Abstract:Parkinson's disease is the second most common neurodegenerative disease. In the vast majority of cases the origin is not genetic and the cause is not well understood, although progressive accumulation of α-synuclein aggregates appears central to the pathogenesis. Currently, treatments that slow disease progression are lacking, and there are no robust biomarkers that can facilitate the development of such treatments or act as aids in early diagnosis. Therefore, we have defined metabolomic changes in the brain a… Show more
“…Additionally, ornithine was associated with cognitive impairment and was also found in plasma metabolomics profiles in acute TBI rats (Fei et al, 2017;Wu et al, 2014). In the case of taurine and hypotaurine metabolism, the pathway enrichment analysis suggested its dysregulation in Alzheimer's disease and the development of perturbed markers in Parkinson's disease (Graham et al, 2018;Gui, Liu, Zhang, Lv, & Hu, 2015). Conversely, the results from (Menzie, Prentice, & Wu, 2013) and (Wen et al, 2018) highlighted that taurine and hypotaurine metabolism can protect neurons against inflammatory response or may be related to hypoxic preconditioning.…”
Background: Traumatic brain injury (TBI) has increased in rank among traumatic injuries worldwide. Traumatic brain injury is a serious obstacle given that its complex pathology represents a long-term process. Recently, systems biology strategies such as metabolomics to investigate the multifactorial nature of TBI have facilitated attempts to find biomarkers and probe molecular pathways for its diagnosis and therapy.
Methods:This study included a group of 20 rats with controlled cortical impact and a group of 20 sham rats. We utilized mNSS tests to investigate neurological metabolic impairments on day 1 and day 3. Furthermore, we applied metabolomics and bioinformatics to determine the metabolic perturbation caused by TBI during the acute period in the hippocampus tissue of controlled cortical impact (CCI) rats. Notably, TBI-protein-metabolite subnetworks identified from a database were assessed for associations between metabolites and TBI by the dysregulation of related enzymes and transporters.
Results:Our results identified 7 and 8 biomarkers on day 1 and day 3, respectively.Additionally, related pathway disorders showed effects on arginine and proline metabolism as well as taurine and hypotaurine metabolism on day 3 in acute TBI.Furthermore, according to metabolite-protein database searches, 25 metaboliteprotein pairs were established as causally associated with TBI. Further, bioinformation indicated that these TBI-associated proteins mainly take part in 5′-nucleotidase activity and carboxylic acid transmembrane transport. In addition, interweaved networks were constructed to show that the development of TBI might be affected by metabolite-related proteins and their protein pathways.
Conclusion:The overall results show that acute TBI is susceptible to metabolic disorders, and the joint metabolite-protein network analysis provides a favorable prediction of TBI pathogenesis mechanisms in the brain. The signatures in the hippocampus might be promising for the development of biomarkers and pathways relevant to acute TBI and could further guide testable predictions of the underlying mechanism of TBI.
“…Additionally, ornithine was associated with cognitive impairment and was also found in plasma metabolomics profiles in acute TBI rats (Fei et al, 2017;Wu et al, 2014). In the case of taurine and hypotaurine metabolism, the pathway enrichment analysis suggested its dysregulation in Alzheimer's disease and the development of perturbed markers in Parkinson's disease (Graham et al, 2018;Gui, Liu, Zhang, Lv, & Hu, 2015). Conversely, the results from (Menzie, Prentice, & Wu, 2013) and (Wen et al, 2018) highlighted that taurine and hypotaurine metabolism can protect neurons against inflammatory response or may be related to hypoxic preconditioning.…”
Background: Traumatic brain injury (TBI) has increased in rank among traumatic injuries worldwide. Traumatic brain injury is a serious obstacle given that its complex pathology represents a long-term process. Recently, systems biology strategies such as metabolomics to investigate the multifactorial nature of TBI have facilitated attempts to find biomarkers and probe molecular pathways for its diagnosis and therapy.
Methods:This study included a group of 20 rats with controlled cortical impact and a group of 20 sham rats. We utilized mNSS tests to investigate neurological metabolic impairments on day 1 and day 3. Furthermore, we applied metabolomics and bioinformatics to determine the metabolic perturbation caused by TBI during the acute period in the hippocampus tissue of controlled cortical impact (CCI) rats. Notably, TBI-protein-metabolite subnetworks identified from a database were assessed for associations between metabolites and TBI by the dysregulation of related enzymes and transporters.
Results:Our results identified 7 and 8 biomarkers on day 1 and day 3, respectively.Additionally, related pathway disorders showed effects on arginine and proline metabolism as well as taurine and hypotaurine metabolism on day 3 in acute TBI.Furthermore, according to metabolite-protein database searches, 25 metaboliteprotein pairs were established as causally associated with TBI. Further, bioinformation indicated that these TBI-associated proteins mainly take part in 5′-nucleotidase activity and carboxylic acid transmembrane transport. In addition, interweaved networks were constructed to show that the development of TBI might be affected by metabolite-related proteins and their protein pathways.
Conclusion:The overall results show that acute TBI is susceptible to metabolic disorders, and the joint metabolite-protein network analysis provides a favorable prediction of TBI pathogenesis mechanisms in the brain. The signatures in the hippocampus might be promising for the development of biomarkers and pathways relevant to acute TBI and could further guide testable predictions of the underlying mechanism of TBI.
“…Currently, a novel approach towards the utilization of bile acids in PD is being considered. Since, to date, no reliable biomarkers of PD exist, Graham et al investigated alterations in bile acid profiles as potential biomarkers used in early diagnosis of PD [129,148]. In this respect, prodromal mouse model of PD was used to measure serum concentrations of 18 bile acids.…”
Section: Tudca In Neurodegenerative Diseasesmentioning
Tauroursodeoxycholic acid (TUDCA) is a naturally occurring hydrophilic bile acid that has been used for centuries in Chinese medicine. Chemically, TUDCA is a taurine conjugate of ursodeoxycholic acid (UDCA), which in contemporary pharmacology is approved by Food and Drug Administration (FDA) for treatment of primary biliary cholangitis. Interestingly, numerous recent studies demonstrate that mechanisms of TUDCA functioning extend beyond hepatobiliary disorders. Thus, TUDCA has been demonstrated to display potential therapeutic benefits in various models of many diseases such as diabetes, obesity, and neurodegenerative diseases, mostly due to its cytoprotective effect. The mechanisms underlying this cytoprotective activity have been mainly attributed to alleviation of endoplasmic reticulum (ER) stress and stabilization of the unfolded protein response (UPR), which contributed to naming TUDCA as a chemical chaperone. Apart from that, TUDCA has also been found to reduce oxidative stress, suppress apoptosis, and decrease inflammation in many in-vitro and in-vivo models of various diseases. The latest research suggests that TUDCA can also play a role as an epigenetic modulator and act as therapeutic agent in certain types of cancer. Nevertheless, despite the massive amount of evidence demonstrating positive effects of TUDCA in pre-clinical studies, there are certain limitations restraining its wide use in patients. Here, molecular and cellular modes of action of TUDCA are described and therapeutic opportunities and limitations of this bile acid are discussed.
“…In a previous study by our group, we identified Bile Acid metabolism as one of the major biochemical pathways to be perturbed in the brain of a mouse model of prodromal PD [10]. Bile acids are molecules derived from cholesterol in hepatocytes and are used to emulsify fats in the small intestine and promote fat digestion and absorption [11,12].…”
For people with Parkinson’s disease (PD), considered the most common neurodegenerative disease behind Alzheimer’s disease, accurate diagnosis is dependent on many factors; however, misdiagnosis is extremely common in the prodromal phases of the disease, when treatment is thought to be most effective. Currently, there are no robust biomarkers that aid in the early diagnosis of PD. Following previously reported work by our group, we accurately measured the concentrations of 18 bile acids in the serum of a prodromal mouse model of PD. We identified three bile acids at significantly different concentrations (p < 0.05) when mice representing a prodromal PD model were compared with controls. These include ω-murichoclic acid (MCAo), tauroursodeoxycholic acid (TUDCA) and ursodeoxycholic acid (UDCA). All were down-regulated in prodromal PD mice with TUDCA and UDCA at significantly lower levels (17-fold and 14-fold decrease, respectively). Using the concentration of three bile acids combined with logistic regression, we can discriminate between prodromal PD mice from control mice with high accuracy (AUC (95% CI) = 0.906 (0.777–1.000)) following cross validation. Our study highlights the need to investigate bile acids as potential biomarkers that predict PD and possibly reflect the progression of manifest PD.
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