be investigated. Given the key roles of astrocytes in synapse formation, plasticity, and function, we sought to investigate the impact of AβOs on astrocytes, and to determine whether this impact is related to the deleterious actions of AβOs on synapses. We found that AβOs interact with astrocytes, cause astrocyte activation and trigger abnormal generation of reactive oxygen species, which is accompanied by impairment of astrocyte neuroprotective potential in vitro We further show that both murine and human astrocyte conditioned media (CM) increase synapse density, reduce AβOs binding, and prevent AβO-induced synapse loss in cultured hippocampal neurons. Both a neutralizing anti-transforming growth factor-β1 (TGF-β1) antibody and siRNA-mediated knockdown of TGF-β1, previously identified as an important synaptogenic factor secreted by astrocytes, abrogated the protective action of astrocyte CM against AβO-induced synapse loss. Notably, TGF-β1 prevented hippocampal dendritic spine loss and memory impairment in mice that received an intracerebroventricular infusion of AβOs. Results suggest that astrocyte-derived TGF-β1 is part of an endogenous mechanism that protects synapses against AβOs. By demonstrating that AβOs decrease astrocyte ability to protect synapses, our results unravel a new mechanism underlying the synaptotoxic action of AβOs in AD.SIGNIFICANCE STATEMENT Alzheimer's disease is characterized by progressive cognitive decline, mainly attributed to synaptotoxicity of the amyloid-β oligomers (AβOs). Here, we investigated the impact of AβOs in astrocytes, a less known subject. We show that astrocytes prevent synapse loss induced by AβOs, via production of transforming growth factor-β1 (TGF-β1). We found that AβOs trigger morphological and functional alterations in astrocytes, and impair their neuroprotective potential. Notably, TGF-β1 reduced hippocampal dendritic spine loss and memory impairment in mice that received intracerebroventricular infusions of AβOs. Our results describe a new mechanism underlying the toxicity of AβOs and indicate novel therapeutic targets for Alzheimer's disease, mainly focused on TGF-β1 and astrocytes.

Project description:This study examined volatile anesthetic-mediated protection against intestinal ischemia-reperfusion injury (IRI).Intestinal IRI is a devastating complication in the perioperative period leading to systemic inflammation and multiorgan dysfunction. Volatile anesthetics, including isoflurane, have anti-inflammatory effects. We aimed to determine whether isoflurane, given after intestinal ischemia, protects against intestinal IRI and the mechanisms involved in this protection.: After IACUC approval, mice were anesthetized with pentobarbital and subjected to 30 minutes of superior mesenteric artery ischemia, followed by 4 hours of equianesthetic doses of pentobarbital or isoflurane. Five hours after reperfusion, small intestine tissues were analyzed for morphological injury, apoptosis, neutrophil infiltration, proinflammatory mRNAs, and TGF-(Transforming Growth Factor-)?1 levels. We also assessed hepatic and renal injury after intestinal IRI.Intestinal IRI with pentobarbital led to significant small intestinal dysfunction with increased mucosal injury, TUNEL (transferase biotin-dUTP nick end-labeling)-positive cells, neutrophil infiltration, and proinflammatory mRNAs as well as elevated plasma alanine aminotransferase and creatinine levels. Isoflurane exposure after IRI led to significant attenuation of intestinal, hepatic, and renal injuries. Furthermore, the protective effects of isoflurane were abolished by treatment with a TGF-?1 neutralizing antibody before induction of IRI. Finally, isoflurane exposure led to increased TGF-?1 levels in intestinal epithelial cells and in plasma.Our findings demonstrate that isoflurane post-conditioning protects against small intestinal injury and hepatic and renal dysfunction after severe intestinal IRI via induction of intestinal epithelial TGF-?1. Our findings support therapeutic applications of volatile anesthetics during the intraoperative and postoperative periods and imply an important role of TGF-?1 signaling in modulating multiorgan injury.

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Dataset Information

Transforming Growth Factor-? Protects against Inflammation-Related Atherosclerosis in South African CKD Patients.

Publications

Transforming Growth Factor-<i>β</i> Protects against Inflammation-Related Atherosclerosis in South African CKD Patients.

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