Objective Nicotinamide adenine dinucleotide phosphate(NADPH)oxidases(NOXs)are known as major sources of reactive oxygen species(ROS),yet their role in regulating cellular antioxidative metabolism and ferroptosis is un...Objective Nicotinamide adenine dinucleotide phosphate(NADPH)oxidases(NOXs)are known as major sources of reactive oxygen species(ROS),yet their role in regulating cellular antioxidative metabolism and ferroptosis is unclear.This study assessed the expression and clinical relevance of NOXs across pan-cancer and investigated the role of NOX4 in colorectal cancer progression Methods We analyzed transcriptomic and survival data from The Cancer Genome Atlas(TCGA)for NOXs across 22 types of solid tumors.A CRISPR library targeting NOXs was developed for potential therapeutic target screening in colorectal cancer cells(CRCs).Techniques such as CRISPR-knockout cell lines,1,2-13C-glucose tracing,PI staining,BrdU assays,and coimmunoprecipitation were employed to elucidate the function of NOX4 in CRCs.Results NOX4 emerged as a key therapeutic target for colorectal cancer from TCGA data.CRISPR screening highlighted its essential role in CRC survival,with functional experiments confirming that NOX4 upregulation promotes cell survival and proliferation.The interaction of NOX4 with glucose‑6‑phosphate dehydrogenase(G6PD)was found to enhance the pentose phosphate pathway(PPP),facilitating ROS clearance and protecting CRCs against ferroptosis.Conclusions This study identified NOX4 as a novel ferroptosis suppressor and a therapeutic target for the treatment of colorectal cancer.The findings suggest that a coupling between NADPH oxidase enzyme NOX4 and the PPP regulates ferroptosis and reveal an accompanying metabolic vulnerability for therapeutic targeting in colorectal cancer.展开更多
Disruption of the circadian clock can affect starvation resistance,but the molecular mechanism is still unclear.Here,we found that starvation resistance was significantly reduced in the core gene BmPer deficient mutan...Disruption of the circadian clock can affect starvation resistance,but the molecular mechanism is still unclear.Here,we found that starvation resistance was significantly reduced in the core gene BmPer deficient mutant silkworms(Per^(−/−)),but the mutant's starvation resistance increased with larval age.Under natural physiological conditions,the weight of mutant 5th instar larvae was significantly increased compared to wild type,and the accumulation ability of triglycerides and glycogen in the fat bodies was upregulated.However,under starvation conditions,the weight consumption of mutant larvae was increased and cholesterol utilization was intensified.Transcriptome analysis showed that beta-oxidation was significantly upregulated under starvation conditions,fatty acid synthesis was inhibited,and the expression levels of genes related to mitochondrial function were significantly changed.Further investigations revealed that the redox balance,which is closely related to mitochondrial metabolism,was altered in the fat bodies,the antioxidant level was increased,and the pentose phosphate pathway,the source of reducing power in cells,was activated.Our findings suggest that one of the reasons for the increased energy burden observed in mutants is the need to maintain a more robust redox balance in metabolic tissues.This necessitates the diversion of more glucose into the pentose phosphate pathway to ensure an adequate supply of reducing power.展开更多
BACKGROUND UDP-glucose 6-dehydrogenase(UGDH)is a key enzyme in glucuronic acid metabolism and acts as a key mediator in several cancer developmental signaling pathways.AIM To offer a more systematic and comprehensive ...BACKGROUND UDP-glucose 6-dehydrogenase(UGDH)is a key enzyme in glucuronic acid metabolism and acts as a key mediator in several cancer developmental signaling pathways.AIM To offer a more systematic and comprehensive elucidation of the involvement of UGDH in the onset and progression of various malignancies.METHODS The role of UGDH in cancer was investigated via public databases.The data were analyzed via various R packages and websites,including TISIDB,cBioPortal,STRING,Cytoscape,GSCALite,and CancerSEA.A rat hepatocellular carcinoma(HCC)model was established via the intraperitoneal injection of diethylnitrosamine.Hematoxylin-eosin staining,Masson staining,Ki67 and UGDH immunohistochemical staining,and ARG1 immunofluorescence staining of liver tissues were performed.Real-time quantitative PCR and Western blotting were used to detect UGDH expression.The UGDH gene was knocked down in Huh7 cells,and CCK8 and nude mouse tumor xenograft assays were performed.RESULTS High UGDH expression is associated with poor clinical outcomes in HCC,lung adenocarcinoma,lung squamous cell carcinoma,and sarcoma patients and is differentially expressed across molecular and immune subtypes.UGDH is primarily involved in the pentose and glucuronate interconversion pathway.Its expression is positively correlated with T helper,Tcm,and Th2 cells in most cancers.Moreover,experimental results demonstrated that UGDH expression is elevated in HCC tissues and that its downregulation inhibits HCC cell proliferation.CONCLUSION Our study revealed that UGDH could be a valuable prognostic biomarker and potential therapeutic target in many cancers,especially liver and lung cancer.UGDH could promote HCC cell proliferation,potentially by modulating the pentose and glucuronate interconversion pathways.展开更多
Energy metabolism is significantly reprogrammed in many human cancers, and these alterations confer many advantages to cancer cells, including the pro- motion of biosynthesis, ATP generation, detoxification and suppor...Energy metabolism is significantly reprogrammed in many human cancers, and these alterations confer many advantages to cancer cells, including the pro- motion of biosynthesis, ATP generation, detoxification and support of rapid proliferation. The pentose phos- phate pathway （PPP） is a major pathway for glucose catabolism. The PPP directs glucose flux to its oxi- dative branch and produces a reduced form of nico- tinamide adenine dinucleotide phosphate （NADPH）, an essential reductant in anabolic processes. It has become clear that the PPP plays a critical role in regulating cancer cell growth by supplying cells with not only ribose-5-phosphate but also NADPH for detoxification of intracellular reactive oxygen species, reductive biosynthesis and ribose biogenesis. Thus, alteration of the PPP contributes directly to cell pro- liferation, survival and senescence. Furthermore, recent studies have shown that the PPP is regulated oncogenically and/or metabolically by numerous fac- tors, including tumor suppressors, oncoproteins and intracellular metabolites. Dysregulation of PPP flux dramatically impacts cancer growth and survival. Therefore, a better understanding of how the PPP is reprogrammed and the mechanism underlying the balance between glycolysis and PPP flux in cancer will be valuable in developing therapeutic strategies targeting this pathway.展开更多
Nutlin-3a is a MDM2 antagonist and preclinical drug that activates p53. Cells with MDM2 gene amplification are especially prone to Nutlin-3a-induced apoptosis, though the basis for this is unclear. Glucose metabolism ...Nutlin-3a is a MDM2 antagonist and preclinical drug that activates p53. Cells with MDM2 gene amplification are especially prone to Nutlin-3a-induced apoptosis, though the basis for this is unclear. Glucose metabolism can inhibit apoptosis in response to Nutlin-3a through mechanisms that are incompletely understood. Glucose metabolism through the pentose phosphate pathway （PPP） produces NADPH that can protect cells from potentially lethal reactive oxygen species （ROS）. We compared apoptosis and glucose metabolism in cancer cells with and without MDM2 gene amplification treated with Nutlin-3a. Apoptosis in MDM2-amplified cells was associated with a reduction in glycolysis and the PPP, reduced NADPH, increased ROS, and depletion of the transcription factor SP1, which normally promotes PPP gene expression. In contrast, glycolysis and the PPP were maintained or increased in MDM2 non-amplified cells treated with Nutlin-3a. This was dependent on p53-mediated AKT activation and was associated with maintenance of SP1 and continued expression of PPP genes. Knockdown or inhibition of AKT, SP1, or the PPP sensitized MDM2-non-amplified cells to apoptosis. The data indicate that p53 promotes AKT and SP1-dependent activation of the PPP that protects cells from Nutlin-3a-induced apoptosis. These findings provide insight into how glucose metabolism reduces Nutlin-3a-induced apoptosis, and also provide a mechanism for the heightened sensitivity of MDM2-amplified cells to apoptosis in response to Nutlin-3a.展开更多
The well-resolved absorption spectra of D-xylose,D-ribose,D-arabinose,D-lyxose and other related substances in the spectral region between 0.3 and 2.0 THz are measured using tera-hertz time-domain spectroscopy(THz-TDS...The well-resolved absorption spectra of D-xylose,D-ribose,D-arabinose,D-lyxose and other related substances in the spectral region between 0.3 and 2.0 THz are measured using tera-hertz time-domain spectroscopy(THz-TDS)at 295 K.Comparing the absorption spectra of different chemicals,we can distinguish the samples easily.Thus THz-TDS is demonstrated to be a power and characteristic spectral tool,which is highly sensitive to the minor changes of the molecular structures and can be applied to detect and analyze similar materials.展开更多
Transketolase （TK）, a thiamine diphosphate （ThDP）-dependent enzyme, catalyzes several key reactions of nonoxidative branch of pentose phosphate pathway. TK is a homodimer with two active sites that locate at the i...Transketolase （TK）, a thiamine diphosphate （ThDP）-dependent enzyme, catalyzes several key reactions of nonoxidative branch of pentose phosphate pathway. TK is a homodimer with two active sites that locate at the interface between the contacting monomers. Both ThDP and bivalent cations are strictly needed for TK activation, just like that for all ThDPdependent enzymes. TK exists in all organisms that have been investigated. Up to now, one TK gene （TKT） and two transketolase-like genes （TKTL1 and TKTL2） have been identified in human genome. TKTL1 is reported to play a pivotal role in carcinogenesis and may have important implications in the nutrition and future treatment of patients with cancer. Research- ers have found TK variants and reduced activities of TK enzyme in patients with neurodegenerative diseases, diabetes, and cancer. Recent studies indicated TK as a novel role in the prevention and therapy of these diseases.展开更多
Changes in main biochemical respiratory pathways in dormant nectarine floral buds were studied with nectarine trees （Prunus persica.var, nectariana cv. Shuguang） in order to determine the function of respiration in ...Changes in main biochemical respiratory pathways in dormant nectarine floral buds were studied with nectarine trees （Prunus persica.var, nectariana cv. Shuguang） in order to determine the function of respiration in dormancy release. Oxygen-electrode system and respiratory inhibitors were used to measure total respiratory rates and rates of respiratory pathways. Results showed that chilling deficiency blocked the transition of respiratory mode, and made buds stay in a state of high level pentose phosphate pathway （PPP） and low level tricarboxylie acid cycle （TCA）. The decline of PPP and activation of TCA occurred synchronously with the release of dormancy. In addition, the inhibition of PPP stimulated a respiration increase related with TCA. It could be concluded that the function of PPP activation in dormancy release might be limited and PPP declination inducing TCA activation might be part of respiration mode transition mechanism during bud sprouting.展开更多
Xylose, as β-1,4-linked xylan, makes up much of the hemicel ulose in cel wal s of cereal carbohydrates fed to pigs. As inclusion of fibrous ingredients in swine diets continues to increase, supplementation of carbohy...Xylose, as β-1,4-linked xylan, makes up much of the hemicel ulose in cel wal s of cereal carbohydrates fed to pigs. As inclusion of fibrous ingredients in swine diets continues to increase, supplementation of carbohydrases, such as xylanase,is of interest. However, much progress is warranted to achieve consistent enzyme efficacy, including an improved understanding of the utilization and energetic contribution of xylanase hydrolysis product（i.e. xylooligosaccharides or monomeric xylose）. This review examines reports on xylose absorption and metabolism in the pig and identifies gaps in this knowledge that are essential to understanding the value of carbohydrase hydrolysis products in the nutrition of the pig. Xylose research in pigs was first reported in 1954, with only sporadic contributions since. Therefore, this review also discusses relevant xylose research in other monogastric species, including humans. In both pigs and poultry, increasing purified D-xylose inclusion general y results in linear decreases in performance, efficiency, and diet digestibility. However,supplementation levels studied thus far have ranged from 5% to 40%, while theoretical xylose release due to xylanase supplementation would be less than 4%. More than 95% of ingested D-xylose disappears before the terminal ileum but mechanisms of absorption have yet to be ful y elucidated. Some data support the hypothesis that mechanisms exist to handle low xylose concentrations but become overwhelmed as luminal concentrations increase. Very little is known about xylose metabolic utilization in vertebrates but it is wel recognized that a large proportion of dietary xylose appears in the urine and significantly decreases the metabolizable energy available from the diet. Nevertheless, evidence of labeled D-xylose-1-^（14）C appearing as expired^（14）CO_2 in both humans and guinea pigs suggests that there is potential,although small, for xylose oxidation. It is yet to be determined if pigs develop increased xylose metabolic capacity with increased adaptation time to diets supplemented with xylose or xylanase. Overall, xylose appears to be poorly utilized by the pig, but it is important to consider that only one study has been reported which supplemented D-xylose dietary concentrations lower than 5%. Thus, more comprehensive studies testing xylose metabolic effects at dietary concentrations more relevant to swine nutrition are warranted.展开更多
The effects of exogenous gibberellic acid (GA(3)) and abscisic acid (ABA) on the total respiratory rate, percentages of total respiratory rate contributed by respiratory pathways [Embden-Meyerhof- Parnas Pathway (EMP)...The effects of exogenous gibberellic acid (GA(3)) and abscisic acid (ABA) on the total respiratory rate, percentages of total respiratory rate contributed by respiratory pathways [Embden-Meyerhof- Parnas Pathway (EMP), Pentose Phosphate Pathway (PPP), and Tricarboxylic Acid Cycle (TCA)], and conversion of starch to soluble sugars in the buds of black currants during secondary bud burst were investigated to determine the relationship between respiratory rates and secondary bud burst. 'Adelinia', a black currant cultivar that is prone to secondary bud burst after the first harvest, was used in this study. Mature bushes of Adelinia were sprayed with 30 mg/L GA(3) and 50 mg/L ABA to manipulate bud burst. The results showed that exogenous applications of GA(3) and ABA had opposite effects on bud respiratory rate. Generally, GA(3) treatment increased the total respiratory rate and respiratory rate of the TCA and PPP, and the respiratory rates after GA(3) treatment were higher than those of control. While ABA treatment mostly decreased the total respiratory rate and the respiratory rate of TCA and PPP in buds in comparison to control. In terms of the percentage of the three respiratory rates in comparison to the total respiratory rate, GA(3) treatment significantly increased the percentage of TCA and PPP respiratory rate in comparison to the control (P < 0.01), whereas ABA decreased the rates. GA(3) significantly increased the content of soluble sugars and decreased the starch content, while the starch content in buds after ABA treatment was significantly higher than that of the control. All results showed that PPP is a critical process for the second bud burst in black currants. While the EMP-TCA pathway is still dominant in bud respiration, provides a series of basic materials and energy (ATP). The conversion of starch to soluble sugars is essential for bud burst. Thus, we conclude that an energy shortage is a main contributor in ABA inhibition of the secondary bud burst of black currants.展开更多
The thermophilic filamentous fungus, Thermomyces lanuginosus produces the largest amount of xylanase reported. In addition to this, it expresses large amount of other enzymes that have been used industrially or have a...The thermophilic filamentous fungus, Thermomyces lanuginosus produces the largest amount of xylanase reported. In addition to this, it expresses large amount of other enzymes that have been used industrially or have academic interest. Thus, this fungus has a potential to be applied for biomass conversion to produce biofuel or other applications. In this study, the Biolog system was used to characterize the utilisation and growth of T. lanuginosus on 95 carbon sources. The carbohydrates based compounds, both single sugars and oligosaccharide, showed the best utilisation profile, with the pentose sugar xylose inducing the highest growth, followed by trehelose, raffinose, D-mannose turanose fructose and glucose. Among oligosaccharides, sucrose had the highest mycelium formation followed by stachyose, maltose, maltotriose, glycogen and dextrin. Interestingly the fungus also grew well on cellobiose suggesting that this fungus can produce cellulose hydrolysing proteins. D-alanine was the best amino acid to promote fungal growth while the effect of other amino acids tested was similar to the control. These results demonstrate the ability of this fungus to grow relatively well on most plant based compounds thus making this fungus a possible candidate for plant biomass conversion which can be applied to a number of biotechnological applications including biofuel production.展开更多
Nicotinamide adenine dinucleotide phosphate(NADPH) oxidase is the main source of ROS(intracellular reactive oxygen species), ROS plays an important role in a variety of tumor, the ROS mediated by NADPH oxidase increas...Nicotinamide adenine dinucleotide phosphate(NADPH) oxidase is the main source of ROS(intracellular reactive oxygen species), ROS plays an important role in a variety of tumor, the ROS mediated by NADPH oxidase increase the expression of hypoxia inducing factor alpha(HIF-α) through multiple signaling pathways in tumor, and HIFcould be regulated and controlled by downstream multiple targeted genes such as vascular endothelial growth factor(VEGF), glucose transporter(GLUT) to promote tumor angiogenesis, cell energy metabolism reprogram and tumor metastasis.HIF-α, meanwhile, also can regulate the expression of NADPH oxidase by ROS, thus further promote development of tumor.In this review, we will summarize the functions of NADPH in tumorigenesis and discuss their potential implications in cancer therapy.展开更多
Glucose-6-phosphate dehydrogenase(G6PD),the first rate-limiting enzyme of the pentose phosphate pathway(PPP),is aberrantly activated in multiple types of human cancers,governing the progression of tumor cells as well ...Glucose-6-phosphate dehydrogenase(G6PD),the first rate-limiting enzyme of the pentose phosphate pathway(PPP),is aberrantly activated in multiple types of human cancers,governing the progression of tumor cells as well as the efficacy of anticancer therapy.Here,we discovered that cyclindependent kinase 5(CDK5)rewired glucose metabolism from glycolysis to PPP in breast cancer(BC)cells by activating G6PD to keep intracellular redox homeostasis under oxidative stress.Mechanistically,CDK5-phosphorylated G6PD at Thr-91 facilitated the assembly of inactive monomers of G6PD into active dimers.More importantly,CDK5-induced pho-G6PD was explicitly observed specifically in tumor tissues in human BC specimens.Pharmacological inhibition of CDK5 remarkably abrogated G6PD phosphorylation,attenuated tumor growth and metastasis,and synergistically sensitized BC cells to polyADP-ribose polymerase(PARP)inhibitor Olaparib,in xenograft mouse models.Collectively,our results establish the crucial role of CDK5-mediated phosphorylation of G6PD in BC growth and metastasis and provide a therapeutic regimen for BC treatment.展开更多
The oxidative pentose phosphate(OPP)pathway provides metabolic intermediates for the shikimate pathway and directs carbon flow to the biosynthesis of aromatic amino acids(AAAs),which serve as basic protein building bl...The oxidative pentose phosphate(OPP)pathway provides metabolic intermediates for the shikimate pathway and directs carbon flow to the biosynthesis of aromatic amino acids(AAAs),which serve as basic protein building blocks and precursors of numerous metabolites essential for plant growth.However,genetic evidence linking the two pathways is largely unclear.In this study,we identified 6-phosphogluconate dehydrogenase 2(PGD2),the rate-limiting enzyme of the cytosolic OPP pathway,through suppressor screening of arogenate dehydrogenase 2(adh2)in Arabidopsis.Our data indicated that a single amino acid substitution at position 63(glutamic acid to lysine)of PGD2 enhanced its enzyme activity by facilitating the dissociation of products from the active site of PGD2,thus increasing the accumulation of AAAs and partially restoring the defective phenotype of adh2.Phylogenetic analysis indicated that the point mutation occurred in a well-conserved amino acid residue.Plants with different amino acids at this conserved site of PGDs confer diverse catalytic activities,thus exhibiting distinct AAAs producing capability.These findings uncover the genetic link between the OPP pathway and AAAs biosynthesis through PGD2.The gain-of-function point mutation of PGD2 identified here could be considered as a potential engineering target to alter the metabolic flux for the production of AAAs and downstream compounds.展开更多
Aim:Gastric cancer(GC)is one of the common malignant tumors,and most patients with advanced GC often develop chemotherapy resistance,resulting in poor chemotherapy efficacy.Therefore,it is crucial to clarify the speci...Aim:Gastric cancer(GC)is one of the common malignant tumors,and most patients with advanced GC often develop chemotherapy resistance,resulting in poor chemotherapy efficacy.Therefore,it is crucial to clarify the specific mechanisms of their chemotherapy resistance.Methods:In this study,we analyzed the correlation between fos-related antigen-1(Fra-1)and chemotherapy resistance in GC using bioinformatics,cell counting kit-8(CCK8),and 5-ethynyl-2’-deoxyuridine(EDU)combined with flow cytometry;furthermore,we used energy metabolomics sequencing,combined with ChIP-qPCR technology,to elucidate the specific role of Fra-1 in chemotherapy resistance of GC cells and its related mechanisms.Results:We found that high Fra-1 expression was closely related to chemotherapeutic drugs in GC cells,as demonstrated by bioinformatics analysis combined with EDU and CCK8 experiments.Energy metabolomics combined with in vitro cellular experimental analysis revealed that the pentose phosphate pathway(PPP)was activated in GC cells with high Fra-1 expression,along with an increase in the synthesis of metabolites such as nicotinamide adenine dinucleotide phosphate(NADPH)and glutathione(GSH),a decrease in the level of reactive oxygen species(ROS),and the inhibition of their ferroptosis.In addition,ChIP-qPCR experiments confirmed that Fra-1 binds to the promoter of glucose-6-phosphate dehydrogenase(G6PD),a key rate-limiting enzyme of the PPP,and transcriptionally regulates its expression,which in turn activates the PPP and promotes chemotherapy resistance in GC cells.Conclusion:Our research findings suggest that Fra-1 activates the PPP by upregulating G6PD transcriptional activity and inhibiting its ubiquitination level,inhibiting ferroptosis in GC cells and inducing chemoresistance.This provides an experimental basis for screening potential molecular targets for chemotherapy resistance in GC patients.展开更多
Hepatocellular carcinoma(HCC)is an aggressive human cancer with increasing incidence worldwide.Multiple efforts have been made to explore pharmaceutical therapies to treat HCC,such as targeted tyrosine kinase inhibito...Hepatocellular carcinoma(HCC)is an aggressive human cancer with increasing incidence worldwide.Multiple efforts have been made to explore pharmaceutical therapies to treat HCC,such as targeted tyrosine kinase inhibitors,immune based therapies and combination of chemotherapy.However,limitations exist in current strategies including chemoresistance for instance.Tumor initiation and progression is driven by reprogramming of metabolism,in particular during HCC development.Recently,metabolic associated fatty liver disease(MAFLD),a reappraisal of new nomenclature for nonalcoholic fatty liver disease(NAFLD),indicates growing appreciation of metabolism in the pathogenesis of liver disease,including HCC,thereby suggesting new strategies by targeting abnormal metabolism for HCC treatment.In this review,we introduce directions by highlighting the metabolic targets in glucose,fatty acid,amino acid and glutamine metabolism,which are suitable for HCC pharmaceutical intervention.We also summarize and discuss current pharmaceutical agents and studies targeting deregulated metabolism during HCC treatment.Furthermore,opportunities and challenges in the discovery and development of HCC therapy targeting metabolism are discussed.展开更多
Cystine/glutamate antiporter solute carrier family 7 member 11(SLC7A11;also known as xCT)plays a key role in antioxidant defense by mediating cystine uptake,promoting glutathione synthesis,and maintaining cell surviva...Cystine/glutamate antiporter solute carrier family 7 member 11(SLC7A11;also known as xCT)plays a key role in antioxidant defense by mediating cystine uptake,promoting glutathione synthesis,and maintaining cell survival under oxidative stress conditions.Recent studies showed that,to prevent toxic buildup of highly insoluble cystine inside cells,cancer cells with high expression of SLC7A11(SLC7A11high)are forced to quickly reduce cystine to more soluble cysteine,which requires substantial NADPH supply from the glucose-pentose phosphate pathway(PPP)route,thereby inducing glucose-and PPP-dependency in SLC7A11high cancer cells.Limiting glucose supply to SLC7A11high cancer cells results in significant NADPH“debt”,redox“bankruptcy”,and subsequent cell death.This review summarizes our current understanding of NADPH-generating and-consuming pathways,discusses the opposing role of SLC7A11 in protecting cells from oxidative stresseinduced cell death such as ferroptosis but promoting glucose starvationeinduced cell death,and proposes the concept that SLC7A11-mediated cystine uptake acts as a double-edged sword in cellular redox regulation.A detailed understanding of SLC7A11 in redox biology may identify metabolic vulnerabilities in SLC7A11high cancer for therapeutic targeting.展开更多
Glucose-6-phosphate dehydrogenase （G6PDH, E.C. 1.1.1.49） and 6-phosphogluconate dehydrogenase （6PGDH, EC 1.1.1.44） are both key enzymes of the pentose phosphate pathway （PPP）. The OsG6PDH1 and Os6PGDH1 genes enc...Glucose-6-phosphate dehydrogenase （G6PDH, E.C. 1.1.1.49） and 6-phosphogluconate dehydrogenase （6PGDH, EC 1.1.1.44） are both key enzymes of the pentose phosphate pathway （PPP）. The OsG6PDH1 and Os6PGDH1 genes encoding cytosolic G6PDH and cytosolic 6PGDH were Isolated from rice （Oryza sativa L.）. We have shown that Os6PGDH1 gene was up-regulated by salt stress. Here we reported the isolation and characterization of Os6PGDH2 from rice, which encode the plastidic counterpart of 6PGDH. Genomic organization analysis indicated that OsG6PDH1 and OsG6PDH2 genes contain multiple introns, whereas two Os6PGDH1 and Os6PGDH2 genes have no introns in their translated regions. In a step towards understanding the functions of the pentose phosphate pathway in plants in response to various abiotic stresses, the expressions of four genes in the rice seedlings treated by drought, cold, high salinity and abscisic acid （ABA） were investigated. The results show that OsG6PDH1 and OsG6PDH2 are not markedly regulated by the abiotic stresses detected. However, the transcript levels of both Os6PGDH1 and Os6PGDH2 are up-regulated in rice seedlings under drought, cold, high salinity and ABA treatments. Meanwhile, the enzyme activities of G6PDH and 6PGDH in the rice seedlings treated by various abiotic stresses were Investigated. Like the mRNA expression patterns, G6PDH activity remains constant but the 6PGDH Increases steadily during the treatments. Taken together, we suggest that the pentose phosphate pathway may play an important role in rice responses to abiotic stresses and the second key enzyme of PPP, 6PGDH, may function as a regulator controlling the efficiency of the pathway under abiotic stresses.展开更多
Cancer cells remodel their metabolic network to adapt to variable nutrient availability. Pentose phosphate pathway(PPP) plays protective and biosynthetic roles by oxidizing glucose to generate reducing power and ribos...Cancer cells remodel their metabolic network to adapt to variable nutrient availability. Pentose phosphate pathway(PPP) plays protective and biosynthetic roles by oxidizing glucose to generate reducing power and ribose. How cancer cells modulate PPP activity in response to glucose supply remains unclear. Here we show that ribose-5-phosphate isomerase A(RPIA), an enzyme in PPP, directly interacts with co-activator associated arginine methyltransferase 1(CARM1) and is methylated at arginine 42(R42). R42 methylation up-regulates the catalytic activity of RPIA. Furthermore, glucose deprivation strengthens the binding of CARM1 with RPIA to induce R42 hypermethylation. Insufficient glucose supply links to RPIA hypermethylation at R42, which increases oxidative PPP flux. RPIA methylation supports ROS clearance by enhancing NADPH production and fuels nucleic acid synthesis by increasing ribose supply. Importantly, RPIA methylation at R42 significantly potentiates colorectal cancer cell survival under glucose starvation. Collectively, RPIA methylation connects glucose availability to nucleotide synthesis and redox homeostasis.展开更多
Mitochondria-associated endoplasmic reticulum membranes(MAM)play a key role in mitochondrial dynamics and function and in hepatic insulin action.Whereas mitochondria are important regulators of energy metabolism,the n...Mitochondria-associated endoplasmic reticulum membranes(MAM)play a key role in mitochondrial dynamics and function and in hepatic insulin action.Whereas mitochondria are important regulators of energy metabolism,the nutritional regulation of MAM in the liver and its role in the adaptation of mitochondria physiology to nutrient availability are unknown.In this study,we found that the fasted to postprandial transition reduced the number of endoplasmic reticulum-mitochondria contact points in mouse liver.Screening of potential hormonal/metabolic signals revealed glucose as the main nutritional regulator of hepatic MAM integrity both in vitro and in vivo.Glucose reduced organelle interactions through the pentose phosphate-protein phosphatase 2A(PP-PP2A)pathway,induced mitochondria fission,and impaired respiration.Blocking MAM reduction counteracted glucose-induced mitochondrial alterations.Furthermore,disruption of MAM integrity mimicked effects of glucose on mitochondria dynamics and function.This glucose-sensing system is deficient in the liver of insulin-resistant ob/ob and cyclophilin D-KO mice,both characterized by chronic disruption of MAM integrity,mitochondrial fission,and altered mitochondrial respiration.These data indicate that MAM contribute to the hepatic glucose-sensing system,allowing regulation of mitochondria dynamics and function during nutritional transition.Chronic disruption of MAM may participate in hepatic mitochondrial dysfunction associated with insulin resistance.展开更多
基金supported by the National Natural Science Foundation of China(No.81802917 and No.82102969)the Huai’an Natural Science Research Program(No.HAB202101).
文摘Objective Nicotinamide adenine dinucleotide phosphate(NADPH)oxidases(NOXs)are known as major sources of reactive oxygen species(ROS),yet their role in regulating cellular antioxidative metabolism and ferroptosis is unclear.This study assessed the expression and clinical relevance of NOXs across pan-cancer and investigated the role of NOX4 in colorectal cancer progression Methods We analyzed transcriptomic and survival data from The Cancer Genome Atlas(TCGA)for NOXs across 22 types of solid tumors.A CRISPR library targeting NOXs was developed for potential therapeutic target screening in colorectal cancer cells(CRCs).Techniques such as CRISPR-knockout cell lines,1,2-13C-glucose tracing,PI staining,BrdU assays,and coimmunoprecipitation were employed to elucidate the function of NOX4 in CRCs.Results NOX4 emerged as a key therapeutic target for colorectal cancer from TCGA data.CRISPR screening highlighted its essential role in CRC survival,with functional experiments confirming that NOX4 upregulation promotes cell survival and proliferation.The interaction of NOX4 with glucose‑6‑phosphate dehydrogenase(G6PD)was found to enhance the pentose phosphate pathway(PPP),facilitating ROS clearance and protecting CRCs against ferroptosis.Conclusions This study identified NOX4 as a novel ferroptosis suppressor and a therapeutic target for the treatment of colorectal cancer.The findings suggest that a coupling between NADPH oxidase enzyme NOX4 and the PPP regulates ferroptosis and reveal an accompanying metabolic vulnerability for therapeutic targeting in colorectal cancer.
基金supported by the National Natural Science Foundation of China(Grant No.32172794 to S.-Q.X.and 32302817 to J.-F.Q.)the Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD to S.-Q.X.)Postgraduate Research&Practice Innovation Program of Jiangsu Province(KYCX23_3259 to R.-J.P)。
文摘Disruption of the circadian clock can affect starvation resistance,but the molecular mechanism is still unclear.Here,we found that starvation resistance was significantly reduced in the core gene BmPer deficient mutant silkworms(Per^(−/−)),but the mutant's starvation resistance increased with larval age.Under natural physiological conditions,the weight of mutant 5th instar larvae was significantly increased compared to wild type,and the accumulation ability of triglycerides and glycogen in the fat bodies was upregulated.However,under starvation conditions,the weight consumption of mutant larvae was increased and cholesterol utilization was intensified.Transcriptome analysis showed that beta-oxidation was significantly upregulated under starvation conditions,fatty acid synthesis was inhibited,and the expression levels of genes related to mitochondrial function were significantly changed.Further investigations revealed that the redox balance,which is closely related to mitochondrial metabolism,was altered in the fat bodies,the antioxidant level was increased,and the pentose phosphate pathway,the source of reducing power in cells,was activated.Our findings suggest that one of the reasons for the increased energy burden observed in mutants is the need to maintain a more robust redox balance in metabolic tissues.This necessitates the diversion of more glucose into the pentose phosphate pathway to ensure an adequate supply of reducing power.
基金Supported by National Natural Science Foundation of China,No.82405314Horizontal Project of Dongzhimen Hospital,No.HX-DZM-202405+1 种基金Project of Beijing University of Chinese Medicine,No.DZMG-QNZX-24015Traditional Chinese Medicine Foundation of Xiamen,No.XWZY-2023-0616.
文摘BACKGROUND UDP-glucose 6-dehydrogenase(UGDH)is a key enzyme in glucuronic acid metabolism and acts as a key mediator in several cancer developmental signaling pathways.AIM To offer a more systematic and comprehensive elucidation of the involvement of UGDH in the onset and progression of various malignancies.METHODS The role of UGDH in cancer was investigated via public databases.The data were analyzed via various R packages and websites,including TISIDB,cBioPortal,STRING,Cytoscape,GSCALite,and CancerSEA.A rat hepatocellular carcinoma(HCC)model was established via the intraperitoneal injection of diethylnitrosamine.Hematoxylin-eosin staining,Masson staining,Ki67 and UGDH immunohistochemical staining,and ARG1 immunofluorescence staining of liver tissues were performed.Real-time quantitative PCR and Western blotting were used to detect UGDH expression.The UGDH gene was knocked down in Huh7 cells,and CCK8 and nude mouse tumor xenograft assays were performed.RESULTS High UGDH expression is associated with poor clinical outcomes in HCC,lung adenocarcinoma,lung squamous cell carcinoma,and sarcoma patients and is differentially expressed across molecular and immune subtypes.UGDH is primarily involved in the pentose and glucuronate interconversion pathway.Its expression is positively correlated with T helper,Tcm,and Th2 cells in most cancers.Moreover,experimental results demonstrated that UGDH expression is elevated in HCC tissues and that its downregulation inhibits HCC cell proliferation.CONCLUSION Our study revealed that UGDH could be a valuable prognostic biomarker and potential therapeutic target in many cancers,especially liver and lung cancer.UGDH could promote HCC cell proliferation,potentially by modulating the pentose and glucuronate interconversion pathways.
基金We apologize to those authors whose excellent work could not be cited due to space constraints. This work was supported by the Start-Up Package Fund from Tsinghua University to J.P. and the grant （Grants No. 2010CB912804 and 31030046 to WM） from National Natural Science Foundation of China.
文摘Energy metabolism is significantly reprogrammed in many human cancers, and these alterations confer many advantages to cancer cells, including the pro- motion of biosynthesis, ATP generation, detoxification and support of rapid proliferation. The pentose phos- phate pathway （PPP） is a major pathway for glucose catabolism. The PPP directs glucose flux to its oxi- dative branch and produces a reduced form of nico- tinamide adenine dinucleotide phosphate （NADPH）, an essential reductant in anabolic processes. It has become clear that the PPP plays a critical role in regulating cancer cell growth by supplying cells with not only ribose-5-phosphate but also NADPH for detoxification of intracellular reactive oxygen species, reductive biosynthesis and ribose biogenesis. Thus, alteration of the PPP contributes directly to cell pro- liferation, survival and senescence. Furthermore, recent studies have shown that the PPP is regulated oncogenically and/or metabolically by numerous fac- tors, including tumor suppressors, oncoproteins and intracellular metabolites. Dysregulation of PPP flux dramatically impacts cancer growth and survival. Therefore, a better understanding of how the PPP is reprogrammed and the mechanism underlying the balance between glycolysis and PPP flux in cancer will be valuable in developing therapeutic strategies targeting this pathway.
文摘Nutlin-3a is a MDM2 antagonist and preclinical drug that activates p53. Cells with MDM2 gene amplification are especially prone to Nutlin-3a-induced apoptosis, though the basis for this is unclear. Glucose metabolism can inhibit apoptosis in response to Nutlin-3a through mechanisms that are incompletely understood. Glucose metabolism through the pentose phosphate pathway （PPP） produces NADPH that can protect cells from potentially lethal reactive oxygen species （ROS）. We compared apoptosis and glucose metabolism in cancer cells with and without MDM2 gene amplification treated with Nutlin-3a. Apoptosis in MDM2-amplified cells was associated with a reduction in glycolysis and the PPP, reduced NADPH, increased ROS, and depletion of the transcription factor SP1, which normally promotes PPP gene expression. In contrast, glycolysis and the PPP were maintained or increased in MDM2 non-amplified cells treated with Nutlin-3a. This was dependent on p53-mediated AKT activation and was associated with maintenance of SP1 and continued expression of PPP genes. Knockdown or inhibition of AKT, SP1, or the PPP sensitized MDM2-non-amplified cells to apoptosis. The data indicate that p53 promotes AKT and SP1-dependent activation of the PPP that protects cells from Nutlin-3a-induced apoptosis. These findings provide insight into how glucose metabolism reduces Nutlin-3a-induced apoptosis, and also provide a mechanism for the heightened sensitivity of MDM2-amplified cells to apoptosis in response to Nutlin-3a.
基金This work was supported by the National Natural Science Foundation of China(Grant Nos.20373086,10574134)promoted by Research Programs of Chinese Academy of Sciences.
文摘The well-resolved absorption spectra of D-xylose,D-ribose,D-arabinose,D-lyxose and other related substances in the spectral region between 0.3 and 2.0 THz are measured using tera-hertz time-domain spectroscopy(THz-TDS)at 295 K.Comparing the absorption spectra of different chemicals,we can distinguish the samples easily.Thus THz-TDS is demonstrated to be a power and characteristic spectral tool,which is highly sensitive to the minor changes of the molecular structures and can be applied to detect and analyze similar materials.
基金the National Natural Science Foundation of China (No. 30870871).
文摘Transketolase （TK）, a thiamine diphosphate （ThDP）-dependent enzyme, catalyzes several key reactions of nonoxidative branch of pentose phosphate pathway. TK is a homodimer with two active sites that locate at the interface between the contacting monomers. Both ThDP and bivalent cations are strictly needed for TK activation, just like that for all ThDPdependent enzymes. TK exists in all organisms that have been investigated. Up to now, one TK gene （TKT） and two transketolase-like genes （TKTL1 and TKTL2） have been identified in human genome. TKTL1 is reported to play a pivotal role in carcinogenesis and may have important implications in the nutrition and future treatment of patients with cancer. Research- ers have found TK variants and reduced activities of TK enzyme in patients with neurodegenerative diseases, diabetes, and cancer. Recent studies indicated TK as a novel role in the prevention and therapy of these diseases.
基金supported by the National 863 Program of China(2005AA247041)Key Projects in the National Science and Technology Pillar Program during the 11th Five-Year Plan period,China(2006BAD07B06)
文摘Changes in main biochemical respiratory pathways in dormant nectarine floral buds were studied with nectarine trees （Prunus persica.var, nectariana cv. Shuguang） in order to determine the function of respiration in dormancy release. Oxygen-electrode system and respiratory inhibitors were used to measure total respiratory rates and rates of respiratory pathways. Results showed that chilling deficiency blocked the transition of respiratory mode, and made buds stay in a state of high level pentose phosphate pathway （PPP） and low level tricarboxylie acid cycle （TCA）. The decline of PPP and activation of TCA occurred synchronously with the release of dormancy. In addition, the inhibition of PPP stimulated a respiration increase related with TCA. It could be concluded that the function of PPP activation in dormancy release might be limited and PPP declination inducing TCA activation might be part of respiration mode transition mechanism during bud sprouting.
基金supported in part by grants from Iowa Pork Producers Association and Elanco Animal Health
文摘Xylose, as β-1,4-linked xylan, makes up much of the hemicel ulose in cel wal s of cereal carbohydrates fed to pigs. As inclusion of fibrous ingredients in swine diets continues to increase, supplementation of carbohydrases, such as xylanase,is of interest. However, much progress is warranted to achieve consistent enzyme efficacy, including an improved understanding of the utilization and energetic contribution of xylanase hydrolysis product（i.e. xylooligosaccharides or monomeric xylose）. This review examines reports on xylose absorption and metabolism in the pig and identifies gaps in this knowledge that are essential to understanding the value of carbohydrase hydrolysis products in the nutrition of the pig. Xylose research in pigs was first reported in 1954, with only sporadic contributions since. Therefore, this review also discusses relevant xylose research in other monogastric species, including humans. In both pigs and poultry, increasing purified D-xylose inclusion general y results in linear decreases in performance, efficiency, and diet digestibility. However,supplementation levels studied thus far have ranged from 5% to 40%, while theoretical xylose release due to xylanase supplementation would be less than 4%. More than 95% of ingested D-xylose disappears before the terminal ileum but mechanisms of absorption have yet to be ful y elucidated. Some data support the hypothesis that mechanisms exist to handle low xylose concentrations but become overwhelmed as luminal concentrations increase. Very little is known about xylose metabolic utilization in vertebrates but it is wel recognized that a large proportion of dietary xylose appears in the urine and significantly decreases the metabolizable energy available from the diet. Nevertheless, evidence of labeled D-xylose-1-^（14）C appearing as expired^（14）CO_2 in both humans and guinea pigs suggests that there is potential,although small, for xylose oxidation. It is yet to be determined if pigs develop increased xylose metabolic capacity with increased adaptation time to diets supplemented with xylose or xylanase. Overall, xylose appears to be poorly utilized by the pig, but it is important to consider that only one study has been reported which supplemented D-xylose dietary concentrations lower than 5%. Thus, more comprehensive studies testing xylose metabolic effects at dietary concentrations more relevant to swine nutrition are warranted.
基金financially supported by National Natural Science Foundation of China(31201584)‘Yong Talents’Project of Northeast Agricultural University(16QC07)+2 种基金the Postdoctoral Fund of Heilongjiang Province(LBH-Z11236)the Science and Technology Research Project by Education Department of Heilongjiang Province(12511050)the Doctoral Fund Project of the Northeast Agricultural University(2010RCB21)
文摘The effects of exogenous gibberellic acid (GA(3)) and abscisic acid (ABA) on the total respiratory rate, percentages of total respiratory rate contributed by respiratory pathways [Embden-Meyerhof- Parnas Pathway (EMP), Pentose Phosphate Pathway (PPP), and Tricarboxylic Acid Cycle (TCA)], and conversion of starch to soluble sugars in the buds of black currants during secondary bud burst were investigated to determine the relationship between respiratory rates and secondary bud burst. 'Adelinia', a black currant cultivar that is prone to secondary bud burst after the first harvest, was used in this study. Mature bushes of Adelinia were sprayed with 30 mg/L GA(3) and 50 mg/L ABA to manipulate bud burst. The results showed that exogenous applications of GA(3) and ABA had opposite effects on bud respiratory rate. Generally, GA(3) treatment increased the total respiratory rate and respiratory rate of the TCA and PPP, and the respiratory rates after GA(3) treatment were higher than those of control. While ABA treatment mostly decreased the total respiratory rate and the respiratory rate of TCA and PPP in buds in comparison to control. In terms of the percentage of the three respiratory rates in comparison to the total respiratory rate, GA(3) treatment significantly increased the percentage of TCA and PPP respiratory rate in comparison to the control (P < 0.01), whereas ABA decreased the rates. GA(3) significantly increased the content of soluble sugars and decreased the starch content, while the starch content in buds after ABA treatment was significantly higher than that of the control. All results showed that PPP is a critical process for the second bud burst in black currants. While the EMP-TCA pathway is still dominant in bud respiration, provides a series of basic materials and energy (ATP). The conversion of starch to soluble sugars is essential for bud burst. Thus, we conclude that an energy shortage is a main contributor in ABA inhibition of the secondary bud burst of black currants.
文摘The thermophilic filamentous fungus, Thermomyces lanuginosus produces the largest amount of xylanase reported. In addition to this, it expresses large amount of other enzymes that have been used industrially or have academic interest. Thus, this fungus has a potential to be applied for biomass conversion to produce biofuel or other applications. In this study, the Biolog system was used to characterize the utilisation and growth of T. lanuginosus on 95 carbon sources. The carbohydrates based compounds, both single sugars and oligosaccharide, showed the best utilisation profile, with the pentose sugar xylose inducing the highest growth, followed by trehelose, raffinose, D-mannose turanose fructose and glucose. Among oligosaccharides, sucrose had the highest mycelium formation followed by stachyose, maltose, maltotriose, glycogen and dextrin. Interestingly the fungus also grew well on cellobiose suggesting that this fungus can produce cellulose hydrolysing proteins. D-alanine was the best amino acid to promote fungal growth while the effect of other amino acids tested was similar to the control. These results demonstrate the ability of this fungus to grow relatively well on most plant based compounds thus making this fungus a possible candidate for plant biomass conversion which can be applied to a number of biotechnological applications including biofuel production.
文摘Nicotinamide adenine dinucleotide phosphate(NADPH) oxidase is the main source of ROS(intracellular reactive oxygen species), ROS plays an important role in a variety of tumor, the ROS mediated by NADPH oxidase increase the expression of hypoxia inducing factor alpha(HIF-α) through multiple signaling pathways in tumor, and HIFcould be regulated and controlled by downstream multiple targeted genes such as vascular endothelial growth factor(VEGF), glucose transporter(GLUT) to promote tumor angiogenesis, cell energy metabolism reprogram and tumor metastasis.HIF-α, meanwhile, also can regulate the expression of NADPH oxidase by ROS, thus further promote development of tumor.In this review, we will summarize the functions of NADPH in tumorigenesis and discuss their potential implications in cancer therapy.
基金supported by grants from the Natural Science Foundation of Jiangsu Province(BK20222009,China)the National Natural Science Foundation of China(32341005)+1 种基金National Natural Science Foundation of China-Youth Program(32300762,China),Guangdong Basic and Applied Basic Research Foundation(2021B1515120016,China)the Key Research and the Nature Science Foundation of Jiangsu Province(BK20210027,China),and the Jiangsu Innovative and Enterpreneurial Talent Programme(JSSCBS20211488,China).
文摘Glucose-6-phosphate dehydrogenase(G6PD),the first rate-limiting enzyme of the pentose phosphate pathway(PPP),is aberrantly activated in multiple types of human cancers,governing the progression of tumor cells as well as the efficacy of anticancer therapy.Here,we discovered that cyclindependent kinase 5(CDK5)rewired glucose metabolism from glycolysis to PPP in breast cancer(BC)cells by activating G6PD to keep intracellular redox homeostasis under oxidative stress.Mechanistically,CDK5-phosphorylated G6PD at Thr-91 facilitated the assembly of inactive monomers of G6PD into active dimers.More importantly,CDK5-induced pho-G6PD was explicitly observed specifically in tumor tissues in human BC specimens.Pharmacological inhibition of CDK5 remarkably abrogated G6PD phosphorylation,attenuated tumor growth and metastasis,and synergistically sensitized BC cells to polyADP-ribose polymerase(PARP)inhibitor Olaparib,in xenograft mouse models.Collectively,our results establish the crucial role of CDK5-mediated phosphorylation of G6PD in BC growth and metastasis and provide a therapeutic regimen for BC treatment.
基金supported by the National Key Research and Development Program of China(2019YFA0903900)the National Natural Science Foundation of China(32300233)+1 种基金Guangdong Provincial Key Laboratory of Synthetic Genomics(2023B1212060054)Shenzhen Key Laboratory of Synthetic Genomics(ZDSYS201802061806209).
文摘The oxidative pentose phosphate(OPP)pathway provides metabolic intermediates for the shikimate pathway and directs carbon flow to the biosynthesis of aromatic amino acids(AAAs),which serve as basic protein building blocks and precursors of numerous metabolites essential for plant growth.However,genetic evidence linking the two pathways is largely unclear.In this study,we identified 6-phosphogluconate dehydrogenase 2(PGD2),the rate-limiting enzyme of the cytosolic OPP pathway,through suppressor screening of arogenate dehydrogenase 2(adh2)in Arabidopsis.Our data indicated that a single amino acid substitution at position 63(glutamic acid to lysine)of PGD2 enhanced its enzyme activity by facilitating the dissociation of products from the active site of PGD2,thus increasing the accumulation of AAAs and partially restoring the defective phenotype of adh2.Phylogenetic analysis indicated that the point mutation occurred in a well-conserved amino acid residue.Plants with different amino acids at this conserved site of PGDs confer diverse catalytic activities,thus exhibiting distinct AAAs producing capability.These findings uncover the genetic link between the OPP pathway and AAAs biosynthesis through PGD2.The gain-of-function point mutation of PGD2 identified here could be considered as a potential engineering target to alter the metabolic flux for the production of AAAs and downstream compounds.
基金supported by the National Natural Sciences Foundation of China(82273219)the Hunan Provincial Natural Science Foundation(2024JJ6623)the innovation project of Central South University[grant numbers 2024ZZTS0530](for Zeng F).
文摘Aim:Gastric cancer(GC)is one of the common malignant tumors,and most patients with advanced GC often develop chemotherapy resistance,resulting in poor chemotherapy efficacy.Therefore,it is crucial to clarify the specific mechanisms of their chemotherapy resistance.Methods:In this study,we analyzed the correlation between fos-related antigen-1(Fra-1)and chemotherapy resistance in GC using bioinformatics,cell counting kit-8(CCK8),and 5-ethynyl-2’-deoxyuridine(EDU)combined with flow cytometry;furthermore,we used energy metabolomics sequencing,combined with ChIP-qPCR technology,to elucidate the specific role of Fra-1 in chemotherapy resistance of GC cells and its related mechanisms.Results:We found that high Fra-1 expression was closely related to chemotherapeutic drugs in GC cells,as demonstrated by bioinformatics analysis combined with EDU and CCK8 experiments.Energy metabolomics combined with in vitro cellular experimental analysis revealed that the pentose phosphate pathway(PPP)was activated in GC cells with high Fra-1 expression,along with an increase in the synthesis of metabolites such as nicotinamide adenine dinucleotide phosphate(NADPH)and glutathione(GSH),a decrease in the level of reactive oxygen species(ROS),and the inhibition of their ferroptosis.In addition,ChIP-qPCR experiments confirmed that Fra-1 binds to the promoter of glucose-6-phosphate dehydrogenase(G6PD),a key rate-limiting enzyme of the PPP,and transcriptionally regulates its expression,which in turn activates the PPP and promotes chemotherapy resistance in GC cells.Conclusion:Our research findings suggest that Fra-1 activates the PPP by upregulating G6PD transcriptional activity and inhibiting its ubiquitination level,inhibiting ferroptosis in GC cells and inducing chemoresistance.This provides an experimental basis for screening potential molecular targets for chemotherapy resistance in GC patients.
基金supported by the National Natural Science Foundation of China(No.82070883)Scientific Research Foundation for high-level faculty,China Pharmaceutical University(Nanjing,China)。
文摘Hepatocellular carcinoma(HCC)is an aggressive human cancer with increasing incidence worldwide.Multiple efforts have been made to explore pharmaceutical therapies to treat HCC,such as targeted tyrosine kinase inhibitors,immune based therapies and combination of chemotherapy.However,limitations exist in current strategies including chemoresistance for instance.Tumor initiation and progression is driven by reprogramming of metabolism,in particular during HCC development.Recently,metabolic associated fatty liver disease(MAFLD),a reappraisal of new nomenclature for nonalcoholic fatty liver disease(NAFLD),indicates growing appreciation of metabolism in the pathogenesis of liver disease,including HCC,thereby suggesting new strategies by targeting abnormal metabolism for HCC treatment.In this review,we introduce directions by highlighting the metabolic targets in glucose,fatty acid,amino acid and glutamine metabolism,which are suitable for HCC pharmaceutical intervention.We also summarize and discuss current pharmaceutical agents and studies targeting deregulated metabolism during HCC treatment.Furthermore,opportunities and challenges in the discovery and development of HCC therapy targeting metabolism are discussed.
基金This work was supported by the Andrew Sabin Family Fellow Award from The University of Texas MD Anderson Cancer Center,KC180131 fromDepartment of Defense Kidney Cancer Research Program,R01CA181196 and R01CA244144 from the National Institutes of Health(to B.G.).
文摘Cystine/glutamate antiporter solute carrier family 7 member 11(SLC7A11;also known as xCT)plays a key role in antioxidant defense by mediating cystine uptake,promoting glutathione synthesis,and maintaining cell survival under oxidative stress conditions.Recent studies showed that,to prevent toxic buildup of highly insoluble cystine inside cells,cancer cells with high expression of SLC7A11(SLC7A11high)are forced to quickly reduce cystine to more soluble cysteine,which requires substantial NADPH supply from the glucose-pentose phosphate pathway(PPP)route,thereby inducing glucose-and PPP-dependency in SLC7A11high cancer cells.Limiting glucose supply to SLC7A11high cancer cells results in significant NADPH“debt”,redox“bankruptcy”,and subsequent cell death.This review summarizes our current understanding of NADPH-generating and-consuming pathways,discusses the opposing role of SLC7A11 in protecting cells from oxidative stresseinduced cell death such as ferroptosis but promoting glucose starvationeinduced cell death,and proposes the concept that SLC7A11-mediated cystine uptake acts as a double-edged sword in cellular redox regulation.A detailed understanding of SLC7A11 in redox biology may identify metabolic vulnerabilities in SLC7A11high cancer for therapeutic targeting.
基金Suported by the Ph.D Foundation Program from the Ministry of Education （20050307013）, the National Natural Science Foundation of China （30470921）, the Jiangsu Provincial Natural Science Foundation of China （BK2005090） and the Changjiang Scholars and Innovative Research Team in University （PCSIRT）.The nucleotide sequences reported in this paper have been deposited in GenBank under the accession numbers AY078072, AY339367, AF486280 and AY278362, respectively,
文摘Glucose-6-phosphate dehydrogenase （G6PDH, E.C. 1.1.1.49） and 6-phosphogluconate dehydrogenase （6PGDH, EC 1.1.1.44） are both key enzymes of the pentose phosphate pathway （PPP）. The OsG6PDH1 and Os6PGDH1 genes encoding cytosolic G6PDH and cytosolic 6PGDH were Isolated from rice （Oryza sativa L.）. We have shown that Os6PGDH1 gene was up-regulated by salt stress. Here we reported the isolation and characterization of Os6PGDH2 from rice, which encode the plastidic counterpart of 6PGDH. Genomic organization analysis indicated that OsG6PDH1 and OsG6PDH2 genes contain multiple introns, whereas two Os6PGDH1 and Os6PGDH2 genes have no introns in their translated regions. In a step towards understanding the functions of the pentose phosphate pathway in plants in response to various abiotic stresses, the expressions of four genes in the rice seedlings treated by drought, cold, high salinity and abscisic acid （ABA） were investigated. The results show that OsG6PDH1 and OsG6PDH2 are not markedly regulated by the abiotic stresses detected. However, the transcript levels of both Os6PGDH1 and Os6PGDH2 are up-regulated in rice seedlings under drought, cold, high salinity and ABA treatments. Meanwhile, the enzyme activities of G6PDH and 6PGDH in the rice seedlings treated by various abiotic stresses were Investigated. Like the mRNA expression patterns, G6PDH activity remains constant but the 6PGDH Increases steadily during the treatments. Taken together, we suggest that the pentose phosphate pathway may play an important role in rice responses to abiotic stresses and the second key enzyme of PPP, 6PGDH, may function as a regulator controlling the efficiency of the pathway under abiotic stresses.
基金supported by the Ministry of Science and Technology(2019YFA0801703)the National Natural Science Foundation of China(81790250,81790253 and 91959202)the Innovation Program of Shanghai Municipal Education Commission(N173606)。
文摘Cancer cells remodel their metabolic network to adapt to variable nutrient availability. Pentose phosphate pathway(PPP) plays protective and biosynthetic roles by oxidizing glucose to generate reducing power and ribose. How cancer cells modulate PPP activity in response to glucose supply remains unclear. Here we show that ribose-5-phosphate isomerase A(RPIA), an enzyme in PPP, directly interacts with co-activator associated arginine methyltransferase 1(CARM1) and is methylated at arginine 42(R42). R42 methylation up-regulates the catalytic activity of RPIA. Furthermore, glucose deprivation strengthens the binding of CARM1 with RPIA to induce R42 hypermethylation. Insufficient glucose supply links to RPIA hypermethylation at R42, which increases oxidative PPP flux. RPIA methylation supports ROS clearance by enhancing NADPH production and fuels nucleic acid synthesis by increasing ribose supply. Importantly, RPIA methylation at R42 significantly potentiates colorectal cancer cell survival under glucose starvation. Collectively, RPIA methylation connects glucose availability to nucleotide synthesis and redox homeostasis.
基金supported by INSERM,the national research agency (ANR-09-JCJC-0116 to J.R.).E.T.and P.T.were supported by a research fellowship from French government of higher education and researchsupported for 6 months by a research fellowship from the Fondation pour la Recherche Me´dicale (FDT20140931004).
文摘Mitochondria-associated endoplasmic reticulum membranes(MAM)play a key role in mitochondrial dynamics and function and in hepatic insulin action.Whereas mitochondria are important regulators of energy metabolism,the nutritional regulation of MAM in the liver and its role in the adaptation of mitochondria physiology to nutrient availability are unknown.In this study,we found that the fasted to postprandial transition reduced the number of endoplasmic reticulum-mitochondria contact points in mouse liver.Screening of potential hormonal/metabolic signals revealed glucose as the main nutritional regulator of hepatic MAM integrity both in vitro and in vivo.Glucose reduced organelle interactions through the pentose phosphate-protein phosphatase 2A(PP-PP2A)pathway,induced mitochondria fission,and impaired respiration.Blocking MAM reduction counteracted glucose-induced mitochondrial alterations.Furthermore,disruption of MAM integrity mimicked effects of glucose on mitochondria dynamics and function.This glucose-sensing system is deficient in the liver of insulin-resistant ob/ob and cyclophilin D-KO mice,both characterized by chronic disruption of MAM integrity,mitochondrial fission,and altered mitochondrial respiration.These data indicate that MAM contribute to the hepatic glucose-sensing system,allowing regulation of mitochondria dynamics and function during nutritional transition.Chronic disruption of MAM may participate in hepatic mitochondrial dysfunction associated with insulin resistance.
