Cycle Activity Research Articles

Oxidative stress in animals exposed to cypermethrin: mechanisms of development and possible risks

The purpose of the study is to establish the mechanisms of development of oxidative stress during long-term low-dose exposure to cypermethrin on the animal organism and to substantiate possible risks. The work was carried out using Wistar rats, which were intragastrically injected daily with cypermethrin at a dose of 1/1000 LD50 for 60 and 120 days. At the same time, control animals received an appropriate volume of saline solution inside. When removing animals from the experiment, blood was taken to determine the number of red blood cells, the concentration of hemoglobin, glucose, lactic and uric acids, and total bilirubin. In the study of erythrocytes and liver, biochemical parameters characterizing carbohydrate and purine metabolism, processes of xenobiotics biotransformation, pro- and antioxidant processes were determined. Long-term lowdose exposure to cypermethrin for 60 days causes hematotoxic effects in animals, enhancement of xenobiotic biotransformation processes, and slight compensatory restructuring of metabolic processes in the liver. Exposure to 1/1000 LD50 of cypermethrin for 120 days, in addition to the above effects, causes the development of acidosis, enhances pro-oxidant processes, and suppresses the function of the antioxidant defense system and the pentose cycle. The decrease in the activity of the liver antioxidant system is due to glutathione deficiency due to the activation of xenobiotic biotransformation systems and suppression of the activity of glutathione reductase and glucose-6- phosphate dehydrogenase, which ultimately leads to the development of oxidative stress. Long-term exposure of animals to low doses of cypermethrin causes hemolysis of erythrocytes, lactic acidosis, activation of prooxidant systems, and inhibition of the antioxidant defense system. Deficiency of carbohydrates and suppression of the activity of the pentose cycle indicate a decrease in the functional activity of the liver and an increased risk of immunosuppression.

Untargeted Metabolomics Reveals Alterations of Rhythmic Pulmonary Metabolism in IPF.

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive condition characterized by the impairment of alveolar epithelial cells. Despite continued research efforts, the effective therapeutic medication is still absent due to an incomplete understanding of the underlying etiology. It has been shown that rhythmic alterations are of significant importance in the pathophysiology of IPF. However, a comprehensive understanding of how metabolite level changes with circadian rhythms in individuals with IPF is lacking. Here, we constructed an extensive metabolite database by utilizing an unbiased reference system culturing with 13C or 15N labeled nutrients. Using LC-MS analysis via ESI and APCI ion sources, 1300 potential water-soluble metabolites were characterized and applied to evaluate the metabolic changes with rhythm in the lung from both wild-type mice and mice with IPF. The metabolites, such as glycerophospholipids and amino acids, in WT mice exhibited notable rhythmic oscillations. The concentrations of phospholipids reached the highest during the fast state, while those of amino acids reached their peak during fed state. Similar diurnal variations in the metabolite rhythm of amino acids and phospholipids were also observed in IPF mice. Although the rhythmic oscillation of metabolites in the urea cycle remained unchanged, there was a significant up-regulation in their levels in the lungs of IPF mice. 15N-ammonia in vivo isotope tracing further showed an increase in urea cycle activity in the lungs of mice with IPF, which may compensate for the reduced efficiency of the hepatic urea cycle. In sum, our metabolomics database and method provide evidence of the periodic changes in lung metabolites, thereby offering valuable insights to advance our understanding of metabolic reprogramming in the context of IPF.

Effects of unpredictable chronic mild stress on the cellular redox state and mitochondrial energy homeostasis in rat adipose tissue: A comprehensive metabolic study.

Unpredictable chronic mild stress (UCMS) leads to variable metabolic effects. Oxidative stress (OS) of adipose tissue (AT) and mitochondrial energy homeostasis is little investigated. This work studied the effects of UCMS on OS and the antioxidant/redox status in AT and mitochondrial energy homeostasis in rats. Twenty-four male Wistar rats (180-220 g) were divided into two equal groups; the normal control (NC) group and the UCMS group which were exposed to various stresses for 28 days. An indirect calorimetry machine was used to measure volumes of respiratory gases (VO2 & VCO2 ), total energy expenditure (TEE), and food intake (FI). The AT depots were collected, weighed, and used for measuring activities and gene expression of key antioxidant enzymes (GPx1, SOD, CAT, GR, GCL, and GS), OS marker levels including superoxide anion (SA), peroxynitrite radical (PON), nitric oxide (NO), hydrogen peroxide (H2 O2 ), lipid peroxides (LPO), t-protein carbonyl content (PCC), and reduced/oxidized glutathione levels (GSH, GSSG). Additionally, AT mitochondrial fractions were used to determine the activities of the tricarboxylic acid cycle (TCA) cycle enzymes (CS, α-KGDH, ICDH, SDH, MDH), respiratory chain complexes I-III, II-III, IV, the nicotinamide coenzymes NAD+ , NADH, and ATP/ADP levels. Compared with the NC group, the UCMS group showed very significantly increased OS marker levels, lowered antioxidant enzyme activities and gene expression, as well as lowered TCA cycle and respiratory chain activity and NAD+ , NADH, and ATP levels (p < .001 for all comparisons). Besides, the UCMS group had lowered TEE and insignificant FI and weight gain. In conclusion, AT of the UCMS-subjected rats showed a state of disturbed redox balance linked to disrupted energy homeostasis producing augmentation of AT.

THU125 Altered Pro-opiomelanocortin (POMC) Neuron Function Characterizes Energy Expenditure Dysfunction And Increased Body Weight Linked To Fragile X Gene Mutation

Abstract Disclosure: R.E. Ruggiero-Ruff: None. P. Villa: None. S. Abu Hijleh: None. B. Avalos: None. N. DiPatrizio: None. D. Coss: None. Obesity is a world-wide epidemic that has become a major public health concern. Obesity increases the risk of cardiovascular disease, type 2 diabetes, stroke, and dementia. Children and adolescents with Fragile X syndrome (FXS), the most common cause of inherited intellectual disability, have higher rates of obesity compared to peers. FXS is caused by a mutation of the Fragile X messenger ribonucleoprotein gene (FMR1), which leads to the loss of FMRP, a ubiquitously expressed mRNA binding protein. Food intake and energy expenditure are regulated by orexigenic neuropeptide Y (NPY)/agouti-related protein (AgRP) and anorexigenic pro-opiomelanocortin (POMC) neurons from the hypothalamus. While our understanding of mechanisms of intellectual disability in FXS patients is beginning to emerge, the role of FMR1 gene in the hypothalamus is unknown. In this study, we used a knock-out (KO) mouse model to analyze if obesity in FXS patients stems from dysregulation of the hypothalamic circuitry regulating food intake and energy expenditure. Consistent with what is seen in the human population, KO males weigh more than their WT littermates. There were no differences in growth hormone or basal or fasting glucose levels. There was no difference in food intake, however KO males exhibited lower locomotor activity in the dark cycle, during their active phase. Since POMC neurons regulate energy expenditure in addition to food intake, we analyzed POMC neuron number, using immunohistochemistry. We determined fewer POMC neurons in KO male mice compared to WT. AgRP/NPY neurons modulate POMC neurons through GABAergic neuronal transmission. We determined that KO males have increased obligatory GABAa receptor subunit on POMC neurons. We also analyzed GABAa receptor and vesicular GABA transporter (VGAT) apposition on POMC neurons to identify synaptic receptors and indeed, KO males had significantly higher levels of GABAa-VGAT appositions, indicating increased synaptic input. In summary, our results suggest a role for FMR1 in the regulation of POMC neuronal activity in the regulation of locomotor activity and point to a role in modulating motor activity and energy expenditure in obese Fragile X patients. Presentation: Thursday, June 15, 2023

Penerapan Model Pembelajaran Think Talk Write untuk Meningkatkan Hasil Belajar Siswa pada Tema Daerah Tempat Tinggalku di Kelas IV SD PAB 23 Patumbak

This study aims to improve student learning outcomes in class IV SD PAB 23 with the theme "Where I Live" by applying the Think Talk Write Learning Model. This research was conducted in class IV SD PAB 23 Patumbak. This research is a class action research (Classroom Action Research). The subjects in this study were 25 grade IV SD PAB 23 Patumbak students, 13 male students and 12 female students. Instruments and data collection techniques used in this study are observation and tests. From the observation results, it is known that the overall teacher activity in cycle I with the application of the Think Talk Write Learning Model is 72.7% in the sufficient category. The results of observations of student activity as a whole in cycle I, namely 70% in the sufficient category with the percentage of completeness of student learning outcomes in cycle I was 70.8% in the sufficient category. Overall teacher activity in cycle II was 81.81% in the good category. Overall student activity in cycle II was 82.5% in the good category with the percentage of completeness of student learning outcomes in cycle II was 80.32% in the good category. Overall teacher activity in cycle III was 93.18% in the very good category. Overall student activity in cycle III, which is 92.5% in the very good category with the percentage value of the completeness of student learning outcomes in cycle III is 92.36% in the Very Good category. Thus it can be concluded that the Application of the Think Talk Write Learning Model can improve results student learning on the theme The Area Where I Live, class IV SD PAB 23 Patumbak..

Penerapan Model Pembelajaran Inkuiri Terbimbing untuk Meningkatkan Hasil Belajar Siswa pada Mata Pelajaran IPA di Kelas V SDN 060/XI Pendung Hiang

Application of the Guided Inquiry Learning Model in science subject for fifth grade students of SDN 060/XI Pendung Hiang, where this Guided Inquiry Learning Model is a learning model that is structured based on constructivist theory which emphasizes student activity, independence and the development of intensive team learning. This research is a class action research (Classroom Action Research), which consists of four components in each cycle, namely planning, action, observation, and reflection, carried out to find out whether the application of the Learning Model Guided Inquiry, the learning outcomes of class V students at SDN 060/XI Pendung Hiang can be increased. The subjects in this study were 16 students of class V SDN 060/XI Pendung Hiang. To collect data, the authors use tests in each cycle and observation sheets. As for the data analysis technique, namely with descriptive qualitative and quantitative descriptive data analysis techniques. Qualitative descriptive is used in analyzing observational or observational data, while quantitative descriptive is used to provide an overview or draw conclusions based on the results of learning tests conducted in each cycle. From the results of this study, it was obtained that the percentage of observations of student activity in the first cycle was 56.25%, and 87,5% in the second cycle. Meanwhile, student learning outcomes also increased from cycle I 62,5%, increasing to 81% in cycle II. Thus it can be concluded that the application of the guided inquiry learning model to science lessons can increase student activity in class V SDN 060/XI Pendung Hiang. The results of the analysis of student learning outcomes in each cycle showed that the ability level of fifth grade students at SDN 060/XI Pendung Hiang had increased, this was seen after the application of the Guided Inquiry Learning Model, seen in cycle I the average student score was 71 and in cycle II the average is 81. This shows that science learning outcomes increase after the application of the Guided Inquiry Learning Model.

Peningkatan Keaktifan dan Hasil Belajar Matematika Melalui Strategi Pembelajaran Rotating Trio Exchange (RTE)

This research aims to increase the activity and learning outcomes of class IX B students at SMPN 5 Rangkasbitung, Lebak Regency on the topic of Curviliniear Solid Figures by implementing the Rotating Trio Exchange (RTE) learning strategy. The research method used is Classroom Action Research consisting of three cycles where each cycle consists of two actions. Research data was obtained from test results, observations, questionnaires and interviews. The research results show that there is an increase in learning outcomes and student activity in each cycle after learning using the Rotating Trio Exchange (RTE) strategy. The average student learning outcome in cycle 1 is 57.33, increasing to 71.50 in cycle 2 and in cycle 3 becomes 72.29 with class completion in cycle 3 76.67%, while the average student activity in cycle 3 reached 80.33% so the research is said successful. The interview results show that students are interested in the RTE learning strategy because it can increase student participation in the learning process.

Cosmic radiation exposure of airline crews in France over the period 2015–2019

Cosmic particle flux increases with latitude and altitude and is significantly higher on-board aircraft than at ground level. Furthermore, its intensity depends on solar activity and eruptions. Due to their professional activity, flight crews (FCs) may receive an annual dose of some millisieverts. Therefore, the European directive adopted in 1996 requires the aircraft operators to assess the dose. The effective dose is to be estimated using various experimental and calculation means. In France, it is carried out by the computerized system for flight assessment of exposure to cosmic radiation SIEVERTPN, which sends to SISERI, the national dose registry, the monthly effective dose of each crew member. The average annual effective dose of French FCs was 2.19 mSv in 2019, i.e. between the standard permissible limits set for the public and the limit set for occupationally exposed persons. The effective dose received by the most exposed French FCs increased during the period 2015–2019 and that could be due to the solar cycle effect, changes in the staff flight time or the aircraft model. It can also be noted that more technical flight crews (TFCs) received a dose greater than 5 mSv over the 2016 to 2019 period than commercial flight crew (CFCs). Our study indicates that the number of FCs having received a dose greater than 5 mSv also increased over the period 2016 to 2019. Some parameters, that may affect the assessment of the aircrew effective dose, are not considered in SIEVERTPN calculations, as for example the Forbush decreases and the location in the plane. Lastly, several factors lead us to expect a decrease in the doses received by French aircrew staff in the coming years, such as the peak activity of the 25th eleven-year solar cycle expected in July 2025. However, some unexpected events, as for instance the war in Ukraine, can alter this prediction.

Systematic investigation of mitochondrial transfer between cancer cells and Tcells at single-cell resolution.

Mitochondria (MT) participate in most metabolic activities of mammalian cells. A near-unidirectional mitochondrial transfer from Tcells to cancer cells was recently observed to "metabolically empower" cancer cells while "depleting immune cells," providing new insights into tumor-T cell interaction and immune evasion. Here, we leverage single-cell RNA-seq technology and introduce MERCI, a statistical deconvolution method for tracing and quantifying mitochondrial trafficking between cancer and Tcells. Through rigorous benchmarking and validation, MERCI accurately predicts the recipient cells and their relative mitochondrial compositions. Application of MERCI to human cancer samples identifies a reproducible MT transfer phenotype, with its signature genes involved in cytoskeleton remodeling, energy production, and TNF-α signaling pathways. Moreover, MT transfer is associated with increased cell cycle activity and poor clinical outcome across different cancer types. In summary, MERCI enables systematic investigation of an understudied aspect of tumor-T cell interactions that may lead to the development of therapeutic opportunities.

Penerapan Model Pembelajaran Think Talk Write untuk Meningkatkan Hasil Belajar Siswa pada Tema Daerah Tempat Tinggalku di Kelas IV SD PAB 23 Patumbak

This study aims to improve student learning outcomes in class IV SD PAB 23 with the theme "Where I Live" by applying the Think Talk Write Learning Model. This research was conducted in class IV SD PAB 23 Patumbak. This research is a class action research (Classroom Action Research). The subjects in this study were 25 grade IV SD PAB 23 Patumbak students, 13 male students and 12 female students. Instruments and data collection techniques used in this study are observation and tests. From the observation results, it is known that the overall teacher activity in cycle I with the application of the Think Talk Write Learning Model is 72.7% in the sufficient category. The results of observations of student activity as a whole in cycle I, namely 70% in the sufficient category with the percentage of completeness of student learning outcomes in cycle I was 70.8% in the sufficient category. Overall teacher activity in cycle II was 81.81% in the good category. Overall student activity in cycle II was 82.5% in the good category with the percentage of completeness of student learning outcomes in cycle II was 80.32% in the good category. Overall teacher activity in cycle III was 93.18% in the very good category. Overall student activity in cycle III, which is 92.5% in the very good category with the percentage value of the completeness of student learning outcomes in cycle III is 92.36% in the Very Good category. Thus it can be concluded that the Application of the Think Talk Write Learning Model can improve results student learning on the theme The Area Where I Live, class IV SD PAB 23 Patumbak..

Integrating Puzzles and STAD Model in Teaching Angle Measurement to Elementary School Third Graders: An Action Research Study

The purpose of this study was to improve the process (student activity and response) and learning outcomes of mathematics in the application of the STAD type cooperative learning model with puzzle media on the material for measuring angles for grade 3 students. Puzzle learning media applied in grade 3 about angles included sorting large sizes. angles, recognize and make the types of angles. This study uses classroom action research through at least two cycles to determine the improvement. If there is no improvement, then proceed to the third cycle and so on, until there is an increase. For data analysis using the percentage of classical completeness of the average percentage of observations. The results showed that the percentage of classical student activity in the first cycle was 63.13% with moderate success and 85.27% in the second cycle classical student activity with high success. The results of student responses using interviews in cycle I and cycle II both received 9 positive comments and 1 negative comment. This is a lot of students who give positive comments so that the response is said to be good. Meanwhile, the learning outcomes test in the first cycle with the classical percentage of 57.1% and in the second cycle as many as 29 students who completed the classical percentage 82.8% with an increase of 25.7% from the previous cycle. The conclusion that can be drawn from the research results is an increase in the percentage of student activity, student responses and learning outcomes.

Mitochondrial Metabolism in the Spotlight: Maintaining Balanced RNAP III Activity Ensures Cellular Homeostasis.

RNA polymerase III (RNAP III) holoenzyme activity and the processing of its products have been linked to several metabolic dysfunctions in lower and higher eukaryotes. Alterations in the activity of RNAP III-driven synthesis of non-coding RNA cause extensive changes in glucose metabolism. Increased RNAP III activity in the S. cerevisiae maf1Δ strain is lethal when grown on a non-fermentable carbon source. This lethal phenotype is suppressed by reducing tRNA synthesis. Neither the cause of the lack of growth nor the underlying molecular mechanism have been deciphered, and this area has been awaiting scientific explanation for a decade. Our previous proteomics data suggested mitochondrial dysfunction in the strain. Using model mutant strains maf1Δ (with increased tRNA abundance) and rpc128-1007 (with reduced tRNA abundance), we collected data showing major changes in the TCA cycle metabolism of the mutants that explain the phenotypic observations. Based on 13C flux data and analysis of TCA enzyme activities, the present study identifies the flux constraints in the mitochondrial metabolic network. The lack of growth is associated with a decrease in TCA cycle activity and downregulation of the flux towards glutamate, aspartate and phosphoenolpyruvate (PEP), the metabolic intermediate feeding the gluconeogenic pathway. rpc128-1007, the strain that is unable to increase tRNA synthesis due to a mutation in the C128 subunit, has increased TCA cycle activity under non-fermentable conditions. To summarize, cells with non-optimal activity of RNAP III undergo substantial adaptation to a new metabolic state, which makes them vulnerable under specific growth conditions. Our results strongly suggest that balanced, non-coding RNA synthesis that is coupled to glucose signaling is a fundamental requirement to sustain a cell's intracellular homeostasis and flexibility under changing growth conditions. The presented results provide insight into the possible role of RNAP III in the mitochondrial metabolism of other cell types.

Improving Teacher Talk To Enhance Teacher – Students Interaction (An Action Research at SMP Negeri 1 Bangun Purba)

The purposes of the study were to find out the interaction pattern in the classroom during the teaching-learning activity, to find out the effort might be done to improve teacher talk and to know how to enhance teacher-students interaction through improving the teacher talk. An Action Research was conducted with the object of this study was teacher talk delivered by the teacher of SMP N 1 Bangun Purba and the interaction pattern in the teaching-learning activity at the seventh grader students of VII-4. The activity of action research consisted of planning, acting, observing and reflecting. In cycle 1, a discussion about certain material related with the teacher talk and interaction was conducted. The result of interaction in the pre cycle activity was also given in cycle 1. The same activity was conducted in cycle 2, a discussion and interaction analysis of the cycle 1 was delivered to the teacher. Those activities were done outside the classroom. An analysis instrument from Moskowitz named Foreign Language Interaction Analysis (FLINT) was used to analyze the teacher talk and the interaction. An interview and questionnaire were conducted to know the teacher and students opinion of the research. All the collected data was described qualitatively. The report of the research consisted of descriptive of some facts and events occurred during the research. The result of the research showed that the pattern of interaction was mostly started by the teacher and giving information category was the most pattern occurred. The action research phases, the given suggestions and discussion succeeded to improve the teacher talk. The teacher talk was not dominating and the students got more opportunities to interact. It was shown by the decrement of the teacher talk percentage occurred in teaching-learning activity. The teacher talk in pre cycle activity was 66.2%, 64% in cycle 1 and 57.3% in cycle 2. The teacher also succeeded to enhance the interaction in the classroom. The students become more responsive and participate actively in the teaching-learning activity. The enhancement of interaction was shown by the students‘ response. In the pre cycle the students talk achieved 28.3%, 22.5% in cycle 1 and 37.5% in cycle 2. Based on the result above, it can be concluded that the teacher talk had been improved and the interaction showed an enhancement through the students‘ response. Giving reflection to the teacher talk can improve the talk to be better and giving suggestion based on the theory of certain expert can be beneficial input to improve the teacher talk and creating interactive situation in the classroom.

Abstract PO-032: Association of a polymorphic variant in JMJD1C with tumor recurrence after adjuvant chemoradiation therapy in head and neck squamous cell carcinoma

Abstract Background: Adjuvant chemoradiation therapy (CRT) is the standard treatment for locally advanced head and neck squamous cell carcinomas (HNSCCs). Over 50% of HNSCC cases are diagnosed at the locally advanced stage, with in-field persistence and recurrence major causes of morbidity and poor survival outcome. Apart from human papillomavirus (HPV) status, there are no predictive biomarkers for CRT outcomes. CRT lethality arises from unrepaired double strand breaks (DSBs) in DNA. Recent work has suggested that dynamic changes in lysine modification of chromatin regulate DSB repair. This study investigated the association of germline single nucleotide polymorphisms (SNPs) in lysine-modifying genes with DSB repair and CRT outcomes in HNSCC. Methods: Blood specimens and associated retrospective clinical data from HNSCC patients (n=90; age range=41-89, median age 64; males=69, females=21) were obtained under IRB# 21-9921. The patients had HPV-negative tumors in the larynx or oral cavity, and had received radiation, with some receiving concurrent chemotherapy. Patients receiving concurrent chemotherapy were: 40% in disease-free group, 21% in recurrence disease group, and 38% in never disease-free group. The patients were segregated into 3 groups: disease-free (n=30), recurrent disease (n=28), and never-disease free (n=32). DNA from blood was genotyped for specific germline SNPs in lysine-modifying genes. Isogenic HNSCC lines (Cal-27, SCC9) carrying either the wild type (WT) or homozygous SNP were generated using CRISPR/Cas9 technology, and bulk RNA sequencing and immunofluorescence (IF)-based studies were performed to assess cellular pathways affected. Results: A homozygous variant SNP in the coding region of JMJD1C was significantly enriched in the disease-free group (n=21/30) versus the recurrent disease (n=3/28) and never disease-free (n=2/32) groups (p=0.0003, OR=0, Fisher’s Exact test). Analysis of SNP frequency in large population datasets found that while it was abundant in European Americans (EAs), it is relatively rare in African Americans (AAs) (EA= 0.3139 vs. AA=0.072; gnomAD population). Cal-27 JMJD1C SNP cells were significantly enriched for altered mRNA levels of genes associated with DNA repair, replication, cell cycle, oxidative phosphorylation, and histone kinase activity versus CAL-27 with WT JMJD1C (q-value&amp;lt;0.05). The SCC9 JMJD1C SNP cells were significantly enriched in extracellular matrix organization, cytokine-cytokine receptor interaction, and humoral immune response versus SCC9 with WT JMJD1C (q-value&amp;lt;0.05). On irradiation, the JMJD1C SNP cells had robust activation of the DSB repair pathway (BRCA1- mediated repair foci) versus the WT cell lines. Conclusion and future work: This work provides novel insight into a germline SNP in a lysine-modifying gene effecting DSB repair and associating with CRT outcomes in HNSCC. It may serve as a predictive biomarker for recurrence. Future research will explore racial disparities in tumor recurrence and confirm results in larger HNSCC datasets. Citation Format: Adria Hasan, Elena V. Demidova, Shreya M. Shah, Philip Czyzewicz, Karthik Devarajan, Thomas Galloway, Barbara Burtness, Erica A. Golemis, Joshua E. Meyer, Sanjeevani Arwesd. Association of a polymorphic variant in JMJD1C with tumor recurrence after adjuvant chemoradiation therapy in head and neck squamous cell carcinoma [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Innovating through Basic, Clinical, and Translational Research; 2023 Jul 7-8; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2023;29(18_Suppl):Abstract nr PO-032.

Combination of tea catechins and ornithine effectively activates the urea cycle: an in vitro and human pilot study.

Accumulation of ammonia causes central and peripheral fatigue. This study aimed to investigate the synergistic effect of tea catechins and low-dose ornithine in activating the urea cycle to reduce blood ammonia levels during exercise. We used hepatocyte-like cells derived from human-induced pluripotent stem (iPS) cells to assess the effect of tea catechins combined with ornithine on urea cycle activity. The urea production and expression of key genes involved in the metabolism of urea were investigated. We then examined the synergistic improvement in ammonia metabolism by tea catechins in combination with ornithine in a human pilot study. Tea catechins combined with ornithine increased urea cycle activity in hepatocyte-like cells derived from human iPS cells. Intake of 538.6mg of tea catechins with 1592mg of ornithine for 2 consecutive days during exercise loading suppressed the exercise-induced increase in the blood ammonia concentration as well as stabilized blood glucose levels. Controlling the levels of ammonia, a toxic waste produced in the body, is important in a variety of situations, including exercise. The present study suggests that a heterogeneous combination of polyphenols and amino acids efficiently suppresses elevated ammonia during exercise in humans by a mechanism that includes urea cycle activation. This study was registered in the University Hospital Medical Information Network Clinical Trial Registry (No. UMIN000035484, dated January 8, 2019).

Nitric oxide cycle activity in rat biceps femoris muscle under conditions of bacterial lipopolysaccharide influence, experimental metabolic syndrome and their combination

There is evidence that long-term organism stimulation with bacterial lipopolysaccharides (LPS), which promotes the secretion of pro-inflammatory cytokines and nitric oxide, may play an important role in metabolic syndrome (MetS) development. Changes in NO production under conditions of MetS have different directions and depend on a specific organ. The purpose of this work was to study the production of nitric oxide and its metabolites in the biceps femoris muscle of rats under conditions of lipopolysaccharide stimulation of the organism, metabolic syndrome and their combination. The study was conducted for 60 days on 24 male Wistar rats divided into control, MetS, LPS and LPS+MetS groups. MetS was reproduced by adding 20% fructose solution to food, LPS stimulation was carried out by intraperitoneal injection of S. typhi LPS. It was demonstrated that stimulation of the rat organism with LPS under conditions of experimental metabolic syndrome increased the production of nitric oxide by L-arginine-dependent pathway, but limited metabolic syndrome-induced increase in nitric oxide production by L-arginine-independent pathway, reduced the concentration of S-nitrosothiols, while increasing the concentration of peroxynitrites and nitrites in the biceps femoris muscle of rats. Keywords: bacterial lipopolysaccharide, biceps femoris, metabolic syndrome, nitric oxide, reactive nitrogen species

Dietary Supplementation with Lauric Acid Improves Aerobic Endurance in Sedentary Mice via Enhancing Fat Mobilization and Glyconeogenesis

BackgroundLauric acid (LA), a major, natural, medium-chain fatty acid, is considered an efficient energy substrate for intense exercise and in patients with long-chain fatty acid β-oxidation disorders. However, few studies have focused on the role of LA in exercise performance and related glucolipid metabolism in vivo. ObjectivesWe aimed to investigate the effect of dietary supplementation with LA on exercise performance and related metabolic mechanisms. MethodsMale C57BL/6N mice (14 wk old) were fed a basal diet or a diet containing 1% LA, and a series of exercise tests, including a high-speed treadmill test, aerobic endurance exercises, a 4-limb hanging test, and acute aerobic exercises, were performed. ResultsDietary supplementation with 1.0% LA accelerated the recovery from fatigue after explosive exercise (P < 0.05) and improved aerobic endurance and muscle strength in sedentary mice (P = 0.039). Lauric acid intake not only changed muscle fatty acid profiles, including increases in C12:0 and n–6/n–3 PUFAs (P < 0.001) and reductions in C18:0, C20:4n–6, C22:6n–3, and n–3 PUFAs (P < 0.05) but also enhanced fat mobilization from adipose tissue and fatty acid oxidation in the liver, at least partly via the AMP-activated protein kinase–acetyl CoA carboxylase pathway (P < 0.05). Likewise, LA supplementation promoted liver glyconeogenesis and conserved muscular glycogen during acute aerobic exercise (P < 0.05), which was accompanied by an increase in the mitochondrial DNA copy number and Krebs cycle activity in skeletal muscle (P < 0.05). ConclusionsDietary supplemental LA serves as an efficient energy substrate for sedentary mice to improve aerobic exercise endurance and muscle strength through regulation of glucolipid metabolism. These findings imply that LA supplementation might be a promising nutritional strategy to improve aerobic exercise performance in sedentary people.

Immune perturbation network identifies an EMT subtype with chromosomal instability and tumor immune-desert microenvironment

Most gastric cancer (GC) subtypes are identified through transcriptional profiling overlooking dynamic changes and interactions in gene expression. Based on the background network of global immune genes, we constructed sample-specific edge-perturbation matrices and identified four molecular network subtypes of GC (MNG). MNG-1 displayed the best prognosis and vigorous cell cycle activity. MNG-2 was enriched by immune-hot phenotype with the potential for immunotherapy response. MNG-3 and MNG-4 were identified with epithelial-mesenchymal transition (EMT) peculiarity and worse prognosis, termed EMT subtypes. MNG-3 was characterized by low mutational burden and stromal cells and considered areplica of previous subtypes associated with poor prognosis. Notably, MNG-4 was considered a previously undefined subtype with a dismal prognosis, characterized by chromosomal instability and immune-desert microenvironment. This subtype tended to metastasize and was resistant to respond to immunotherapy. Pharmacogenomics analysis showed three therapeutic agents (NVP-BEZ235, LY2606368, and rutin)were potential interventions for MNG-4.

Integrated transcriptome and proteome analysis indicates potential biomarkers of prostate cancer in offspring of pregnant rats exposed to a phthalate mixture during gestation and lactation

As the second leading cause of death for cancer among men worldwide, prostate cancer (PCa) prevention and detection remain a critical challenge. One aspect of PCa research is the identification of common environmental agents that may increase the risk of initiation and progression of PCa. Endocrine disrupting chemicals (EDCs) are strong candidates for risk factors, partially because they alter essential pathways for prostate gland development and oncogenesis. Phthalates correspond to a set of commercially used plasticizers that humans are exposed to ubiquitously. Here, we show that maternal exposure to a phthalate mixture interferes with the expression profile of mRNA and proteins in the ventral prostate of offspring and increases the susceptibility to prostate adenocarcinomas in aged animals. The data highlight Ubxn11, Aldoc, Kif5c, Tubb4a, Tubb3, Tubb2, Rab6b and Rab3b as differentially expressed targets in young and adult offspring descendants (PND22 and PND120). These phthalate-induced targets were enriched for pathways such as: dysregulation in post-translational protein modification (PTPM), cell homeostasis, HSP90 chaperone activity, gap junctions, and kinases. In addition, the Kif5c, Tubb3, Tubb2b and Tubb4a targets were enriched for impairment in cell cycle and GTPase activity. Furthermore, these targets showed strong relationships with 12 transcriptional factors (TF), which regulate the phosphorylation of eight protein kinases. The correlation of TF-kinases is associated with alterations in immune system, RAS/ErbB/VEGF/estrogen/HIF-1 signaling pathways, cellular senescence, cell cycle, autophagy, and apoptosis. Downregulation of KIF5C, TUBB3 and RAB6B targets is associated with poor prognosis in patients diagnosed with adenocarcinoma. Collectively, this integrative investigation establishes the post-transcriptional mechanisms in the prostate that are modulated by maternal exposure to phthalate mixture during gestation and lactation.

Regulation of early seedling establishment and root development in Arabidopsis thaliana by light and carbohydrates

Main conclusionRoot development is regulated by sucrose and light during early seedling establishment through changes in the auxin response and chromatin topology.Light is a key environmental signal that regulates plant growth and development. The impact of light on development is primarily analyzed in the above-ground tissues, but little is known about the mechanisms by which light shapes the architecture of underground roots. Our study shows that carbohydrate starvation during skotomorphogenesis is accompanied by compaction of nuclei in the root apical meristem, which prevents cell cycle progression and leads to irreversible root differentiation in the absence of external carbohydrates, as evidenced by the lack of DNA replication and increased numbers of nuclei with specific chromatin characteristics. In these conditions, induction of photomorphogenesis was unable to restore seedling growth, as overall root growth was compromised. The addition of carbohydrates, either locally or systemically by transferring seedlings to sugar-containing medium, led to the induction of adventitious root formation with rapid recovery of seedling growth. Conversely, transferring in vitro carbohydrate-grown seedlings from light to dark transiently promoted cell elongation and significantly reduced root meristem size, but did not primarily affect cell cycle kinetics. We show that, in the presence of sucrose, dark incubation does not affect zonation in the root apical meristem but leads to shortening of the proliferative and transition zones. Sugar starvation led to a rapid increase in lysine demethylation of histone H3 at position K9, which preceded a rapid decline in cell cycle activity and activation of cell differentiation. In conclusion, carbohydrates are required for cell cycle activity, epigenetics reprogramming and for postmitotic cell elongation and auxin-regulated response in the root apical meristem.