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Frontiers in Endocrinology 2023Metabolic reprogramming is involved in different stages of tumorigenesis. There are six widely recognized tumor-associated metabolic pathways, including cholesterol...
BACKGROUND
Metabolic reprogramming is involved in different stages of tumorigenesis. There are six widely recognized tumor-associated metabolic pathways, including cholesterol catabolism process, fatty acid metabolism, glutamine metabolic process, glycolysis, one carbon metabolic process, and pentose phosphate process. This study aimed to classify gastric cancer patients into different metabolic bio-similar clusters.
METHOD
We analyzed six tumor-associated metabolic pathways and calculated the metabolic pathway score through RNA-seq data using single sample gene set enrichment analysis. The consensus clustering analysis was performed to classify patients into different bio-similar clusters by multi-dimensional scaling. Kaplan-Meier curves were presented between different metabolic bio-similar groups for OS analysis.
RESULTS
A training set of 370 patients from the Cancer Genome Atlas database with primary gastric cancer was chosen. Patients were classified into four metabolic bio-similar clusters, which were identified as metabolic non-specificity, metabolic-active, cholesterol-silence, and metabolic-silence clusters. Survival analysis showed that patients in metabolic-active cluster and metabolic-silence cluster have significantly poor prognosis than other patients (=0.031). Patients in metabolic-active cluster and metabolic-silence cluster had significantly higher intra-tumor heterogeneity than other patients (=0.032). Further analysis was performed in metabolic-active cluster and cholesterol-silence cluster. Three cell-cycle-related pathways, including G2M checkpoints, E2F targets, and MYC targets, were significantly upregulated in metabolic-active cluster than in cholesterol-silence cluster. A validation set of 192 gastric cancer patients from the Gene Expression Omnibus data portal verified that metabolic bio-similar cluster can predict prognosis in gastric cancer.
CONCLUSION
Our study established a multi-dimension metabolic prognostic model in gastric cancer, which may be feasible for predicting clinical outcome.
Topics: Humans; Stomach Neoplasms; Prognosis; Lipid Metabolism; Carcinogenesis; Cholesterol
PubMed: 38144563
DOI: 10.3389/fendo.2023.1228136 -
Scientific Reports Feb 2024Over-consumption of fructose in adults and children has been linked to increased risk of non-alcoholic fatty liver disease (NAFLD). Recent studies have highlighted the...
Over-consumption of fructose in adults and children has been linked to increased risk of non-alcoholic fatty liver disease (NAFLD). Recent studies have highlighted the effect of fructose on liver inflammation, fibrosis, and immune cell activation. However, little work summarizes the direct impact of fructose on macrophage infiltration, phenotype, and function within the liver. We demonstrate that chronic fructose diet decreased Kupffer cell populations while increasing transitioning monocytes. In addition, fructose increased fibrotic gene expression of collagen 1 alpha 1 (Col1a1) and tissue metallopeptidase inhibitor 1 (Timp1) as well as inflammatory gene expression of tumor necrosis factor alpha (Tnfa) and expression of transmembrane glycoprotein NMB (Gpnmb) in liver tissue compared to glucose and control diets. Single cell RNA sequencing (scRNAseq) revealed fructose elevated expression of matrix metallopeptidase 12 (Mmp12), interleukin 1 receptor antagonist (Il1rn), and radical S-adenosyl methionine domain (Rsad2) in liver and hepatic macrophages. In vitro studies using IMKC and J774.1 cells demonstrated decreased viability when exposed to fructose. Additionally, fructose increased Gpnmb, Tnfa, Mmp12, Il1rn, and Rsad2 in unpolarized IMKC. By mass spectrometry, C13 fructose tracing detected fructose metabolites in glycolysis and the pentose phosphate pathway (PPP). Inhibition of the PPP further increased fructose induced Il6, Gpnmb, Mmp12, Il1rn, and Rsad2 in nonpolarized IMKC. Taken together, fructose decreases cell viability while upregulating resolution and anti-inflammatory associated genes in Kupffer cells.
Topics: Child; Humans; Kupffer Cells; Fructose; Pentose Phosphate Pathway; Matrix Metalloproteinase 12; Liver; Non-alcoholic Fatty Liver Disease; Fibrosis; Phenotype
PubMed: 38369593
DOI: 10.1038/s41598-024-54272-w -
PloS One 2023Growing evidence is demonstrating the connection between the microbiota gut-brain axis and neurodevelopment. Microbiota colonization occurs before the maturation of many...
Growing evidence is demonstrating the connection between the microbiota gut-brain axis and neurodevelopment. Microbiota colonization occurs before the maturation of many neural systems and is linked to brain health. Because of this it has been hypothesized that the early microbiome interactions along the gut-brain axis evolved to promote advanced cognitive functions and behaviors. Here, we performed a pilot study with a multidisciplinary approach to test if the microbiota composition of infants is associated with measures of early cognitive development, in particular neural rhythm tracking; language (forward speech) versus non-language (backwards speech) discrimination; and social joint attention. Fecal samples were collected from 56 infants between four and six months of age and sequenced by shotgun metagenomic sequencing. Of these, 44 performed the behavioral Point and Gaze test to measure joint attention. Infants were tested on either language discrimination using functional near-infrared spectroscopy (fNIRS; 25 infants had usable data) or neural rhythm tracking using electroencephalogram (EEG; 15 had usable data). Infants who succeeded at the Point and Gaze test tended to have increased Actinobacteria and reduced Firmicutes at the phylum level; and an increase in Bifidobacterium and Eggerthella along with a reduction in Hungatella and Streptococcus at the genus level. Measurements of neural rhythm tracking associated negatively to the abundance of Bifidobacterium and positively to the abundance of Clostridium and Enterococcus for the bacterial abundances, and associated positively to metabolic pathways that can influence neurodevelopment, including branched chain amino acid biosynthesis and pentose phosphate pathways. No associations were found for the fNIRS language discrimination measurements. Although the tests were underpowered due to the small pilot sample sizes, potential associations were identified between the microbiome and measurements of early cognitive development that are worth exploring further.
Topics: Humans; Infant; Pilot Projects; Gastrointestinal Microbiome; Microbiota; Bacteria; Feces; Brain
PubMed: 37556397
DOI: 10.1371/journal.pone.0288689 -
Biomedicine & Pharmacotherapy =... Aug 2023Huangqi-Danshen decoction (HDD), a Chinese herbal preparation, is effective in clinical treatment of chronic kidney disease (CKD). However, the underlying mechanism...
Huangqi-Danshen decoction (HDD), a Chinese herbal preparation, is effective in clinical treatment of chronic kidney disease (CKD). However, the underlying mechanism remains to be clarified. In this study, we aimed to investigate the role of HDD in the regulation of renal glucose metabolism in a CKD mouse model. The 0.2% adenine-induced CKD mouse model was administered HDD extract at a dose of 6.8 g/kg/day for 4 weeks. Detection of renal glucose metabolites was performed by ultra-performance liquid chromatography-tandem mass spectrometry. The expression of renal fibrosis and glucose metabolism-related proteins was tested by Western blotting, immunohistochemistry, and immunofluorescence. The results showed that HDD treatment could significantly reduce serum creatinine (0.36 ± 0.10 mg/dL vs. 0.51 ± 0.07 mg/dL, P < 0.05) and blood urea nitrogen (40.02 ± 3.73 mg/dL vs. 62.91 ± 10 mg/dL, P < 0.001) levels, and improve renal pathological injury and fibrosis. Aberrant glucose metabolism was found in the kidneys of CKD mice, manifested by enhanced glycolysis and pentose phosphate pathway, and tricarboxylic acid cycle inhibition, which could be partially restored by HDD treatment. Furthermore, HDD regulated the expression of hexokinase 2, phosphofructokinase, pyruvate kinase M2, pyruvate dehydrogenase E1, oxoglutarate dehydrogenase, and glucose-6-phosphate dehydrogenase in CKD mice. In conclusion, HDD protected against adenine-induced CKD, reshaped glucose metabolism profiles, and restored the expression of key enzymes of glucose metabolism in the kidneys of CKD mice. This study sheds light on targeting glucose metabolism for the treatment of CKD and screening small molecule compounds from herbal medicine to slow CKD progression.
Topics: Mice; Animals; Salvia miltiorrhiza; Renal Insufficiency, Chronic; Kidney; Disease Models, Animal; Fibrosis; Pentose Phosphate Pathway; Glucose; Adenine
PubMed: 37315436
DOI: 10.1016/j.biopha.2023.114989 -
Current Oncology (Toronto, Ont.) Dec 2023Preclinical and clinical studies have suggested potential synergies of combining poly (ADP-ribose) polymerase (PARP) inhibitors and novel hormonal therapies (NHT) for... (Review)
Review
Preclinical and clinical studies have suggested potential synergies of combining poly (ADP-ribose) polymerase (PARP) inhibitors and novel hormonal therapies (NHT) for patients with metastatic castration-resistant prostate cancer (mCRPC). We systematically searched PubMed, ClinicalTrials.gov and ASCO-GU annual meeting abstracts up to March 2023 to identify potential phase III trials reporting the use of combining PARP inhibitors with NHT in the first-line setting for mCRPC. A total of four phase III trials met the criteria for subsequent review. Emerging data suggested that the radiographic progression-free survival (rPFS) was significantly longer in the PARP inhibitor combined with NHT group versus the placebo plus NHT group for the first-line setting of biomarker-unselected mCRPC patients, especially for patients with homologous recombination repair (HRR) mutation (HRR m), and with the greatest benefit for BRCA1/2 mutation (BRCA1/2 m) populations. Final overall survival (OS) data of the PROpel trial indicated a significant improvement in median OS for mCRPC patients with HRR m and BRCA1/2 m receiving olaparib + abiraterone. Prior taxane-based chemotherapy might not influence the efficacy of the combination. Compared with the current standard-of-care therapies, combining NHT with PARP inhibitors could achieve a significant survival benefit in the first-line setting for mCRPC patients with HRR and BRCA1/2 mutations.
Topics: Male; Humans; Poly(ADP-ribose) Polymerase Inhibitors; Prostatic Neoplasms, Castration-Resistant; BRCA1 Protein; Ribose; BRCA2 Protein; Antineoplastic Agents
PubMed: 38132385
DOI: 10.3390/curroncol30120751 -
Nutrients Sep 2023Erythritol is a non-nutritive sugar replacement that can be endogenously produced by humans. Witkowski et al. reported that elevated circulating erythritol is associated... (Review)
Review
Erythritol is a non-nutritive sugar replacement that can be endogenously produced by humans. Witkowski et al. reported that elevated circulating erythritol is associated with adverse cardiovascular events in three independent cohorts, demonstrated in vitro and ex vivo that erythritol promotes platelet activation, and showed faster clotting time in mice injected with erythritol. It was concluded that erythritol fosters enhanced thrombosis. This narrative review presents additional evidence that needs to be considered when evaluating these data and conclusions. We conducted a search of all studies related to erythritol exposure with focus on those that reported vascular health outcomes. Patients with chronically elevated erythritol levels due to inborn errors of metabolism do not exhibit higher platelet activation or thrombosis risk. Most long-term studies in which animals consumed high levels of erythritol do not support its role in platelet activation and thrombosis formation. Clinical data on the effects of chronic intake of erythritol are limited. Erythritol may be merely a marker of dysregulation in the Pentose Phosphate Pathway caused by impaired glycemia. However, this suggestion and the findings of Witkowski et al. need to be further examined. Clinical trials examining the long-term effects of erythritol consumption on cardiometabolic outcomes are required to test the causality between dietary erythritol and cardiometabolic risk. Until supportive data from these trials are available, it cannot be concluded that dietary erythritol promotes platelet activation, thrombosis, and cardiometabolic risk.
Topics: Humans; Mice; Animals; Erythritol; Diet; Pentose Phosphate Pathway; Causality; Cardiovascular Diseases
PubMed: 37764794
DOI: 10.3390/nu15184011 -
Frontiers in Cell and Developmental... 2023Acute kidney injury (AKI) induces significant energy metabolic reprogramming in renal tubular epithelial cells (TECs), thereby altering lipid, glucose, and amino acid... (Review)
Review
Acute kidney injury (AKI) induces significant energy metabolic reprogramming in renal tubular epithelial cells (TECs), thereby altering lipid, glucose, and amino acid metabolism. The changes in lipid metabolism encompass not only the downregulation of fatty acid oxidation (FAO) but also changes in cell membrane lipids and triglycerides metabolism. Regarding glucose metabolism, AKI leads to increased glycolysis, activation of the pentose phosphate pathway (PPP), inhibition of gluconeogenesis, and upregulation of the polyol pathway. Research indicates that inhibiting glycolysis, promoting the PPP, and blocking the polyol pathway exhibit a protective effect on AKI-affected kidneys. Additionally, changes in amino acid metabolism, including branched-chain amino acids, glutamine, arginine, and tryptophan, play an important role in AKI progression. These metabolic changes are closely related to the programmed cell death of renal TECs, involving autophagy, apoptosis, necroptosis, pyroptosis, and ferroptosis. Notably, abnormal intracellular lipid accumulation can impede autophagic clearance, further exacerbating lipid accumulation and compromising autophagic function, forming a vicious cycle. Recent studies have demonstrated the potential of ameliorating AKI-induced kidney damage through calorie and dietary restriction. Consequently, modifying the energy metabolism of renal TECs and dietary patterns may be an effective strategy for AKI treatment.
PubMed: 38054182
DOI: 10.3389/fcell.2023.1276217 -
ELife Aug 2023In vertebrates with elongated auditory organs, mechanosensory hair cells (HCs) are organised such that complex sounds are broken down into their component frequencies...
In vertebrates with elongated auditory organs, mechanosensory hair cells (HCs) are organised such that complex sounds are broken down into their component frequencies along a proximal-to-distal long (tonotopic) axis. Acquisition of unique morphologies at the appropriate position along the chick cochlea, the basilar papilla, requires that nascent HCs determine their tonotopic positions during development. The complex signalling within the auditory organ between a developing HC and its local niche along the cochlea is poorly understood. Using a combination of live imaging and NAD(P)H fluorescence lifetime imaging microscopy, we reveal that there is a gradient in the cellular balance between glycolysis and the pentose phosphate pathway in developing HCs along the tonotopic axis. Perturbing this balance by inhibiting different branches of cytosolic glucose catabolism disrupts developmental morphogen signalling and abolishes the normal tonotopic gradient in HC morphology. These findings highlight a causal link between graded morphogen signalling and metabolic reprogramming in specifying the tonotopic identity of developing HCs.
Topics: Animals; Chickens; Cochlea; Organ of Corti; Hair Cells, Auditory; Glucose
PubMed: 37539863
DOI: 10.7554/eLife.86233 -
Biotechnology For Biofuels and... Oct 2023Mycosporine-like amino acids (MAAs), including shinorine and porphyra-334, are gaining attention as safe natural sunscreens. The production of MAAs has been achieved in...
BACKGROUND
Mycosporine-like amino acids (MAAs), including shinorine and porphyra-334, are gaining attention as safe natural sunscreens. The production of MAAs has been achieved in diverse microbial hosts, including Saccharomyces cerevisiae. While S. cerevisiae is the most extensively studied model yeast, the oleaginous yeast Yarrowia lipolytica has emerged as a promising candidate for the synthesis of valuable products. In this study, we explored the potential of Y. lipolytica as a host for producing MAAs, utilizing its advantages such as a robust pentose phosphate pathway flux and versatile carbon source utilization.
RESULTS
We produced MAAs in Y. lipolytica by introducing the MAA biosynthetic genes from cyanobacteria Nostoc punctiforme and Anabaena variabilis. These genes include mysA, mysB, and mysC responsible for producing mycosporine-glycine (MG) from sedoheptulose 7-phosphate (S7P). The two strains utilize different enzymes, D-Ala-D-Ala ligase homologue (MysD) in N. punctiforme and NRPS-like enzyme (MysE) in A. variabilis, for amino acid conjugation to MG. MysE specifically generated shinorine, a serine conjugate of MG, while MysD exhibited substrate promiscuity, yielding both shinorine and a small amount of porphyra-334, a threonine conjugate of MG. We enhanced MAAs production by selecting mysA, mysB, and mysC from A. variabilis and mysD from N. punctiforme based on their activities. We further improved production by strengthening promoters, increasing gene copies, and introducing the xylose utilization pathway. Co-utilization of xylose with glucose or glycerol increased MAAs production by boosting the S7P pool through the pentose phosphate pathway. Overexpressing GND1 and ZWF1, key genes in the pentose phosphate pathway, further enhanced MAAs production. The highest achieved MAAs level was 249.0 mg/L (207.4 mg/L shinorine and 41.6 mg/L of porphyra-334) in YP medium containing 10 g/L glucose and 10 g/L xylose.
CONCLUSIONS
Y. lipolytica was successfully engineered to produce MAAs, primarily shinorine. This achievement involved the introduction of MAA biosynthetic genes from cyanobacteria, establishing xylose utilizing pathway, and overexpressing the pentose phosphate pathway genes. These results highlight the potential of Y. lipolytica as a promising yeast chassis strain for MAAs production, notably attributed to its proficient expression of MysE enzyme, which remains non-functional in S. cerevisiae, and versatile utilization of carbon sources like glycerol.
PubMed: 37899467
DOI: 10.1186/s13068-023-02415-y -
Cancer Drug Resistance (Alhambra,... 2023Cancer cells adapt to environmental changes and alter their metabolic pathways to promote survival and proliferation. Metabolic reprogramming not only allows tumor cells... (Review)
Review
A comprehensive overview of recent developments on the mechanisms and pathways of ferroptosis in cancer: the potential implications for therapeutic strategies in ovarian cancer.
Cancer cells adapt to environmental changes and alter their metabolic pathways to promote survival and proliferation. Metabolic reprogramming not only allows tumor cells to maintain a reduction-oxidation balance by rewiring resources for survival, but also causes nutrient addiction or metabolic vulnerability. Ferroptosis is a form of regulated cell death characterized by the iron-dependent accumulation of lipid peroxides. Excess iron in ovarian cancer amplifies free oxidative radicals and drives the Fenton reaction, thereby inducing ferroptosis. However, ovarian cancer is characterized by ferroptosis resistance. Therefore, the induction of ferroptosis is an exciting new targeted therapy for ovarian cancer. In this review, potential metabolic pathways targeting ferroptosis were summarized to promote anticancer effects, and current knowledge and future perspectives on ferroptosis for ovarian cancer therapy were discussed. Two therapeutic strategies were highlighted in this review: directly inducing the ferroptosis pathway and targeting metabolic vulnerabilities that affect ferroptosis. The overexpression of SLC7A11, a cystine/glutamate antiporter SLC7A11 (also known as xCT), is involved in the suppression of ferroptosis. xCT inhibition by ferroptosis inducers (e.g., erastin) can promote cell death when carbon as an energy source of glucose, glutamine, or fatty acids is abundant. On the contrary, xCT regulation has been reported to be highly dependent on the metabolic vulnerability. Drugs that target intrinsic metabolic vulnerabilities (e.g., GLUT1 inhibitors, PDK4 inhibitors, or glutaminase inhibitors) predispose cancer cells to death, which is triggered by decreased nicotinamide adenine dinucleotide phosphate generation or increased reactive oxygen species accumulation. Therefore, therapeutic approaches that either directly inhibit the xCT pathway or target metabolic vulnerabilities may be effective in overcoming ferroptosis resistance. Real-time monitoring of changes in metabolic pathways may aid in selecting personalized treatment modalities. Despite the rapid development of ferroptosis-inducing agents, therapeutic strategies targeting metabolic vulnerability remain in their infancy. Thus, further studies must be conducted to comprehensively understand the precise mechanism linking metabolic rewiring with ferroptosis.
PubMed: 37842240
DOI: 10.20517/cdr.2023.49