RPLC Analysis Identify Unique Metabolomics Profiles Of SD Disease?

The present results showed that daily protection with caffeine attenuated the increase in MDA levels in AlCl3-intoxicated rats. Supporting the present finding, previous studies have revealed the antioxidant potential of caffeine against lipid peroxidation in various animal models of neurologic diseases, including Alzheimer’s disease (Prasanthi et al., 2010), epilepsy (Souza et al., 2013) and Parkinson's disease (Khadrawy et al., 2017). It has been demonstrated that caffeine has the ability to scavenge reactive oxygen species (Devasagayam et al., 1996) and modulated the brain antioxidant system through increasing the content of GSH and activities of antioxidant enzymes like glutathione reductase and superoxide dismutase (Abreu et al., 2011). Generally, the antioxidant capacity of caffeine was similar to that of the established biological antioxidant GSH and significantly higher than ascorbic acid (Devasagayam et al., 1996). Accordingly, this may explain the ability of caffeine to attenuate lipid peroxidation induced by AlCl3 in the current study via direct scavenging of reactive oxygen species or by increasing GSH content and antioxidant enzymes activities.

Similarly, an increase in the levels of lipid peroxidation was observed in Aβ-induced rat hippocampal cells, confirming previous reports [17]. Enzymatic antioxidants such as SOD, catalase, and GPX act as the cellular antioxidant defense mechanism against free radicals. Since NADPH is required for the regeneration of catalase from its inactive form, catalase activity might be decreased in Aβ induced toxicity due to reduced NADPH levels. In this study, we have reported that Honokiol treatment significantly increased the enzymatic antioxidant activities in APP-CHO cells. In addition, non-enzymatic antioxidants like GSH also exhibited beneficial neuroprotective effects against oxidative stress. GSH is an endogenous nonenzymatic antioxidant that prevents damage to cellular components caused by ROS such as free radicals and peroxides. GSH is oxidized to glutathione disulfide (GSSG) by ROS, thereby causing a reduction in the level of GSH. GR reduces GSSG to GSH via NADPH, which in turn is released by glucose-6-phosphate dehydrogenase [18]. Honokiol treatment upregulated the activity of these antioxidants in APP-CHO cells. In addition to oxidative stress, a strong association between insulin resistance and the development of AD has been demonstrated. Several studies have reported that insulin resistance (IR), an underlying characteristic of type 2 diabetes, is an important risk factor for AD

The HEXA gene provides instruction for making part of an enzyme called beta-hexosaminidase A, which plays a very critical role in the brain and spinal cord. This enzyme is found in the lysosomes, which are the structures in cells that break down toxic substances and their job is that of a recycling center. Beta-hexosaminidase A helps break down a fatty substance called GM2 ganglioside. The mutations in the HEXA gene disrupt the activity of beta-hexosaminidase A, which prevents the enzyme from breaking down GM2 ganglioside. As a result, this substance accumulates to toxic levels, particularly in the neutrons in the brain and also the spinal cord. Damage by the buildup of GM2 ganglioside leads to the destruction of the neurons; Causing signs and symptoms of Tay-Sachs disease.

“Without Hex-A, a fatty substance, or lipid, called GM2 ganglioside accumulates abnormally in cells, especially in the nerve cells of the brain. This ongoing accumulation causes progressive damage to the cells.”http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0024672/

Mitochondrial dysfunction and oxidative stress have been consistently observed in brains of PD patients. There is increasing pharmacological and genetic evidence sustain a link between PD and mitochondrial respiratory chain dysfunction, particular a deficit in mitochondrial complex I (Franco-Iborra et al., 2015). Accidental exposure to 1-methyl-4-phenyl-1,2,3,4-tetrahydropyridine (MPTP), an mitochondrial complex I inhibitor, has been known to result in acute and irreversible syndrome that was almost indistinguishable from PD (Calne and Langston, 1983; Langston and Ballard, 1983). Later on, mitochondrial complex I inhibition has been identified in the brains of sporadic PD patients (Schapira et al., 1990). In addition, chronic systemic inhibition of mitochondrial complex I by pesticide rotenone has been found to link to sporadic PD (Betarbet et al., 2000). Interestingly, mitochondrial complex I deficiency has been found not only in the postmortem substantia nigra but also in cerebral cortex (Schapira et al., 1990), which is consistent to the cortical glucose hypometabolism observed in PD patients. Indeed, the pathology of PD has been found to involve several brain regions other than the SNc and many neurotransmitters other than dopamine (Lang and Obeso, 2004a, b). PD models using MPTP and rotenone have now been used extensively in PD research (Beal,

A dysfunction of an enzyme in the peroxisome leads to the accumulation of very long-chain fatty acids (VLCFA) in several areas (several areas of what?) including the central nervous tissue(CNS). The accumulation of VLCFA is toxic leading to the death of neuroglial cells like the oligodendrocytes and astrocytes. Astrocytes in normal conditions regulate the composition of the blood-barrier in the central nervous system; The olygodendorocytes form the myelin sheath that covers the axons and facilitate the effective propagation of action terminals from the neuron to the target cells (Amerman 390). This disorder (what disorder) is caused by a mutation in the ABCD1 gene of the X-chromosome, it causes the demyelination of the neurons in the CNS inhibiting the integration of the information from sensory stimuli and the proper response to them, causing eventually death. X-linked disorders are present are a wide variety of phenotypes, CCALD is the most common and presents only on boys between the age of 4 and 12. CCALD is a rapidly progressive disease, its deteriorates the patient health in a matter of years, and due to its complexity, its commonly misdiagnosed (Engelen).

The second group of demyelinating diseases,hereditary metabolic disorders, are degenerative diseases and include, among others, the eight identified leukodystrophies (5). Here, 'leuko' means 'white', and refers to the white matter (myelin sheaths) of the central nervous system, and 'dystrophy' means 'imperfect growth or development' (2).. The majority of the leukodystrophies are storage disorders, where the absence or malfunctioning of an enzyme results in the toxic accumulation of chemical substances (5) In each of the so far identified leukodystrophies only one of the

Gaucher disease (GD) is an autosomal recessive inborn error in the pathway of sphingolipid catabolism. Biochemically, this disease is characterized by a deficiency of lysosomal β-glucosidase (glucocerebrosidase GCase, E.C.3.2.1.45) enzyme due to the mutation of GBA gene [1]. The natural substrate of this lysosomal enzyme is glucocerebroside (also called glycosylceramide) mainly present on the cytoplasmic face of cellular membranes and on the cell surface. Lysosomal β-glucosidases play a key role in recycling of this substrate by degradation of glucospingolipid from membranes of apoptatic white blood cells and senescent red blood cells. Genetic mutations of GBA gene affect the enzyme`s catalytic activity and stability and results in the storage

Additionally, carrying out chromosomal microarray was also significant since it also revealed the presence of pathogenic number changes as well as the possibilities of microdeletion that is considered a risk factor with regards to autism, intellectual disability, seizures, as well as malformations. Similarly, measurement of antibodies in three of the samples was also ideal because it provided information of the level – whether high-positive 0r low-positive – of the antibody which is known to block the folate from binding to folate transporter from the blood to the brain. Finally, carrying out a workup for the metabolic disorders following the guidelines suggest by Rossignol & Frye (2011) was also ideal. This is because it enabled determine the elevation levels of biochemical markers that are known for their contribution to mitochondrial dysfunction. These steps were indeed significant because, as is apparent in literature, they give a vivid comprehension on how reduction in mitochondrial roles define mitochondrial deficiencies.

Hydrolysis of GM2 ganglioside is catalyzed in lysosomes by β-hexosaminidase A (HEXA) and a non-enzymic factor, GM2 activator (GM2A), is essentially required in the catabolic reaction in vivo.

One mechanism is the aggregation of the misfolded alpha-synuclein proteins, causing the death of the dopaminergic neurons in the brain tissue (Dauer and Przedborski, 2003; Sultana et al. 2011). A second proposed mechanism is mitochondrial dysfunction, causing oxidative stress on the neurons promoting the activation of ROS (reactive oxygen spcies) thus causing apoptosis of the neuronal cells (Dauer and Przedborski, 2003; Zhang et al. 2012). Other mechanisms and links between these two proposed models have been suggested but further research is necessary to determine the direct pathways of neuronal death in PD. The root to the biochemical alteration in the dopaminergic neurons is a mixture of environmental effects and exposures as well as genetic factors. The genetic inheritance of Parkinson’s disease only affects approximately 10% of persons with PD (Shahaduzzaman et al. 2013) and is usually inherited from a direct relative (Elbaz and Tranchant, 2007). Environmental factors such as exposure to pesticides, traumatic brain injury, and age are believed to contribute to the development of PD and pose a possible threat to mutation of the genes involved in PD (Hassan et al. 2015). The multifactor of the involvement of environmental factors as well as genetic factors are believed to attribute for the majority of cases of

Refsum disease is an inborn error of lipid metabolism classically characterized by a tetrad of clinical abnormalities: retinitis pigmentosa, peripheral neuropathy, cerebellar ataxia, and elevated protein levels in the cerebrospinal fluid (CSF) without an increase in the number of cells. It is inherited in an autosomal recessive pattern. The prevalence of Refsum disease is unknown, although the condition is thought to be uncommon. The fact that most individuals described in the literature have been identified in the United Kingdom and Norway, where awareness of Refsum disease is high, suggests that the true prevalence of Refsum disease may be much higher than currently reported.

The present findings showed that the daily oral administration of AlCl3 induced a significant increase in the levels of cortical, hippocampal and striatal lipid peroxidation marker MDA recording +55.20%, +128.32% and +427.39%, respectively above the control values. In addition, NO level increased significantly by +100%, +72.22% and +57.14%, in the cortex, hippocampus and striatum respectively of AlCl3-treated rats. Protection of AlCl3-intoxicated rats with caffeine attenuated the increased values of MDA and NO in the studied brain regions to non significant changes from the control (Figure 1).

Male and female proximal-tubule select IR/IGF double KO mice were bred and genotyped at Georgetown University. The mice were fed control or a high-fructose diet for 4 weeks. The mice were euthanized humanely and kidneys were collected for analysis. Western blots were completed on whole kidney homogenates to assess the expression of Napi-2, KHK, GLUT5, IR, IGFR and NHE3. Electrolyte levels were measured in urine and plasma using EasyLyte electrolyte analyzer. We found that across both sexes, the expression of GLUT5 and was increased in fructose diet in both WT and KO

Metabolomic analysis of changes to plasma metabolome following dietary depletion and supplementation of thiamine pyrophosphate (TPP) in mice