The effect of high-intensity interval training on type 2 diabetic muscle: A metabolomics-based study.

Background: This study aimed to investigate the effect of eight weeks of high-intensity interval training (HIIT) on muscle metabolism in rats with type 2 diabetes (T2D) using metabolomics approaches. Methods: 20 male Wistar rats at the age of 8 weeks-were assigned to four groups of five, each in the group randomly: control (CTL), type 2 diabetes (DB), HIIT (EX), and type 2 diabetes + HIIT (DBX). T2D was induced by two months of a high-fat diet plus a single dose of streptozotocin (35 mg/kg). Rats in the EX and DBX groups performed eight weeks of HIIT (running at 80-100 % of Vmax, 4-10 intervals). NMR spectroscopy was used to determine the changes in the muscle metabolome profile after training. Results: Changes in metabolite abundance following exercise revealed distinct clustering in multivariate analysis. The essential metabolite changes between the DB and CTL groups were arginine metabolism, purine metabolism, phosphate pathway, amino sugar metabolism, glutathione metabolism, and aminoacyl-tRNA biosynthesis. However, Arginine biosynthesis, pyrimidine metabolism, aminoacyl-tRNA biosynthesis, and alanine, aspartate, and glutamate metabolism were altered between the DBX and DB groups. Conclusion: These results suggest that eight weeks of HIIT could reverse metabolic changes induced by T2D in rat muscles, contributing to reduced FBG and HOMA-IR levels.

Anti-Cancer Effect of Dorema Ammoniacum Gum by Targeting Metabolic Reprogramming by Regulating APC, P53, KRAS Gene Expression in HT-29 Human Colon Cancer Cells.

Background: Colorectal cancer is a heterogeneous disease that leads to metabolic disorders due to multiple upstream genetic and molecular changes and interactions. The development of new therapies, especially herbal medicines, has received much global attention. Dorema ammoniacum is a medicinal plant. Its gum is used in healing known ailments. Studying metabolome profiles based on nuclear magnetic resonance 1HNMR as a non-invasive and reproducible tool can identify metabolic changes as a reflection of intracellular fluxes, especially in drug responses. This study aimed to investigate the anti-cancer effects of different gum extracts on metabolic changes and their impact on gene expression in HT-29 cell. Methods: Extraction of Dorema ammoniacum gum with hexane, chloroform, and dichloromethane organic solvents was performed. Cell inhibition growth percentage and IC50 were assessed. Following treating the cells with dichloromethane extract, p53, APC, and KRAS gene expression were determined. 1HNMR spectroscopy was conducted. Eventually, systems biology software tools interpreted combined metabolites and genes simultaneously. Results: The lowest determined IC50 concentration was related to dichloromethane solvent, and the highest was hexane and chloroform. The expression of the KRAS oncogene gene decreased significantly after treatment with dichloromethane extract compared to the control group, and the expression of tumor suppressor gene p53 and APC increased significantly. Most gene-altered convergent metabolic phenotypes. Conclusion: This study's results indicate that the dichloromethane solvent of Dorema ammoniacum gum exhibits its antitumor properties by altering the expression of genes involved in HT-29 cells and the consequent change in downstream metabolic reprogramming.

Aromatic amino acids play a harmonizing role in prostate cancer: A metabolomics-based cross-sectional study.

BACKGROUND: Prostate cancer (PCa) is a common health problem worldwide. The rate of this disease is likely to grow by 2021. PCa is a heterogeneous disorder, and various biochemical factors contribute to the development of this disease. The metabolome is the complete set of metabolites in a cell or biological sample and represents the downstream end product of the omics. Hence, to model PCa by computational systems biology, a preliminary metabolomics-based study was used to compare the metabolome profile pattern between healthy and PCa men. OBJECTIVE: This study was carried out to highlight energy metabolism modification and assist the prognosis and treatment of disease with unique biomarkers. MATERIALS AND METHODS: In this cross-sectional research, 26 men diagnosed with stage-III PCa and 26 healthy men with normal PSA levels were enrolled. Urine was analyzed with proton nuclear magnetic resonance ( 1 H-NMR) spectroscopy, accompanied by the MetaboAnalyst web-based platform tool for metabolomics data analysis. Partial least squares regression discriminant analysis was applied to clarify the separation between the two groups. Outliers were documented and metabolites determined, followed by identifying biochemical pathways. RESULTS: Our findings reveal that modifications in aromatic amino acid metabolism and some of their metabolites have a high potential for use as urinary PCa biomarkers. Tryptophan metabolism (p < 0.001), tyrosine metabolism (p < 0.001), phenylalanine, tyrosine and tryptophan biosynthesis (p < 0.001), phenylalanine metabolism (p = 0.01), ubiquinone and other terpenoid-quinone biosynthesis (p = 0.19), nitrogen metabolism (p = 0.21), and thiamine metabolism (p = 0.41) with Q 2 (0.198) and R 2 (0.583) were significantly altered. CONCLUSION: The discriminated metabolites and their pathways play an essential role in PCa causes and harmony.

Xanthatin Induces Leishmanicidal Activity by Affecting Carbon Metabolism in Amastigotes.

Cutaneous leishmaniasis is caused by protozoa of the genus Leishmania and spread by sandflies. The standard therapy for this ailment is the first-line medication of pentavalent antimonial and the second drug line of pentamidine amphotericin B. All are practiced over the years and exhibit adverse toxicity effects. Herbal product-derived medicine is a promising potential source for treating parasitic diseases. Xanthatin, a xanthanolide sesquiterpene lactone, is isolated from Xanthium strumarium L. treats several ailments in many countries. In the present study, we investigated the leishmanicidal activity of the xanthatin by using a metabolomics-based analysis in J774 macrophages and amastigotes phases in Leishmania major. Xanthatin was isolated and identified by NMR spectroscopy. Macrophage toxicity of xanthatin performed by MTT assay. Macrophages infected by the L. major's promastigote stationary phase, the infection rate (IR), and multiplication index (MI) were calculated. Axenic amastigotes were treated with xanthatin. Cell quenching and metabolite extraction were performed, and the metabolome profile was analyzed with NMR spectroscopy. Outliers were classified by using multivariate statistical analysis software, and relevant metabolites and pathways were worked out. The xanthatin IC50 rate defined 0.75 µg/mL base on macrophages viability and also in-vitro activity of xanthatin on amastigotes showed the best leishmanicidal activity in IR and MI values of 53% and 62.5%, respectively. Xanthatin altered amino sugars and nucleotide sugars metabolism, starch and sucrose metabolism, cyanoamino acid, and galactose metabolism. Our finding revealed that the main target of xanthatin is carbon metabolism, which is an essential step for amastigotes virulence.

Metabolomics Based Study of the Antileishmanial Activity of Xanthium strumarium Leaf Extract on Promastigotes Phases of Leishmania major by Proton NMR Spectroscopy.

BACKGROUND: Xanthium strumarium L. is extensively used as a traditional herb to treat many diseases and is also known as a source of phytochemicals. It has been used traditionally to treat trypanosomiasis, malaria fever, eczema, cancer, ulcer, fever, herpes headache, and skin lesion such as leishmaniasis. In this preliminary study, nuclear magnetic resonance (NMR)-metabolomics approaches was used to evaluate the inhibitory effects and metabolic alterations caused by leaf extract of X. strumarium on the stationary phases of promastigotes in Leishmania major. METHODS: The promastigotes were cultured in Biochemistry Laboratory at Pasteur Institute of Iran in 2017, stationary phases were obtained from 5 to 6 day-old cultures and treated with different concentrations of the plant's extract. Antileishmanial activity was assayed by MTT method and cell metabolites were extracted. 1H NMR spectroscopy was applied, and outliers were separated using multivariate statistical analysis. RESULTS: The most affected metabolic pathways in the experimental groups were limited to amino sugar and nucleotide sugar metabolism, cyanoamino acid metabolism, starch and sucrose metabolism, butanoate metabolism, and galactose metabolism. CONCLUSION: The ethanolic leaf extract of X. strumarium is a potent growth inhibitor of Leishmania major and can affect vital metabolic pathways of Leishmania promastigotes. The assay provided new perspectives on the development of novel treatment strategies for leishmanial activity derived from natural products.

(1)H NMR- based metabolomics approaches as non- invasive tools for diagnosis of endometriosis.

BACKGROUND: So far, non-invasive diagnostic approaches such as ultrasound, magnetic resonance imaging, or blood tests do not have sufficient diagnostic power for endometriosis disease. Lack of a non-invasive diagnostic test contributes to the long delay between onset of symptoms and diagnosis of endometriosis. OBJECTIVE: The present study focuses on the identification of predictive biomarkers in serum by pattern recognition techniques and uses partial least square discriminant analysis, multi-layer feed forward artificial neural networks (ANNs) and quadratic discriminant analysis (QDA) modeling tools for the early diagnosis of endometriosis in a minimally invasive manner by (1)H- NMR based metabolomics. MATERIALS AND METHODS: This prospective cohort study was done in Pasteur Institute, Iran in June 2013. Serum samples of 31 infertile women with endometriosis (stage II and III) who confirmed by diagnostic laparoscopy and 15 normal women were collected and analyzed by nuclear magnetic resonance spectroscopy. The model was built by using partial least square discriminant analysis, QDA, and ANNs to determine classifier metabolites for early prediction risk of disease. RESULTS: The levels of 2- methoxyestron, 2-methoxy estradiol, dehydroepiandrostion androstendione, aldosterone, and deoxy corticosterone were enhanced significantly in infertile group. While cholesterol and primary bile acids levels were decreased. QDA model showed significant difference between two study groups. Positive and negative predict value levels obtained about 71% and 78%, respectively. ANNs provided also criteria for detection of endometriosis. CONCLUSION: The QDA and ANNs modeling can be used as computational tools in noninvasive diagnose of endometriosis. However, the model designed by QDA methods is more efficient compared to ANNs in diagnosis of endometriosis patients.

Metabolomics-Based Study of Logarithmic and Stationary Phases of Promastigotes in Leishmania major by 1H NMR Spectroscopy.

BACKGROUND: Cutaneous leishmaniasis is one of the most important parasitic diseases in humans. In this disease, one of the responsible organisms is Leishmania major, which is transmitted by sandfly vector. There are specific differences in biochemical profiles and metabolite pathways in logarithmic and stationary phases of Leishmania parasites. In the present study, 1H NMR spectroscopy was used to examine the metabolites outliers in the logarithmic and stationary phases of promastigotes in L. major to enlighten more about the transmission mechanism in metacyclogenesis of L. major. METHODS: Promastigote was cultured, logarithmic and stationary phases were separated by the peanut agglutinin, and cell metabolites were extracted. 1H NMR spectroscopy was applied, and outliers were analyzed using principal component analysis. RESULTS: The most altered metabolites in stationary and logarithmic phases were limited to citraconic acid, isopropylmalic acid, L-leucine, ornithine, caprylic acid, capric acid, and acetic acid. CONCLUSION: 1H NMR spectroscopy could play an important role in the characterization of metabolites in biochemical pathways during a metacyclogenesis process. These metabolites and their pathways can help in exploiting a transmission mechanism in metacyclogenesis, and outcoming data might be used in the metabolic network reconstruction of L. major modeling.

NMR-based metabonomics survey in rats envenomed by Hemiscorpius lepturus venom.

About 1% of scorpion stings in Iran have been reported in cities and more than 5% in rural areas. The genus Hemiscorpous lepturus belongs to the family Hemiscorpiidae that is endemic in the south-western province of Khoozestan and other parts of western Iran. Although this species is responsible for only 10% of the reported stings, it is also responsible for 95% of mortalities. The heavy cytotoxic and neurotoxic venomous effects of scorpion sting may cause serious disorders such as erythema, purpuric changes, bulla, necrosis and ulcer, either alone or in combination. The toxic effects of H. lepturus venom cause vast changes in both primary and secondary metabolites of the victim, which finally lead to death if not treated early enough. Metabolomics is the systematic study of chemical fingerprints resulting from cytotoxic and pathogenic reactions of cells. We studied the toxic mechanism of H. lepturus venom on metabolome profiling of the victims along with biochemical pathways, organs and physiological detectable effects of this venom by the help of (1)H NMR. Our results showed that pyrimidine, histidine and tyrosine metabolisms, and steroid hormone biosynthesis were the most affected pathways. The major action of the crude venom is on the pancreas, and also on the nerve cells, spleen and mitochondria, causing acute seizures, which resemble the early markers of myocardial injury and seizure disorders.