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Introduction: Pike perch (Sander Lucioperca) is a predatory freshwater fish, which is highly popular amongst consumers, owing to its white flesh with a delicate structure and mild flavor. Compared to wild pike perch, the diet of farmed ones has shifted fromnatural food to artificial feeds. These changes would affect the gut flora of the pike perch. Endogenous metabolites of the intestinal flora are transferred through the gut-liver axis, which affects the physiological functions of the host. By studying wild and farmed individuals of the pike perch, novel insights into the stability of the intestinal flora can be provided. Methods and results: In this study, we measured various immune parameters in the blood, liver and intestine of wild and farmed pike perch using enzyme activity assays and real-time fluorescence quantitative PCR. Gut microbes were also collected for 16S rRNA gene sequencing. Our results showed that the serum lowdensity lipoprotein cholesterol (LDL-C) levels were twice as high in the wild group as in the farmed group. Furthermore, the activities of glutamate pyruvate transaminase (GPT) and glutamate oxaloacetate transaminase (GOT) in the intestinal tissues of the wild group were 733.91 U/g and 375.35 U/g, which were significantly higher than those of the farmed group. Expression of IL10 in the liver of farmed pike perch was also 4-fold higher than that of wild pike perch. The expression of genes related to the p53-BAX/Bcl2 signaling pathway was higher in both intestinal and liver tissues of wild pike perch compared with farmed. 16S rRNA gene analysis of the gut microflora showed a high relative abundance of Cetobacterium in the gut of farmed pike perch. Conclusion: As a result, our study indicates that dietary differences affect the diversity, composition and relative abundance of the gut flora of the pike perch. Meanwhile, it affects the glycolipid metabolism and immunomodulation of pike perch. [ABSTRACT FROM AUTHOR]

The endoplasmic reticulum (ER) plays a pivotal role in protein folding and secretion, Ca2+ storage, and lipid synthesis in eukaryotic cells. When the burden of protein synthesis and folding required to be handled exceeds the processing capacity of the ER, the accumulation of misfolded/unfolded proteins triggers ER stress. In response to short-term ER stress, the unfolded protein response (UPR) is activated to allow cells to survive. When ER stress is severe and sustained, it typically provokes cell death through multiple approaches. It is well documented that ER stress and metabolic deregulation are functionally intertwined, both are considered contributing factors to the pathogenesis of liver diseases, including non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), ischemia/reperfusion (I/R) injury, viral hepatitis, liver fibrosis, and hepatocellular carcinoma (HCC). Hepatocytes are rich in smooth and rough ER, which harbor metabolic enzymes that are capable of sensing alterations in various nutritional status and external stimuli. Extensive research has focused on the molecular mechanism linking ER stress with metabolic enzymes. The purpose of this review is to summarize the current knowledge regarding the effects of ER stress on metabolic enzymes in various liver diseases and to provide potential therapeutic strategies for chronic liver diseases via targeting UPR.

One-carbon metabolism is a universal metabolic process that mediates the transfer of one-carbon units for purine and thymidine synthesis. One-carbon metabolism has been found to be dysregulated in various cancer types due to its role in production of purine and pyrimidine nucleotides, epigenetic program, and redox homeostasis. One-carbon metabolism is composed a network of onecarbon metabolic enzymes. Disturbing the expression and enzymatic activity of these one-carbon metabolic enzymes could lead to fluctuations of metabolites in the tumor microenvironment. Serine hydroxymethyltransferases (SHMTs) and methylenetetrahydrofolate dehydrogenases (MTHFDs) are gradually recognized as important one-carbon metabolic enzymes for regulating tumor initiation and development, representing potential therapeutic targets for anti-tumor strategies. In the review, we primarily focused on the role of SHMTs and MTHFDs in cancer. Several inhibitors targeting MTHFDs and SHMTs have exert its potential to decrease tumor burden and inhibit tumor proliferation, highlighting the potential of targeting one-carbon metabolic enzymes for anti-cancer strategies. [ABSTRACT FROM AUTHOR]

Lymphatic endothelial cells (LECs) line lymphatic vessels, which play an important role in the transport of lymph fluid throughout the human body. An organized lymphatic network develops via a process termed “lymphangiogenesis.” During development, LECs respond to growth factor signaling to initiate the formation of a primary lymphatic vascular network. These LECs display a unique metabolic profile, preferring to undergo glycolysis even in the presence of oxygen. In addition to their reliance on glycolysis, LECs utilize other metabolic pathways such as fatty acid β-oxidation, ketone body oxidation, mitochondrial respiration, and lipid droplet autophagy to support lymphangiogenesis. This review summarizes the current understanding of metabolic regulation of lymphangiogenesis. Moreover, it highlights how LEC metabolism is implicated in various pathological conditions.

Study objectiveLack of blood pressure control is often seen in hypertensive patients concomitantly taking antituberculosis medications due to the complex drug-drug interactions between rifampin and antihypertensive drugs. Therefore, it is of clinical importance to understand the underlying mechanisms of these interactions to help formulate recommendations on the use of antihypertensive drugs in patients taking these medications concomitantly. Our objective was to assess the reliability of the Biopharmaceutics Drug Disposition Classification System (BDDCS) to predict potential interactions between rifampin and antihypertensive drugs and thus provide recommendations on the choice of antihypertensive drugs in patients receiving rifampin.DesignEvidence-based in vitro and in vivo predictions of drug-drug interactions.Measurements and main resultsWe systematically evaluated interactions between rifampin and antihypertensive drugs using the theory of the BDDCS, taking into consideration the role of drug transporters and metabolic enzymes involved in these interactions. We provide recommendations on the selection of antihypertensive drugs for patients with tuberculosis. Antihypertensive drugs approved by the U.S. Food and Drug Administration and the China National Medical Products Administration were included in this study. The drugs were classified into four categories under the BDDCS classification. Detailed information on cytochrome P450 (CYP) enzymes and drug transporters for each antihypertensive drug was searched in PubMed and other electronic databases. This information was combined with the effects of rifampin on CYP enzymes and drug transporters, and the direction and relative extent of the potential interactions between rifampin and antihypertensive drugs were predicted. Recommendations were then made using the theory of BDDCS. A thorough systematic literature review was performed, and data from all published human studies and case reports were summarized for the validation of our predictions. Interventional and observational studies published in PubMed and two Chinese databases (CNKI and WanFang) through December 16, 2019, were included, and data were extracted for validation of the predictions. Using the BDDCS theory, class 3 active drugs were predicted to exhibit minimal interactions with rifampin. On reviewing case reports and pre-post studies, the predictions we made were found to be reliable. When antituberculosis medications that include rifampin are started in patients with hypertension, it is recommended that the use of calcium channel blockers and classes 1 and 2 β-blockers be avoided. Angiotensin-converting enzyme inhibitors, olmesartan, class 3 β-blockers, spironolactone, and hydrochlorothiazide would be preferable because clinically relevant interactions would not be expected.ConclusionApplication of the BDDCS to predict interactions between rifampin and antihypertensive drugs for patients with both tuberculosis and hypertension was found to be reliable. It should be noted, however, that based on the CYP enzyme and drug transporter information we reviewed, the mechanisms of all of the interactions could not be elucidated, and the predictions are only based on theory. The real effects of rifampin on antihypertensive drugs need to be further observed. More studies in both animals and humans are needed in the future.

Coilia nasus is a precious migratory fish typical to the Yangtze River Basin of China. It is locally referred to as the "Three delicious fish of the Yangtze River, " with its fresh meat being particularly delicious and popular. In recent years, wild C. nasus numbers in the Yangtze River Basin have been decreasing due to environmental changes and illegal overfishing, among other reasons. To attenuate the availability of C. nasus, the Shanghai Fisheries Research Institute has successfully established an indoor artificial breeding and pond culture program in 2011. The research and development of C. nasus artificial breeding technologies have steadily progressed, though the artificial breeding yield of C. nasus remains relatively low. In addition, related research on the artificial cultivation of C. nasus is still in its infancy. Research on C. nasus in China and abroad mainly focuses on gonad development, breeding technology, muscle nutrient composition, and growth performance. No reports exist on the effects of brackish water culture conditions on the physiology of C. nasus. Given its economic importance, it would be of great value to evaluate the changes in the digestive, antioxidant, nonspecific immune capacity, and metabolic rates of C. nasus from brackish water (natural seawater in Hangzhou Bay, salinity 8.7~12.5) to freshwater aquaculture, to determine the breeding conditions of C. nasus, and to improve the artificial breeding yield and related technology. To investigate the differences in digestive capacity, antioxidant capacity, nonspecific immune capacity, and metabolic rates of C. nasus in brackish water and freshwater aquaculture conditions, the experiment adopted the pond interbreeding method. Two groups were established: A brackish aquaculture group and a freshwater aquaculture group (control group). Each group was housed in a single aquaculture pond with an area of 0.17 hm2. 500 C. nasus were stocked in each pond and moved to a Takifugu obscurus pond for a seven-month aquaculture experiment. At the end of the experiment, 12 C. nasus were randomly selected from each group and randomly divided into three replicates. Four C. nasus samples were selected from each replicate. The liver, intestine, stomach, and cecum of C. nasus were dissected on an ice plate and carefully removed to prepare a 10% homogenate. The activities of digestive enzymes, antioxidant enzymes, nonspecific immune enzymes, and metabolic enzymes and the total protein content were measured using a kit produced by the Nanjing Jiancheng Bioengineering Institute. The activities of digestive enzymes, antioxidant enzymes, nonspecific immunity enzymes, and metabolic enzymes in brackish water and freshwater aquaculture environments were compared and analyzed in a seven-month aquaculture experiment using the same batch of artificially bred C. nasus. The growth and survival rates of C. nasus cultured in brackish water (hereafter referred to as brackish water C. nasus) were significantly higher than that in the freshwater (hereafter referred to as freshwater C. nasus) (P < 0.05). The digestive ability of protein and starch in brackish water C. nasus was higher than that of freshwater C. nasus, while the digestive ability was weakened. Among them, the activity of amylase (AMS) in the four organs of brackish water C. nasus was higher than those in freshwater, but not significantly so (P > 0.05). The activities of protease in the liver and stomach were significantly higher than those in freshwater C. nasus (P < 0.05), and the activities of lipase (LPS) in the liver and cecum were significantly lower than those in freshwater C. nasus (P < 0.05). The order of AMS and protease activity of brackish water C. nasus was: cecum > intestine > stomach > liver, while the order of LPS activity was intestine > cecum > stomach > liver. The order of AMS, protease, and LPS activity of freshwater C. nasus was: cecum > intestine > stomach > liver. Brackish water had significant effects on antioxidant, nonspecific immunity, and metabolic abilities, and the activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-PX), and malondialdehyde (MDA) in the liver of C. nasus were significantly increased, while the activity of catalase (CAT) was significantly decreased (P < 0.05). The activities of alkaline phosphatase (AKP) and acid phosphatase (ACP) in the liver of C. nasus in brackish water were significantly lower than those in freshwater (P < 0.05). Brackish water had no significant effect on the activity of aspartate aminotransferase (AST), but it significantly reduced the activity of alanine aminotransferase (ALT). In summary, brackish water aquaculture conditions promoted the growth of C. nasus; increased the survival rate; improved the ability of C. nasus to digest protein and starch; improved the immunity of fish; and reduced the influence of external stresses by decreasing the activities of AKP, ACP, and ALT enzymes and increasing the activities of SOD and GSH-PX enzymes. This study also found that C. nasus living in brackish water, as a result of maintaining the internal osmotic balance, significantly reduced ALT enzyme activity and reduced urea production and emission, thereby reducing the pollution of the direct environment. Therefore, brackish water is more suitable for the aquaculture of C. nasus, and it is recommended that brackish water (salinity of 8.7~12.5) be used for aquaculture of 1+ age C. nasus individuals in the future. The results of this study provide a scientific basis for the improvement of artificial breeding technology, improving the yield of C. nasus, and the development of special compound feed for C. nasus.

Abstract Background Maintenance of cancer stem‐like cell (CSC) stemness supported by aberrantly regulated cancer cell metabolism is critical for CSC self‐renewal and tumor progression. As a key glycolytic enzyme, hexokinase 2 (HK2) plays an instrumental role in aerobic glycolysis and tumor progression. However, whether HK2 directly contribute to CSC stemness maintenance in small cell lung cancer (SCLC) is largely unclear. In this study, we aimed to investgate whether HK2 independent of its glycolytic activity is directly involved in stemness maintenance of CSC in SCLC. Methods Immunoblotting analyses were conducted to determine the expression of HK2 in SCLC CSCs and their differentiated counterparts. CSC‐like properties and tumorigenesis of SCLC cells with or without HK2 depletion or overexpression were examined by sphere formation assay and xenograft mouse model. Immunoprecipitation and mass spectrometry analyses were performed to identify the binding proteins of CD133. The expression levels of CD133‐associated and CSC‐relevant proteins were evaluated by immunoblotting, immunoprecipitation, immunofluorescence, and immunohistochemistry assay. RNA expression levels of Nanog, POU5F1, Lin28, HK2, Prominin‐1 were analyzed through quantitative reverse transcription PCR. Polyubiquitination of CD133 was examined by in vitro or in vivo ubiquitination assay. CD133+ cells were sorted by flow cytometry using an anti‐CD133 antibody. Results We demonstrated that HK2 expression was much higher in CSCs of SCLC than in their differentiated counterparts. HK2 depletion inhibited CSC stemness and promoted CSC differentiation. Mechanistically, non‐mitochondrial HK2 directly interacted with CD133 and enhanced CD133 expression without affecting CD133 mRNA levels. The interaction of HK2 and CD133 promoted the binding of the deubiquitinase ubiquitin‐specific protease 11 (USP11) to CD133, thereby inhibiting CD133 polyubiquitylation and degradation. HK2‐mediated upregulation of CD133 expression enhanced the expression of cell renewal regulators, SCLC cell stemness, and tumor growth in mice. In addition, HK2 expression was positively correlated with CD133 expression in human SCLC specimens, and their expression levels were associated with poor prognosis of SCLC patients. Conclusions These results revealed a critical non‐metabolic function of HK2 in promotion of cancer cell stemness. Our findings provided new insights into the multifaceted roles of HK2 in tumor development.

Abstract Background Bladder cancer is the most common malignant tumor of the urinary system. Surgical resection and chemotherapy are the two mainstream treatments for bladder cancer. However, the outcomes are not satisfactory for patients with advanced bladder cancer. There is a need to further explore more effective targeted therapeutic strategies. Methods Proteomics were performed to compare protein expression differences between human bladder cancer tissues and adjacent normal tissues. The function of GPD1 on bladder cancer cells were confirmed through in vivo and in vitro assays. Transcriptomics and metabolomics were performed to reveal the underlying mechanisms of GPD1. Virtual screening was used to identify allosteric activator of GPD1. Results Here, we used proteomics to find that GPD1 expression was at low levels in bladder cancer tissues. Further investigation showed that GPD1 overexpression significantly promoted apoptosis in bladder cancer cells. Based on transcriptomics and metabolomics, GPD1 promotes Ca2+ influx and apoptosis of tumor cells via the lysoPC-PAFR-TRPV2 axis. Finally, we performed a virtual screening to obtain the GPD1 allosteric activator wedelolactone and demonstrated its ability to inhibit bladder tumor growth in vitro and in vivo. Conclusions This study suggests that GPD1 may act as a novel tumor suppressor in bladder cancer. Pharmacological activation of GPD1 is a potential therapeutic approach for bladder cancer.

The age-related loss of the cognitive function is a growing concern for global populations. Many factors that determine cognitive resilience or dementia also have metabolic functions. However, this duality is not universally appreciated when the action of that factor occurs in tissues external to the brain. Thus, we examined a set of genes involved in dementia, i.e., those related to vascular dementia, Alzheimer's disease, Parkinson's disease, and the human metabolism for activity in 12 metabolically active tissues. Mining the Genotype-Tissue Expression (GTEx) data showed that most of these metabolism–dementia (MD) genes (62 of 93, 67%) exhibit a higher median expression in any of the metabolically active tissues than in the brain. After identifying that several MD genes served as blood-based biomarkers of longevity in other studies, we examined the impact of the intake of food, nutrients, and other dietary factors on the expression of MD genes in whole blood in the Framingham Offspring Study (n = 2134). We observed positive correlations between flavonoids and HMOX1, taurine and UQCRC1, broccoli and SLC10A2, and myricetin and SLC9A8 (p < 2.09 × 10−4). In contrast, dairy protein, palmitic acid, and pie were negatively correlated, respectively, with the expression of IGF1R, CSF1R, and SLC9A8, among others (p < 2.92 × 10−4). The results of this investigation underscore the potential contributions of metabolic enzyme activity in non-brain tissues to the risk of dementia. Specific epidemiological or intervention studies could be designed using specific foods and nutrients or even dietary patterns focused on these foods and nutrients that influence the expression of some MD genes to verify the findings presented here. [ABSTRACT FROM AUTHOR]

Abstract Background Malaria remains one of the most devastating diseases globally, and the control of mosquitoes as the vector is mainly dependent on chemical insecticides. Elevated temperatures associated with future warmer climates could affect mosquitoes' metabolic enzyme expression and increase insecticide resistance, making vector control difficult. Understanding how mosquito rearing temperatures influence their susceptibility to insecticide and expression of metabolic enzymes could aid in the development of novel tools and strategies to control mosquitoes in a future warmer climate. This study evaluated the effects of temperature on the susceptibility of Anopheles gambiae sensu lato (s.l.) mosquitoes to pyrethroids and their expression of metabolic enzymes. Methods Anopheles gambiae s.l. eggs obtained from laboratory-established colonies were reared under eight temperature regimes (25, 28, 30, 32, 34, 36, 38, and 40 °C). Upon adult emergence, 3- to 5-day-old female non-blood-fed mosquitoes were used for susceptibility tests following the World Health Organization (WHO) bioassay protocol. Batches of 20–25 mosquitoes from each temperature regime (25–34 °C) were exposed to two pyrethroid insecticides (0.75% permethrin and 0.05% deltamethrin). In addition, the levels of four metabolic enzymes (α-esterase, β-esterase, glutathione S-transferase [GST], and mixed-function oxidase [MFO]) were examined in mosquitoes that were not exposed and those that were exposed to pyrethroids. Results Mortality in An. gambiae s.l. mosquitoes exposed to deltamethrin and permethrin decreased at temperatures above 28 °C. In addition, mosquitoes reared at higher temperatures were more resistant and had more elevated enzyme levels than those raised at low temperatures. Overall, mosquitoes that survived after being exposed to pyrethroids had higher levels of metabolic enzymes than those that were not exposed to pyrethroids. Conclusions This study provides evidence that elevated temperatures decreased An. gambiae s.l. mosquitoes' susceptibility to pyrethroids and increased the expression of metabolic enzymes. This evidence suggests that elevated temperatures projected in a future warmer climate could increase mosquitoes' resistance to insecticides and complicate malaria vector control measures. This study therefore provides vital information, and suggests useful areas of future research, on the effects of temperature variability on mosquitoes that could guide vector control measures in a future warmer climate. Graphical Abstract

Although the functions of metabolic enzymes and nuclear receptors in controlling physiological homeostasis have been established, their crosstalk in modulating metabolic disease has not been explored. Genetic ablation of the xenobiotic-metabolizing cytochrome P450 enzyme CYP2E1 in mice markedly induced adipose browning and increased energy expenditure to improve obesity. CYP2E1 deficiency activated the expression of hepatic peroxisome proliferator-activated receptor alpha (PPARα) target genes, including fibroblast growth factor (FGF) 21, that upon release from the liver, enhanced adipose browning and energy expenditure to decrease obesity. Nineteen metabolites were increased in Cyp2e1-null mice as revealed by global untargeted metabolomics, among which four compounds, lysophosphatidylcholine and three polyunsaturated fatty acids were found to be directly metabolized by CYP2E1 and to serve as PPARα agonists, thus explaining how CYP2E1 deficiency causes hepatic PPARα activation through increasing cellular levels of endogenous PPARα agonists. Translationally, a CYP2E1 inhibitor was found to activate the PPARα–FGF21–beige adipose axis and decrease obesity in wild-type mice, but not in liver-specific Ppara-null mice. The present results establish a metabolic crosstalk between PPARα and CYP2E1 that supports the potential for a novel anti-obesity strategy of activating adipose tissue browning by targeting the CYP2E1 to modulate endogenous metabolites beyond its canonical role in xenobiotic-metabolism.

To explore the relationship between genetic polymorphisms of metabolic enzymes such as CYP1A1, CYP2D6, GSTM1, GSTT1, and GSTP1 and idiopathic male infertility. By observing the efficacy of antioxidants in the treatment of idiopathic male infertility, the effect of metabolic enzyme gene polymorphisms on antioxidant therapy in patients with idiopathic male infertility was prospectively studied. This case–control study included 310 men with idiopathic infertility and 170 healthy controls. The cytochrome P450 1A1 (CYP1A1), cytochrome P450 2D6 (CYP2D6), glutathione S-transferase M1 (GSTM1), glutathione S-transferase T1 (GSTT1), and glutathione S-transferase P1 (GSTP1) genotypes in peripheral blood samples were analyzed by polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism (PCR-RFLP). The idiopathic male infertility group was treated with vitamin C, vitamin E, and coenzyme Q10 for 3 months and followed up for 6 months. GSTM1(−), GSTT1(−), and GSTM1/T1(−/−) in the idiopathic male infertility groups were more common than those in the control group. The sperm concentration, motility, viability, mitochondrial membrane potential (MMP), and seminal plasma total antioxidant capacity (T-AOC) level in patients with GSTM1(−), GSTT1(−), and GSTM1/T1(−/−) were lower than those in wild-type carriers, and the sperm DNA fragmentation index (DFI), 8-hydroxy-2'-deoxyguanosine (8-OH-dG), and malondialdehyde (MDA) and nitric oxide (NO) levels were higher. Therefore, oxidative damage may play an important role in the occurrence and development of idiopathic male infertility, but antioxidant therapy is not effective in male infertility patients with GSTM1 and GSTT1 gene deletions.

Introduction: Pike perch ( Sander Lucioperca ) is a predatory freshwater fish, which is highly popular amongst consumers, owing to its white flesh with a delicate structure and mild flavor. Compared to wild pike perch, the diet of farmed ones has shifted from natural food to artificial feeds. These changes would affect the gut flora of the pike perch. Endogenous metabolites of the intestinal flora are transferred through the gut-liver axis, which affects the physiological functions of the host. By studying wild and farmed individuals of the pike perch, novel insights into the stability of the intestinal flora can be provided., Methods and Results: In this study, we measured various immune parameters in the blood, liver and intestine of wild and farmed pike perch using enzyme activity assays and real-time fluorescence quantitative PCR. Gut microbes were also collected for 16S rRNA gene sequencing. Our results showed that the serum low-density lipoprotein cholesterol (LDL-C) levels were twice as high in the wild group as in the farmed group. Furthermore, the activities of glutamate pyruvate transaminase (GPT) and glutamate oxaloacetate transaminase (GOT) in the intestinal tissues of the wild group were 733.91 U/g and 375.35 U/g, which were significantly higher than those of the farmed group. Expression of IL10 in the liver of farmed pike perch was also 4-fold higher than that of wild pike perch. The expression of genes related to the p53-BAX/Bcl2 signaling pathway was higher in both intestinal and liver tissues of wild pike perch compared with farmed. 16S rRNA gene analysis of the gut microflora showed a high relative abundance of Cetobacterium in the gut of farmed pike perch., Conclusion: As a result, our study indicates that dietary differences affect the diversity, composition and relative abundance of the gut flora of the pike perch. Meanwhile, it affects the glycolipid metabolism and immunomodulation of pike perch., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Wang, Li, Sun, Lu, Zhao, Liu, Wang and Zheng.)

Aerobic glycolysis is an emerging hallmark of many human cancers, as cancer cells are defined as a "metabolically abnormal system". Carbohydrates are metabolically reprogrammed by its metabolizing and catabolizing enzymes in such abnormal cancer cells. Normal cells acquire their energy from oxidative phosphorylation, while cancer cells acquire their energy from oxidative glycolysis, known as the "Warburg effect". Energy–metabolic differences are easily found in the growth, invasion, immune escape and anti-tumor drug resistance of cancer cells. The glycolysis pathway is carried out in multiple enzymatic steps and yields two pyruvate molecules from one glucose (Glc) molecule by orchestral reaction of enzymes. Uncontrolled glycolysis or abnormally activated glycolysis is easily observed in the metabolism of cancer cells with enhanced levels of glycolytic proteins and enzymatic activities. In the "Warburg effect", tumor cells utilize energy supplied from lactic acid-based fermentative glycolysis operated by glycolysis-specific enzymes of hexokinase (HK), keto-HK-A, Glc-6-phosphate isomerase, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase, phosphofructokinase (PFK), phosphor-Glc isomerase (PGI), fructose-bisphosphate aldolase, phosphoglycerate (PG) kinase (PGK)1, triose phosphate isomerase, PG mutase (PGAM), glyceraldehyde-3-phosphate dehydrogenase, enolase, pyruvate kinase isozyme type M2 (PKM2), pyruvate dehydrogenase (PDH), PDH kinase and lactate dehydrogenase. They are related to glycolytic flux. The key enzymes involved in glycolysis are directly linked to oncogenesis and drug resistance. Among the metabolic enzymes, PKM2, PGK1, HK, keto-HK-A and nucleoside diphosphate kinase also have protein kinase activities. Because glycolysis-generated energy is not enough, the cancer cell-favored glycolysis to produce low ATP level seems to be non-efficient for cancer growth and self-protection. Thus, the Warburg effect is still an attractive phenomenon to understand the metabolic glycolysis favored in cancer. If the basic properties of the Warburg effect, including genetic mutations and signaling shifts are considered, anti-cancer therapeutic targets can be raised. Specific therapeutics targeting metabolic enzymes in aerobic glycolysis and hypoxic microenvironments have been developed to kill tumor cells. The present review deals with the tumor-specific Warburg effect with the revisited viewpoint of recent progress. [ABSTRACT FROM AUTHOR]

Background: Bladder cancer is the most common malignant tumor of the urinary system. Surgical resection and chemotherapy are the two mainstream treatments for bladder cancer. However, the outcomes are not satisfactory for patients with advanced bladder cancer. There is a need to further explore more effective targeted therapeutic strategies. Methods: Proteomics were performed to compare protein expression differences between human bladder cancer tissues and adjacent normal tissues. The function of GPD1 on bladder cancer cells were confirmed through in vivo and in vitro assays. Transcriptomics and metabolomics were performed to reveal the underlying mechanisms of GPD1. Virtual screening was used to identify allosteric activator of GPD1. Results: Here, we used proteomics to find that GPD1 expression was at low levels in bladder cancer tissues. Further investigation showed that GPD1 overexpression significantly promoted apoptosis in bladder cancer cells. Based on transcriptomics and metabolomics, GPD1 promotes Ca2+ influx and apoptosis of tumor cells via the lysoPC-PAFR-TRPV2 axis. Finally, we performed a virtual screening to obtain the GPD1 allosteric activator wedelolactone and demonstrated its ability to inhibit bladder tumor growth in vitro and in vivo. Conclusions: This study suggests that GPD1 may act as a novel tumor suppressor in bladder cancer. Pharmacological activation of GPD1 is a potential therapeutic approach for bladder cancer. [ABSTRACT FROM AUTHOR]

Abstract Background Efficient and selective utilization of metabolic substrates is one of the key strategies in high-altitude animals to cope with hypoxia and hypothermia. Previous findings have shown that the energy substrate utilization of highland animals varies with evolutionary history and phylogeny. The heart is a proxy for the cardiopulmonary system, and the metabolic substrate utilization in the myocardium is also under the strong selective pressure of chronically hypoxic and hypothermic environments. However, little information is available on the physiological adjustments in relation to metabolic substrate utilization in the myocardium for coping with high-altitude environments. Methods We compared the metabolic enzyme activities, including hexokinase (HK), phosphofructokinase (PFK), pyruvate kinase (PK), citrate synthase (CS), carnitine palmitoyl transferase 1 (CPT-1), lactic dehydrogenase (LDH), and creatine kinase (CK), and metabolic substrate contents including glucose (Glu), triglyceride (TG), and free fatty acid (FFA) in the myocardium of a typical human commensal species, Eurasian Tree Sparrows (Passer montanus) between the Qinghai-Tibet Plateau (the QTP, 3230 m) and low altitude population (Shijiazhuang, 80 m), and between sexes. Results Among the seven metabolic enzymes and three substrates investigated, we identified no significant differences in PK, CPT-1, HK, CS, LDH, and CK activities and TG content of the myocardium between high and low altitude populations. However, the QTP sparrows had significantly lower Glu content and PFK activities but higher FFA content relative to their lowland counterparts. In addition, male sparrows had higher myocardial HK and CS activities relative to females, independent of altitude. Conclusions Our results showed that the QTP sparrows elevated fatty acid utilization rather than glucose preference in the myocardium relative to lowland counterpart, which contributes to uncovering both the physiological adjustments for adapting to the extreme conditions of the QTP, intraspecifically.

The endoplasmic reticulum (ER) plays a pivotal role in protein folding and secretion, Ca2+ storage, and lipid synthesis in eukaryotic cells. When the burden of protein synthesis and folding required to be handled exceeds the processing capacity of the ER, the accumulation of misfolded/unfolded proteins triggers ER stress. In response to short-term ER stress, the unfolded protein response (UPR) is activated to allow cells to survive. When ER stress is severe and sustained, it typically provokes cell death through multiple approaches. It is well documented that ER stress and metabolic deregulation are functionally intertwined, both are considered contributing factors to the pathogenesis of liver diseases, including non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), ischemia/reperfusion (I/R) injury, viral hepatitis, liver fibrosis, and hepatocellular carcinoma (HCC). Hepatocytes are rich in smooth and rough ER, which harbor metabolic enzymes that are capable of sensing alterations in various nutritional status and external stimuli. Extensive research has focused on the molecular mechanism linking ER stress with metabolic enzymes. The purpose of this review is to summarize the current knowledge regarding the effects of ER stress on metabolic enzymes in various liver diseases and to provide potential therapeutic strategies for chronic liver diseases via targeting UPR. [Display omitted] [ABSTRACT FROM AUTHOR]

The development of recessive resistance by loss of susceptibility is a consistent strategy to combat and limit damages caused by plant viruses. Susceptibility genes can be turned into resistances, a feat that can either be selected among the plant's natural diversity or engineered by biotechnology. Here, we summarize the current knowledge on the phosphoglycerate kinases (PGK), which have emerged as a new class of susceptibility factors to single-stranded positive RNA viruses, including potyviruses. PGKs are metabolic enzymes involved in glycolysis and the carbon reduction cycle, encoded by small multigene families in plants. To fulfil their role in the chloroplast and in the cytosol, PGKs genes encode differentially addressed proteins. Here, we assess the diversity and homology of chloroplastic and cytosolic PGKs sequences in several crops and review the current knowledge on their redundancies during plant development, taking Arabidopsis as a model. We also show how PGKs have been shown to be involved in susceptibility—and resistance—to viruses. Based on this knowledge, and drawing from the experience with the well-characterized translation initiation factors eIF4E, we discuss how PGKs genes, in light of their subcellular localization, function in metabolism, and susceptibility to viruses, could be turned into efficient genetic resistances using genome editing techniques. [ABSTRACT FROM AUTHOR]

Background: Malaria remains one of the most devastating diseases globally, and the control of mosquitoes as the vector is mainly dependent on chemical insecticides. Elevated temperatures associated with future warmer climates could affect mosquitoes' metabolic enzyme expression and increase insecticide resistance, making vector control difficult. Understanding how mosquito rearing temperatures influence their susceptibility to insecticide and expression of metabolic enzymes could aid in the development of novel tools and strategies to control mosquitoes in a future warmer climate. This study evaluated the effects of temperature on the susceptibility of Anopheles gambiae sensu lato (s.l.) mosquitoes to pyrethroids and their expression of metabolic enzymes. Methods: Anopheles gambiae s.l. eggs obtained from laboratory-established colonies were reared under eight temperature regimes (25, 28, 30, 32, 34, 36, 38, and 40 °C). Upon adult emergence, 3- to 5-day-old female non-blood-fed mosquitoes were used for susceptibility tests following the World Health Organization (WHO) bioassay protocol. Batches of 20–25 mosquitoes from each temperature regime (25–34 °C) were exposed to two pyrethroid insecticides (0.75% permethrin and 0.05% deltamethrin). In addition, the levels of four metabolic enzymes (α-esterase, β-esterase, glutathione S-transferase [GST], and mixed-function oxidase [MFO]) were examined in mosquitoes that were not exposed and those that were exposed to pyrethroids. Results: Mortality in An. gambiae s.l. mosquitoes exposed to deltamethrin and permethrin decreased at temperatures above 28 °C. In addition, mosquitoes reared at higher temperatures were more resistant and had more elevated enzyme levels than those raised at low temperatures. Overall, mosquitoes that survived after being exposed to pyrethroids had higher levels of metabolic enzymes than those that were not exposed to pyrethroids. Conclusions: This study provides evidence that elevated temperatures decreased An. gambiae s.l. mosquitoes' susceptibility to pyrethroids and increased the expression of metabolic enzymes. This evidence suggests that elevated temperatures projected in a future warmer climate could increase mosquitoes' resistance to insecticides and complicate malaria vector control measures. This study therefore provides vital information, and suggests useful areas of future research, on the effects of temperature variability on mosquitoes that could guide vector control measures in a future warmer climate. [ABSTRACT FROM AUTHOR]

Although the functions of metabolic enzymes and nuclear receptors in controlling physiological homeostasis have been established, their crosstalk in modulating metabolic disease has not been explored. Genetic ablation of the xenobiotic-metabolizing cytochrome P450 enzyme CYP2E1 in mice markedly induced adipose browning and increased energy expenditure to improve obesity. CYP2E1 deficiency activated the expression of hepatic peroxisome proliferator-activated receptor alpha (PPAR α) target genes, including fibroblast growth factor (FGF) 21, that upon release from the liver, enhanced adipose browning and energy expenditure to decrease obesity. Nineteen metabolites were increased in Cyp2e1 -null mice as revealed by global untargeted metabolomics, among which four compounds, lysophosphatidylcholine and three polyunsaturated fatty acids were found to be directly metabolized by CYP2E1 and to serve as PPAR α agonists, thus explaining how CYP2E1 deficiency causes hepatic PPAR α activation through increasing cellular levels of endogenous PPAR α agonists. Translationally, a CYP2E1 inhibitor was found to activate the PPAR α –FGF21–beige adipose axis and decrease obesity in wild-type mice, but not in liver-specific Ppara -null mice. The present results establish a metabolic crosstalk between PPAR α and CYP2E1 that supports the potential for a novel anti-obesity strategy of activating adipose tissue browning by targeting the CYP2E1 to modulate endogenous metabolites beyond its canonical role in xenobiotic-metabolism. Metabolism of endogenous PPAR α agonist by CYP2E1 modulates obesity and fatty acid. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: Head and neck squamous cell carcinoma (HNSCC) is still a menace to public wellbeing globally. However, the underlying molecular events influencing the carcinogenesis and prognosis of HNSCC are poorly known. Methods: Gene expression profiles of The Cancer Genome Atlas (TCGA) HNSCC dataset and GSE37991 were downloaded from the TCGA database and gene expression omnibus, respectively. The common differentially expressed metabolic enzymes (DEMEs) between HNSCC tissues and normal controls were screened out. Then a DEME-based molecular signature and a clinically practical nomogram model were constructed and validated. Results: A total of 23 commonly upregulated and 9 commonly downregulated DEMEs were identified in TCGA HNSCC and GSE37991. Gene ontology analyses of the common DEMEs revealed that alpha-amino acid metabolic process, glycosyl compound metabolic process, and cellular amino acid metabolic process were enriched. Based on the TCGA HNSCC cohort, we have built up a robust DEME-based prognostic signature including HPRT1 , PLOD2 , ASNS , TXNRD1 , CYP27B1 , and FUT6 for predicting the clinical outcome of HNSCC. Furthermore, this prognosis signature was successfully validated in another independent cohort GSE65858. Moreover, a potent prognostic signature-based nomogram model was constructed to provide personalized therapeutic guidance for treating HNSCC. In vitro experiment revealed that the knockdown of TXNRD1 suppressed malignant activities of HNSCC cells. Conclusion: Our study has successfully developed a robust DEME-based signature for predicting the prognosis of HNSCC. Moreover, the nomogram model might provide useful guidance for the precision treatment of HNSCC. [ABSTRACT FROM AUTHOR]

The bifunctional enzyme Δ1-pyrroline-5-carboxylate synthase (P5CS) is vital to the synthesis of proline and ornithine, playing an essential role in human health and agriculture. Pathogenic mutations in the P5CS gene (ALDH18A1) lead to neurocutaneous syndrome and skin relaxation connective tissue disease in humans, and P5CS deficiency seriously damages the ability to resist adversity in plants. We have recently found that P5CS forms cytoophidia in vivo and filaments in vitro. However, it is difficult to appreciate the function of P5CS filamentation without precise structures. Using cryo-electron microscopy, here we solve the structures of Drosophila full-length P5CS in three states at resolution from 3.1 to 4.3 Å. We observe distinct ligand-binding states and conformational changes for the GK and GPR domains, respectively. Divergent helical filaments are assembled by P5CS tetramers and stabilized by multiple interfaces. Point mutations disturbing those interfaces prevent P5CS filamentation and greatly reduce the enzymatic activity. Our findings reveal that filamentation is crucial for the coordination between the GK and GPR domains, providing a structural basis for the catalytic function of P5CS filaments.

BackgroundHead and neck squamous cell carcinoma (HNSCC) is still a menace to public wellbeing globally. However, the underlying molecular events influencing the carcinogenesis and prognosis of HNSCC are poorly known.MethodsGene expression profiles of The Cancer Genome Atlas (TCGA) HNSCC dataset and GSE37991 were downloaded from the TCGA database and gene expression omnibus, respectively. The common differentially expressed metabolic enzymes (DEMEs) between HNSCC tissues and normal controls were screened out. Then a DEME-based molecular signature and a clinically practical nomogram model were constructed and validated.ResultsA total of 23 commonly upregulated and 9 commonly downregulated DEMEs were identified in TCGA HNSCC and GSE37991. Gene ontology analyses of the common DEMEs revealed that alpha-amino acid metabolic process, glycosyl compound metabolic process, and cellular amino acid metabolic process were enriched. Based on the TCGA HNSCC cohort, we have built up a robust DEME-based prognostic signature including HPRT1, PLOD2, ASNS, TXNRD1, CYP27B1, and FUT6 for predicting the clinical outcome of HNSCC. Furthermore, this prognosis signature was successfully validated in another independent cohort GSE65858. Moreover, a potent prognostic signature-based nomogram model was constructed to provide personalized therapeutic guidance for treating HNSCC. In vitro experiment revealed that the knockdown of TXNRD1 suppressed malignant activities of HNSCC cells.ConclusionOur study has successfully developed a robust DEME-based signature for predicting the prognosis of HNSCC. Moreover, the nomogram model might provide useful guidance for the precision treatment of HNSCC.

Mass spectrometry imaging (MSI) serves as an emerging tool for spatial profiling of metabolic dysfunction in ischemic tissue. Prior to MSI data analysis, commonly used staining methods, e.g., triphenyltetrazole chloride (TTC) staining, need to be implemented on the adjacent tissue for delineating lesion area and evaluating infarction, resulting in extra consumption of the tissue sample as well as morphological mismatch. Here, we propose an in situ ratiometric MSI method for simultaneous demarcation of lesion border and spatial annotation of metabolic and enzymatic signatures in ischemic tissue on identical tissue sections. In this method, the ion abundance ratio of a reactant pair in the TCA cycle, e.g., fumarate to malate, is extracted pixel-by-pixel from an ambient MSI dataset of ischemic tissue and used as a surrogate indicator for metabolic activity of mitochondria to delineate lesion area as if the tissue has been chemically stained. This method is shown to be precise and robust in identifying lesions in brain tissues and tissue samples from different ischemic models including heart, liver, and kidney. Furthermore, the proposed method allows screening and predicting metabolic and enzymatic alterations which are related to mitochondrial dysfunction. Being capable of concurrent lesion identification, in situ metabolomics analysis, and screening of enzymatic alterations, the ratiometric MSI method bears great potential to explore ischemic damages at both metabolic and enzymatic levels in biological research.

Background: Efficient and selective utilization of metabolic substrates is one of the key strategies in high-altitude animals to cope with hypoxia and hypothermia. Previous findings have shown that the energy substrate utilization of highland animals varies with evolutionary history and phylogeny. The heart is a proxy for the cardiopulmonary system, and the metabolic substrate utilization in the myocardium is also under the strong selective pressure of chronically hypoxic and hypothermic environments. However, little information is available on the physiological adjustments in relation to metabolic substrate utilization in the myocardium for coping with high-altitude environments. Methods: We compared the metabolic enzyme activities, including hexokinase (HK), phosphofructokinase (PFK), pyruvate kinase (PK), citrate synthase (CS), carnitine palmitoyl transferase 1 (CPT-1), lactic dehydrogenase (LDH), and creatine kinase (CK), and metabolic substrate contents including glucose (Glu), triglyceride (TG), and free fatty acid (FFA) in the myocardium of a typical human commensal species, Eurasian Tree Sparrows (Passermontanus) between the Qinghai-Tibet Plateau (the QTP, 3230 m) and low altitude population (Shijiazhuang, 80 m), and between sexes. Results: Among the seven metabolic enzymes and three substrates investigated, we identified no significant differences in PK, CPT-1, HK, CS, LDH, and CK activities and TG content of the myocardium between high and low altitude populations. However, the QTP sparrows had significantly lower Glu content and PFK activities but higher FFA content relative to their lowland counterparts. In addition, male sparrows had higher myocardial HK and CS activities relative to females, independent of altitude. Conclusions: Our results showed that the QTP sparrows elevated fatty acid utilization rather than glucose preference in the myocardium relative to lowland counterpart, which contributes to uncovering both the physiological adjustments for adapting to the extreme conditions of the QTP, intraspecifically. [ABSTRACT FROM AUTHOR]

The Indian butter catfish, Ompok bimaculatus (Bloch, 1794), is a high-value catfish that has gained immense consumer preference in South-East Asia. However, information on the nutritional requirements of this species is scanty. Hence, an experiment was conducted to evaluate the effects of varying dietary lipid levels on growth, body composition, and activities of digestive and metabolic enzymes in larvae. Three isonitrogenous (40% crude protein) diets were formulated by supplementing fish and vegetable oil (1:1) at 4.5% (D1), 7% (D2), and 9.5% (D3) levels (containing crude lipid 5.7%, 8.0%, and 10.45%, respectively in diets D1-D3) to a fish meal- and oilcake-based formulated diet. Experimental diets were fed to butter catfish larvae (0.15 ± 0.01 g) in triplicate groups for a period of 42 days. Proximate compositions of the experimental diets, as well as fish carcass, were analyzed using standard procedures (AOAC 2005). Digestive and metabolic enzyme activities were analyzed at the completion of the experiment by standard methodology. Butter catfish larvae fed the diet D2 (8% crude lipid) resulted in the best performance in terms of weight gain (final weight 1.40 ± 0.07 g), net weight gain (1.31 ± 0.06 g), specific growth rate (5.50 ± 0.05% · day-1), and protein efficiency ratio (2.39 ± 0.17). The highest lipid deposition (2.90 ± 0.12%) in the carcass was also recorded in fish reared on diet D2. The final weight, net weight gain, protein efficiency ratio, and specific growth rate were significantly (P < 0.05) higher in D2 having 8% lipid. Moisture and lipid contents of the whole body were significantly (P < 0.05) higher in larvae fed diet D2. Amylase activity in fish significantly (P < 0.05) decreased with increasing dietary lipid levels. The maximum alkaline protease, pepsin, and lipase activities were noticed in the larvae fed diet D2. Progressive decrease in liver glucose-6-phosphate dehydrogenase activities and significant increase (P < 0.05) in the activities of neoglucogenic enzymes (glucose-6-phosphatase and fructose-1,6-bis phosphatase) were noticed with an increase in dietary lipid levels. Significantly lower (P < 0.05) activities of LDH, ALT, and AST were recorded in the group fed diet D2. Results of the study indicated that 8% crude lipid in the diet could assure optimum growth and survival of butter catfish larvae during early development. An appraisal on growth, body composition, and digestive as well as metabolic function in the butter catfish larvae recorded in the study might provide some important information to consider application of formulated diets for the larviculture of Ompok bimaculatus. [ABSTRACT FROM AUTHOR]

The development of recessive resistance by loss of susceptibility is a consistent strategy to combat and limit damages caused by plant viruses. Susceptibility genes can be turned into resistances, a feat that can either be selected among the plant’s natural diversity or engineered by biotechnology. Here, we summarize the current knowledge on the phosphoglycerate kinases (PGK), which have emerged as a new class of susceptibility factors to single-stranded positive RNA viruses, including potyviruses. PGKs are metabolic enzymes involved in glycolysis and the carbon reduction cycle, encoded by small multigene families in plants. To fulfil their role in the chloroplast and in the cytosol, PGKs genes encode differentially addressed proteins. Here, we assess the diversity and homology of chloroplastic and cytosolic PGKs sequences in several crops and review the current knowledge on their redundancies during plant development, taking Arabidopsis as a model. We also show how PGKs have been shown to be involved in susceptibility—and resistance—to viruses. Based on this knowledge, and drawing from the experience with the well-characterized translation initiation factors eIF4E, we discuss how PGKs genes, in light of their subcellular localization, function in metabolism, and susceptibility to viruses, could be turned into efficient genetic resistances using genome editing techniques.

Lymphatic endothelial cells (LECs) line lymphatic vessels, which play an important role in the transport of lymph fluid throughout the human body. An organized lymphatic network develops via a process termed "lymphangiogenesis." During development, LECs respond to growth factor signaling to initiate the formation of a primary lymphatic vascular network. These LECs display a unique metabolic profile, preferring to undergo glycolysis even in the presence of oxygen. In addition to their reliance on glycolysis, LECs utilize other metabolic pathways such as fatty acid β-oxidation, ketone body oxidation, mitochondrial respiration, and lipid droplet autophagy to support lymphangiogenesis. This review summarizes the current understanding of metabolic regulation of lymphangiogenesis. Moreover, it highlights how LEC metabolism is implicated in various pathological conditions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Simeroth and Yu.)

Ovarian cancer is one of the most malignant gynecological cancers around the world. In spite of multiple treatment options, the five-year survival rate is still very low. Several metabolism alterations are described as a hallmark in cancers, but alterations of lipid metabolism in ovarian cancer have been paid less attention. To explore new markers/targets for accurate diagnosis, prognosis, and therapeutic treatments based on metabolic enzyme inhibitors, here, we reviewed available literature and summarized several key metabolic enzymes in lipid metabolism of ovarian cancer. In this review, the rate limiting enzymes associated with fatty acid synthesis (FASN, ACC, ACLY, SCD), the lipid degradation related enzymes (MAGL, CPT, 5-LO, COX2), and the receptors related to lipid uptake (FABP4, CD36, LDLR), which promote the development of ovarian cancer, were analyzed and evaluated. We also focused on the review of application of current metabolic enzyme inhibitors for the treatment of ovarian cancer through which the potential therapeutic agents may be developed for ovarian cancer therapy.

Polymerization of metabolic enzymes into micron-scale assemblies is an emerging mechanism for regulating their activity. CTP synthase (CTPS) is an essential enzyme in the biosynthesis of the nucleotide CTP and undergoes regulated and reversible assembly into large filamentous structures in organisms from bacteria to humans. The purpose of these assemblies is unclear. A major challenge to addressing this question has been the inability to abolish assembly without eliminating CTPS protein. Here we demonstrate that a recently reported point mutant in CTPS, Histidine 355A (H355A), prevents CTPS filament assembly in vivo and dominantly inhibits the assembly of endogenous wild-type CTPS in the Drosophila ovary. Expressing this mutant in ovarian germline cells, we show that disruption of CTPS assembly in early stage egg chambers reduces egg production. This effect is exacerbated in flies fed the glutamine antagonist 6-diazo-5-oxo-L-norleucine, which inhibits de novo CTP synthesis. These findings introduce a general approach to blocking the assembly of polymerizing enzymes without eliminating their catalytic activity and demonstrate a role for CTPS assembly in supporting egg production, particularly under conditions of limited glutamine metabolism. This article has an associated First Person interview with the first author of the paper.

The bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase (MTHFD2) is a mitochondrial one-carbon folate metabolic enzyme whose role in cancer was not known until recently. MTHFD2 is highly expressed in embryos and a wide range of tumors but has low or absent expression in most adult differentiated tissues. Elevated MTHFD2 expression is associated with poor prognosis in both hematological and solid malignancy. Its depletion leads to suppression of multiple malignant phenotypes including proliferation, invasion, migration, and induction of cancer cell death. The non-metabolic functions of this enzyme, especially in cancers, have thus generated considerable research interests. This review summarizes current knowledge on both the metabolic functions and non-enzymatic roles of MTHFD2. Its expression, potential functions, and regulatory mechanism in cancers are highlighted. The development of MTHFD2 inhibitors and their implications in pre-clinical models are also discussed.

Cyclic dimeric adenosine 3′,5′-monophosphate (c-di-AMP) is an emerging second messenger in bacteria and archaea that is synthesized from two molecules of ATP by diadenylate cyclases and degraded to pApA or two AMP molecules by c-di-AMP-specific phosphodiesterases. Through binding to specific protein- and riboswitch-type receptors, c-di-AMP regulates a wide variety of prokaryotic physiological functions, including maintaining the osmotic pressure, balancing central metabolism, monitoring DNA damage and controlling biofilm formation and sporulation. It mediates bacterial adaptation to a variety of environmental parameters and can also induce an immune response in host animal cells. In this review, we discuss the phylogenetic distribution of c-di-AMP-related enzymes and receptors and provide some insights into the various aspects of c-di-AMP signaling pathways based on more than a decade of research. We emphasize the key role of c-di-AMP in maintaining bacterial osmotic balance, especially in Gram-positive bacteria. In addition, we discuss the future direction and trends of c-di-AMP regulatory network, such as the likely existence of potential c-di-AMP transporter(s), the possibility of crosstalk between c-di-AMP signaling with other regulatory systems, and the effects of c-di-AMP compartmentalization. This review aims to cover the broad spectrum of research on the regulatory functions of c-di-AMP and c-di-AMP signaling pathways. [ABSTRACT FROM AUTHOR]

Metabolic disorders have a large heritable component, and have increased markedly in human populations over the past few generations. Genome‐wide association studies of metabolic traits typically find a substantial unexplained fraction of total heritability, suggesting an important role of spontaneous mutation. An alternative explanation is that epigenetic effects contribute significantly to the heritable variation. Here, we report a study designed to quantify the cumulative effects of spontaneous mutation on adenosine metabolism in the nematode Caenorhabditis elegans, including both the activity and concentration of two metabolic enzymes and the standing pools of their associated metabolites. The only prior studies on the effects of mutation on metabolic enzyme activity, in Drosophila melanogaster, found that total enzyme activity presents a mutational target similar to that of morphological and life‐history traits. However, those studies were not designed to account for short‐term heritable effects. We find that the short‐term heritable variance for most traits is of similar magnitude as the variance among MA lines. This result suggests that the potential heritable effects of epigenetic variation in metabolic disease warrant additional scrutiny. [ABSTRACT FROM AUTHOR]

Ovarian cancer is one of the most malignant gynecological cancers around the world. In spite of multiple treatment options, the five-year survival rate is still very low. Several metabolism alterations are described as a hallmark in cancers, but alterations of lipid metabolism in ovarian cancer have been paid less attention. To explore new markers/targets for accurate diagnosis, prognosis, and therapeutic treatments based on metabolic enzyme inhibitors, here, we reviewed available literature and summarized several key metabolic enzymes in lipid metabolism of ovarian cancer. In this review, the rate limiting enzymes associated with fatty acid synthesis (FASN, ACC, ACLY, SCD), the lipid degradation related enzymes (MAGL, CPT, 5-LO, COX2), and the receptors related to lipid uptake (FABP4, CD36, LDLR), which promote the development of ovarian cancer, were analyzed and evaluated. We also focused on the review of application of current metabolic enzyme inhibitors for the treatment of ovarian cancer through which the potential therapeutic agents may be developed for ovarian cancer therapy. [ABSTRACT FROM AUTHOR]

The application of mass spectrometry imaging (MSI) for the study of spatiotemporal alterations of the metabolites in tumors has brought a number of significant biological results. At present, metabolite profiling based on MSI is typically performed on frozen tissue sections; however, the majority of clinical specimens need to be fixed in tissue fixative to avoid autolysis and to preserve antigenicity. In this study, we present the global impacts of different fixatives on the MS imaging of gastric cancer tissue metabolites. The MSI performances of 17 kinds of metabolites, such as amino acids, polyamines, cholines, organic acids, polypeptides, nucleotides, nucleosides, nitrogen bases, cholesterols, fatty acids, and phospholipids, in untreated, 10% formalin–, 4% paraformaldehyde–, acetone-, and 95% ethanol–fixed gastric cancer tissues were thoroughly explored for the first time. Furthermore, we also investigated the spatial expressions of 6 metabolic enzymes, namely, GLS, FASN, CHKA, PLD2, cPLA2, and EGFR, closely related to tumor-associated metabolites. Immunohistochemical staining carried out on the same tissue sections‚ which have undergone MSI analysis‚ suggests that enzymatic characterization is feasible after metabolite imaging. Combining the spatial signatures of metabolites and pathway-related metabolic enzymes in heterogeneous tumor tissues offers an insight to understand the complex tumor metabolism. [ABSTRACT FROM AUTHOR]

The bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase (MTHFD2) is a mitochondrial one-carbon folate metabolic enzyme whose role in cancer was not known until recently. MTHFD2 is highly expressed in embryos and a wide range of tumors but has low or absent expression in most adult differentiated tissues. Elevated MTHFD2 expression is associated with poor prognosis in both hematological and solid malignancy. Its depletion leads to suppression of multiple malignant phenotypes including proliferation, invasion, migration, and induction of cancer cell death. The non-metabolic functions of this enzyme, especially in cancers, have thus generated considerable research interests. This review summarizes current knowledge on both the metabolic functions and non-enzymatic roles of MTHFD2. Its expression, potential functions, and regulatory mechanism in cancers are highlighted. The development of MTHFD2 inhibitors and their implications in pre-clinical models are also discussed. [ABSTRACT FROM AUTHOR]

One-carbon metabolism is a universal metabolic process that mediates the transfer of one-carbon units for purine and thymidine synthesis. One-carbon metabolism has been found to be dysregulated in various cancer types due to its role in production of purine and pyrimidine nucleotides, epigenetic program, and redox homeostasis. One-carbon metabolism is composed a network of one-carbon metabolic enzymes. Disturbing the expression and enzymatic activity of these one-carbon metabolic enzymes could lead to fluctuations of metabolites in the tumor microenvironment. Serine hydroxymethyltransferases (SHMTs) and methylenetetrahydrofolate dehydrogenases (MTHFDs) are gradually recognized as important one-carbon metabolic enzymes for regulating tumor initiation and development, representing potential therapeutic targets for anti-tumor strategies. In the review, we primarily focused on the role of SHMTs and MTHFDs in cancer. Several inhibitors targeting MTHFDs and SHMTs have exert its potential to decrease tumor burden and inhibit tumor proliferation, highlighting the potential of targeting one-carbon metabolic enzymes for anti-cancer strategies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhang and Wang.)

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Cyanobacteria possess an atypical tricarboxylic acid (TCA) cycle with various bypasses. Previous studies have suggested that a cyclic flow through the TCA cycle is not essential for cyanobacteria under normal growth conditions. The cyanobacterial TCA cycle is, thus, different from that in other bacteria, and the biochemical properties of enzymes in this TCA cycle are less understood. In this study, we reveal the biochemical characteristics of malate dehydrogenase (MDH) from Synechocystis sp. PCC 6803 MDH (SyMDH). The optimal temperature of SyMDH activity was 45–50°C and SyMDH was more thermostable than MDHs from other mesophilic microorganisms. The optimal pH of SyMDH varied with the direction of the reaction: pH 8.0 for the oxidative reaction and pH 6.5 for the reductive reaction. The reductive reaction catalysed by SyMDH was activated by magnesium ions and fumarate, indicating that SyMDH is regulated by a positive feedback mechanism. The Km-value of SyMDH for malate was approximately 210-fold higher than that for oxaloacetate and the Km-value for NAD+ was approximately 19-fold higher than that for NADH. The catalytic efficiency of SyMDH for the reductive reaction, deduced from kcat-values, was also higher than that for the oxidative reaction. These results indicate that SyMDH is more efficient in the reductive reaction in the TCA cycle, and it plays key roles in determining the direction of the TCA cycle in this cyanobacterium.

Drug combinatorial therapy is a promising strategy for combating complex diseases due to its fewer side effects, lower toxicity and better efficacy. However, it is not feasible to determine all the effective drug combinations in the vast space of possible combinations given the increasing number of approved drugs in the market, since the experimental methods for identification of effective drug combinations are both labor- and time-consuming. In this study, we conducted systematic analysis of various types of features to characterize pairs of drugs. These features included information about the targets of the drugs, the pathway in which the target protein of a drug was involved in, side effects of drugs, metabolic enzymes of the drugs, and drug transporters. The latter two features (metabolic enzymes and drug transporters) were related to the metabolism and transportation properties of drugs, which were not analyzed or used in previous studies. Then, we devised a novel improved naïve Bayesian algorithm to construct classification models to predict effective drug combinations by using the individual types of features mentioned above. Our results indicated that the performance of our proposed method was indeed better than the naïve Bayesian algorithm and other conventional classification algorithms such as support vector machine and K-nearest neighbor. [ABSTRACT FROM AUTHOR]

(Pre-partum supplementation of heit-chrose on post-partum blood profile and recovery of body weight of dairy cows) ABSTRACT. This study aimed to determine the profile of blood, metabolic enzymes and recovery of body weight in dairy cows fed diet supplemented with Heit-CHrose (Feed supplement containing saponins, allicin, organic mineral: Se, Cr, and Zn). The experiments were conducted with 4 treatments, R0 : control diet (CP 13,79% and TDN 67,2%), R1 : R0 supplemented with organic minerals (Cr 1,5 ppm; Se 0,3 ppm; Zn-Lyzinat 40 ppm), R2 : Ro supplemented with Heit-CHrose are given in the component feeding, and R3 : Ro supplemented with Heit-CHrose are given in total mixed ration (TMR). Data were tested using analysis of variance with a completely randomized design using four replications, and HSD test. The results showed that the supplementation of Heit-CHrose to the diet of dairy cows gave significant effect (P 0.01) on blood glucose and recovery of body weight, but had no effect (P 0.05) on hemoglobin, blood urea nitrogen (BUN), total protein and blood cholesterol and metabolic enzyme (alkali phospatase). Supplementation of Heit Chrose in dairy cows diet with component feeding and TMR increases blood glucose and recovery of body weight.

The nutritional potential of protein isolate from rubber seed (RPI) in the diets of Labeo rohita (initial average weight 4.45 ± 0.01 g) was assessed in a 60 days feeding trial. Five isonitrogenous (32.62 ± 0.13 CP Kg −1 ) and isocaloric (18.47 ± 0.08 MJ kg −1 ) experimental diets were formulated with graded level of RPI like 0%, 25%, 50%, 75%, or 100% in replacement for soybean protein isolate (SPI), and designated as Control, RPI25, RPI50, RPI75, RPI100, respectively. The RPI contributed 0%, 13%, 26%, 39% or 52% of the total dietary protein in the diets. Each diets were randomly assigned to 15 experimental tanks containing 12 fish in triplicates and fed to satiation twice daily at 10:00 h and 18:00 h. At the end of the feeding trial, the growth performance and nutrient utilization indices such as percent weight gain (WG%), specific growth rate (SGR), daily growth coefficient (DGC), feed intake (FI), protein efficiency ratio (PER), feed conversion ratio (FCR) and protein retention (PR) values were not significantly (p > 0.05) affected by the dietary treatments irrespective of inclusion levels of RPI. A significantly higher (p < 0.05) hepatosomatic index (HSI) was recorded in the control and RPI 50 group compared to other treatment groups (p < 0.05). The intestinal somatic index (ISI) and Survival rate were similar (p > 0.05) in all the groups. The apparent digestibility coefficients (ADCs) of dry matter and protein for fish fed the control and RPI 100 diets were found to be similar, while RPI 50 and RPI 75 groups exhibited a significantly lower value corresponding to the protease enzyme activity. The whole body compositions and digestive/metabolic enzymes activities among the various groups did not differ significantly (p > 0.05). The serum cholesterol and triglyceride levels were found to be significantly higher (p < 0.05) in the control compared to the RPI fed groups. Significantly higher serum glucose level was recorded in RPI 50, while a reverse was seen in the liver glycogen contents. Overall, this study clearly showed that RPI from rubber seed can serve as alternative protein source in the diets of L. rohita fingerlings without any adverse effects on growth, nutrient utilization and physio-metabolic responses. [ABSTRACT FROM AUTHOR]

Contexts:Exposure to environmental pollutants such as carbon tetrachloride (CCl4) causes liver injuries. There are claims that extracts fromSyzygium aromaticum(Linn.) Merrill & L.M.Perry, (Myrtaceae) protects from such injuries. Objective:This study investigates the protective effects of cold-pressedS. aromaticumoil (CO) against CCl4-induced liver toxicity in rats. Materials and methods:CO was orally administered to rats in two doses (100 and 200 mg/kg) along with CCl4(1 mL/kg in olive oil) for 8 weeks. Indices of liver and kidney functions, lipid profile, and peroxidation were evaluated in rats’ serum and tissues. Fatty acids and bioactive lipids of CO were analyzed. Results:High levels of monounsaturated fatty acids (39.7%) and polyunsaturated fatty acids (42.1%) were detected in CO. The oil contained high amounts of tocols and phenolics. The LD50value at 24 h was approximately 5950 mg/kg. Treatment with 200 mg/kg CO resulted in a decrease of creatinine, urea, and uric acid levels to 0.86, 32.6, and 2.99 mg/dL, respectively. Levels of TL, TC, TAG, LDL-C, and VLDL-C were decreased to 167, 195.3, 584.5, 74.6, and 39.0 mg/L, respectively, after 8 weeks of treatment. Hepatic malondialdehyde levels were reduced and glutathione levels were elevated in CO-treated rats. CO reduced the activities of AST, ALT, and ALP as well as kidney function markers, protein, and lipid profiles, respectively. Histopathological examination of liver indicated that CO treatment reduced fatty degenerations, cytoplasmic vacuolization, and necrosis. Conclusion:CO possessed a protective effect against CCl4-induced hepatotoxicity in rats, mediated possibly by the antioxidant properties of the oil. [ABSTRACT FROM AUTHOR]

Accumulating evidence from the last decade has shown that many pharmaceutical excipients are not pharmacologically inert but instead have effects on metabolic enzymes and/or drug transporters. Hence, the absorption, distribution, metabolism, and elimination (ADME) of active pharmaceutical ingredients (APIs) may be altered due to the modulation of their metabolism and transport by excipients. The impact of excipients is a potential concern for Biopharmaceutics Classification System (BCS)-based biowaivers, particularly as the BCS-based biowaivers have been extended to class 3 drugs in certain dosage forms. The presence of different excipients or varying amounts of excipients between formulations may result in bio-inequivalence. The excipient impact may lead to significant variations in clinical outcomes as well. The aim of this paper is to review the recent findings of excipient effects on gastrointestinal (GI) absorption, focusing on their interactions with the metabolic enzymes and transporters in the GI tract. A wide range of commonly used excipients such as binders, diluents, fillers, solvents, and surfactants are discussed here. We summarized the reported effects of those excipients on GI tract phase I and phase II enzymes, uptake and efflux transporters, and relevant clinical significance. This information can enhance our understanding of excipient influence on drug absorption and is useful in designing pharmacokinetic studies and evaluating the resultant data. [ABSTRACT FROM AUTHOR]