Perturbation Of Energy Metabolism Research Articles

Titanium dioxide nanoparticles induce energy perturbation by stimulating glycolytic metabolic profile in rats

The safety of titanium dioxide nanoparticles (TiO2-NPs) remains uncertain due to a scarcity of data regarding its absorption, distribution, elimination, and potential adverse effects following oral exposure. As emerging evidence suggests perturbations in energy metabolism play a pivotal role in the toxicity induced by various toxicants, this investigation aimed to assess the effect of TiO2-NPs on the activities of specific glycolytic enzymes in rats. In this study, seventy-two (72) male Wistar rats (200 ± 20g) were divided into 12 groups, each consisting of 6 animals. The rats were orally exposed to TiO2-NPs (8-12nm) at doses of 50, 150, and 250 mg/kg body weight (BW) for durations of 4, 8, and 12 weeks. The control groups received distilled water. The results showed that, except for the 150 mg/kg BW dose of 12 weeks, TiO2-NPs exposure led to an up-regulation in hexokinase activity in lymphocytes, plasma, erythrocytes, and the liver. Hepatic and lymphocyte aldolase activities were also up-regulated, except at 8 and 12 weeks for the 50 and 150 mg/kg BW doses, where slight decreases were observed. Plasma aldolase increased, except at 12 weeks for 150 mg/kg BW dose, while erythrocyte aldolase increased only during the 4 and 8-week exposure but decreased throughout the 12-week exposure. Notably, compared to erythrocyte lactate dehydrogenase activity, which decreased, a consistent pattern observed in lymphocytes, plasma, and hepatic enzymes was a down-regulation at 8 and 12 weeks for the 50 and 150 mg/kg BW doses of TiO2-NPs. In other instances, and time intervals, lactate dehydrogenase was up-regulated. The data from this study underscores that exposure to TiO2-NPs can disrupt the glycolytic pathway of energy metabolism, particularly during the initial 4 weeks of exposure. These perturbations are characterized by increased glycolytic enzymes activity in the lymphocytes, plasma, and the liver.

Exploring the anti-ischemic stroke potential of wogonoside: Insights from Nrf2/Sirt3 signaling pathway and UPLC-TripleTOF-MS/MS-based metabolomics

Ischemic stroke, accounting for 80 % of all strokes, is a major cause of morbidity and mortality worldwide. However, effective and safe pharmacotherapy options for ischemic injury are limited. This study investigated the therapeutic effects of wogonoside, a compound derived from Radix Scutellariae, on ischemia/reperfusion (I/R) injury. The results showed that wogonoside treatment had significant therapeutic effects in rats with middle cerebral artery occlusion. It effectively reduced mortality rates, neurological deficits, cerebral infarct size, and brain water content. In an in vitro model using PC12 cells, wogonoside activated the Nrf2/Sirt3 signaling pathway. This activation contributed to the attenuation of oxidative damage and inflammation. Metabolomics analysis revealed increased levels of γ-aminobutyric acid (GABA) and glutathione in response to wogonoside treatment, suggesting their potential as therapeutic biomarkers for ischemic stroke. Additionally, wogonoside restored perturbed energy metabolism, including the tricarboxylic acid cycle. Wogonoside has the potential to ameliorate cerebral ischemic injury by targeting GABA-related amino acid metabolism, energy metabolism, and glutathione metabolism, maintaining redox homeostasis, and attenuating oxidative stress. These findings provide valuable insights into the protective mechanisms of wogonoside in cerebral I/R injury and highlight the promising therapeutic approach of wogonoside in the treatment of ischemic stroke.

Redox imbalance and metabolic defects in the context of Alzheimer disease.

Redox reactions play a critical role for intracellular processes, including pathways involved in metabolism and signaling. Reactive oxygen species (ROS) act either as second messengers or generators of protein modifications, fundamental mechanisms for signal transduction. Disturbance of redox homeostasis is associated with many disorders. Among these, Alzheimer's disease is a neurodegenerative pathology that presents hallmarks of oxidative damage such as increased ROS production, decreased activity of antioxidant enzymes, oxidative modifications of macromolecules, and changes in mitochondrial homeostasis. Interestingly, alteration of redox homeostasis is closely associated with defects of energy metabolism, involving both carbohydrates and lipids, the major energy fuels for the cell. As the brain relies exclusively on glucose metabolism, defects of glucose utilization represent a harmful event for the brain. During aging, a progressive perturbation of energy metabolism occurs resulting in brain hypometabolism. This condition contributes to increase neuronal cell vulnerability ultimately resulting in cognitive impairment. The current review discusses the crosstalk between alteration of redox homeostasis and brain energy defects that seems to act in concert in promoting Alzheimer's neurodegeneration.

Disturbed brain energy metabolism in a rodent model of DYT-TOR1A dystonia

DYT-TOR1A (DYT1) dystonia, characterized by reduced penetrance and suspected environmental triggers, is explored using a “second hit” DYT-TOR1A rat model. We aim to investigate the biological mechanisms driving the conversion into a dystonic phenotype, focusing on the striatum's role in dystonia pathophysiology.Sciatic nerve crush injury was induced in ∆ETorA rats, lacking spontaneous motor abnormalities, and wild-type (wt) rats. Twelve weeks post-injury, unbiased RNA-sequencing was performed on the striatum to identify differentially expressed genes (DEGs) and pathways. Fenofibrate, a PPARα agonist, was introduced to assess its effects on gene expression. 18F-FDG autoradiography explored metabolic alterations in brain networks.Low transcriptomic variability existed between naïve wt and ∆ETorA rats (17 DEGs). Sciatic nerve injury significantly impacted ∆ETorA rats (1009 DEGs) compared to wt rats (216 DEGs). Pathway analyses revealed disruptions in energy metabolism, specifically in fatty acid β-oxidation and glucose metabolism. Fenofibrate induced gene expression changes in wt rats but failed in ∆ETorA rats. Fenofibrate increased dystonia-like movements in wt rats but reduced them in ∆ETorA rats. 18F-FDG autoradiography indicated modified glucose metabolism in motor and somatosensory cortices and striatum in both ∆ETorA and wt rats post-injury.Our findings highlight perturbed energy metabolism pathways in DYT-TOR1A dystonia, emphasizing compromised PPARα agonist efficacy in the striatum. Furthermore, we identify impaired glucose metabolism in the brain network, suggesting a potential shift in energy substrate utilization in dystonic DYT-TOR1A rats. These results contribute to understanding the pathophysiology and potential therapeutic targets for DYT-TOR1A dystonia.

Early Low-Grade Inflammation Induced by High-Salt Diet in Sprague Dawley Rats Involves Th17/Treg Axis Dysregulation, Vascular Wall Remodeling, and a Shift in the Fatty Acid Profile.

Unrestricted increased table salt (NaCl) intake is associated with oxidative stress and inflammation, leading to endothelial dysfunction and atherosclerosis. However, data on salt-induced immunomodulatory effects in the earliest phase of salt loading are scarce. In the present study, an animal model of short-term salt loading was employed, including male Sprague Dawley rats consuming a high-salt diet (HSD; 4% NaCl) or standard laboratory chow (low-salt; LSD; 0.4% NaCl) during a 7-day period. The contribution of angiotensin II (ANGII) suppression was tested by adding a group of rats on a high-salt diet receiving ANGII infusions. Samples of peripheral blood/mesenteric lymph node leukocytes, brain blood vessels, and serum samples were processed for flow cytometry, quantitative real-time PCR, total proteome analysis, and multiplex immunoassay. Data analysis revealed the up-regulation of Il 6 gene in the microcirculation of high-salt-fed rats, accompanied by an increased serum level of TNF-alpha cytokine. The high-salt diet resulted in increased proportion of serum mono-unsaturated fatty acids and saturated fatty acids, reduced levels of linoleic (C18:2 ω-6) and α-linolenic (C18:3 ω-3) acid, and increased levels of palmitoleic acid (C16:1 ω-7). The high-salt diet had distinct, lymphoid compartment-specific effects on leukocyte subpopulations, which could be attributed to the increased expression of salt-sensitive SGK-1 kinase. Complete proteome analysis revealed high-salt-diet-induced vascular tissue remodeling and perturbations in energy metabolism. Interestingly, many of the observed effects were reversed by ANGII supplementation. Low-grade systemic inflammation induced by a HSD could be related to suppressed ANGII levels. The effects of HSD involved changes in Th17 and Treg cell distribution, vascular wall remodeling, and a shift in lipid and arachidonic acid metabolism.

Histopathological, physiological, and multi-omics insights into the hepatotoxicity mechanism of nanopolystyrene and/or diclofenac in Mylopharyngodon piceus

Nanopolystyrene (NP) and diclofenac (DCF) are common environmental contaminants in the aquatic ecosystem; therefore, the present study aimed to investigate the hepatotoxicity of NP and/or DCF exposure on aquatic organisms and the underlying mechanisms. Juvenile Mylopharyngodon piceus were used as a model organism to study the effects of NP and/or DCF exposure at environmentally relevant concentrations for 21 days. Subchronic exposure to NP and/or DCF resulted in liver histological damage. In the NP group, the presence of large lipid droplets was observed, whereas the DCF group exhibited marked hepatic sinusoidal dilatation accompanied by inflammation. Additionally, this exposure induced liver oxidative stress, as evidenced by the changes in several physiological parameters, including catalase (CAT), glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), total antioxidant capacity (T-AOC), reactive oxygen species (ROS), and malondialdehyde (MDA). Integrated transcriptomic and metabolomic analysis was performed to further investigate the molecular mechanism underlying hepatotoxicity. Multi-omics analysis demonstrated, for the first time to our knowledge, that NP induced hepatic steatosis mainly through activating the glycerol-3-phosphate pathway and inhibiting VLDL assembly by targeting several key enzyme genes including GPAT, DGAT, ACSL, APOB, and MTTP. Furthermore, NP exposure disrupted arachidonic acid metabolism, which induced the release of inflammatory factors and inhibited the release of anti-inflammatory factors, ultimately causing liver inflammation in M. piceus. In contrast, DCF induced interleukin production and downregulated KLF2, causing hepatic sinusoidal dilatation with inflammation in juvenile M. piceus, which is consistent with the finding of JAK–STAT signaling pathway activation. In addition, the upregulated AMPK signaling pathway in the DCF group suggested perturbation of energy metabolism. Collectively, these findings provide novel insights into the molecular mechanism of the multiple hepatotoxicity endpoints of NP and/or DCF exposure in aquatic organisms.

Metabolic Basis of Circadian Dysfunction in Parkinson's Disease.

Parkinson's disease (PD) is one of the most common neurodegenerative disorders. The management of PD is a challenging aspect for general physicians and neurologists. It is characterized by the progressive loss of dopaminergic neurons. Impaired α-synuclein secretion and dopamine release may cause mitochondrial dysfunction and perturb energy metabolism, subsequently altering the activity and survival of dopaminergic neurons, thus perpetuating the neurodegenerative process in PD. While the etiology of PD remains multifactorial, emerging research indicates a crucial role of circadian dysfunction in its pathogenesis. Researchers have revealed that circadian dysfunction and sleep disorders are common among PD subjects and disruption of circadian rhythms can increase the risk of PD. Hence, understanding the findings of circadian biology from translational research in PD is important for reducing the risk of neurodegeneration and for improving the quality of life. In this review, we discuss the intricate relationship between circadian dysfunction in cellular metabolism and PD by summarizing the evidence from animal models and human studies. Understanding the metabolic basis of circadian dysfunction in PD may shed light on novel therapeutic approaches to restore circadian rhythm, preserve dopaminergic function, and ameliorate disease progression. Further investigation into the complex interplay between circadian rhythm and PD pathogenesis is essential for the development of targeted therapies and interventions to alleviate the burden of this debilitating neurodegenerative disorder.

Promising use of metformin in treating neurological disorders: biomarker-guided therapies.

Neurological disorders are a diverse group of conditions that affect the nervous system and include neurodegenerative diseases (Alzheimer's disease, multiple sclerosis, Parkinson's disease, Huntington's disease), cerebrovascular conditions (stroke), and neurodevelopmental disorders (autism spectrum disorder). Although they affect millions of individuals around the world, only a limited number of effective treatment options are available today. Since most neurological disorders express mitochondria-related metabolic perturbations, metformin, a biguanide type II antidiabetic drug, has attracted a lot of attention to be repurposed to treat neurological disorders by correcting their perturbed energy metabolism. However, controversial research emerges regarding the beneficial/detrimental effects of metformin on these neurological disorders. Given that most neurological disorders have complex etiology in their pathophysiology and are influenced by various risk factors such as aging, lifestyle, genetics, and environment, it is important to identify perturbed molecular functions that can be targeted by metformin in these neurological disorders. These molecules can then be used as biomarkers to stratify subpopulations of patients who show distinct molecular/pathological properties and can respond to metformin treatment, ultimately developing targeted therapy. In this review, we will discuss mitochondria-related metabolic perturbations and impaired molecular pathways in these neurological disorders and how these can be used as biomarkers to guide metformin-responsive treatment for the targeted therapy to treat neurological disorders.

Mystery of bisphenol F-induced nonalcoholic fatty liver disease-like changes: Roles of Drp1-mediated abnormal mitochondrial fission in lipid droplet deposition

As one of the major substitutes for bisphenol A (BPA), bisphenol F (BPF) has been widely used. Our previous study demonstrated that BPF exposure facilitates lipid droplet deposition in hepatic cells, contributing to nonalcoholic fatty liver disease (NAFLD)-like changes. However, the underlying mechanisms remain poorly understood. Here, with a metabolic cage system, we observed the perturbation of energy metabolism in mice treated with BPF. BPF obviously suppressed metabolic capacity, which manifested as decreased energy expenditure, low O2 consumption and CO2 levels in mice. Consistent with the in vivo results, a Seahorse XF Cell Mito Stress Test showed significant reductions in mitochondrial ATP production capacity, maximum respiratory capacity, and residual respiratory capacity after BPF treatment in an in vitro study. Electron microscopy revealed a striking increase in mitochondrial fission that was synchronous with excessive expression and activation of dynamin-related protein 1 (Drp1). Intriguingly, chemical inhibition of Drp1 by Mdivi-1 and/or silencing of Drp1 dramatically hampered mitochondrial fission and ameliorated BPF-induced lipid droplet deposition both in mouse liver and human hepatic cells. Mechanistically, mitochondrial dynamics imbalance played prominent roles in these processes, since suppression of Drp1 by chemical inhibition or knockdown substantially reversed BPF-induced mitochondrial fission and ameliorated the suppression of mitochondrial metabolism as well as excessive mitochondrial ROS, which was verified to be key to lipid droplet deposition. Collectively, the findings of the current study reveal previously unrecognized effects involving Drp1-mediated mitochondrial injury in BPF-induced lipid droplet deposition. Therefore, targeted intervention against mitochondrial dysfunction may be a promising therapeutic strategy for BPF-induced NAFLD-like changes.

Methanolic extract of Buchholzia coriacea seed (MEBCS) attenuates lipopolysaccharide-induced perturbations of energy metabolizing enzymes in mice

The safety of lipopolysaccharide (LPS)-containing foods has been questioned and the concerns are understandable. Buchholzia coriacea seeds have been widely applied in folkloric medicine due to their nutritional and therapeutic potential. The aim of the study is to evaluate the attenuation of methanolic extract of Buchholzia coriacea seed (MEBCS) on LPS-induced energy metabolism perturbations. Eighteen BALB/c mice were divided into three groups of 6 mice each. Group 1 (control) received distilled water and physiological saline for 7 days. Group 2 (LPS only) received 4 mg/Kg LPS intraperitoneally on the 7th day of administration, while Group 3 (LPS+MEBCS) were pre-treated with 250 mg/kg MEBCS orally for 6 days prior to administration of LPS (4 mg/kg) on the 7th day. The experimental animals were sacrificed afterward. Glycolytic and oxidative phosphorylation enzymes were assessed in the heart, kidney, spleen, lymphocytes, and erythrocytes. Glycolytic enzymes (lactate dehydrogenase, hexokinase, aldolase, and NADase) and oxidative phosphorylation enzymes such malate dehydrogenase, succinate dehydrogenase and electron transport complexes I+III, II+III, and IV) activities were significantly decreased (P> 0.05) by LPS. Pre-treatment with MEBCS attenuates the decrease in activity observed. The findings of this study indicated that MEBCS has the potential of attenuating perturbations of energy metabolism induced by lipopolysaccharides.

Deciphering mechanism of Zhishi-Xiebai-Guizhi Decoction against hypoxia/reoxygenation injury in cardiomyocytes by cell metabolomics: Regulation of oxidative stress and energy acquisition

Myocardial ischemia/reperfusion (MI/R) injury is a life-threatening syndrome with high morbidity and mortality. Zhishi-Xiebai-Guizhi Decoction (ZSXBGZD) is a classic traditional Chinese medicine formula, used to treat cardiovascular diseases for centuries. However, its underlying medicinal mechanism has not been clearly elucidated, which hinders its widespread application. Here, the curative effects and therapeutic mechanism of ZSXBGZD against MI/R were addressed based on an integration of pharmaceutical evaluation and cellular metabolomics. First, a hypoxia/reoxygenation (H/R) model in H9c2 cells was employed to resemble MI/R and multiple pharmacological indicators were performed to assess the efficacy of ZSXBGZD. The results showed that ZSXBGZD possessed exceptional ability in attenuating cardiomyocyte injury, concerning oxidative stress, mitochondrial dysfunction, energy acquisition and cell apoptosis. Furthermore, a cell metabolomics approach based on HILIC and UPLC-Q-TOF-MS coupled with multivariate analysis was conducted to explore the metabolic regulation of ZSXBGZD. 38 differential polar metabolites related to H/R were uncovered, and 34 of them were reversed to normal state after the treatment of ZSXBGZD, revealing the perturbations of energy metabolism and amino acid metabolism. Moreover, formula decomposition justified the combination of single herbs to form ZSXBZGD and confirmed the pivotal status of Allii Macrostemonis Bulbus and Trichosanthis Fructus.

L-threonine promotes healthspan by expediting ferritin-dependent ferroptosis inhibition in C. elegans

The pathways that impact longevity in the wake of dietary restriction (DR) remain still ill-defined. Most studies have focused on nutrient limitation and perturbations of energy metabolism. We showed that the L-threonine was elevated in Caenorhabditis elegans under DR, and that L-threonine supplementation increased its healthspan. Using metabolic and transcriptomic profiling in worms that were fed with RNAi to induce loss of key candidate mediators. L-threonine supplementation and loss-of-threonine dehydrogenaseincreased the healthspan by attenuating ferroptosis in a ferritin-dependent manner. Transcriptomic analysis showed that FTN-1 encoding ferritin was elevated, implying FTN-1 is an essential mediator of longevity promotion. Organismal ferritin levels were positively correlated with chronological aging and L-threonine supplementation protected against age-associated ferroptosis through the DAF-16 and HSF-1 pathways. Our investigation uncovered the role of a distinct and universal metabolite, L-threonine, in DR-mediated improvement in organismal healthspan, suggesting it could be an effective intervention for preventing senescence progression and age-induced ferroptosis.

The metabolic nature of inflammatory bowel diseases.

Crohn's disease and ulcerative colitis, phenotypically comprising a spectrum of inflammatory bowel diseases (IBDs), spread globally during the westernization of lifestyle and dietary habits over the past few decades. Here, we review experimental and clinical evidence for the metabolic nature of gut inflammation in IBD and delineate distinct parallels to the inflammatory state in metabolic diseases. Experimental evidence indicates that excessive intake of specific macronutrients in a Western diet fuels an inflammatory response in the gut by exploiting sensors of innate immunity and perturbation of gut microbial metabolism. Genetic IBD risk partly affects metabolism and stress signalling of innate immunity, and immunometabolism controls susceptibility to gut inflammation. Epidemiological and clinical studies indicate that specific nutrients in the Western diet pose a risk for the development of IBD and a poor disease course. Translational studies in IBD indicate perturbation of energy metabolism in immune cells and perturbation of gut microbial metabolism, which can be shaped by diet. In turn, dietary restriction by exclusive enteral nutrition induces remission in patients with IBD. Collectively, these studies support a metabolic underpinning of gut inflammation in IBD as described for metabolic inflammation in obesity and related disorders.

Serum Free Fatty Acids Independently Predict Adverse Outcomes in Acute Heart Failure Patients

Background: Perturbation of energy metabolism exacerbates cardiac dysfunction, serving as a potential therapeutic target in congestive heart failure. Although circulating free fatty acids (FFAs) are linked to insulin resistance and risk of coronary heart disease, it still remains unclear whether circulating FFAs are associated with the prognosis of patients with acute heart failure (AHF).Methods: This single-center, observational cohort study enrolled 183 AHF patients (de novo heart failure or decompensated chronic heart failure) in the Second Affiliated Hospital, Zhejiang University School of Medicine. All-cause mortality and heart failure (HF) rehospitalization within 1 year after discharge were investigated. Serum FFAs were modeled as quartiles as well as a continuous variable (per SD of FFAs). The restricted cubic splines and cox proportional hazards models were applied to evaluate the association between the serum FFAs level and all-cause mortality or HF rehospitalization.Results: During a 1-year follow-up, a total of 71 (38.8%) patients had all-cause mortality or HF rehospitalization. The levels of serum FFAs positively contributed to the risk of death or HF rehospitalization, which was not associated with the status of insulin resistance. When modeled with restricted cubic splines, the serum FFAs increased linearly for the incidence of death or HF rehospitalization. In a multivariable analysis adjusting for sex, age, body-mass index, coronary artery disease, diabetes mellitus, hypertension, left ventricular ejection fraction and N-terminal pro-brain natriuretic peptid, each SD (303.07 μmol/L) higher FFAs were associated with 26% higher risk of death or HF rehospitalization (95% confidence interval, 2–55%). Each increasing quartile of FFAs was associated with differentially elevated hazard ratios for death or HF rehospitalization of 1 (reference), 1.71 (95% confidence interval, [0.81, 3.62]), 1.41 (95% confidence interval, [0.64, 3.09]), and 3.18 (95% confidence interval, [1.53, 6.63]), respectively.Conclusion: Serum FFA levels at admission among patients with AHF were associated with an increased risk of adverse outcomes. Additional studies are needed to determine the causal-effect relationship between FFAs and acute cardiac dysfunction and whether FFAs could be a potential target for AHF management.

Deciphering the physiological response of Escherichia coli under high ATP demand.

One long‐standing question in microbiology is how microbes buffer perturbations in energy metabolism. In this study, we systematically analyzed the impact of different levels of ATP demand in Escherichia coli under various conditions (aerobic and anaerobic, with and without cell growth). One key finding is that, under all conditions tested, the glucose uptake increases with rising ATP demand, but only to a critical level beyond which it drops markedly, even below wild‐type levels. Focusing on anaerobic growth and using metabolomics and proteomics data in combination with a kinetic model, we show that this biphasic behavior is induced by the dual dependency of the phosphofructokinase on ATP (substrate) and ADP (allosteric activator). This mechanism buffers increased ATP demands by a higher glycolytic flux but, as shown herein, it collapses under very low ATP concentrations. Model analysis also revealed two major rate‐controlling steps in the glycolysis under high ATP demand, which could be confirmed experimentally. Our results provide new insights on fundamental mechanisms of bacterial energy metabolism and guide the rational engineering of highly productive cell factories.

Toxicity of the novel fungicide oxathiapiprolin to Chlorella vulgaris: Assessments at different levels of biological organization

Oxathiapiprolin (Otp) is the first successful oxysterol-binding protein (OSBP) inhibitor in oomycete control. It is regarded as a significant milestone in the history of fungicide discoveries and has vast application prospects. There is little available information on the ecotoxicity of Otp to aquatic organisms. In this study, we evaluated the toxic effects of Otp in the Chlorella vulgaris (C. vulgaris). The results revealed the acute toxicity of Otp to C. vulgaris, with a 96-h median effective concentration for growth inhibition of 0.74 mg/L. When algal cells were exposed to 0.5 and 1.5 mg/L Otp, their chlorophyll and carotenoid contents dropped dramatically. As suggested by the significant increase in reactive oxygen species (ROS) and malondialdehyde (MDA) levels and the remarkable changes in the activity of a series of antioxidant enzymes, Otp induces production of ROS, resulting in oxidative damage. In addition, Otp can damage cell structures and could destroy membrane integrity. Finally, the changes in endogenous substances indicated that Otp can perturb energy metabolism and photosynthesis in C. vulgaris cells. The experimental results suggest that Otp can have toxic effects on algal cells by disturbing photosynthesis and causing oxidative damage and abnormal energy metabolism in C. vulgaris cells.

Impaired mitochondrial functions and energy metabolism in MPTP-induced Parkinson's disease: comparison of mice strains and dose regimens.

Heterogenous diseases such as Parkinson's disease (PD) needs an efficient animal model to enhance understanding of the underlying mechanisms and to develop therapeutics. MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), a neurotoxin, has been widely used to replicate the pathophysiology of PD in rodents, however, the knowledge about its effects on energy metabolism is limited. Moreover, susceptibility to different dose regimens of MPTP also varies among mice strains. Thus, the present study compares the effect of acute and sub-acute MPTP administration on mitochondrial functions in C57BL/6 and BALB/c mice. In addition, activity of enzymes involved in energy metabolism was also studied along with behavioural alterations. The findings show that acute dose of MPTP in C57BL/6 mice had more profound effect on the activity of electron transport chain complexes. Further, the activity of MAO-B was increased following acute and sub-acute MPTP administration in C57BL/6 mice. However, no significant change was observed in BALB/c mice. Acute MPTP treatment resulted in decreased mitochondrial membrane potential along with increasedswelling of mitochondria in C57BL/6 mice. In addition, perturbations were observed in hexokinase, the rate limiting enzyme of glycolysis and pyruvate dehydrogenase, the enzymes that connects glycolysis and TCA cycle. The activity of TCA cycle enzymes; citrate synthase, aconitase, isocitrate dehydrogenase and fumarase were also altered following MPTP intoxication. Furthermore, acute MPTP administration led to drastic reduction in dopamine levels in striatum of C57BL/6 as compared to BALB/c mice. Behavioral tests such as open field, narrow beam walk and footprint analysis revealed severe impairment in locomotor activity in C57BL/6 mice. These results clearly demonstrate that C57BL/6 strain is more vulnerable to MPTP-induced mitochondrial dysfunctions, perturbations in energy metabolism and motor defects as compared to BALB/c strain. Thus, the findings suggest that the dose and strain of mice need to be considered for pre-clinical studies using MPTP-induced model of Parkinson's disease.

Metabolic Changes in Mouse Plasma after Acute Diquat Poisoning by UPLC-MS/MS

Introduction: Diquat is a fast-acting contact herbicide and plant dehydrating agent. The oral lethal dose 50 (LD50) of diquat in mice is about 125 mg/kg. The purpose of this study is to research the metabolomics in mouse plasma after acute diquat poisoning. Method: These mice were divided into two groups (the control group and acute diquat poisoning group). The control group was given normal saline by gavage. The acute diquat poisoning group was given 50 mg/kg diquat. UPLC-MS/MS was used to determinate the small molecule organic acid in mouse plasma. Results: Compare to the control group, the L-lysine, Adenine, L-Alanine, L-Valine, Lactic acid, Inosine, Adenosine, LTryptophan, L-Tyrosine, L-Arginine, L-Phenylalanine, L-Methionine, Citric acid, Fructose, L-Glutamine, Malic acid, LAspartic acid and Pyruvic acid increased in the acute diquat poisoning group (p<0.05); while the L-Histidine decreased (p<0.05). Conclusion: The results of metabolites increased or decreased, indicating that acute diquat poisoning induced amino acid metabolism and energy metabolism perturbations in mice.

Untargeted metabolomics analysis by gas chromatography/time-of-flight mass spectrometry of human serum from methamphetamine abusers.

Methamphetamine (METH) abuse has become a global public health problem. However, the potential mechanisms involving METH-induced metabolic disorders have thus far remained poorly understood. Metabolomics can provide a clue for the cause of apparent changes and consequently be used to investigate the METH-induced dysregulation of metabolite expression and the mechanism of metabolic disorder mechanism. This laboratory investigation included 80 METH abusers and 80 healthy people. The serum metabolites were detected and analysed by gas chromatography/time-of-flight mass spectrometry. Raw data were processed with the software MS DIAL, which includes deconvolution, peak alignment and compound identification. The data matrix was processed by univariate and multivariate analyses for significant metabolite screening with the criteria of variable importance in projection values > 1, fold change > 1.5 and the t test (p value < 0.05). Significant differences in 16 metabolites (deoxycholic acid, cholic acid, hydroxylamine, etc.) in serum were found between the METH abuse group and the control group. Energy metabolic pathways and several amino acid metabolic pathways (alanine, aspartic acid and glutamate metabolism and tryptophan metabolism) were primarily involved. Further analysis indicated that the area under the receiver operating characteristic curve (AUC) was 0.998 for these 16 metabolites. Among the metabolites, three carbohydrates (d-ribose, cellobiose and maltotriose) had an AUC of 0.975, which were determined as potential markers of abuse. We observed metabolic disturbances in METH abusers, particularly perturbation in energy metabolism and amino acid metabolism, which can provide new insights into the search for biomarkers and the mechanisms underlying the adverse effects of METH on human health.

Muscle Function Differences between Patients with Bulbar and Spinal Onset Amyotrophic Lateral Sclerosis. Does It Depend on Peripheral Glucose?

Background: One of the pathogenic mechanisms of ALS disease is perturbed energy metabolism particularly glucose metabolism. Given the substantial difference in the severity and the prognosis of the disease, depending on whether it has a bulbar or spinal onset, the aim of the study was to determine metabolic differences between both types of ALS, as well as the possible relationship with muscle function. Materials and Methods: A descriptive, analytical, quantitative, and transversal study was carried out in hospitals and Primary Care centers in the region of Valencia, Spain. Fasting glucose and alkaline phosphatase (AP) levels in venous blood, muscle percentage, fat percentage, muscle strength (MRC scale), and functional capacity (Barthel Index) were measured in 31 patients diagnosed with ALS (20 with spinal onset ALS and 11 with bulbar onset ALS). A healthy control of 29 people was included. Results: No significant differences were observed in blood AP and glucose levels between spinal onset and bulbar onset ALS patients. However, a significant positive correlation was observed between the mean values of both substances in patients with spinal onset ALS. Moreover, a lower percentage of muscle mass and a higher percentage of fat mass were also seen in spinal ALS patients, who also presented lower muscle strength and lower functional capacity. Conclusion: The results of this study seem to point to a possible difference in the peripheral use of glucose between patients with bulbar onset ALS and spinal onset ALS, who appear to have possible insulin resistance. These metabolic differences could explain the lower muscle percentage and lower muscular function in spinal onset ALS patients, although further studies are required.