Glucose-induced CRL4COP1-p53 axis amplifies glycometabolism to drive tumorigenesis.

The diabetes-cancer association remains underexplained. Here, we describe a glucose-signaling axis that reinforces glucose uptake and glycolysis to consolidate the Warburg effect and overcome tumor suppression. Specifically, glucose-dependent CK2 O-GlcNAcylation impedes its phosphorylation of CSN2, a modification required for the deneddylase CSN to sequester Cullin RING ligase 4 (CRL4). Glucose, therefore, elicits CSN-CRL4 dissociation to assemble the CRL4COP1 E3 ligase, which targets p53 to derepress glycolytic enzymes. A genetic or pharmacologic disruption of the O-GlcNAc-CK2-CSN2-CRL4COP1 axis abrogates glucose-induced p53 degradation and cancer cell proliferation. Diet-induced overnutrition upregulates the CRL4COP1-p53 axis to promote PyMT-induced mammary tumorigenesis in wild type but not in mammary-gland-specific p53 knockout mice. These effects of overnutrition are reversed by P28, an investigational peptide inhibitor of COP1-p53 interaction. Thus, glycometabolism self-amplifies via a glucose-induced post-translational modification cascade culminating in CRL4COP1-mediated p53 degradation. Such mutation-independent p53 checkpoint bypass may represent the carcinogenic origin and targetable vulnerability of hyperglycemia-driven cancer.

Glucose-oxygen coupling can serve as a biomarker for neuroinflammation-related genetic variants.

The single-nucleotide polymorphism rs3197999 in the macrophage-stimulating protein 1 gene is a missense variant. Studies have indicated that macrophage-stimulating protein 1 mediates neuronal loss and synaptic plasticity damage, and overexpression of the macrophage-stimulating protein 1 gene leads to the excessive activation of microglial cells, thereby resulting in an elevation of cerebral glucose metabolism. Traditional diagnostic models may be disrupted by neuroinflammation, making it difficult to predict the pathological status of patients solely based on single-modal images. We hypothesize that the macrophage-stimulating protein 1 rs3197999 single-nucleotide polymorphism may lead to imbalances in glucose and oxygen metabolism, thereby influencing cognitive resilience and the progression of Alzheimer's disease. In this study, we found that among 121 patients with mild cognitive impairment, carriers of the macrophage-stimulating protein 1 rs3197999 risk allele showed a significant reduction in the coupling of glucose and oxygen metabolism in the dorsolateral prefrontal cortex region. However, the rs3197999 variant did not induce significant differences in glucose metabolism and neuronal activity signals. Furthermore, the rs3197999 risk allele correlated with a higher rate of increase in clinical dementia score, mediated by the coupling of glucose and oxygen metabolism.

PGD: Shared gene linking polycystic ovary syndrome and endometrial cancer, influencing proliferation and migration through glycometabolism.

The relationship among polycystic ovary syndrome (PCOS), endometrial cancer (EC), and glycometabolism remains unclear. We explored shared genes between PCOS and EC, using bioinformatics to unveil their pathogenic connection and influence on EC prognosis. Gene Expression Omnibus datasets GSE226146 (PCOS) and GSE196033 (EC) were used. A protein-protein interaction (PPI) network was constructed to identify the central genes. Candidate markers were screened using dataset GSE54250. Differences in marker expression were confirmed in mouse PCOS and human EC tissues using RT-PCR and immunohistochemistry. The effect of PGD on EC proliferation and migration was explored using Ki-67 and Transwell assays. PGD's impact on the glycometabolic pathway within carbon metabolism was assessed by quantifying glucose content and lactic acid production. R software identified 31 common genes in GSE226146 and GSE196033. Gene Ontology functional classification revealed enrichment in the "purine nucleoside triphosphate metabolism process," with key Kyoto Encyclopedia of Genes and Genomes pathways related to "carbon metabolism." The PPI network identified 15 hub genes. HK2, NDUFS8, PHGDH, PGD, and SMAD3 were confirmed as candidate markers. The RT-PCR analysis validated distinct HK2 and PGD expression patterns in mouse PCOS ovarian tissue and human EC tissue, as well as in normal and EC cells. Transfection experiments with Ishikawa cells further confirmed PGD's influence on cell proliferation and migration. Suppression of PGD expression impeded glycometabolism within the carbon metabolism of EC cells, suggesting PGD as a significant PCOS risk factor impacting EC proliferation and migration through modulation of single carbon metabolism. These findings highlight PGD's pivotal role in EC onset and prognosis.

MicroRNA-148a-3p suppresses the glycolysis and Cell proliferation by targeting transmembrane protein 54 in liver cancer.

Liver cancer is the fourth most lethal cancer, but the treatment options for liver cancer are usually limited. Metabolic reprogramming is a hallmark of malignancy, ensuring activated cell glycolysis and increased macromolecular precursors required for the proliferation and migration of exuberant cancer cells. MicroRNAs (miRNAs) have been reported to participate in cancer metabolic shifts mainly by directly silencing the expression of specific genes. Here, we identified miR-148a-3p as a negative regulator for glycometabolism and cell proliferation in liver cancer. miR-148a-3p directly targets the 3'UTR of transmembrane protein 54 (TMEM54), leading to the significant inhibition of lactate production, glucose consumption, intracellular ATP level and extracellular acidification rate (ECAR), as well as the repression of the proliferation and colony formation ability of liver cancer cells. miR-148a-3p expression is often down-regulated in liver cancer tissues. In addition, there was a negative correlation between the expression levels of miR-148a-3p and TMEM54 in liver cancer tissues. Moreover, the low miR-148a-3p expression levels or high TMEM54 expression levels were associated with poorer prognosis in hepatocellular carcinoma (HCC) patients. Together, these findings support that the miR-148a-3p/TMEM54 regulatory pathway regulates the glycometabolism and cell proliferation in liver cancer, which is a possible target for the diagnosis and treatment of liver cancer.

Excessive Tryptophan and Phenylalanine Induced Pancreatic Injury and Glycometabolism Disorder in Grower-finisher Pigs.

BACKGROUND: The increase in circulating insulin levels is associated with the onset of type 2 diabetes (T2D), and the levels of branched-chain amino acids and aromatic amino acids (AAAs) are altered in T2D, but whether AAAs play a role in insulin secretion and signaling remains unclear. OBJECTIVES: This study aimed to investigate the effects of different AAAs on pancreatic function and on the use of insulin in finishing pigs. METHODS: A total of 18 healthy finishing pigs (Large White) with average body weight of 100 ± 1.15 kg were randomly allocated to 3 dietary treatments: Con, a normal diet supplemented with 0.68% alanine; Phe, a normal diet supplemented with 1.26% phenylalanine; and Trp, a normal diet supplemented with 0.78% tryptophan. The 3 diets were isonitrogenous. There were 6 replicates in each group. RESULTS: Herein, we investigated the effects of tryptophan and phenylalanine on pancreatic function and the use of insulin in finishing pigs and found that the addition of tryptophan and phenylalanine aggravated pancreatic fat deposition, increased the relative content of saturated fatty acids, especially palmitate (C16:0) and stearate (C18:0), and the resulting lipid toxicity disrupted pancreatic secretory function. We also found that tryptophan and phenylalanine inhibited the growth and secretion of ß-cells, downregulated the gene expression of the PI3K/Akt pathway in the pancreas and liver, and reduced glucose utilization in the liver. CONCLUSIONS: Using fattening pigs as a model, multiorgan combined analysis of the insulin-secreting organ pancreas and the main insulin-acting organ liver, excessive intake of tryptophan and phenylalanine will aggravate pancreatic damage leading to glucose metabolism disorders, providing new evidence for the occurrence and development of T2D.

RP11-495P10.1 promotes HCC cell proliferation by regulating reprogramming of glucose metabolism and acetylation of the NR4A3 promoter via the PDK1/PDH axis.

The incidence and related death of hepatocellular carcinoma (HCC) have increased over the past decades. However, the molecular mechanisms underlying HCC pathogenesis are not fully understood. Long noncoding RNA (lncRNA) RP11-495P10.1 has been proven to be closely associated with the progression of prostate cancer, but its role and specific mechanism in HCC are still unknown. Here, we identify that RP11-495P10.1 is highly expressed in HCC tissues and cells and contributes to the proliferation of HCC cells. Moreover, this study demonstrates that RP11-495P10.1 affects the proliferation of HCC by negatively regulating the expression of nuclear receptor subfamily 4 group a member 3 (NR4A3). Glycometabolism reprogramming is one of the main characteristics of tumor cells. In this study, we discover that RP11-495P10.1 regulates glycometabolism reprogramming by changing the expression of pyruvate dehydrogenase kinase 1 (PDK1) and pyruvate dehydrogenase (PDH), thus contributing to the proliferation of HCC cells. Furthermore, knockdown of RP11-495P10.1 increases enrichment of H3K27Ac in the promoter of NR4A3 by promoting the activity of PDH and the production of acetyl-CoA, which leads to the increased transcription of NR4A3. Altogether, RP11-495P10.1 promotes HCC cell proliferation by regulating the reprogramming of glucose metabolism and acetylation of the NR4A3 promoter via the PDK1/PDH axis, which provides an lncRNA-oriented therapeutic strategy for the diagnosis and treatment of HCC.

Polystyrene microplastics disturb maternal glucose homeostasis and induce adverse pregnancy outcomes.

Pregnant women are a special group that is sensitive to adverse external stimuli, causing metabolic abnormalities and adverse pregnancy outcomes. Microplastics (MPs), an environmental pollutant widely used in various fields, can induce a variety of toxic responses in mammals. Recent studies verified an association between MPs and metabolic disorders. Our research built a gestational mouse model in which polystyrene microplastics (PS-MPs) of 1 µm size were consumed at concentrations of 0.1, 1, and 10 mg/L during pregnancy. Results indicated that PS-MPs induced placental malfunction and fetal growth retardation. Significant glucose disorders, decreased liver function, hepatic inflammation, and oxidative stress were also observed after PS-MPs exposure. The hepatic SIRT1/IRS1/PI3K pathway was inhibited in the 10 mg/L PS-MPs exposure group. Our study found that PS-MPs activated inflammatory response and oxidative stress by increasing hepatic lipopolysaccharide (LPS) that inhibited the hepatic SIRT1/IRS1/PI3K pathway, ultimately leading to insulin resistance, glucose metabolism disorders, and adverse pregnancy outcomes. This study provides a basis for preventing environment-related gestational diabetes and concomitant adverse pregnancy outcomes.

Inhibition of Expression of the Circadian Clock Gene Cryptochrome 1 Causes Abnormal Glucometabolic and Cell Growth in Bombyx mori Cells.

Cryptochrome is the earliest discovered photoreceptor protein in organisms. However, the effect of CRY (BmCRY), the clock protein in Bombyx mori, on the body or cell metabolism remains unclear. In this study, we continuously interfered with the expression of the BmCry1 gene (Cry1-KD) in the silkworm ovary cell line (BmN), and the BmN cells developed abnormally, with accelerated cell growth and a smaller nucleus. Metabolomics was used to identify the cause of the abnormal development of Cry1-KD cells based on gas chromatography/liquid chromatography-mass spectrometry. A total of 56 differential metabolites including sugars, acids, amino acids, and nucleotides were identified in wild-type and Cry1-KD cells. KEGG enrichment analysis showed that BmCry1 knockdown resulted in significantly upregulated glycometabolism in BmN cells, indicated by glucose-6-phosphate, fructose-6-phosphate, and pyruvic acid levels. The activities of key enzymes BmHK, BmPFK, and BmPK as well as their mRNA levels further confirmed that the glycometabolism level of Cry1-KD cells was significantly increased. Our results show that a possible mechanism of BmCry1 knockdown leading to abnormal cell development is the elevated level of glucose metabolism in cells.

Combining Metabolomics and Transcriptomics to Reveal the Regulatory Mechanism of Taproot Enlargement in Panax ginseng.

Ginseng is regarded as the "king of herbs" in China, with its roots and rhizomes used as medicine, and it has a high medicinal value. In order to meet the market demand, the artificial cultivation of ginseng emerged, but different growth environments significantly affect the root morphology of garden ginseng. In this study, we used ginseng cultivated in deforested land (CF-CG) and ginseng cultivated in farmland (F-CG) as experimental materials. These two phenotypes were explored at the transcriptomic and metabolomic levels so as to understand the regulatory mechanism of taproot enlargement in garden ginseng. The results show that, compared with those of F-CG, the thickness of the main roots in CF-CG was increased by 70.5%, and the fresh weight of the taproots was increased by 305.4%. Sucrose, fructose and ginsenoside were significantly accumulated in CF-CG. During the enlargement of the taproots of CF-CG, genes related to starch and sucrose metabolism were significantly up-regulated, while genes related to lignin biosynthesis were significantly down-regulated. Auxin, gibberellin and abscisic acid synergistically regulated the enlargement of the taproots of the garden ginseng. In addition, as a sugar signaling molecule, T6P might act on the auxin synthesis gene ALDH2 to promote the synthesis of auxin and, thus, participate in the growth and development of garden ginseng roots. In summary, our study is conducive to clarifying the molecular regulation mechanism of taproot enlargement in garden ginseng, and it provides new insights for the further exploration of the morphogenesis of ginseng roots.

OBHS Drives Abnormal Glycometabolis Reprogramming via GLUT1 in Breast Cancer.

Due to the poor metabolic conditions fomenting the emergence of the Warburg effect (WE) phenotype, abnormal glycometabolism has become a unique and fundamental research topic in the field of tumor biology. Moreover, hyperglycemia and hyperinsulinism are associated with poor outcomes in patients with breast cancer. However, there are a few studies on anticancer drugs targeting glycometabolism in breast cancer. We hypothesized that Oxabicycloheptene sulfonate (OBHS), a class of compounds that function as selective estrogen receptor modulators, may hold potential in a therapy for breast cancer glycometabolism. Here, we evaluated concentrations of glucose, glucose transporters, lactate, 40 metabolic intermediates, and glycolytic enzymes using an enzyme-linked immunosorbent assay, Western blotting, and targeted metabolomic analysis in, in vitro and in vivo breast cancer models. OBHS significantly inhibited the expression of glucose transporter 1 (GLUT1) via PI3K/Akt signaling pathway to suppress breast cancer progression and proliferation. Following an investigation of the modulatory effect of OBHS on breast cancer cells, we found that OBHS suppressed the glucose phosphorylation and oxidative phosphorylation of glycolytic enzymes, leading to the decreased biological synthesis of ATP. This study was novel in highlighting the role of OBHS in the remodeling of tumor glycometabolism in breast cancer, and this is worth further investigation of breast cancer in clinical trials.

Molecular and Functional Analysis of Trehalose-6-Phosphate Synthase Genes Enhancing Salt Tolerance in Anoectochilus roxburghii (Wall.) Lindl.

Trehalose is a reducing disaccharide, acting as a protectant against various environmental stresses in numerous organisms. In plants, trehalose-6-phosphate synthase (TPS) plays a crucial role in trehalose biosynthesis. Anoectochilus roxburghii (Wall.) Lindl. is a prominent species of the Anoectochilus genus, widely utilized as a health food. However, the functional analysis of TPS in this species has been limited. In this study, TPS genes were cloned from A. roxburghii. The ArTPS gene, with an open reading frame spanning 2850 bp, encodes 950 amino acids. Comparative and bioinformatics analysis revealed that the homology was presented between the ArTPS protein and TPSs from other plant species. The ORF sequence was utilized to construct a prokaryotic expression vector, Pet28a-ArTPS, which was then transformed into Escherichia coli. The resulting transformants displayed a significant increase in salt tolerance under the stress conditions of 300 mmol/L NaCl. Quantitative RT-PCR analysis demonstrated that the expression of ArTPS genes responded to NaCl stress. The accumulation of G6P was upregulated, whereas the content of T6P exhibited an opposite expression trend. The glycometabolism products, including trehalose, exhibited notable changes under NaCl stress, although their variations may differ in response to stimulation. The content of kinsenoside, a characteristic product of A. roxburghii, was significantly upregulated under NaCl stress. These results suggest that the ArTPS genes function in response to NaCl stimulation and play a key role in polysaccharide and glycoside metabolism in Anoectochilus. This study provides new insights into the engineering modification of the health food A. roxburghii to enhance the medicinal activity of its ingredients.

PINK1-dependent and Parkin-independent mitophagy is involved in reprogramming of glycometabolism in pancreatic cancer cells.

Cancer cells rely on glycolysis to generate ATP for survival. However, inhibiting glycolysis is insufficient for the eradication of cancer cells because glycolysis-suppressed cells undergo metabolic reprogramming toward mitochondrial oxidative phosphorylation. We previously described that upon glycolytic suppression in pancreatic cancer cells, intracellular glycometabolism is shifted toward mitochondrial oxidative phosphorylation in an autophagy-dependent manner for cellular survival. Here, we hypothesized that mitophagy, which selectively degrades mitochondria via autophagy, is involved in mitochondrial activation under metabolic reprogramming. We revealed that glycolytic suppression notably increased mitochondrial membrane potential and mitophagy in a pancreatic cancer cell model (PANC-1). PTEN-induced kinase 1 (PINK1), a ubiquitin kinase that regulates mitophagy in healthy cells, regulated mitochondrial activation through mitophagy by glycolytic suppression. However, Parkin, a ubiquitin ligase regulated by PINK1 in healthy cells to induce mitophagy, was not involved in the PINK1-dependent mitophagy of the cancer glycometabolism. These results imply that cancer cells and healthy cells have different regulatory pieces of machinery for mitophagy, and inhibition of cancer-specific mechanisms may be a potential strategy for cancer therapy targeting metabolic reprogramming.

Turmeric and curcuminiods ameliorate disorders of glycometabolism among subjects with metabolic diseases: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND AND AIMS: Metabolic diseases are globally popular, and a systematic review and meta-analysis of turmeric and curcuminoids on glucose metabolism among people with metabolic diseases was performed. DESIGN: We comprehensively searched Web of Science, PubMed, Ovid (including EMBASE and MEDLINE), Scopus, the Cochrane Library and two Chinese databases, Wanfang and CNKI for RCTs that focused on the effects of turmeric and curcuminoids on fasting blood glucose (FBG), hemoglobin A1C (HbA1c), fasting serum insulin (FSI) and HOMA-IR among patients with metabolic diseases. The FBG and HbA1c were the main outcomes to be analyzed. With random-effects models, separate meta-analyses were conducted by inverse-variance and reported as WMD with 95% CIs. RESULTS: Evidence from 17 RCTs including 22 trials showed that turmeric and curcuminoids lowered FBG by - 7.86 mg/dL (95% CI: -12.04, -3.67 mg/dL; P = 0.0002), HbA1c by - 0.38% (95% CI: -0.52%, -0.23%; P < 0.00001) and HOMA-IR by - 1.01 (95% CI: -1.6, -0.42; P = 0.0008). Moreover, they decreased fasting serum insulin by - 1.69 mU/L (95% CI: -3.22, -0.16 mU/L; P = 0.03) after more than 8 weeks of intervention in a subgroup analysis. CONCLUSIONS: Turmeric and curcuminiods decrease FBG, HbA1c and HOMA-IR significantly among subjects with metabolic disease. Additionally, they may have an effect on FSI concentrations if the intervention period is more than 8 weeks. However, attention should be paid to these outcomes due to the significant heterogeneity.

Characteristics of the gut microbiota in pregnant women with fetal growth restriction.

BACKGROUND: Fetal growth restriction (FGR) in utero leads to failure of fetus to reach the genetically normal growth potential. Currently available means of treating FGR are limited. And it remains unknown how pregnant women who give birth to FGR fetus differ in gut microbiota composition from normal pregnant women. METHODS: In this case-control study, fecal samples were obtained from maternal rectum in the operation room by an obstetrician under strict aseptic conditions. We compared gut microbiota of 14 pregnant women with FGR and 18 normal controls by performing 16S rDNA amplicon sequencing. RESULTS: We identified significant differences in ß-diversity between the FGR and control groups (P < 0.05). At genus level, Bacteroides, Faecalibacterium and Lachnospira were highly abundant in the FGR subjects, which are significantly enriched in Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways related to glycometabolism. CONCLUSION: These findings demonstrated that the distinct composition of the gut microbiota between FGR and normal pregnant women could contribute to an improved understanding of the prevention and treatment of FGR.

Analysis of the complete genome sequence of Lactobacillus delbrueckii ssp. bulgaricus with post-acidification capacity and its influence on yogurt in storage.

In recent years, yogurt has been one of the most popular fermented dairy products and is sold worldwide. In this study, pH and titrated acid changes of 4 strains of Lactobacillus delbrueckii ssp. bulgaricus fermented milk during storage were detected. The difference between L. bulgaricus KLDS1.1011 and KLDS1.0207 was significant, with the latter exhibiting reduced acidity levels. Therefore, we determined the complete genome sequence of the 2 strains. Then the expression of specific genes and common genes related to glucose metabolism and proteolysis of L. bulgaricus KLDS1.1011 and KLDS1.0207 were detected by quantitative real-time reverse-transcription PCR. Analysis indicated that the key enzymes in glycometabolism and proteolysis of L. bulgaricus KLDS1.1011 were significantly different than those of L. bulgaricus KLDS1.0207. The contents of lactose and glucose decreased during storage of L. bulgaricus fermented milk, as determined by HPLC, and the contents of lactic acid and galactose increased, with L. bulgaricus KLDS1.1011 increasing less. With skim milk as a raw material, L. bulgaricus KLDS1.1011, KLDS1.0207, and Streptococcus thermophilus S1 were used as fermentation strains to yield yogurt at 42°C, and sensory evaluation was compared with yogurt fermented by commercial starter cultures. Yogurt from L. bulgaricus KLDS1.1011 was the highest-rated. Therefore, the study may provide guidelines for the development of yogurt starters.

Metformin-induced AMPK activation suppresses larval growth and molting probably by disrupting 20E synthesis and glycometabolism in fall webworm, Hyphantria cunea Drury.

Metformin, considered to be a potent AMPK activator, is widely used for clinical therapy of cancer and diabetes due to its distinct function in regulating cell energy balance and body metabolism. However, the effect of metformin-induced AMPK activation on the growth and development of insects remains largely unknown. In the present study, we focused on the role of metformin in regulating the growth and development of Hyphantria cunea, a notorious defoliator in the forestry. Firstly, we obtained the complete coding sequences of HcAMPKα2, HcAMPKß1, HcAMPKγ2 from H. cunea, which encoded a protein of 512, 281, and 680 amino acids respectively. Furthermore, the phylogenetic analysis revealed that these three subunits were highly homologous with the AMPK subunits from other lepidopteran species. According to the bioassay, we found metformin remarkably restrained the growth and development of H. cunea larvae, and caused molting delayed and body weight reduced. In addition, expressions of HcAMPKα2, HcAMPKß1, and HcAMPKγ2 were upregulated 3.30-, 5.93- and 5.92-folds at 24 h after treatment, confirming that metformin activated AMPK signaling at the transcriptional level in H. cunea larvae. Conversely, the expressions of two vital Halloween genes (HcCYP306A1 and HcCYP314A1) in the 20E synthesis pathway were remarkably suppressed by metformin. Thus, we presumed that metformin delayed larval molting probably by impeding 20E synthesis in the H. cunea larvae. Finally, we found that metformin accelerated glycogen breakdown, elevated in vivo trehalose level, promoted chitin synthesis, and upregulated transcriptions of the genes in chitin synthesis pathway. Taken together, the findings provide a new insight into the molecular mechanisms by which AMPK regulates carbohydrate metabolism and chitin synthesis in insects.

Photosynthetic Efficiency and Glyco-Metabolism Changes in Artificial Triploid Loquats Contribute to Heterosis Manifestation.

Previous studies indicated that extensive genetic variations could be generated due to polyploidy, which is considered to be closely associated with the manifestation of polyploid heterosis. Our previous studies confirmed that triploid loquats demonstrated significant heterosis, other than the ploidy effect, but the underlying mechanisms are largely unknown. This study aimed to overcome the narrow genetic distance of loquats, increase the genetic variation level of triploid loquats, and systematically illuminate the heterosis mechanisms of triploid loquats derived from two cross combinations. Here, inter-simple sequence repeats (ISSRs) and simple sequence repeats (SSRs) were adopted for evaluating the genetic diversity, and transcriptome sequencing (RNA-Seq) was performed to investigate gene expression as well as pathway changes in the triploids. We found that extensive genetic variations were produced during the formation of triploid loquats. The polymorphism ratios of ISSRs and SSRs were 43.75% and 19.32%, respectively, and almost all their markers had a PIC value higher than 0.5, suggesting that both ISSRs and SSRs could work well in loquat assisted breeding. Furthermore, our results revealed that by broadening the genetic distance between the parents, genetic variations in triploids could be promoted. Additionally, RNA-Seq results suggested that numerous genes differentially expressed between the triploids and parents were screened out. Moreover, KEGG analyses revealed that "photosynthetic efficiency" and "glyco-metabolism" were significantly changed in triploid loquats compared with the parents, which was consistent with the results of physiological indicator analyses, leaf micro-structure observations, and qRT-PCR validation. Collectively, our results suggested that extensive genetic variations occurred in the triploids and that the changes in the "photosynthetic efficiency" as well as "glyco-metabolism" of triploids might have further resulted in heterosis manifestation in the triploid loquats.

Dietary betaine and/or TMAO affect hepatic lipid accumulation and glycometabolism of Megalobrama amblycephala exposed to a high-carbohydrate diet.

A 12-week experiment was conducted to explore the effects of betaine and/or TMAO on growth, hepatic health, gut microbiota, and serum metabolites in Megalobrama amblycephala fed with high-carbohydrate diets. The diets were as follows: CD group (control diet, 28.5% carbohydrate), HCD group (high-carbohydrate diet, 38.2% carbohydrate), HBD group (betaine-added diet, 38.3% carbohydrate + 1.2% betaine), HTD group (TMAO-added diet, 38.2% carbohydrate + 0.2% TMAO), and HBT group (diet added with both betaine and TMAO, 38.2% carbohydrate + 1.2% betaine + 0.2% TMAO). The results showed that the hepatosomatic index (HSI); whole-body crude fat; hepatic lipid accumulation; messenger RNA expression levels of gk, fpbase, g6pase, ahas, and bcat; serum branched-chain amino acids (BCAAs); ratio of Firmicutes-to-Bacteroidetes; and abundance of the genus Aeromonas were all significantly increased, while the abundance levels of the genus Lactobacillus and phyla Tenericutes and Bacteroidetes were drastically decreased in the HCD group. Compared with the HCD group, the HSI; whole-body crude fat; hepatic lipid accumulation; expression levels of fbpase, g6pase, pepck, ahas, and bcat; circulating BCAA; ratio of Firmicutes-to-Bacteroidetes; and abundance levels of the genus Aeromonas and phyla Tenericutes and Bacteroidetes were significantly downregulated in the HBD, HTD, and HBT groups. Meanwhile, the expression levels of pk were drastically upregulated in the HBD, HTD, and HBT groups as well as the abundance of Lactobacillus in the HBT group. These results indicated that the supplementation of betaine and/or TMAO in high-carbohydrate diets could affect the hepatic lipid accumulation and glycometabolism of M. amblycephala by promoting glycolysis, inhibiting gluconeogenesis and biosynthesis of BCAA, and mitigating the negative alteration of gut microbiota. Among them, the combination of betaine and TMAO had the best effect.

Promoting cell proliferation, cell cycle progression, and glycolysis: Glycometabolism-related genes act as prognostic signatures for prostate cancer.

BACKGROUND: The Warburg effect seen in most solid tumors occurs only in the late stages of prostate cancer (PCa). Currently, the management of patients with low-risk localized PCa and patients after radical therapy remains a challenge. Our objective here was to evaluate glycometabolism-related genes as prognostic signatures for PCa. METHODS: The International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA) databases and glycometabolism-related gene sets were obtained online. Glycometabolic prognostic signatures were identified and validated in a TCGA cohort and tested in an ICGC cohort. We used the gene set enrichment analysis to reveal biological processes associated with the glycometabolism-related signatures. Novel glycometabolism-related genes were selected for verifying their oncogenic phenotypes in vitro. RESULTS: Two glycometabolic prognostic signatures were applied respectively to construct risk score formulas for PCa. Survival and receiver operating characteristic curve analyses were performed to detect the value of these prognostic signatures. We performed univariate and multivariate Cox regression analyses in the TCGA cohort, demonstrating the independence of the prognostic signatures. Three glycometabolism-related genes were found to be novel PCa-associated genes. These were shown to affect proliferation, cell cycle progression, and glycolysis of DU145 and PC3 cells in different degrees. CONCLUSION: The present research represents the first glycometabolic and high-throughput investigation on PCa, revealing potential biomarkers and treatment targets. We confirm the vital role of glycometabolism in PCa and provide essential resources for future exploration of metabolism in PCa.

Yes associated protein 1 promotes resistance to 5-fluorouracil in gastric cancer by regulating GLUT3-dependent glycometabolism reprogramming of tumor-associated macrophages.

The antimetabolite 5-fluorouracil (5-FU) is a widely used chemotherapy regimen for the treatment of gastric cancer (GC). However, resistance to 5-FU remains a major drawback in the clinical use. The treatments of anti-tumor chemo-agents recruit tumor associated macrophages (TAMs) which are highly implicated in the chemoresistance development, but the underlying molecular mechanism is unclear. Here, we demonstrate that YAP1 is overexpressed in resistant GC tissues compared to sensitive GC tissues. Further, IL-3 secreted by YAP1-overexpressed GC could skew macrophage polarization to M2-like phenotype and inducing GLUT3-depended glycolysis program. Meanwhile, polarized M2 macrophages enhance 5-FU resistance in tumor cells by secreting CCL8 and activating phosphorylation of JAK1/STAT3 signaling pathway.