Comparative plasma metabolomic analysis to identify biomarkers for lead-induced cognitive impairment

Nong, Yuan; Zhang, Xing; Mai, Tingyu; Cai, Jiansheng; Liu, Jiaqi; Lai, Keng Po; Zhang, Zhiyong

doi:10.1016/j.cbi.2022.110143

Cited by 10 publications

(7 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Transcriptional analysis of pCS-treated mice indicates a more generalised inhibitory effect of the toxin upon neural activity, which may also be expected to impair cognitive abilities. Further analysis will be needed to explore this aspect of pCS action, but it does align with previous studies linking pCS and impaired cognition in humans 58 and mice 59,60 . Our description of the EGFR as a major mediator of pCS actions in the brain may point to potential therapeutic strategies; several EGFR inhibitors (e.g., erlotinib, gefitinib) and monoclonal antibodies (e.g., cetuximab, necitumumab) are currently licenced for clinical use, suggesting there may be scope for broader use in CKD.…”

Section: Discussionsupporting

confidence: 54%

“…In our study, animals exposed for one month to pCS exhibited an approximately 30% increase in tracer permeability across the BBB; it may be that the degree of permeability deficit caused in this study was insufficient to impair cognition to a degree detectable using the tests employed. Notably, previous studies employing higher pCS concentrations have shown the metabolite to impair cognition in both humans 61 and mice 59 .…”

Section: Discussionmentioning

confidence: 92%

See 1 more Smart Citation

Cerebrovascular damage caused by the gut microbe/host co-metabolitep-cresol sulfate is prevented by blockade of the EGF receptor

Shah

Knausenberger

Connell

et al. 2022

Preprint

View full text Add to dashboard Cite

Chronic kidney disease is linked to impaired cognitive function and increased neurovascular disease risk even after correction for classical risk factors. The mechanism(s) underlying these links are unclear but may involve interactions of uraemic toxins with the blood-brain barrier (BBB). Here, we studied how the major uraemic toxinp-cresol sulfate (pCS) could affect BBB integrity. Exposure of human hCMEC/D3 endothelial cells to pCS dose-dependently increased paracellular permeability and disrupted intercellular tight junctions, a permeabilising effect mirrored in mice. Whole brain RNAseq analysis identified pCS-mediated suppression of neuronal activity, transcription and mitochondrial respiration pathways.In vitrostudies identified pCS binding to the epidermal growth factor receptor (EGFR), leadingviaannexin A1 and STAT3 signalling to mobilisation of matrix metalloproteinase (MMP)-2/9. Confirming this pathwayin vivo, the BBB damaging effects of pCS were prevented by pre-treatment with the EGFR antagonist erlotinib or the MMP2/9 inhibitor SB-3CT. Finally, hCMEC/D3 cells exposed to haemodialysis patient serum, but not to that of healthy donors, showed an erlotinib-sensitive increase in paracellular permeability that closely correlated in size to the total serum pCS content. Overall, we define a pathway linking the uraemic toxin pCS with BBB damage suggesting that targeting the EGFR may be useful in mitigating against cerebrovascular damage in chronic kidney disease.Translational StatementPatients with chronic kidney disease (CKD) have increased risk of cognitive impairment and stroke, pathologies associated cerebromicrovascular disease, but it is not clear why. Here, we show that the uraemic toxin p-cresol sulfate impairs BBB functionin vitroandin vivothrough EGFR-dependent MMP mobilisation. Importantly, serum from haemodialysis patients can also impair permeability of anin vitroBBB model, an effect prevented by EGFR inhibition, and proportional in magnitude to serum pCS content. Our data suggest that existing EGFR inhibitory drugs might have utility in preventing cerebral small vessel disease in CKD patients.

show abstract

Section: Discussionsupporting

confidence: 54%

Section: Discussionmentioning

confidence: 92%

Cerebrovascular damage caused by the gut microbe/host co-metabolitep-cresol sulfate is prevented by blockade of the EGF receptor

Shah

Knausenberger

Connell

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…PAGln levels are inversely correlated with the cortical volume and directly correlated with neurofilament light chain levels . A study in the U.S. reported that PAGln levels were higher in women with short sleep duration (<7 h) compared to medium sleep duration (7–8 h), hence, strongly associating PAGln levels and sleep-related disorders which can further lead to neurological complications. , Altered concentrations of phenylacetylglutamine are seen among autism spectrum disorder (ASD) patients when compared to non-ASD individuals. , Another evidence elucidating the role of altered phenylacetylglutamine levels was association with memory and executive functioning impairment among patients with renal disorders receiving dialysis. , Also a comparative metabolomic analysis identified dysregulated phenylacetyl- l -glutamine as a potential biomarker for cognitive impairment induced by lead . The altered levels of PAGln are correlated with the initiation and progression of CVD, stroke, neurological disorders, and other disorders depicted in Table .…”

Section: Pagln In Neurological Disordersmentioning

confidence: 99%

“… 83 , 84 Also a comparative metabolomic analysis identified dysregulated phenylacetyl- l -glutamine as a potential biomarker for cognitive impairment induced by lead. 85 The altered levels of PAGln are correlated with the initiation and progression of CVD, stroke, neurological disorders, and other disorders depicted in Table 1 .…”

Section: Pagln In Neurological Disordersmentioning

confidence: 99%

Role of the Gut Bacteria-Derived Metabolite Phenylacetylglutamine in Health and Diseases

Krishnamoorthy,

Kalyan,

Hediyal

et al. 2024

ACS Omega

View full text Add to dashboard Cite

Over the past few decades, it has been well established that gut microbiotaderived metabolites can disrupt gut function, thus resulting in an array of diseases. Notably, phenylacetylglutamine (PAGln), a bacterial derived metabolite, has recently gained attention due to its role in the initiation and progression of cardiovascular and cerebrovascular diseases. This meta-organismal metabolite PAGln is a byproduct of amino acid acetylation of its precursor phenylacetic acid (PAA) from a range of dietary sources like egg, meat, dairy products, etc. The microbiota-dependent metabolism of phenylalanine produces PAA, which is a crucial intermediate that is catalyzed by diverse microbial catalytic pathways. PAA conjugates with glutamine and glycine in the liver and kidney to predominantly form phenylacetylglutamine in humans and phenylacetylglycine in rodents. PAGln is associated with thrombosis as it enhances platelet activation mediated through the GPCRs receptors α2A, α2B, and β2 ADRs, thereby aggravating the pathological conditions. Clinical evidence suggests that elevated levels of PAGln are associated with pathology of cardiovascular, cerebrovascular, and neurological diseases. This Review further consolidates the microbial/biochemical synthesis of PAGln and discusses its role in the above pathophysiologies.

show abstract

“…However, a score of behavioral abnormalities may not prove a useful biomarker. In a study looking at plasma metabolite in two groups of adults, those with low plasma Pb level and high cognition vs. those with high plasma Pb level and low cognition, a significant reduction in docosahexaenoic acid, glycoursodeoxycholic acid, and arachidonic acid, and significant induction of p-cresol sulfate and phenyl acetyl-l-glutamine were observed [52]. Markers of tubule dysfunction, such as NAG [53] and kidney injury molecule 1(KIM-1) [54], have been associated with Pb-induced nephrotoxicity.…”

Section: Leadmentioning

confidence: 99%

E-Waste and Metal Contamination in the Environment: Health Effects

Dockrell¹,

Purchase²,

Price³

2023

Trace Metals in the Environment

View full text Add to dashboard Cite

It is predicted that electronic waste (e-waste) derived principally from discarded electronic equipment will reach 74 million metric tonnes by 2030. In addition, urbanisation and industrialisation have contributed to metal contamination in the environment. E-waste is often deposed of in low-income countries adversely affecting the health of the working population. The main sources of e-contamination are soil, dust, and food matrices. Drinking water can also be contaminated with heavy metals such as arsenic (As), cadmium (Cd), mercury (Hg), and lead (Pb) causing a major health concern. Exposure to pollutants present in waste is a common cause of kidney and other diseases primarily amongst children in developing countries. Sensitive monitoring procedures are needed to improve the rate of detection and monitoring of the possible adverse effects on the population exposed to significant quantities of e-waste.

show abstract

Comparative plasma metabolomic analysis to identify biomarkers for lead-induced cognitive impairment

Cited by 10 publications

References 41 publications

Cerebrovascular damage caused by the gut microbe/host co-metabolitep-cresol sulfate is prevented by blockade of the EGF receptor

Cerebrovascular damage caused by the gut microbe/host co-metabolitep-cresol sulfate is prevented by blockade of the EGF receptor

Role of the Gut Bacteria-Derived Metabolite Phenylacetylglutamine in Health and Diseases

E-Waste and Metal Contamination in the Environment: Health Effects

Contact Info

Product

Resources

About