Dissecting Target Toxic Tissue and Tissue Specific Responses of Irinotecan in Rats Using Metabolomics Approach.
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ABSTRACT:
SUBMITTER: Yao Y
PROVIDER: S-EPMC5344918 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:One of the primary objectives of plant biotechnology is to increase resistance to abiotic stresses, such as salinity. Salinity is a major abiotic stress and increasing crop resistant to salt continues to the present day as a major challenge. Salt stress disturbs cellular environment leading to protein misfolding, affecting normal plant growth and causing agricultural losses worldwide. The advent of state-of-the-art technologies such as high throughput mRNA sequencing (RNA-seq) has revolutionized whole-transcriptome analysis by allowing, with high precision, to measure changes in gene expression. In this work, we used tissue-specific RNA-seq to gain insight into the Petunia hybrida transcriptional responses under NaCl stress using a controlled hydroponic system. Roots and leaves samples were taken from a continuum of 48 h of acute 150 mM NaCl. This analysis revealed a set of tissue and time point specific differentially expressed genes, such as genes related to transport, signal transduction, ion homeostasis as well as novel and undescribed genes, such as Peaxi162Scf00003g04130 and Peaxi162Scf00589g00323 expressed only in roots under salt stress. In this work, we identified early and late expressed genes in response to salt stress while providing a core of differentially express genes across all time points and tissues, including the trehalose-6-phosphate synthase 1 (TPS1), a glycosyltransferase reported in salt tolerance in other species. To test the function of the novel petunia TPS1 allele, we cloned and showed that TPS1 is a functional plant gene capable of complementing the trehalose biosynthesis pathway in a yeast tps1 mutant. The list of candidate genes to enhance salt tolerance provided in this work constitutes a major effort to better understand the detrimental effects of salinity in petunia with direct implications for other economically important Solanaceous species.
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Project description:We report a method for analyzing spatial metabolomics at single cell level. In human fibrotic liver samples, we identified a novel hepatocyte subpopulation via SEAM and spatial transcriptomics using modified protocol of Geo-sea. For Geo-seq, we generated cDNA libraries from Hepa69-high (Proximal), Hepa69-low (Distal) and Fibrotic (FB) regions. The differential gene expression analysis between Hepa69-high and Hepa69-low indicates that genes from solute carrier transporter families were elevated in Hepa69-high group.
2020-08-22 | GSE153463 | GEO
Project description:Moderate calorie restriction (CR) (∼60% of ad libitum, AL, intake) has been associated with numerous favorable physiological outcomes in many species, and the insulin/IGF-1 and mTOR signaling pathways have each been proposed as potential mediators for many of CR's bioeffects. However, few studies have assessed the widely held idea that CR induces the down-regulation of the insulin/IGF-1 and/or mTOR pathways in multiple tissues. Accordingly, we analyzed the phosphorylation status of 11 key signaling proteins from the insulin/IGF-1 (IR(Tyr1162/1163), IGF-1R(Tyr1135/1136), IRS-1(Ser312), PTEN(Ser380), Akt(Ser473), GSK3α(Ser21), GSK3β(Ser9)) and mTOR (TSC2(Ser939), mTOR(Ser2448), P70S6K(Thr412), RPS6(Ser235/236)) pathways in 11 diverse tissues [liver, kidney, lung, aorta, two brain regions (cortex and cerebellum), and two slow-twitch and three fast-twitch skeletal muscles] from 9-month-old male AL and CR Fischer 344 x Brown Norway rats. The rats were studied under two conditions: with endogenous insulin levels (i.e., AL>CR) and with insulin infused during a hyperinsulinemic-euglycemic clamp so that plasma insulin concentrations were matched between the two diet groups. The most striking and consistent effect of CR was greater pAkt in 3 of the 5 skeletal muscles of CR vs. AL rats. There were no significant CR effects on the mTOR signaling pathway and no evidence that CR caused a general attenuation of mTOR signaling across the tissues studied. Rather than supporting the premise of a global downregulation of insulin/IGF-1 and/or mTOR signaling in many tissues, the current results revealed clear tissue-specific CR effects for the insulin signaling pathway without CR effects on the mTOR signaling pathway.
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Project description:Renal cell carcinoma (RCC) is the most common form of kidney malignancy. RCC is more common among men with a 2/1 male/female incidence ratio worldwide. Given the underlying epidemiological differences in the RCC incidence between males and females, we explored the gender specific 1H NMR serum metabolic profiles of RCC patients and their matched controls. A number of differential metabolites were shared by male and female RCC patients. These RCC specific changes included lower lactate, threonine, histidine, and choline levels together with increased levels of pyruvate, N-acetylated glycoproteins, beta-hydroxybutyrate, acetoacetate, and lysine. Additionally, serum lactate/pyruvate ratio was a strong predictor of RCC status regardless of gender. Although only moderate changes in metabolic profiles were observed between control males and females there were substantial gender related differences among RCC patients. Gender specific metabolic features associated with RCC status were identified suggesting that different metabolic panels could be leveraged for a more precise diagnostic.
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Project description:Main conclusionSalinity induced metabolite responses resulted in differential accumulation of flavonoids and antioxidant metabolites in shoots and roots suggesting improved antioxidant capacity in providing salt-adaptive phenotype of tef seedling. Tef [(Eragrostis tef) (Zucc.) Trotter] is an important 'cash crop' of Ethiopia grown mainly for human food, and development of elite tef cultivars with better performance is vital to Ethiopian farmers and breeders. Soil salinity is one of the key constraints that affects tef yield in the Ethiopian lowlands and Rift valley where cultivation of tef is limited. Being a minor crop, the responses of tef towards salinity is unknown. Salinity involves physiological and metabolite reprogramming that can have major impact on germination and seedling establishment. Here we evaluate the in vitro effect of NaCl on tef germination and associate this with metabolomic approaches to suggest salt tolerance mechanisms. In this study, 19 tef varieties were screened for NaCl tolerance and were investigated using untargeted metabolomics. Screened tef varieties showed differential germination rates with NaCl treatment varying from < 20 to 100%. Viable seedlings exposed to NaCl exhibited purple-red pigment accumulation in the roots except for Beten and Tullu nasy varieties. Metabolite comparisons between shoots and roots showed significant differences and, in particular, roots of salt tolerant tef varieties accumulated flavonoid derivatives as well as sugars and cell wall associated metabolites. These metabolic changes were correlated with patterns of antioxidant capacities and total flavonoid content in shoots and roots and suggested a mitigating response by tef to salinity. Our study highlights the role of flavonoid accumulation following salt stress on tef seedlings and further these findings could be used as targets for selective tef breeding.
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Project description:Bottromycin A2 is a structurally unique ribosomally synthesized and post-translationally modified peptide (RiPP) that possesses potent antibacterial activity towards multidrug-resistant bacteria. The structural novelty of bottromycin stems from its unprecedented macrocyclic amidine and rare β-methylated amino acid residues. The N-terminus of a precursor peptide (BtmD) is converted into bottromycin A2 by tailoring enzymes encoded in the btm gene cluster. However, little was known about key transformations in this pathway, including the unprecedented macrocyclization. To understand the pathway in detail, an untargeted metabolomic approach that harnesses mass spectral networking was used to assess the metabolomes of a series of pathway mutants. This analysis has yielded key information on the function of a variety of previously uncharacterized biosynthetic enzymes, including a YcaO domain protein and a partner protein that together catalyze the macrocyclization.
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Project description:BACKGROUND:Intrauterine growth restriction (IUGR) may program metabolic alterations affecting physiological functions and lead to diseases in later life. The adipose tissue is an important organ influencing energy homeostasis. The present study was aimed at exploring the consequences of IUGR on the retroperitoneal adipose tissue of adult male and female rats, using a proteomic approach. METHODS AND RESULTS:Pregnant Wistar rats were fed with balanced chow, either ad libitum (control group) or restricted to 50 % of control intake (restricted group) during the whole gestation. The offspring were weaned to ad libitum chow and studied at 4 months of age. Retroperitoneal fat was analyzed by two-dimensional gel electrophoresis followed by mass spectrometry. Both male and female restricted groups had low body weight at birth and at weaning but normal body weight at adulthood. The restricted males had normal fat pads weight and serum glucose levels, with a trend to hyperinsulinemia. The restricted females had increased fat pads weight with normal glucose and insulin levels. The restricted males showed up-regulated levels of proteasome subunit ? type 3, branched-chain-amino-acid aminotransferase, elongation 1- alpha 1, fatty acid synthase levels, cytosolic malate dehydrogenase and ATP synthase subunit alpha. These alterations point to increased proteolysis and lipogenesis rates and favoring of ATP generation. The restricted females showed down-regulated levels of L-lactate dehydrogenase perilipin-1, mitochondrial branched-chain alpha-keto acid dehydrogenase E1, and transketolase. These findings suggest impairment of glycemic control, stimulation of lipolysis and inhibition of proteolysis, pentose phosphate pathway and lipogenesis rates. In both genders, several proteins involved in oxidative stress and inflammation were affected, in a pattern compatible with impairment of these responses. CONCLUSIONS:The proteomic analysis of adipose tissue showed that, although IUGR affected pathways of substrate and energy metabolism in both males and females, important gender differences were evident. While IUGR males displayed alterations pointing to a predisposition to later development of obesity, the alterations observed in IUGR females pointed to a metabolic status of established obesity, in agreement with their increased fat pads mass.
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Project description:Dysfunction of adipose tissue could lead to insulin resistance, obesity and type 2 diabetes. Thus, our present study aimed to investigate metabolites alterations in white adipose tissue (WAT) of diabetic GK rats after IT surgery. Ten-week-old male diabetic GK rats were randomly subjected to IT and Sham-IT surgery. Six weeks later, the untargeted metabolomics in WAT of diabetic GK rats was performed. Differential metabolites were selected according to the coefficient of variation (CV) of quality control (QC) sample <30%, variable importance in the projection (VIP) >1 and P < 0.05. Then, the hierarchical clustering of differential metabolites was conducted and the KEGG database was used for metabolic pathway analysis. A total of 50 (in positive ion mode) and 68 (in negative ion mode) metabolites were identified as differential metabolites in WAT of diabetic GK rats between IT group and Sham-IT group, respectively. These differential metabolites were well clustered, which in descending order of the number of involved differential metabolites is ubiquinone and other terpenoid-quinone biosynthesis, AMPK signalling pathway, pantothenate and CoA biosynthesis, ferroptosis, vitamin digestion and absorption, glycerophospholipid metabolism, phenylalanine metabolism, steroid hormone biosynthesis, neuroactive ligand-receptor interaction, porphyrin and chlorophyll metabolism and bile secretion, and correlated with the parameters of body weight, food intake, WAT mass and glucose metabolism, which were significantly improved after IT surgery. The differential metabolites in WAT of diabetic GK rats were mainly related to the pathway of energy metabolism, and correlated with the improved phenotypes of diabetic GK rats after IT surgery.
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Project description:BackgroundConstructing a reliable animal model for preclinical treatment of secondary lymphedema is challenging because the anatomical characteristics near the lymph nodes are understudied. Therefore, this study examined the detailed anatomical relationship between the axillary lymph node flaps (ALNFs) and brachial lymph node flaps (BLNFs) in the forelimb of Sprague-Dawley (SD) rats.Materials and methodsTen male rats, weighing 250-300 g, were used. The ALNFs and BLNFs on either side of the rat forelimbs were dissected. The two lymph node flaps (LNFs) were immediately harvested to analyze their physical characteristics (via imaging process software) and microscopic structure (via histology examinations).ResultsA total of 20 ALNFs and BLNFs from 10 rats were harvested and analyzed. ALNF dissection was simpler and lasted a shorter time than BLNF dissection (p < 0.0001). The left LNFs were more difficult to dissect than the right LNFs (p < 0.0001). In physical characteristics of LNFs, the area (p < 0.001) of LNFs and the number of lymph nodes (p < 0.0001) associated with ALNFs were greater than those associated with BLNFs, but the pedicle lengths of ALNFs were shorter than that of BLNFs (p < 0.0001). No significant difference in the diameter of the venous and arterial pedicles was noted between the two LNFs (p > 0.05).ConclusionThis study reported detailed physical characteristics of ALNFs and BLNFs in SD rat forelimbs, assessing the respective area of LNFs, number of lymph nodes, and lengths and diameters of vascular pedicles. Moreover, this study suggested an efficient method to perform a study of LNFs by describing the operation process and repeatedly measuring the operation time.
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Project description:BackgroundRecognition of stress and mobilization of adequate "fight-or-flight" responses is key for survival and health. Previous studies have shown that exposure of Caenorhabditis elegans to pathogens or toxins simultaneously stimulates cellular stress and detoxification responses and aversive behavior. However, whether a coordinated regulation exists between cytoprotective stress responses and behavioral defenses remains unclear.ResultsHere, we show that exposure of C. elegans to high concentrations of naturally attractive food-derived odors, benzaldehyde and diacetyl, induces toxicity and food avoidance behavior. Benzaldehyde preconditioning activates systemic cytoprotective stress responses involving DAF-16/FOXO, SKN-1/Nrf2, and Hsp90 in non-neuronal cells, which confer both physiological (increased survival) and behavioral tolerance (reduced food avoidance) to benzaldehyde exposure. Benzaldehyde preconditioning also elicits behavioral cross-tolerance to the structurally similar methyl-salicylate, but not to the structurally unrelated diacetyl. In contrast, diacetyl preconditioning augments diacetyl avoidance, weakens physiological diacetyl tolerance, and does not induce apparent molecular defenses. The inter-tissue connection between cellular and behavioral defenses is mediated by JNK-like stress-activated protein kinases and the neuropeptide Y receptor NPR-1. Reinforcement of the stressful experiences using spaced training forms stable stress-specific memories. Memory retrieval by the olfactory cues leads to avoidance of food contaminated by diacetyl and context-dependent behavioral decision to avoid benzaldehyde only if there is an alternative, food-indicative odor.ConclusionsOur study reveals a regulatory link between conserved cytoprotective stress responses and behavioral avoidance, which underlies "fight-or-flight" responses and facilitates self-protection in real and anticipated stresses. These findings imply that variations in the efficiency of physiological protection during past episodes of stress might shape current behavioral decisions.
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