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BioRxiv : the Preprint Server For... May 2024The adult mammalian heart has limited regenerative capacity following injury, leading to progressive heart failure and mortality. Recent studies have identified the...
The adult mammalian heart has limited regenerative capacity following injury, leading to progressive heart failure and mortality. Recent studies have identified the spiny mouse ( ) as a unique model for mammalian cardiac isch3emic resilience, exhibiting enhanced recovery after myocardial infarction (MI) compared to commonly used laboratory mouse strains. However, the underlying cellular and molecular mechanisms behind this unique response remain poorly understood. In this study, we comprehensively characterized the metabolic characteristics of cardiomyocytes in compared to the non-regenerative . We utilized single-nucleus RNA sequencing (snRNA-seq) in sham-operated animals and 1, 3, and 7 days post-myocardial infarction to investigate cardiomyocytes' transcriptomic and metabolomic profiles in response to myocardial infarction. Complementary targeted metabolomics, stable isotope-resolved metabolomics, and functional mitochondrial assays were performed on heart tissues from both species to validate the transcriptomic findings and elucidate the metabolic adaptations in cardiomyocytes following ischemic injury. Transcriptomic analysis revealed that cardiomyocytes inherently upregulate genes associated with glycolysis, the pentose phosphate pathway, and glutathione metabolism while downregulating genes involved in oxidative phosphorylation (OXPHOS). These metabolic characteristics are linked to decreased reactive oxygen species (ROS) production and increased antioxidant capacity. Our targeted metabolomic studies in heart tissue corroborated these findings, showing a shift from fatty acid oxidation to glycolysis and ancillary biosynthetic pathways in at baseline with adaptive changes post-MI. Functional mitochondrial studies indicated a higher reliance on glycolysis in compared to , underscoring the unique metabolic phenotype of hearts. Stable isotope tracing experiments confirmed a shift in glucose utilization from oxidative phosphorylation in . In conclusion, our study identifies unique metabolic characteristics of cardiomyocytes that contribute to their enhanced ischemic resilience following myocardial infarction. These findings provide novel insights into the role of metabolism in regulating cardiac repair in adult mammals. Our work highlights the importance of inherent and adaptive metabolic flexibility in determining cardiomyocyte ischemic responses and establishes as a valuable model for studying cardiac ischemic resilience in adult mammals.
PubMed: 38826249
DOI: 10.1101/2024.05.22.595229 -
Journal of Hepatology May 2024Crotonylation, a crotonyl-CoA-based non-enzymatic protein translational modification, affects diverse biological processes, such as spermatogenesis, tissue injury,...
BACKGROUND & AIMS
Crotonylation, a crotonyl-CoA-based non-enzymatic protein translational modification, affects diverse biological processes, such as spermatogenesis, tissue injury, inflammation, and neuropsychiatric diseases. Crotonylation shows decreased in hepatocellular carcinomas (HCCs), but the mechanism remains unknown. In this study, we aim to describe the role of glutaryl-CoA dehydrogenase (GCDH) in tumor suppression.
METHODS
Three cohorts containing 40, 248 and 17 pairs of samples were used to evaluate the link between GCDH expression levels and the HCC clinical characteristics as well as anti-PD-1 response. Subcutaneous xenograft, orthotopic xenograft, Trp53; MYC- as well as Ctnnb; MET- driven mouse models were adopted to validate GCDH effects on HCC suppression.
RESULTS
GCDH depletion promoted HCC growth and metastasis, whereas its overexpression reversed these processes. As GCDH converts glutaryl-CoA to crotonyl-CoA to increase crotonylation levels, we performed lysine crotonylome analysis and identified the pentose phosphate pathway (PPP) and glycolysis-related proteins PGD, TKT, and ALDOC as GCDH-induced crotonylation targets. Crotonyl-bound targets showed allosteric effects that controlled their enzymatic activities, leading to decreases in ribose 5-phosphate and lactate production, further limiting the Warburg effect. PPP blockade also stimulated peroxidation, synergizing with senescent modulators to induce senescence in GCDH cells. These cells induced the infiltration of immune cells by the senescence-associated secretory cell phenotype (SASP) to shape an anti-tumor immune microenvironment. Meanwhile, the GCDH population was sensitized to anti-programmed cell death protein 1 (PD-1) therapy.
CONCLUSION
GCDH inhibits HCC progression via crotonylation-induced suppression of the PPP and glycolysis, resulting in HCC cell senescence. The senescent cell further shapes an anti-tumor microenvironment by SASP. The GCDH population is vulnerable to anti-PD-1 therapy because more PD-1+CD8+ T cells are exhibited in GCDH population.
IMPACT AND IMPLICATIONS
GCDH is a favorable prognostic indicator in liver, lung, and renal cancers. In addition, most of GCDH depletion-induced toxic metabolites originate from the liver, accumulate locally, and cannot cross the blood-brain barrier. Therefore, studies on the correlation between GCDH and liver cancer would contribute to discovering the initiation and progression of hepatocellular carcinoma, of which over 70% of patients occupied >2-fold GCDH downregulation. Given that the GCDH and GCDH HCC population can be distinguished based on serum glucose and ammonia levels, it will be worthwhile to evaluate the curative effects of pro-senescent and immune-therapeutic strategies based on the expression levels of GCDH.
PubMed: 38825017
DOI: 10.1016/j.jhep.2024.05.034 -
Biomedicine & Pharmacotherapy =... Jul 2024Metabolic reprogramming plays critical roles in the development and progression of tumor by providing cancer cells with a sufficient supply of nutrients and other... (Review)
Review
Metabolic reprogramming plays critical roles in the development and progression of tumor by providing cancer cells with a sufficient supply of nutrients and other factors needed for fast-proliferating. Emerging evidence indicates that long noncoding RNAs (lncRNAs) are involved in the initiation of metastasis via regulating the metabolic reprogramming in various cancers. In this paper, we aim to summarize that lncRNAs could participate in intracellular nutrient metabolism including glucose, amino acid, lipid, and nucleotide, regardless of whether lncRNAs have tumor-promoting or tumor-suppressor function. Meanwhile, modulation of lncRNAs in glucose metabolic enzymes in glycolysis, pentose phosphate pathway and tricarboxylic acid cycle (TCA) in cancer is reviewed. We also discuss therapeutic strategies targeted at interfering with enzyme activity to decrease the utilization of glucoses, amino acid, nucleotide acid and lipid in tumor cells. This review focuses on our current understanding of lncRNAs participating in cancer cell metabolic reprogramming, paving the way for further investigation into the combination of such approaches with existing anti-cancer therapies.
Topics: Humans; RNA, Long Noncoding; Neoplasms; Animals; Metabolic Networks and Pathways; Gene Expression Regulation, Neoplastic
PubMed: 38824835
DOI: 10.1016/j.biopha.2024.116831 -
MSystems Jun 2024tools such as genome-scale metabolic models have shown to be powerful for metabolic engineering of microorganisms. is a complex aneuploid hybrid between the mesophilic...
UNLABELLED
tools such as genome-scale metabolic models have shown to be powerful for metabolic engineering of microorganisms. is a complex aneuploid hybrid between the mesophilic and the cold-tolerant . This species is of biotechnological importance because it is the primary yeast used in lager beer fermentation and is also a key model for studying the evolution of hybrid genomes, including expression pattern of ortholog genes, composition of protein complexes, and phenotypic plasticity. Here, we created the iSP_1513 GSMM for CBS1513 to allow top-down computational approaches to predict the evolution of metabolic pathways and to aid strain optimization in production processes. The iSP_1513 comprises 4,062 reactions, 1,808 alleles, and 2,747 metabolites, and takes into account the functional redundancy in the gene-protein-reaction rule caused by the presence of orthologous genes. Moreover, a universal algorithm to constrain GSMM reactions using transcriptome data was developed as a python library and enabled the integration of temperature as parameter. Essentiality data sets, growth data on various carbohydrates and volatile metabolites secretion were used to validate the model and showed the potential of media engineering to improve specific flavor compounds. The iSP_1513 also highlighted the different contributions of the parental sub-genomes to the oxidative and non-oxidative parts of the pentose phosphate pathway. Overall, the iSP_1513 GSMM represent an important step toward understanding the metabolic capabilities, evolutionary trajectories, and adaptation potential of in different industrial settings.
IMPORTANCE
Genome-scale metabolic models (GSMM) have been successfully applied to predict cellular behavior and design cell factories in several model organisms, but no models to date are currently available for hybrid species due to their more complex genetics and general lack of molecular data. In this study, we generated a bespoke GSMM, iSP_1513, for this industrial aneuploid hybrid , which takes into account the aneuploidy and functional redundancy from orthologous parental alleles. This model will (i) help understand the metabolic capabilities and adaptive potential of (domestication processes), (ii) aid top-down predictions for strain development (industrial biotechnology), and (iii) allow predictions of evolutionary trajectories of metabolic pathways in aneuploid hybrids (evolutionary genetics).
Topics: Saccharomyces; Metabolic Networks and Pathways; Genome, Fungal; Models, Biological; Metabolic Engineering; Saccharomyces cerevisiae; Evolution, Molecular; Industrial Microbiology
PubMed: 38819150
DOI: 10.1128/msystems.00429-24 -
Advances in Rheumatology (London,... May 2024Research has demonstrated that obesity may be associated with rheumatoid arthritis (RA). In addition, gut microbiota and its metabolites contribute to the occurrence and...
OBJECTIVES
Research has demonstrated that obesity may be associated with rheumatoid arthritis (RA). In addition, gut microbiota and its metabolites contribute to the occurrence and development of RA and obesity. However, the mechanism by which obesity affects RA remains unclear. In this study, we aimed to investigate whether gut microbiota and their metabolites alter the effects of high fat diet (HFD) on the severity of collagen-induced arthritis (CIA) in mice.
METHODS
Briefly, mice were divided into normal group (N), CIA model group (C), HFD group (T), and HFD CIA group (CT). Hematoxylin and Eosin staining(HE) and Safranin O-fast green staining were conducted, and levels of blood lipid and inflammatory cytokines were measured. 16S rDNA sequencing technique and liquid chromatography-mass spectrometry (LC-MS)-based metabolomics were performed to explore changes in the microbiota structure to further reveal the pathomechanism of HFD on CIA.
RESULTS
HFD aggravated the severity of CIA in mice. The CT group had the highest proportion of microbial abundance of Blautia, Oscillibacter, Ruminiclostridium-9, and Lachnospiraceae UCG 006 at the genus level, but had a lower proportion of Alistipes. Additionally, the fecal metabolic phenotype of the combined CT group shows significant changes, with differential metabolites enriched in 9 metabolic pathways, including primary bile acid biosynthesis, arginine biosynthesis, sphingolipid metabolism, purine metabolism, linoleic acid metabolism, oxytocin signaling pathway, aminoacyl-tRNA biosynthesis, the pentose phosphate pathway, and sphingolipid signaling pathway. Correlation analysis revealed that some of the altered gut microbiota genera were strongly correlated with changes in fecal metabolites, total cholesterol (TC), triglyceride (TG), and inflammatory cytokine levels.
CONCLUSIONS
This study shows that HFD may aggravate inflammatory reaction in CIA mice by altering the gut microbiota and metabolic pathways.
Topics: Animals; Diet, High-Fat; Gastrointestinal Microbiome; Mice; Arthritis, Experimental; Cytokines; Male; Severity of Illness Index; Obesity; Disease Models, Animal
PubMed: 38816873
DOI: 10.1186/s42358-024-00382-y -
Molecular Microbiology May 2024Trypanosoma cruzi, a flagellated protozoan, is the causative agent of Chagas disease. The parasite has developed various mechanisms to get through its intricate life...
Trypanosoma cruzi, a flagellated protozoan, is the causative agent of Chagas disease. The parasite has developed various mechanisms to get through its intricate life cycle and adapt to different evolutionary phases. T. cruzi proliferates in the insect vector's digestive tract as an epimastigote form, encountering fluctuating nutrient availability and oxidative stress caused by the digestion of red blood cells from the mammalian host blood meal. To unravel how the parasite's metabolism adapts to these changing conditions, we conducted an analysis of the chemical species present in epimastigote forms. This involved comparing cultured parasites with those subjected to nutritional deficiency or oxidative stress using untargeted metabolomics. We looked at 21 samples: seven biological copies of parasites that were actively growing, seven samples that were put in a medium without nutrients for 3 h, and seven samples that were treated with glucose oxidase for 30 min to make HO continuously. Importantly, in all conditions, parasite viability was maintained when the samples were collected. Upon nutrient removal, we observed a substantial decrease in amino acids and carbohydrate metabolites, accompanied by the accumulation of fatty acids and steroids, with the predominance of inositol and sphingolipid metabolism, along with a simultaneous decrease in the levels of HO. In the presence of HO, a significant rise in components of the pentose pathway and specific amino acids such as methionine and serine occurred, along with pathways related to an increase in antioxidant species metabolism such as ribulose 5-phosphate and glyceric acid. Conversely, fatty acid and steroid levels decrease. We found no common increase in metabolites or lipids. In contrast, eight species (succinic acid, glutamic acid, valine, 2-hydroxyisocaproic acid, alanine, indolelactic acid, proline, and lanosterol) were consumed under both stresses. These findings underscore the rapid and distinct enrichment responses in amino acids, lipids, and carbohydrates required to cope with each different environmental condition. We concluded that T. cruzi presents a flexible metabolism that rapidly adapts to variable changes in the environment.
PubMed: 38814666
DOI: 10.1111/mmi.15279 -
Conservation Physiology 2024Bumblebee populations across the globe are experiencing substantial declines due to climate change, with major consequences for pollination services in both natural and...
Bumblebee populations across the globe are experiencing substantial declines due to climate change, with major consequences for pollination services in both natural and agricultural settings. Using an economically important species, , we explored the physiological mechanisms that may cause susceptibility to extreme heat events. We tested the hypothesis that heat exposure limits the activity of the pentose phosphate pathway (PPP)-a parallel pathway to glycolysis that can use nectar sugar to generate antioxidant potential and combat oxidative stress. Using isotopically labelled glucose, we tracked PPP activity in at rest, during exercise and during a post-exercise recovery period under two different temperature regimes (22°C and 32°C). We found that the PPP is routinely used by at moderate temperatures, but that its activity is markedly reduced when ATP demands are high, such as during periods of exercise and heat exposure. We also exposed to either 22°C or 32°C for 5 hours and assessed levels of oxidative damage (lipid peroxidation, protein carbonyls) and antioxidant potential [reduced (GSH) and oxidized (GSSG) glutathione concentrations]. Interestingly, bees exhibited little oxidative damage after the thermal exposure, but we found a lower GSH:GSSG ratio in 32°C-exposed bees, reflecting lower antioxidant potential. Overall, our study demonstrates that acute heat stress severely limits PPP activity and may constrain antioxidant potential in . The repeated attenuation of this pathway in a warming climate may have more severe physiological consequences for this species, with potential implications for pollination services across North America.
PubMed: 38812726
DOI: 10.1093/conphys/coae031 -
Zhongguo Zhong Yao Za Zhi = Zhongguo... Apr 2024The fecal metabolomics method was employed to investigate the cognitive improvement mechanism of Polygoni Multiflori Radix in Alzheimer's disease(AD) and examine the...
[Experimental study on improvement of cognitive impairment in Alzheimer's disease by different degrees of steaming and sunning of Polygoni Multiflori Radix based on fecal metabolomics].
The fecal metabolomics method was employed to investigate the cognitive improvement mechanism of Polygoni Multiflori Radix in Alzheimer's disease(AD) and examine the effects of different degrees of steaming and sunning on cognitive function in AD model mice. Additionally, the processing principle of Polygoni Multiflori Radix was discussed. Forty-eight 5-month-old APP/PS1 mice were randomly assigned to the following groups: model group, positive group, raw product group, three-steaming and three-sunning product group, six-steaming and six-sunning product group, and nine-steaming and nine-sunning product group. Seven negative control mice from the same litter were included as the blank group. After 150 days of intragastric administration, the learning and memory abilities of mice in each group were assessed by using the Barnes maze and dark avoidance tests. Fecal samples were collected for extensive targeted metabolomics testing. Principal component analysis(PCA), orthogonal partial least squares discriminant analysis(OPLS-DA), and other multivariate statistical methods were utilized to analyze metabolites in mouse feces. Comparison of behavioral results between the model group and different product groups demonstrated that the six-steaming and six-sunning product group exhibited significantly reduced latency in the Barnes maze positioning and navigation test(P<0.05), as well as a notable decrease in the number of errors in the space exploration experiment(P<0.05). Moreover, the latency of mice entering the dark box for the first time in the dark avoidance experiment was significantly prolonged(P<0.05), indicating the best overall improvement in the learning and memory ability of AD model mice. Metabolomics results revealed that compared with the model group, the differential metabolites in other groups in descending order were as follows: six-steaming and six-sunning product group > nine-steaming and nine-sunning product group > raw product group > three-steaming and three-sunning product group, encompassing 146, 120, 95, and 81 potential biomarkers, respectively. Among them, 16 differential metabolites were related to AD disease. Further comparisons based on the degree of processing indicated that the six-steaming and six-sunning product group exhibited the most significant adjustments in total metabolic pathways, particularly regulating the interconversion of pentose and glucuronic acid, as well as amino acid anabolism and other pathways. In summary, the mechanism of Polygoni Multiflori Radix after processing in enhancing the learning and memory ability of APP/PS1 mice may be associated with improved amino acid metabolism and increased energy metabolism in the body. The six-steaming and six-sunning yielded the best outcomes.
Topics: Animals; Alzheimer Disease; Mice; Metabolomics; Feces; Drugs, Chinese Herbal; Cognitive Dysfunction; Male; Polygonum; Humans; Disease Models, Animal; Female; Cognition
PubMed: 38812230
DOI: 10.19540/j.cnki.cjcmm.20231226.301 -
Nature Jun 2024Lignocellulose is mainly composed of hydrophobic lignin and hydrophilic polysaccharide polymers, contributing to an indispensable carbon resource for green...
Lignocellulose is mainly composed of hydrophobic lignin and hydrophilic polysaccharide polymers, contributing to an indispensable carbon resource for green biorefineries. When chemically treated, lignin is compromised owing to detrimental intra- and intermolecular crosslinking that hampers downstream process. The current valorization paradigms aim to avoid the formation of new C-C bonds, referred to as condensation, by blocking or stabilizing the vulnerable moieties of lignin. Although there have been efforts to enhance biomass utilization through the incorporation of phenolic additives, exploiting lignin's proclivity towards condensation remains unproven for valorizing both lignin and carbohydrates to high-value products. Here we leverage the proclivity by directing the C-C bond formation in a catalytic arylation pathway using lignin-derived phenols with high nucleophilicity. The selectively condensed lignin, isolated in near-quantitative yields while preserving its prominent cleavable β-ether units, can be unlocked in a tandem catalytic process involving aryl migration and transfer hydrogenation. Lignin in wood is thereby converted to benign bisphenols (34-48 wt%) that represent performance-advantaged replacements for their fossil-based counterparts. Delignified pulp from cellulose and xylose from xylan are co-produced for textile fibres and renewable chemicals. This condensation-driven strategy represents a key advancement complementary to other promising monophenol-oriented approaches targeting valuable platform chemicals and materials, thereby contributing to holistic biomass valorization.
Topics: Benzhydryl Compounds; Biomass; Catalysis; Cellulose; Chemical Fractionation; Hydrogenation; Lignin; Phenols; Wood; Xylans; Xylose; Fossil Fuels; Textiles
PubMed: 38811733
DOI: 10.1038/s41586-024-07446-5 -
Pest Management Science May 2024Transketolase (TKL, EC 2.2.1.1) is a key enzyme in the pentose phosphate pathway and Calvin cycle, and is expected to act as a herbicidal site-of-action. On the basis of...
BACKGROUND
Transketolase (TKL, EC 2.2.1.1) is a key enzyme in the pentose phosphate pathway and Calvin cycle, and is expected to act as a herbicidal site-of-action. On the basis of TKL, we designed and synthesized a series of 1-oxy-propionamide-pyrazole-3-carboxylate analogues and evaluated their herbicidal activities.
RESULTS
Methyl 1-methyl-5-((1-oxo-1-((4-(trifluoromethyl)phenyl)amino)propan-2-yl)oxy)-1H-pyrazole-3-carboxylate (C23) and methyl 1-methyl-5-((1-oxo-1-((perfluorophenyl)amino)propan-2-yl)oxy)-1H-pyrazole-3-carboxylate (C33) were found to provide better growth-inhibition activities against Digitaria sanguinalis root than those of nicosulfuron, mesotrione and pretilachlor at 200 mg L using the small-cup method. These compounds were also identified as promising compounds in pre-emergence and postemergence herbicidal-activity experiments, with relatively good inhibitory effects toward Amaranthus retroflexus and D. sanguinalis at 150 g ai ha. In addition, enzyme inhibition assays and molecular docking studies revealed that C23 and C33 interact favourably with SvTKL (Setaria viridis TKL).
CONCLUSION
C23 and C33 are promising lead TKL inhibitors for the optimization of new herbicides. © 2024 Society of Chemical Industry.
PubMed: 38808579
DOI: 10.1002/ps.8202