Imbalance In Energy Metabolism Research Articles

Infection and Immunometabolism in the Central Nervous System: A Possible Mechanistic Link Between Metabolic Imbalance and Dementia.

Metabolic syndromes are frequently associated with dementia, suggesting that the dysregulation of energy metabolism can increase the risk of neurodegeneration and cognitive impairment. In addition, growing evidence suggests the link between infections and brain disorders, including Alzheimer’s disease. The immune system and energy metabolism are in an intricate relationship. Infection triggers immune responses, which are accompanied by imbalance in cellular and organismal energy metabolism, while metabolic disorders can lead to immune dysregulation and higher infection susceptibility. In the brain, the activities of brain-resident immune cells, including microglia, are associated with their metabolic signatures, which may be affected by central nervous system (CNS) infection. Conversely, metabolic dysregulation can compromise innate immunity in the brain, leading to enhanced CNS infection susceptibility. Thus, infection and metabolic imbalance can be intertwined to each other in the etiology of brain disorders, including dementia. Insulin and leptin play pivotal roles in the regulation of immunometabolism in the CNS and periphery, and dysfunction of these signaling pathways are associated with cognitive impairment. Meanwhile, infectious complications are often comorbid with diabetes and obesity, which are characterized by insulin resistance and leptin signaling deficiency. Examples include human immunodeficiency virus (HIV) infection and periodontal disease caused by an oral pathogen Porphyromonas gingivalis. This review explores potential interactions between infectious agents and insulin and leptin signaling pathways, and discuss possible mechanisms underlying the relationship between infection, metabolic dysregulation, and brain disorders, particularly focusing on the roles of insulin and leptin.

Результаты исследования содержания 2,3-дифосфоглицерата в эритроцитах пациентов с анемией злокачественного новообразования при раке мочеполовых органов

Every year, more than 6 million people are diagnosed with and more than 4 million people die from cancer all over the world, which is approximately 10% of the total mortality. The incidence of cancer in Ukraine shows a gradual increase, with the number of newly diagnosed patients 304-308 per 100 thousand people. Bladder cancer ranks second in the world among oncological diseases of the urinary system after prostate cancer. In the later stages of diseases, their course may be associated with malignant neoplasm anemia. The purpose of the study was to study the content of 2,3-diphosphoglycerate in erythrocytes of peripheral venous blood of patients with malignant neoplasm anemia with urothelial bladder cancer and prostate cancer, depending on the severity of anemia; to evaluate the possible diagnostic and prognostic value of the studied indicator. Materials and methods. 96 patients (64 men and 32 women) with urothelial bladder cancer were examined. There were 39 patients (28 men and 11 women) among them, the course of their underlying disease was not accompanied by the presence of anemia (first (I) observation group) and 57 patients (36 men and 21 women), the course of their underlying disease was aggravated by malignant neoplasm anemia (second (II) observation group). Also, 48 men with prostate cancer whose course of the disease was not aggravated by malignant neoplasm anemia (19 men) (third (III) observation group) and 29 men (fourth (IV) observation group) were diagnosed with malignant neoplasm anemia. The age of the patients under the survey was from 22 to 79 years old. All patients were examined after verifying the diagnosis and before starting any treatment. The content of 2,3-diphosphoglycerate in erythrocytes of peripheral venous blood was determined by the method of I. S. Luganova, M. N. Blinov (1975). Results and discussion. The content of 2,3-diphosphoglycerate in peripheral venous erythrocytes of patients with malignant neoplasm anemia due to urothelial bladder cancer and prostate cancer has been studied. It was found that malignant neoplasm anemia in patients with urothelial bladder cancer and prostate cancer is associated with an increase in the studied indicator (p<0.05). The article discusses the possible causes and pathogenetic mechanisms of the identified changes. Conclusion. Patients with urothelial bladder cancer and prostate cancer have an imbalance of energy metabolism that occurs in erythrocytes. This process is manifested by an increase in the amount of 2,3-diphosphoglycerate

Integrated metabolomics and proteomics analysis reveals energy metabolism disorders in the livers of sleep-deprived mice

Sleep deprivation (SD) has been linked to impaired mental and physical health, obesity, and various diseases. However, the molecular mechanism underlying the effects of SD in the liver is still unclear. To investigate the metabolome and proteome alterations in the liver, an in vivo model of SD was established based on automated random motion platform techniques by applying a strategy of 10 consecutive days of 20 h of sleep deprivation +4 h of resting. The liver's altered metabolites and proteins were detected by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and data analyses were performed with MetaboAnalyst 5.0. This study found 15 differential metabolites, including 12 upregulated- metabolites and 3 downregulated- metabolites. A total of 493 proteins were differentially regulated, including 377 upregulated- proteins and 116 downregulated- proteins. The glutathione metabolism, fructose and mannose metabolism, and pyruvate metabolism pathways had significant effects on the sleep-deprived mouse livers. These three active pathways cause energy metabolism disorder and may induce obesity. In conclusion, this study demonstrates that SD could change the metabolism of glucose, and specific fatty acids, amino acids, and critical enzymes in the liver, providing a reference for the health effects of insufficient sleep. Significance statementSo far, little is known about the changes in metabolites and proteins in the liver of individuals who suffer from SD. Metabolites and proteins in serum, urine and hypothalamus do not entirely reflect the effects of sleep deprivation on the whole body. In addition, many SD-induced models used the multiplatform water environment method, which causes mice to fall into the water frequently. Under this condition, the physical exertion of mice is extremely high, and it is not suitable for long-term sleep deprivation. The SD induction process has caused some influence on the model. Finally, few studies have elucidated the imbalance of energy metabolism caused by SD to induce obesity from the molecular mechanism. This study used a rotary table deprivation apparatus to trigger SD. This method will not cause excessive consumption and stimulation of mice. Furthermore, this study analyzed the metabolic and proteomic changes in the liver and enriched the range and means of metabolic and proteomic changes in sleep deprived mice. Finally, this research provides reference for elucidating the molecular mechanism of sleep deprivation causing energy metabolism disorders in the liver of mice.

Lung Surfactant Decreases Biochemical Alterations and Oxidative Stress Induced by a Sub-Toxic Concentration of Carbon Nanoparticles in Alveolar Epithelial and Microglial Cells.

Carbon-based nanomaterials are nowadays attracting lots of attention, in particular in the biomedical field, where they find a wide spectrum of applications, including, just to name a few, the drug delivery to specific tumor cells and the improvement of non-invasive imaging methods. Nanoparticles inhaled during breathing accumulate in the lung alveoli, where they interact and are covered with lung surfactants. We recently demonstrated that an apparently non-toxic concentration of engineered carbon nanodiamonds (ECNs) is able to induce oxidative/nitrosative stress, imbalance of energy metabolism, and mitochondrial dysfunction in microglial and alveolar basal epithelial cells. Therefore, the complete understanding of their “real” biosafety, along with their possible combination with other molecules mimicking the in vivo milieu, possibly allowing the modulation of their side effects becomes of utmost importance. Based on the above, the focus of the present work was to investigate whether the cellular alterations induced by an apparently non-toxic concentration of ECNs could be counteracted by their incorporation into a synthetic lung surfactant (DPPC:POPG in 7:3 molar ratio). By using two different cell lines (alveolar (A549) and microglial (BV-2)), we were able to show that the presence of lung surfactant decreased the production of ECNs-induced nitric oxide, total reactive oxygen species, and malondialdehyde, as well as counteracted reduced glutathione depletion (A549 cells only), ameliorated cell energy status (ATP and total pool of nicotinic coenzymes), and improved mitochondrial phosphorylating capacity. Overall, our results on alveolar basal epithelial and microglial cell lines clearly depict the benefits coming from the incorporation of carbon nanoparticles into a lung surfactant (mimicking its in vivo lipid composition), creating the basis for the investigation of this combination in vivo.

Research Progress of Sirtuin4 in Cancer.

Sirtuins (SIRTs) are members of the silent information regulator-2 family. They are a conserved family of nicotinamide adenine dinucleotide-dependent protein lysine deacylases. SIRTS are involved in intricate cellular processes. There are seven subtypes of SIRTs (1–7) in mammals. SIRT4 is located mainly in mitochondria and has various catalytic activities. These enzyme activities give it a diverse range of important biologic functions, such as energy metabolism, oxidative stress, and aging. Cancer is characterized as reprogramming of energy metabolism and redox imbalance, and SIRT4 can affect tumorigenesis. Here, we review the structure, localization, and enzyme activity of SIRT4 and its role in various neoplasms.

Evaluating bloom potential of the green-tide forming alga Ulva ohnoi under ocean acidification and warming

The occurrence of green-tides, whose bloom potential may be increased by various human activities and biogeochemical process, results in enormous economic losses and ecosystem collapse. In this study, we investigated the ecophysiology of the subtropical green-tide forming alga, Ulva ohnoi complex (hereafter: U. ohnoi), under simulated future ocean conditions in order to predict its bloom potential using photosynthesis and growth measurements, and stable isotope analyses. Our mesocosm system included four experimental conditions that simulated the individual and combined effects of elevated CO2 and temperature, namely control (450 μatm CO2 & 20 °C), acidification (900 μatm CO2 & 20 °C), warming (450 μatm CO2 & 25 °C), and greenhouse (900 μatm CO2 & 25 °C). Photosynthetic electron transport rates (rETR) increased significantly under acidification conditions, but net photosynthesis and growth were not affected. In contrast, rETR, net photosynthesis, and growth all decreased significantly under elevated temperature conditions (i.e. both warming and greenhouse). These results represent the imbalance of energy metabolism between electron transport and O2 production that may be expected under ocean acidification conditions. This imbalance appears to be related to carbon and nitrogen assimilation by U. ohnoi. In particular, 13C and 15N discrimination data suggest U. ohnoi prefers CO2 and NH4+ over HCO3− and NO3− as sources of carbon and nitrogen, respectively, and this results in increased N content in the thallus under ocean acidification conditions. Together, our results suggest a trade-off in which the bloom potential of U. ohnoi could increase under ocean acidification due to greater N accumulation and through the saving of energy during carbon and nitrogen metabolism, but that elevated temperatures could decrease U. ohnoi's bloom potential through a decrease in photosynthesis and growth.

Albumin–bilirubin score as a useful predictor of energy malnutrition in patients with hepatocellular carcinoma

Chronic liver diseases, including hepatocellular carcinoma (HCC), lead to an imbalance in energy metabolism. The non-protein respiratory quotient (npRQ), which estimates energy malnutrition, can be evaluated using an indirect calorimeter; however, npRQ measurement is limited in routine work. This study aimed to investigate the relationship between the albumin-bilirubin (ALBI) score and npRQ in patients with HCC. We conducted a retrospective cohort study in 109 patients with HCC who underwent indirect calorimetry and then compared the npRQ with various clinical parameters, including liver function and tumor factors. The median npRQ was 0.82. A significant negative correlation was found between the npRQ and the ALBI score (r=-0.35, p<0.001). The median npRQ in modified ALBI (mALBI) grades 1, 2a, 2b, and 3 were 0.84, 0.86, 0.81, and 0.79, respectively (grade 2a vs. 2b, p=0.002). Factors associated with npRQ <0.85, which is reported to be the best cutoff value for energy malnutrition, were analyzed. On multivariate analysis, the ALBI score (cutoff value,-2.18) was the only significant independent factor (odds ratio, 7.65; p<0.001). The proportion of HCC patients with npRQ <0.85 significantly increased among patients with an ALBI score ≥-2.18 (45/51, 88.2%) compared with those with an ALBI score <-2.18 (29/58, 50%) (p<0.001). The ALBI score might be a useful predictor for energy malnutrition in patients with HCC. In addition, most HCC patients with mALBI grade 2b or 3 can be considered to have energy malnutrition.

Choroby mitochondrialne — co powinien wiedzieć kardiolog?

Mitochondrial diseases (MD) are a heterogeneous group of rare genetically determined disorders, characterized by mitochondrial respiratory chain defect and subsequent energy metabolism imbalance. Due to almost exclusive aerobic metabolism of the heart, cardiac involvement in MD is common and can be accompanied by other manifestations of the multi-organ involvement, but may be also the first or the sole clinical manifestation of MD. All tissues of the heart may be affected but the most frequently affected tissue is the myocardium. The most frequent cardiac manifestation found in MD are cardiomyopathies, but cardiac abnormalities may be varied and include arrhythmias, heart failure, pulmonary hypertension, dilation of the aortic root and pericardial effusion. Given the progressive nature of cardiac involvement in MD associated with poor prognosis and increased mortality and the fact that it can remain asymptomatic until an advanced stage is reached, often due to limited mobility of patients, cardiac screening should be a part of standard management of MD patients. All patients with cardiac involvement should be reviewed by a cardiologist with an experience and understanding of MD.

Aberrant energy metabolism and redox balance in seizure onset zones of epileptic patients

Epilepsy is a disorder that affects around 1% of the population. Approximately one third of patients do not respond to anti-convulsant drugs treatment. To understand the underlying biological processes involved in drug resistant epilepsy (DRE), a combination of proteomics strategies was used to compare molecular differences and enzymatic activities in tissue implicated in seizure onset to tissue with no abnormal activity within patients. Label free quantitation identified 17 proteins with altered abundance in the seizure onset zone as compared to tissue with normal activity. Assessment of oxidative protein damage by protein carbonylation identified additional 11 proteins with potentially altered function in the seizure onset zone. Pathway analysis revealed that most of the affected proteins are involved in energy metabolism and redox balance. Further, enzymatic assays showed significantly decreased activity of transketolase indicating a disruption of the Pentose Phosphate Pathway and diversion of intermediates into purine metabolic pathway, resulting in the generation of the potentially pro-convulsant metabolites. Altogether, these findings suggest that imbalance in energy metabolism and redox balance, pathways critical to proper neuronal function, play important roles in neuronal network hyperexcitability and can be used as a primary target for potential therapeutic strategies to combat DRE. SignificanceEpileptic seizures are some of the most difficult to treat neurological disorders. Up to 40% of patients with epilepsy are resistant to first- and second-line anticonvulsant therapy, a condition that has been classified as refractory epilepsy. One potential therapy for this patient population is the ketogenic diet (KD), which has been proven effective against multiple refractory seizure types However, compliance with the KD is extremely difficult, and carries severe risks, including ketoacidosis, renal failure, and dangerous electrolyte imbalances. Therefore, identification of pathways disruptions or shortages can potentially uncover cellular targets for anticonvulsants, leading to a personalized treatment approach depending on a patient's individual metabolic signature.

Effects of exposure to ambient fine particulate matter on the heart of diet-induced obesity mouse model

Exposure to fine particulate matter (PM2.5) is associated with decreased cardiac function, especially in high risk populations such as obese ones. In this study, impacts of PM2.5 exposure on cardiac function were investigated by using the diet-induced obesity mice model. Mice were fed with normal diet or high-fat diet (HFD) for four weeks and then exposed to phosphate-buffered solution or Taiyuan winter PM2.5 (0.25 mg/kg body/day) through intratracheal instillation for another four weeks. Among physiological indices recorded, heart rate and blood pressure were increased after PM2.5 exposure in the heart of the obese mice. Metabolomics and lipidomics were applied to explore molecular alterations in response to the co-treatment of PM2.5 and HFD. Our results demonstrated both direct impacts on cardiac function and indirect effects resulted from the injury of other organs. Inflammation of lung and hypothalamus may be responsible for the elevation of phenylalanine metabolism in serum and its downstream products: epinephrine and norepinephrine, the catecholamines involves in regulating cardiac system. In intracardiac system, the co-treatment led to imbalance of energy metabolism, in addition to oxidative stress and inflammation. In contrast to the upregulation of glucose and fatty acids uptake and CoA synthesis, levels of ATP, acetyl-CoA and the intermediates in glycolysis pathway decreased in the heart. The results indicated that energy metabolism disorder was possibly one of the important contributing factors to the more severe adverse effects of the combined treatment of HFD and PM2.5.

Research progress of mitochondria as target of traditional Chinese medicines in treatment of heart failure

As the final destination of various cardiovascular abnormalities, heart failure is one of the diseases with the highest morbidity and mortality in the world. Due to its complicated pathogenesis, people urgently need to find new targets and effective treatment. Imbalance in myocardial energy metabolism, an important molecular biological basis for heart failure, affects the contractile and diastolic functions of the heart. As the main source of energy synthesis in cardiomyocytes and an important participant in various signaling pathways, mitochondria plays an indispensable role in the process of cell survival and death and has been considered as a critical target for the treatment of heart failure. Traditional Chinese medicine has a great effect on the treatment of heart failure through multi-components, multi-targets, and multi-channels. In recent years, more and more researches regard mitochondria as the target of traditional Chinese medicine in the treatment of heart failure, and have achieved significant results in improving mitochondrial function, increasing energy metabolism and energy supplement for cardiomyocytes, and resisting against oxidative stress. In this article, researches on the regulation of mitochondria in the treatment of heart failure by traditional Chinese medicine are reviewed from four aspects: mitochondrial biogenesis; mitochondrial electron transport chain and reactive oxygen species(ROS) production; metabolic substrates and metabolic enzymes; and calcium ion transport in the mitochondria. It provides a basis for further research and clinical application in the future.

Systems pharmacology reveals the mechanism of activity of Physalis alkekengi L. var. franchetii against lipopolysaccharide-induced acute lung injury.

Acute lung injury (ALI) is an important cause of mortality of patients with sepsis, shock, trauma, pneumonia, multiple transfusions and pancreatitis. Physalis alkekengi L. var. franchetii (Mast.) Makino (PAF) has been extensively used in Chinese folk medicine because of a good therapeutic effect in respiratory diseases. Here, an integrated approach combining network pharmacology, proton nuclear magnetic resonance‐based metabolomics, histopathological analysis and biochemical assays was used to elucidate the mechanism of PAF against ALI induced by lipopolysaccharide (LPS) in a mouse model. We found that the compounds present in PAF interact with 32 targets to effectively improve the damage in the lung undergoing ALI. We predicted the putative signalling pathway involved by using the network pharmacology and then used the orthogonal signal correction partial least‐squares discriminant analysis to analyse the disturbances in the serum metabolome in mouse. We also used ELISA, RT‐qPCR, Western blotting, immunohistochemistry and TUNEL assay to confirm the potential signalling pathways involved. We found that PAF reduced the release of cytokines, such as TNF‐α, and the accumulation of oxidation products; decreased the levels of NF‐κB, p‐p38, ERK, JNK, p53, caspase‐3 and COX‐2; and enhanced the translocation of Nrf2 from the cytoplasm to the nucleus. Collectively, PAF significantly reduced oxidative stress injury and inflammation, at the same time correcting the energy metabolism imbalance caused by ALI, increasing the amount of antioxidant‐related metabolites and reducing the apoptosis of lung cells. These observations suggest that PAF may be an effective candidate preparation alleviating ALI.

Systems pharmacology reveals the mechanism of activity of Ge-Gen-Qin-Lian decoction against LPS-induced acute lung injury: A novel strategy for exploring active components and effective mechanism of TCM formulae

Acute lung injury (ALI), a severe and life-threatening inflammation of the lung, with high morbidity and mortality, underscoring the urgent need for novel treatments. Ge-Gen-Qin-Lian decoction (GQD), a classic Chinese herbal formula, has been widely used to treat intestine-related diseases in the clinic for centuries. In recent years, a growing number of studies have found that GQD has a favorable anti-inflammatory effect. With the further study on the viscera microbiota, the link between the lungs and the gut—the gut-lung axis has been established. Based on the theory of the gut-lung axis, we used systems pharmacology to explore the effects and mechanisms of GQD treatment in ALI. Hypothesizing that GQD inhibits ALI progression, we used the experimental model of lipopolysaccharide (LPS)-induced ALI in Balb/c mice to evaluate the therapeutic potential of GQD. Our results showed that GQD exerted protective effects against LPS-induced ALI by reducing pulmonary edema and microvascular permeability. Meanwhile, GQD can downregulate the expression of LPS-induced TNF-α, IL-1β, and IL-6 in lung tissue, bronchoalveolar lavage fluid (BLAF), and serum. To further understand the molecular mechanism of GQD in the treatment of ALI, we used the network pharmacology to predict the disease targets of the active components of GQD. Lung tissue and serum samples of the mice were separately analyzed by transcriptomics and metabolomics. KEGG pathway analysis of network pharmacology and transcriptomics indicated that PI3K/Akt signaling pathway was significantly enriched, suggesting that it may be the main regulatory pathway for GQD treatment of ALI. By immunohistochemical analysis and apoptosis detection, it was verified that GQD can inhibit ALI apoptosis through PI3K/Akt signaling pathway. Then, we used the PI3K inhibitor LY294002 to block the PI3K/Akt signaling pathway, and reversely verified that the PI3K/Akt signaling pathway is the main pathway of GQD anti-ALI. In addition, differential metabolites in mice serum samples indicate that GQD can inhibit the inflammatory process of ALI by reversing the imbalance of energy metabolism. Our study showed that, GQD did have a better therapeutic effect on ALI, and initially elucidated its molecular mechanism. Thus, GQD could be exploited to develop novel therapeutics for ALI. Moreover, our study also provides a novel strategy to explore active components and effective mechanism of TCM formula combined with TCM theory to treat ALI.

Beta-Aminoisobutyric Acid Inhibits Hypothalamic Inflammation by Reversing Microglia Activation.

Beta-aminoisobutyric acid (BAIBA), a natural thymine catabolite, is involved in the beneficial effects of exercise on metabolic disorders. In particular, it has been reported to reverse the inflammatory processes observed in the peripheral organs of animal models of obesity. Therefore, this study aimed to investigate whether BAIBA improves hypothalamic inflammation, which is also tightly coupled with the development of obesity. We observed that treatment with BAIBA effectively reversed palmitic acid-induced hypothalamic inflammation and microglial activation in vivo. Consistent with these findings, we confirmed that BAIBA reversed body weight gain and increased adiposity observed in mice fed with a high-fat diet. Collectively, the current findings evidence the beneficial impacts of BAIBA on the imbalance of energy metabolism linked to hypothalamic inflammation.

Pyruvate Dehydrogenase and Tricarboxylic Acid Cycle Enzymes Are Sensitive Targets of Traumatic Brain Injury Induced Metabolic Derangement.

Using a closed-head impact acceleration model of mild or severe traumatic brain injury (mTBI or sTBI, respectively) in rats, we evaluated the effects of graded head impacts on the gene and protein expressions of pyruvate dehydrogenase (PDH), as well as major enzymes of mitochondrial tricarboxylic acid cycle (TCA). TBI was induced in anaesthetized rats by dropping 450 g from 1 (mTBI) or 2 m height (sTBI). After 6 h, 12 h, 24 h, 48 h, and 120 h gene expressions of enzymes and subunits of PDH. PDH kinases and phosphatases (PDK1-4 and PDP1-2, respectively), citrate synthase (CS), isocitrate dehydrogenase (IDH), oxoglutarate dehydrogenase (OGDH), succinate dehydrogenase (SDH), succinyl-CoA synthase (SUCLG), and malate dehydrogenase (MDH) were determined in whole brain extracts (n = 6 rats at each time for both TBI levels). In the same samples, the high performance liquid chromatographic (HPLC) determination of acetyl-coenzyme A (acetyl-CoA) and free coenzyme A (CoA-SH) was performed. Sham-operated animals (n = 6) were used as controls. After mTBI, the results indicated a general transient decrease, followed by significant increases, in PDH and TCA gene expressions. Conversely, permanent PDH and TCA downregulation occurred following sTBI. The inhibitory conditions of PDH (caused by PDP1-2 downregulations and PDK1-4 overexpression) and SDH appeared to operate only after sTBI. This produced almost no change in acetyl-CoA and free CoA-SH following mTBI and a remarkable depletion of both compounds after sTBI. These results again demonstrated temporary or steady mitochondrial malfunctioning, causing minimal or profound modifications to energy-related metabolites, following mTBI or sTBI, respectively. Additionally, PDH and SDH appeared to be highly sensitive to traumatic insults and are deeply involved in mitochondrial-related energy metabolism imbalance.

Chronic oleoylethanolamide treatment attenuates diabetes-induced mice encephalopathy by triggering peroxisome proliferator-activated receptor alpha in the hippocampus

Brain is a site of diabetic end-organ damage. Diabetes-associated cognitive dysfunction, referred as "diabetic encephalopathy" (DE) has been coined for the patients with type 2 diabetes mellitus showing decline in their cognitive function, especially weak episodic memory, cognitive inflexibility and poor psychomotor performance leading towards Alzheimer's disease. Current evidence supported that aberrant synapses, energy metabolism imbalance, advanced glycation end products (AGEs) accumulation and Tau hyperphosphorylation are associated with cognition deficits induced by diabetes. Oleoylethanolamide (OEA), an endogenous peroxisome proliferator-activated receptor alpha (PPARα) agonist, has anti-hyperlipidemia, anti-inflammatory and neuroprotective activities. However, the effect of OEA on DE is unknown. Therefore, we tested its influence against cognitive dysfunction in high fat diet and streptozotocin (HFD + STZ)-induced diabetic C57BL/6J and PPARα−-/- mice using Morris water maze (MWM) test. Neuron staining, dementia markers and neuroplasticity in the hippocampus were assessed to evaluate the neuropathological changes. The results showed that chronic OEA treatment significantly lowered hyperglycemia, recovered cognitive performance, reduced dementia markers, and inhibited hippocampal neuron loss and neuroplasticity impairments in diabetic mice. In contrast, the changes in MWM performance and neuron loss were not observed in PPARα knockout mice via OEA administration. These results indicated that OEA may provide a potential alternative therapeutic for DE by activating PPARα signaling.

The Antioxidative Action of ZTP by Increasing Nrf2/ARE Signal Pathway.

So far, more than 25,000 brain diseases have been shown to be related to oxidative stress. Excessive free radicals and reactive oxygen species (ROS) can attack cells resulting in dysfunctional proteins, lipids, and nucleic acid, finally leading to imbalance of energy metabolism, cell death, gene mutation, and immune reaction. Therefore oxidative stress plays an important role in neuronal diseases. As a traditional Chinese medicine, Zhengtian Pill (ZTP) was reported to have the ability to reduce the blood viscosity of migraine model rats, with increased beta-endorphin, serotonin, adrenaline, and dopamine in brain tissue. Moreover ZTP can effectively accelerate blood circulation and attenuate blood coagulation. However, the molecular mechanisms of ZPT are still unclear. Through the behavioral test we found that ZTP can significantly improve depression-like behavior induced by LPS when rat was treated with ZTP (L 0.17 g/kg, M 0.34 g/kg, and H 0.7 g/kg) intraperitoneal injection once a day for 30 consecutive days. And ZTP can resist oxidative stress (>72 h) for a longer time. And ZTP can promote the levels of ATP and SOD and reduce the levels of ROS and MDA in the brain. At the same time, ZTP can have antioxidant stress through increasing the expression level of Nrf2/HO-1/P38. These results show that ZTP may be a potential antioxidant stress drug for variety of diseases associated with oxidative stress injury.

Aspirin eugenol ester attenuates oxidative injury of vascular endothelial cells by regulating NOS and Nrf2 signalling pathways.

Aspirin eugenol ester (AEE) is a new drug compound synthesized by combining aspirin with eugenol. It was reported to possess anti-thrombotic, anti-atherosclerotic, and anti-oxidative effects. However, its molecular mechanism against oxidative injury is unclear. This study investigated how AEE affected the oxidative injury of vascular endothelial cells in vivo and in vitro. A hamster model of atherosclerosis induced by a high fat diet (HFD) and an in vitro model of oxidative stress, H2 O2 -induced apoptosis of HUVECs, were used to investigate the anti-oxidative effects of AEE. AEE significantly reduced the stimulatory effect of HFD on malondialdehyde, the inhibitory effect of HFD on SOD activity and GSH/GSSG ratio, and the overexpression of inducible NOS (iNOS) in the aorta. In vitro, incubation of HUVECs with H2 O2 led their apoptosis, dysfunctions of the NO systems (including increased iNOS activity, decreased endothelial NOS activity, and increased production of NO), an imbalance in calcium homeostasis and energy metabolism with an increase in intracellular free calcium and decrease in ATP, and a down-regulation of Nrf2. In contrast, in the HUVECs pretreated with 1 μM AEE for 24hr, the above adverse effects induced by H2 O2 were significantly ameliorated. Moreover, the decrease in NO production and activity of iNOS induced by AEE was significantly attenuated in Nrf2-inhibited HUVECs. AEE protects vascular endothelial cells from oxidative injury by regulating NOS and Nrf2 signalling pathways. This suggests that AEE is a novel potential agent for the prevention of atherosclerosis.

Metabolic Biomarkers in Nematode C. elegans During Aging.

Changes in energy metabolism occur not only in diseases such as cancer but also in the normal development and aging processes of various organisms. These metabolic changes result to lead to imbalances in energy metabolism related to cellular and tissue homeostasis. In the model organism C. elegans, which is used to study aging, an imbalance in age-related energy metabolism exists between mitochondrial oxidative phosphorylation and aerobic glycolysis. Cellular lactate and pyruvate are key intermediates in intracellular energy metabolic pathways and can indicate age-related imbalances in energy metabolism. Thus, the cellular lactate/pyruvate ratio can be monitored as a biomarker during aging. Moreover, recent studies have proposed a candidate novel biomarker for aging and age-related declines in the nematode C. elegans.

Small-Scale Colorimetric Assays of Intracellular Lactate and Pyruvate in the Nematode Caenorhabditis elegans.

Lactate and pyruvate are key intermediates of intracellular energy metabolic pathways. Monitoring the lactate/pyruvate ratio in cells helps to determine whether there is an imbalance in age-related energy metabolism between mitochondrial oxidative phosphorylation and aerobic glycolysis. Here, we show the utilization of commercial colorimetric assay kits for lactate and pyruvate in the model organism C. elegans. Recently, the sensitivity and accuracy of the colorimetric/fluorimetric assay kits have been improved greatly by the research and development conducted by reagent manufacturers. The improved reagents have enabled the use of small-scale assays with a 96-well plate in C. elegans. In general, a fluorimetric assay is superior in sensitivity to a colorimetric assay; however, the colorimetric approach is more suitable for the use in common laboratories. Another important issue in these assays for quantitative determination is protein precipitation of homogenized C. elegans samples. In our protein precipitation method, common precipitants (e.g., trichloroacetic acid, perchloric acid and metaphosphoric acid) are used for sample preparation. A protein-free assay sample is prepared by directly adding cold precipitant (final concentration of 5%) during homogenization.